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33a738841cd15b6c81007cd9484cd9e9b2502f11 | wikidoc | Stem cell | Stem cell
For The WikiDoc Living Textbook Of Stem Cell Therapy Directory click here
# Overview
Stem cells are cells found in most, if not all, multi-cellular organisms. They are characterized by the ability to renew themselves through mitotic cell division and differentiating into a diverse range of specialized cell types. Research in the stem cell field grew out of findings by Canadian scientists Ernest A. McCulloch and James E. Till in the 1960s.
The two broad types of mammalian stem cells are: embryonic stem cells that are found in blastocysts, and adult stem cells that are found in adult tissues. In a developing embryo, stem cells can differentiate into all of the specialized embryonic tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing specialized cells, but also maintain the normal turnover of regenerative organs, such as blood, skin or intestinal tissues.
As stem cells can be grown and transformed into specialized cells with characteristics consistent with cells of various tissues such as muscles or nerves through cell culture, their use in medical therapies has been proposed. In particular, embryonic cell lines, autologous embryonic stem cells generated through therapeutic cloning, and highly plastic adult stem cells from the umbilical cord blood or bone marrow are touted as promising candidates.
# Properties of stem cells
The classical definition of a stem cell requires that it possess two properties:
- Self-renewal - the ability to go through numerous cycles of cell division while maintaining the undifferentiated state.
- Potency - the capacity to differentiate into specialized cell types. In the strictest sense, this requires stem cells to be either totipotent or pluripotent - to be able to give rise to any mature cell type, although multipotent or unipotent progenitor cells are sometimes referred to as stem cells.
## Potency definitions
Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.
- Totipotent stem cells are produced from the fusion of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent. These cells can differentiate into embryonic and extraembryonic cell types.
- Pluripotent stem cells are the descendants of totipotent cells and can differentiate into cells derived from any of the three germ layers.
- Multipotent stem cells can produce only cells of a closely related family of cells (e.g. hematopoietic stem cells differentiate into red blood cells, white blood cells, platelets, etc.).
- Unipotent cells can produce only one cell type, but have the property of self-renewal which distinguishes them from non-stem cells (e.g. muscle stem cells).
## Identifying stem cells
The practical definition of a stem cell is the functional definition - the ability to regenerate tissue over a lifetime. For example, the gold standard test for a bone marrow or hematopoietic stem cell (HSC) is the ability to transplant one cell and save an individual without HSCs. In this case, a stem cell must be able to produce new blood cells and immune cells over a long term, demonstrating potency. It should also be possible to isolate stem cells from the transplanted individual, which can themselves be transplanted into another individual without HSCs, demonstrating that the stem cell was able to self-renew.
Properties of stem cells can be illustrated in vitro, using methods such as clonogenic assays, where single cells are characterized by their ability to differentiate and self-renew. As well, stem cells can be isolated based on a distinctive set of cell surface markers. However, in vitro culture conditions can alter the behavior of cells, making it unclear whether the cells will behave in a similar manner in vivo. Considerable debate exists whether some proposed adult cell populations are truly stem cells.
# Embryonic stem cells
Embryonic stem cell lines (ES cell lines) are cultures of cells derived from the epiblast tissue of the inner cell mass (ICM) of a blastocyst or earlier morula stage embryos. A blastocyst is an early stage embryo—approximately four to five days old in humans and consisting of 50–150 cells. ES cells are pluripotent and give rise during development to all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the extra-embryonic membranes or the placenta.
Nearly all research to date has taken place using mouse embryonic stem cells (mES) or human embryonic stem cells (hES). Both have the essential stem cell characteristics, yet they require very different environments in order to maintain an undifferentiated state. Mouse ES cells are grown on a layer of gelatin and require the presence of Leukemia Inhibitory Factor (LIF). Human ES cells are grown on a feeder layer of mouse embryonic fibroblasts (MEFs) and require the presence of basic Fibroblast Growth Factor (bFGF or FGF-2). Without optimal culture conditions or genetic manipulation, embryonic stem cells will rapidly differentiate.
A human embryonic stem cell is also defined by the presence of several transcription factors and cell surface proteins. The transcription factors Oct-4, Nanog, and SOX2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency. The cell surface antigens most commonly used to identify hES cells are the glycolipids SSEA3 and SSEA4 and the keratan sulfate antigens Tra-1-60 and Tra-1-81. The molecular definition of a stem cell includes many more proteins and continues to be a topic of research.
After twenty years of research, there are no approved treatments or human trials using embryonic stem cells. ES cells, being totipotent cells, require specific signals for correct differentiation - if injected directly into the body, ES cells will differentiate into many different types of cells, causing a teratoma. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face. Many nations currently have moratoria on either ES cell research or the production of new ES cell lines. Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source for regenerative medicine and tissue replacement after injury or disease.
# Adult stem cells
The term adult stem cell refers to any cell which is found in a developed organism that has two properties: the ability to divide and create another cell like itself and also divide and create a cell more differentiated than itself. Also known as somatic (from Greek Σωματικóς, "of the body") stem cells and germline (giving rise to gametes) stem cells, they can be found in children, as well as adults. Pluripotent adult stem cells are rare and generally small in number but can be found in a number of tissues including umbilical cord blood. Most adult stem cells are lineage-restricted (multipotent) and are generally referred to by their tissue origin (mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, etc.).
A great deal of adult stem cell research has focused on clarifying their capacity to divide or self-renew indefinitely and their differentiation potential. In mice, pluripotent stem cells are directly generated from adult fibroblast cultures.
While embryonic stem cell potential remains untested, adult stem cell treatments have been used for many years to treat successfully leukemia and related bone/blood cancers through bone marrow transplants. The use of adult stem cells in research and therapy is not as controversial as embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Consequently, more US government funding is being provided for adult stem cell research.
# Lineage
To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells both endowed with stem cell properties. Asymmetric division, on the other hand, produces only one stem cell and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally differentiating into a mature cell. It is possible that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.
An alternative theory is that stem cells remain undifferentiated due to environmental cues in their particular niche. Stem cells differentiate when they leave that niche or no longer receive those signals. Studies in Drosophila germarium have identified the signals dpp and adherins junctions that prevent germarium stem cells from differentiating.
The signals that lead to reprogramming of cells to an embryonic-like state are also being investigated. These signal pathways include several transcription factors including the oncogene c-Myc. Initial studies indicate that transformation of mice cells with a combination of these anti-differentiation signals can reverse differentiation and may allow adult cells to become pluripotent. However, the need to transform these cells with an oncogene may prevent the use of this approach in therapy.
# Treatments
Medical researchers believe that stem cell therapy has the potential to dramatically change the treatment of human disease. A number of adult stem cell therapies already exist, particularly bone marrow transplants that are used to treat leukemia. In the future, medical researchers anticipate being able to use technologies derived from stem cell research to treat a wider variety of diseases including cancer, Parkinson's disease, spinal cord injuries, and muscle damage, amongst a number of other impairments and conditions.
Stem Cell treatments are becoming more widely available, especially for musculoskeletal, peripheral vascular, and peripheral neuropathy indications. Most clinical applications use autologous stem cells and do not involve manipulation of the cells in between harvesting and implantation . Several factors influence the selection of autologus stem cell harvest site and type. In those cases where autologous harvest does not make sense then placental derived cells is a viable alternative.
Other uses for stem cell are still surrounded scientific uncertainty but are gaining in acceptance. While stem cells are already used extensively in research some scientists do not see cell therapy as the first goal of the research, but see the investigation of stem cells as a goal worthy in itself.
# Controversy surrounding human embryonic stem cell research
There exists a widespread controversy over human embryonic stem cell research that emanates from the techniques used in the creation and usage of stem cells. Human embryonic stem cell research is controversial because, with the present state of technology, starting a stem cell line requires the destruction of a human embryo and/or therapeutic cloning. However, recently, it has been shown in principle that embryonic stem cell lines can be generated using a single-cell biopsy similar to that used in preimplantation genetic diagnosis that may allow stem cell creation without embryonic destruction. It is not the entire field of stem cell research, but the specific field of human embryonic stem cell research that is at the centre of an ethical debate.
Opponents of the research argue that embryonic stem cell technologies are a slippery slope to reproductive cloning and can fundamentally devalue human life. Those in the pro-life movement argue that a human embryo is a human life and is therefore entitled to protection.
Contrarily, supporters of embryonic stem cell research argue that such research should be pursued because the resultant treatments could have significant medical potential. It is also noted that excess embryos created for in vitro fertilisation could be donated with consent and used for the research.
The ensuing debate has prompted authorities around the world to seek regulatory frameworks and highlighted the fact that stem cell research represents a social and ethical challenge.
# Key stem cell research events
- 1960s - Joseph Altman and Gopal Das present scientific evidence of adult neurogenesis, ongoing stem cell activity in the brain; their reports contradict Cajal's "no new neurons" dogma and are largely ignored.
- 1963 - McCulloch and Till illustrate the presence of self-renewing cells in mouse bone marrow.
- 1968 - Bone marrow transplant between two siblings successfully treats SCID.
- 1978 - Haematopoietic stem cells are discovered in human cord blood.
- 1981 - Mouse embryonic stem cells are derived from the inner cell mass by scientists Martin Evans, Matthew Kaufman, and Gail R. Martin. Gail Martin is attributed for coining the term "Embryonic Stem Cell".
- 1992 - Neural stem cells are cultured in vitro as neurospheres.
- 1997 - Leukemia is shown to originate from a haematopoietic stem cell, the first direct evidence for cancer stem cells.
- 1998 - James Thomson and coworkers derive the first human embryonic stem cell line at the University of Wisconsin-Madison.
- 2000s - Several reports of adult stem cell plasticity are published.
- 2001 - Scientists at Advanced Cell Technology clone first early (four- to six-cell stage) human embryos for the purpose of generating embryonic stem cells.
- 2003 - Dr. Songtao Shi of NIH discovers new source of adult stem cells in children's primary teeth.
- 2004-2005 - Korean researcher Hwang Woo-Suk claims to have created several human embryonic stem cell lines from unfertilised human oocytes. The lines were later shown to be fabricated.
- 2005 - Researchers at Kingston University in England claim to have discovered a third category of stem cell, dubbed cord-blood-derived embryonic-like stem cells (CBEs), derived from umbilical cord blood. The group claims these cells are able to differentiate into more types of tissue than adult stem cells.
- August 2006 - Rat Induced pluripotent stem cells: the journal Cell publishes Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors".
- October 2006 - Scientists in England create the first ever artificial liver cells using umbilical cord blood stem cells.
- January 2007 - Scientists at Wake Forest University led by Dr. Anthony Atala and Harvard University report discovery of a new type of stem cell in amniotic fluid. This may potentially provide an alternative to embryonic stem cells for use in research and therapy.
- June 2007 - Research reported by three different groups shows that normal skin cells can be reprogrammed to an embryonic state in mice. In the same month, scientist Shoukhrat Mitalipov reports the first successful creation of a primate stem cell line through somatic cell nuclear transfer
- October 2007 - Mario Capecchi, Martin Evans, and Oliver Smithies win the 2007 Nobel Prize for Physiology or Medicine for their work on embryonic stem cells from mice using gene targeting strategies producing genetically engineered mice (known as knockout mice) for gene research.
- November 2007 - Human Induced pluripotent stem cells: Two similar papers released by their respective journals prior to formal publication: in Cell by Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors", and in Science by Junying Yu, et al., from the research group of James Thomson, "Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells": pluripotent stem cells generated from mature human fibroblasts. It is possible now to produce a stem cell from almost any other human cell instead of using embryos as needed previously, albeit the risk of tumorigenesis due to c-myc and retroviral gene transfer remains to be determined.
- January 2008 - Human embryonic stem cell lines were generated without destruction of the embryo
- January 2008 - Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts
- February 2008 - Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach: these iPS cells seem to be more similar to embryonic stem cells than the previous developed iPS cells and not tumorigenic, moreover genes that are required for iPS cells do not need to be inserted into specific sites, which encourages the development of non-viral reprogramming techniques.
# Stem cell funding & policy debate in the US
- 1993 - As per the National Institutes of Health Revitalization Act, Congress and President Bill Clinton give the NIH direct authority to fund human embryo research for the first time.
- 1995 - The U.S. Congress enacts into law an appropriations bill attached to which is the Dickey Amendment which prohibited federally appropriated funds to be used for research where human embryos would be either created or destroyed. This predates the creation of the first human embryonic stem cell lines.
- 1999 - After the creation of the first human embryonic stem cell lines in 1998 by James Thomson of the University of Wisconsin, Harriet Rabb, the top lawyer at the Department of Health and Human Services, releases a legal opinion that would set the course for Clinton Administration policy. Federal funds, obviously, could not be used to derive stem cell lines (because derivation involves embryo destruction). However, she concludes that because human embryonic stem cells "are not a human embryo within the statutory definition," the Dickey-Wicker Amendment does not apply to them. The NIH was therefore free to give federal funding to experiments involving the cells themselves. President Clinton strongly endorses the new guidelines, noting that human embryonic stem cell research promised "potentially staggering benefits." And with the guidelines in place, the NIH begins accepting grant proposals from scientists.
- 02 November, 2004 - California voters approve Proposition 71, which provides $3 billion in state funds over ten years to human embryonic stem cell research.
- 2001-2006 - U.S. President George W. Bush signs an executive order which restricts federally-funded stem cell research on embryonic stem cells to the already derived cell lines. He supports federal funding for embryonic stem cell research on the already existing lines of approximately $100 million and $250 million for research on adult and animal stem cells.
- 5 May, 2006 - Senator Rick Santorum introduces bill number S. 2754, or the Alternative Pluripotent Stem Cell Therapies Enhancement Act, into the U.S. Senate.
- 18 July, 2006 - The U.S. Senate passes the Stem Cell Research Enhancement Act H.R. 810 and votes down Senator Santorum's S. 2754.
- 19 July, 2006 - President George W. Bush vetoes H.R. 810 (Stem Cell Research Enhancement Act), a bill that would have reversed the Gingrich-era appropriations amendment which made it illegal for federal money to be used for research where stem cells are derived from the destruction of an embryo.
- 07 November, 2006 - The people of the U.S. state of Missouri passed Amendment 2, which allows usage of any stem cell research and therapy allowed under federal law, but prohibits human reproductive cloning.
- 16 February, 2007 – The California Institute for Regenerative Medicine became the biggest financial backer of human embryonic stem cell research in the United States when they awarded nearly $45 million in research grants.
# Related Chapters
- The American Society for Cell Biology
- California Institute for Regenerative Medicine
- Genetics Policy Institute
- Cancer stem cells
- Induced pluripotent stem cell (iPS Cell)
- Odontis | Stem cell
For The WikiDoc Living Textbook Of Stem Cell Therapy Directory click here
Editor-in-Chief: Robert G. Schwartz, M.D. [5], Piedmont Physical Medicine and Rehabilitation, P.A.;
# Overview
Stem cells are cells found in most, if not all, multi-cellular organisms. They are characterized by the ability to renew themselves through mitotic cell division and differentiating into a diverse range of specialized cell types. Research in the stem cell field grew out of findings by Canadian scientists Ernest A. McCulloch and James E. Till in the 1960s.[1][2]
The two broad types of mammalian stem cells are: embryonic stem cells that are found in blastocysts, and adult stem cells that are found in adult tissues. In a developing embryo, stem cells can differentiate into all of the specialized embryonic tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing specialized cells, but also maintain the normal turnover of regenerative organs, such as blood, skin or intestinal tissues.
As stem cells can be grown and transformed into specialized cells with characteristics consistent with cells of various tissues such as muscles or nerves through cell culture, their use in medical therapies has been proposed. In particular, embryonic cell lines, autologous embryonic stem cells generated through therapeutic cloning, and highly plastic adult stem cells from the umbilical cord blood or bone marrow are touted as promising candidates.[3]
# Properties of stem cells
The classical definition of a stem cell requires that it possess two properties:
- Self-renewal - the ability to go through numerous cycles of cell division while maintaining the undifferentiated state.
- Potency - the capacity to differentiate into specialized cell types. In the strictest sense, this requires stem cells to be either totipotent or pluripotent - to be able to give rise to any mature cell type, although multipotent or unipotent progenitor cells are sometimes referred to as stem cells.
## Potency definitions
Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.
- Totipotent stem cells are produced from the fusion of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent. These cells can differentiate into embryonic and extraembryonic cell types.
- Pluripotent stem cells are the descendants of totipotent cells and can differentiate into cells derived from any of the three germ layers.
- Multipotent stem cells can produce only cells of a closely related family of cells (e.g. hematopoietic stem cells differentiate into red blood cells, white blood cells, platelets, etc.).
- Unipotent cells can produce only one cell type, but have the property of self-renewal which distinguishes them from non-stem cells (e.g. muscle stem cells).
## Identifying stem cells
The practical definition of a stem cell is the functional definition - the ability to regenerate tissue over a lifetime. For example, the gold standard test for a bone marrow or hematopoietic stem cell (HSC) is the ability to transplant one cell and save an individual without HSCs. In this case, a stem cell must be able to produce new blood cells and immune cells over a long term, demonstrating potency. It should also be possible to isolate stem cells from the transplanted individual, which can themselves be transplanted into another individual without HSCs, demonstrating that the stem cell was able to self-renew.
Properties of stem cells can be illustrated in vitro, using methods such as clonogenic assays, where single cells are characterized by their ability to differentiate and self-renew.[4][5] As well, stem cells can be isolated based on a distinctive set of cell surface markers. However, in vitro culture conditions can alter the behavior of cells, making it unclear whether the cells will behave in a similar manner in vivo. Considerable debate exists whether some proposed adult cell populations are truly stem cells.
# Embryonic stem cells
Embryonic stem cell lines (ES cell lines) are cultures of cells derived from the epiblast tissue of the inner cell mass (ICM) of a blastocyst or earlier morula stage embryos.[6] A blastocyst is an early stage embryo—approximately four to five days old in humans and consisting of 50–150 cells. ES cells are pluripotent and give rise during development to all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the extra-embryonic membranes or the placenta.
Nearly all research to date has taken place using mouse embryonic stem cells (mES) or human embryonic stem cells (hES). Both have the essential stem cell characteristics, yet they require very different environments in order to maintain an undifferentiated state. Mouse ES cells are grown on a layer of gelatin and require the presence of Leukemia Inhibitory Factor (LIF).[7] Human ES cells are grown on a feeder layer of mouse embryonic fibroblasts (MEFs) and require the presence of basic Fibroblast Growth Factor (bFGF or FGF-2).[8] Without optimal culture conditions or genetic manipulation,[9] embryonic stem cells will rapidly differentiate.
A human embryonic stem cell is also defined by the presence of several transcription factors and cell surface proteins. The transcription factors Oct-4, Nanog, and SOX2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency.[10] The cell surface antigens most commonly used to identify hES cells are the glycolipids SSEA3 and SSEA4 and the keratan sulfate antigens Tra-1-60 and Tra-1-81. The molecular definition of a stem cell includes many more proteins and continues to be a topic of research.[11]
After twenty years of research, there are no approved treatments or human trials using embryonic stem cells. ES cells, being totipotent cells, require specific signals for correct differentiation - if injected directly into the body, ES cells will differentiate into many different types of cells, causing a teratoma. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face.[12] Many nations currently have moratoria on either ES cell research or the production of new ES cell lines. Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source for regenerative medicine and tissue replacement after injury or disease.
# Adult stem cells
The term adult stem cell refers to any cell which is found in a developed organism that has two properties: the ability to divide and create another cell like itself and also divide and create a cell more differentiated than itself. Also known as somatic (from Greek Σωματικóς, "of the body") stem cells and germline (giving rise to gametes) stem cells, they can be found in children, as well as adults.[13] Pluripotent adult stem cells are rare and generally small in number but can be found in a number of tissues including umbilical cord blood.[14] Most adult stem cells are lineage-restricted (multipotent) and are generally referred to by their tissue origin (mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, etc.).[15][16]
A great deal of adult stem cell research has focused on clarifying their capacity to divide or self-renew indefinitely and their differentiation potential.[17] In mice, pluripotent stem cells are directly generated from adult fibroblast cultures.[18]
While embryonic stem cell potential remains untested, adult stem cell treatments have been used for many years to treat successfully leukemia and related bone/blood cancers through bone marrow transplants.[19] The use of adult stem cells in research and therapy is not as controversial as embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Consequently, more US government funding is being provided for adult stem cell research.[20]
# Lineage
To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells both endowed with stem cell properties. Asymmetric division, on the other hand, produces only one stem cell and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally differentiating into a mature cell. It is possible that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.[21]
An alternative theory is that stem cells remain undifferentiated due to environmental cues in their particular niche. Stem cells differentiate when they leave that niche or no longer receive those signals. Studies in Drosophila germarium have identified the signals dpp and adherins junctions that prevent germarium stem cells from differentiating.[22][23]
The signals that lead to reprogramming of cells to an embryonic-like state are also being investigated. These signal pathways include several transcription factors including the oncogene c-Myc. Initial studies indicate that transformation of mice cells with a combination of these anti-differentiation signals can reverse differentiation and may allow adult cells to become pluripotent.[24] However, the need to transform these cells with an oncogene may prevent the use of this approach in therapy.
# Treatments
Medical researchers believe that stem cell therapy has the potential to dramatically change the treatment of human disease. A number of adult stem cell therapies already exist, particularly bone marrow transplants that are used to treat leukemia.[25] In the future, medical researchers anticipate being able to use technologies derived from stem cell research to treat a wider variety of diseases including cancer, Parkinson's disease, spinal cord injuries, and muscle damage, amongst a number of other impairments and conditions.[26][27]
Stem Cell treatments are becoming more widely available, especially for musculoskeletal, peripheral vascular, and peripheral neuropathy indications. Most clinical applications use autologous stem cells and do not involve manipulation of the cells in between harvesting and implantation [6]. Several factors influence the selection of autologus stem cell harvest site and type. In those cases where autologous harvest does not make sense then placental derived cells is a viable alternative.
Other uses for stem cell are still surrounded scientific uncertainty but are gaining in acceptance. While stem cells are already used extensively in research some scientists do not see cell therapy as the first goal of the research, but see the investigation of stem cells as a goal worthy in itself.[28]
# Controversy surrounding human embryonic stem cell research
There exists a widespread controversy over human embryonic stem cell research that emanates from the techniques used in the creation and usage of stem cells. Human embryonic stem cell research is controversial because, with the present state of technology, starting a stem cell line requires the destruction of a human embryo and/or therapeutic cloning. However, recently, it has been shown in principle that embryonic stem cell lines can be generated using a single-cell biopsy similar to that used in preimplantation genetic diagnosis that may allow stem cell creation without embryonic destruction.[29] It is not the entire field of stem cell research, but the specific field of human embryonic stem cell research that is at the centre of an ethical debate.
Opponents of the research argue that embryonic stem cell technologies are a slippery slope to reproductive cloning and can fundamentally devalue human life. Those in the pro-life movement argue that a human embryo is a human life and is therefore entitled to protection.
Contrarily, supporters of embryonic stem cell research argue that such research should be pursued because the resultant treatments could have significant medical potential. It is also noted that excess embryos created for in vitro fertilisation could be donated with consent and used for the research.
The ensuing debate has prompted authorities around the world to seek regulatory frameworks and highlighted the fact that stem cell research represents a social and ethical challenge.
# Key stem cell research events
- 1960s - Joseph Altman and Gopal Das present scientific evidence of adult neurogenesis, ongoing stem cell activity in the brain; their reports contradict Cajal's "no new neurons" dogma and are largely ignored.
- 1963 - McCulloch and Till illustrate the presence of self-renewing cells in mouse bone marrow.
- 1968 - Bone marrow transplant between two siblings successfully treats SCID.
- 1978 - Haematopoietic stem cells are discovered in human cord blood.
- 1981 - Mouse embryonic stem cells are derived from the inner cell mass by scientists Martin Evans, Matthew Kaufman, and Gail R. Martin. Gail Martin is attributed for coining the term "Embryonic Stem Cell".
- 1992 - Neural stem cells are cultured in vitro as neurospheres.
- 1997 - Leukemia is shown to originate from a haematopoietic stem cell, the first direct evidence for cancer stem cells.
- 1998 - James Thomson and coworkers derive the first human embryonic stem cell line at the University of Wisconsin-Madison.
- 2000s - Several reports of adult stem cell plasticity are published.
- 2001 - Scientists at Advanced Cell Technology clone first early (four- to six-cell stage) human embryos for the purpose of generating embryonic stem cells.[30]
- 2003 - Dr. Songtao Shi of NIH discovers new source of adult stem cells in children's primary teeth.[31]
- 2004-2005 - Korean researcher Hwang Woo-Suk claims to have created several human embryonic stem cell lines from unfertilised human oocytes. The lines were later shown to be fabricated.
- 2005 - Researchers at Kingston University in England claim to have discovered a third category of stem cell, dubbed cord-blood-derived embryonic-like stem cells (CBEs), derived from umbilical cord blood. The group claims these cells are able to differentiate into more types of tissue than adult stem cells.
- August 2006 - Rat Induced pluripotent stem cells: the journal Cell publishes Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors".
- October 2006 - Scientists in England create the first ever artificial liver cells using umbilical cord blood stem cells.[32][33]
- January 2007 - Scientists at Wake Forest University led by Dr. Anthony Atala and Harvard University report discovery of a new type of stem cell in amniotic fluid.[7] This may potentially provide an alternative to embryonic stem cells for use in research and therapy.[34]
- June 2007 - Research reported by three different groups shows that normal skin cells can be reprogrammed to an embryonic state in mice.[35] In the same month, scientist Shoukhrat Mitalipov reports the first successful creation of a primate stem cell line through somatic cell nuclear transfer[36]
- October 2007 - Mario Capecchi, Martin Evans, and Oliver Smithies win the 2007 Nobel Prize for Physiology or Medicine for their work on embryonic stem cells from mice using gene targeting strategies producing genetically engineered mice (known as knockout mice) for gene research.[37]
- November 2007 - Human Induced pluripotent stem cells: Two similar papers released by their respective journals prior to formal publication: in Cell by Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors", and in Science by Junying Yu, et al., from the research group of James Thomson, "Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells": pluripotent stem cells generated from mature human fibroblasts. It is possible now to produce a stem cell from almost any other human cell instead of using embryos as needed previously, albeit the risk of tumorigenesis due to c-myc and retroviral gene transfer remains to be determined.
- January 2008 - Human embryonic stem cell lines were generated without destruction of the embryo[38]
- January 2008 - Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts[39]
- February 2008 - Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach: these iPS cells seem to be more similar to embryonic stem cells than the previous developed iPS cells and not tumorigenic, moreover genes that are required for iPS cells do not need to be inserted into specific sites, which encourages the development of non-viral reprogramming techniques. [40][41]
# Stem cell funding & policy debate in the US
- 1993 - As per the National Institutes of Health Revitalization Act, Congress and President Bill Clinton give the NIH direct authority to fund human embryo research for the first time.[42]
- 1995 - The U.S. Congress enacts into law an appropriations bill attached to which is the Dickey Amendment which prohibited federally appropriated funds to be used for research where human embryos would be either created or destroyed. This predates the creation of the first human embryonic stem cell lines.
- 1999 - After the creation of the first human embryonic stem cell lines in 1998 by James Thomson of the University of Wisconsin, Harriet Rabb, the top lawyer at the Department of Health and Human Services, releases a legal opinion that would set the course for Clinton Administration policy. Federal funds, obviously, could not be used to derive stem cell lines (because derivation involves embryo destruction). However, she concludes that because human embryonic stem cells "are not a human embryo within the statutory definition," the Dickey-Wicker Amendment does not apply to them. The NIH was therefore free to give federal funding to experiments involving the cells themselves. President Clinton strongly endorses the new guidelines, noting that human embryonic stem cell research promised "potentially staggering benefits." And with the guidelines in place, the NIH begins accepting grant proposals from scientists.[43]
- 02 November, 2004 - California voters approve Proposition 71, which provides $3 billion in state funds over ten years to human embryonic stem cell research.
- 2001-2006 - U.S. President George W. Bush signs an executive order which restricts federally-funded stem cell research on embryonic stem cells to the already derived cell lines. He supports federal funding for embryonic stem cell research on the already existing lines of approximately $100 million and $250 million for research on adult and animal stem cells.
- 5 May, 2006 - Senator Rick Santorum introduces bill number S. 2754, or the Alternative Pluripotent Stem Cell Therapies Enhancement Act, into the U.S. Senate.
- 18 July, 2006 - The U.S. Senate passes the Stem Cell Research Enhancement Act H.R. 810 and votes down Senator Santorum's S. 2754.
- 19 July, 2006 - President George W. Bush vetoes H.R. 810 (Stem Cell Research Enhancement Act), a bill that would have reversed the Gingrich-era appropriations amendment which made it illegal for federal money to be used for research where stem cells are derived from the destruction of an embryo.
- 07 November, 2006 - The people of the U.S. state of Missouri passed Amendment 2, which allows usage of any stem cell research and therapy allowed under federal law, but prohibits human reproductive cloning.[44]
- 16 February, 2007 – The California Institute for Regenerative Medicine became the biggest financial backer of human embryonic stem cell research in the United States when they awarded nearly $45 million in research grants.[45]
# Related Chapters
- The American Society for Cell Biology
- California Institute for Regenerative Medicine
- Genetics Policy Institute
- Cancer stem cells
- Induced pluripotent stem cell (iPS Cell)
- Odontis | https://www.wikidoc.org/index.php/Stem_Cells | |
48351eb7363b4429e2655608a5aa5101e115ab34 | wikidoc | Stomodeum | Stomodeum
# Overview
The stomodeum, also called stomatodeum, is a depression between the brain and the pericardium in an embryo, and is the precursor of the mouth and the anterior lobe of the pituitary gland.
# Structure
The stomodeum is lined by ectoderm, and is separated from the anterior end of the fore-gut by the buccopharyngeal membrane.
This membrane is devoid of mesoderm, being formed by the apposition of the stomodeal ectoderm with the fore-gut endoderm; at the end of the third week it disappears, and thus a communication is established between the mouth and the future pharynx.
# Development
The mouth is developed partly from the stomodeum, and partly from the floor of the anterior portion of the fore-gut.
By the growth of the head end of the embryo, and the formation of the cephalic flexure, the pericardial area and the buccopharyngeal membrane come to lie on the ventral surface of the embryo.
With the further expansion of the brain, and the forward bulging of the pericardium, the buccopharyngeal membrane is depressed between these two prominences. This depression constitutes the stomodeum.
No trace of the membrane is found in the adult; and the communication just mentioned must not be confused with the permanent isthmus faucium.
The lips, teeth, and gums are formed from the walls of the stomodeum, but the tongue is developed in the floor of the pharynx.
# Additional images
- Embryo between eighteen and twenty-one days.
- Under surface of the head of a human embryo about twenty-nine days old.
- Head end of human embryo of about thirty to thirty-one days. | Stomodeum
# Overview
Template:Infobox Embryology
The stomodeum, also called stomatodeum, is a depression between the brain and the pericardium in an embryo, and is the precursor of the mouth and the anterior lobe of the pituitary gland.
# Structure
The stomodeum is lined by ectoderm, and is separated from the anterior end of the fore-gut by the buccopharyngeal membrane.
This membrane is devoid of mesoderm, being formed by the apposition of the stomodeal ectoderm with the fore-gut endoderm; at the end of the third week it disappears, and thus a communication is established between the mouth and the future pharynx.
# Development
The mouth is developed partly from the stomodeum, and partly from the floor of the anterior portion of the fore-gut.
By the growth of the head end of the embryo, and the formation of the cephalic flexure, the pericardial area and the buccopharyngeal membrane come to lie on the ventral surface of the embryo.
With the further expansion of the brain, and the forward bulging of the pericardium, the buccopharyngeal membrane is depressed between these two prominences. This depression constitutes the stomodeum.
No trace of the membrane is found in the adult; and the communication just mentioned must not be confused with the permanent isthmus faucium.
The lips, teeth, and gums are formed from the walls of the stomodeum, but the tongue is developed in the floor of the pharynx.
# Additional images
- Embryo between eighteen and twenty-one days.
- Under surface of the head of a human embryo about twenty-nine days old.
- Head end of human embryo of about thirty to thirty-one days.
# External links
- Diagram at lww.com
- Template:EmbryologyUNC
Template:Gray's
Template:Development of digestive system
de:Stomodeumsv:Stomodeum
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Stomodaeum | |
3949c6201b74abc19af12da34d6d92d7a26f08f9 | wikidoc | Striation | Striation
Striations means a series of ridges, furrows or linear marks, and are used in several ways
- Glacial striation
- Striation (geology), a striation as a result of a geological fault
- In medicine, striated muscle
- Striations can be found in certain glasses. These have been caused by turbulent flow during teeming (pouring) of the glass. | Striation
Striations means a series of ridges, furrows or linear marks, and are used in several ways
- Glacial striation
- Striation (geology), a striation as a result of a geological fault
- In medicine, striated muscle
- Striations can be found in certain glasses. These have been caused by turbulent flow during teeming (pouring) of the glass.
Template:Dab | https://www.wikidoc.org/index.php/Striation | |
056cc4b44dc1c6e1a031b475af1ddd5b2fd8a5ae | wikidoc | Stripping | Stripping
Synonyms and keywords: Air Rotor Stripping, ARS
# Overview
Despite of its application difficulties in adult population air-rotor stripping (ARS) is a commonly used method to alleviate crowding in the permanent dentition. Stripping can be performed
using numerous kinds of rotating instruments, as diamond burs, diamond coated discs and polishing discs.
# Historical Background
Air Rotor Stripping (ARS) is described in 1985 by Sheridan, and based on reduction of mesio−distal interproximal surfaces of posterior teeth to provide required amount of space in dental arch.
# Examples
Images shown below are courtesy of Oral Sökücü DDS and copylefted.
- Before Orthodontic treatment (Frontal view)
- After Orthodontic treatment (Frontal view)
- Before Orthodontic treatment (Lateral view)
- After Orthodontic treatment (Lateral view)
- Before Orthodontic treatment (Intraoral view)
- After Orthodontic treatment (Intraoral view) | Stripping
Synonyms and keywords: Air Rotor Stripping, ARS
# Overview
Despite of its application difficulties in adult population air-rotor stripping (ARS) is a commonly used method to alleviate crowding in the permanent dentition. [1] [2] [3] Stripping can be performed
using numerous kinds of rotating instruments, as diamond burs, diamond coated discs and polishing discs.[4] [5] [6]
# Historical Background
Air Rotor Stripping (ARS) is described in 1985 by Sheridan, and based on reduction of mesio−distal interproximal surfaces of posterior teeth to provide required amount of space in dental arch.
# Examples
Images shown below are courtesy of Oral Sökücü DDS and copylefted.
- Before Orthodontic treatment (Frontal view)
- After Orthodontic treatment (Frontal view)
- Before Orthodontic treatment (Lateral view)
- After Orthodontic treatment (Lateral view)
- Before Orthodontic treatment (Intraoral view)
- After Orthodontic treatment (Intraoral view) | https://www.wikidoc.org/index.php/Stripping | |
cf31cae38ef62dd0b6665bb15f5ed8e7496db08d | wikidoc | Strong AI | Strong AI
Strong AI is a term used by futurists, science fiction writers and forward looking researchers to describe artificial intelligence that matches or exceeds human intelligence. Strong AI is also referred to as the ability to perform "general intelligent action", or as "artificial general intelligence", "artificial consciousness", "sentience", "sapience", "self-awareness" or "consciousness" (although there are subtle differences in the use of each of these terms).
Some references classify artificial intelligence research into "strong AI, applied AI and cognitive simulation." Applied AI (also called "narrow AI" or "weak AI") refers to the use of software to study or accomplish specific problem solving or reasoning tasks that do not encompass (or in some cases, are completely outside of) the full range of human cognitive abilities.
# History
## Origin of the term
The term "strong AI" was adopted from the name of an argument in the philosophy of artificial intelligence first identified by John Searle in 1980. He wanted to distinguish between two different hypotheses about artificial intelligence:
- An artificial intelligence system can think and have a mind.
- An artificial intelligence system can (only) act like it thinks and has a mind.
The first one is called "the strong AI hypothesis" and the second is "the weak AI hypothesis" because the first one makes the stronger statement: it assumes something special has happened to the machine that goes beyond all its abilities that we can test. Searle referred to the "strong AI hypothesis" as "strong AI". This usage, which is fundamentally different than the subject of this article, is common in academic AI research and textbooks.
The term "strong AI" is now used to describe any artificial intelligence system that acts like it has a mind, regardless of whether a philosopher would be able to determine if it actually has a mind or not. As Russell and Norvig write: "Most AI researchers take the weak AI hypothesis for granted, and don't care about the strong AI hypothesis."
AI researchers are interested in a related statement (that some sources confusingly call "the strong AI hypothesis"):
- An artificial intelligence system can think (or act like it thinks) as well or better than people do.
This assertion, which hinges on the breadth and power of machine intelligence, is the subject of this article.
## Strong AI research
Modern AI research began in the middle 50s. The first generation of AI researchers were convinced that strong AI was possible and that it would exist in just a few decades. As AI pioneer Herbert Simon wrote in 1965: "machines will be capable, within twenty years, of doing any work a man can do." Their predictions were the inspiration for Stanley Kubrick and Arthur C. Clarke's character HAL 9000, who accurately embodied what AI researchers believed they could create.
However, in the early 70s, became obvious that researchers had grossly underestimated the difficulty of the project. The agencies that funded AI became skeptical of strong AI and put researchers under increasing pressure to produce useful technology, or "applied AI". By 1974, funding for AI projects was hard find.
As the eighties began, Japan's fifth generation computer project revived interest in strong AI, setting out a ten year timeline that included strong AI goals like "carry on a casual conversation". In response to this and the success of expert systems, both industry and government pumped money back into the field. However, the market for AI spectacularly collapsed in the late 80s and the goals of the fifth generation computer project were never fulfilled. For the second time in 20 years, AI researchers who had predicted the immanent arrival of strong AI had been shown to fundamentally mistaken about what they could accomplish.
By the 1990s, AI researchers had gained a reputation for making promises they could not keep. Many AI researchers today are reluctant to make any kind of prediction at all and avoid any mention of "human level" artificial intelligence, for fear of being labeled a "wild-eyed dreamer." For the most part, researchers today choose to focus on specific sub-problems where they can produce verifiable results and commercial applications, such as neural nets, computer vision or data mining, and most believe that these sub-problems must be solved before machines with strong AI can exist. Interest in direct research into strong AI tends to come from outside the field, from internet entrepreneurs (such as Jeff Hawkins) or from futurists such as Ray Kurzweil.
# Defining strong AI
A computer enters the framework of strong AI if a machine approaches or supersedes human intelligence, if it can do typically human tasks, if it can apply a wide range of background knowledge and has some degree of self-consciousness. John McCarthy stated in his work What is AI? that we still do not have a solid definition of intelligence. Human-bound definitions of measurable intelligence, like IQ, cannot easily be applied to machine intelligence.
The most famous definition of AI was the operational one proposed by Alan Turing in his "Turing test" proposal. There have been very few attempts to create such definition since (some of them are in the AI Project)
A proposal to define a more easily quantifiable measure of artificial intelligence is:
Intelligence is the possession of a model of reality and the ability to use this model to conceive and plan actions and to predict their outcomes. The higher the complexity and precision of the model, the plans, and the predictions, and the less time needed, the higher is the intelligence.
# Research approaches
## Artificial general intelligence
Artificial General Intelligence research aims to create AI that can replicate human-level intelligence completely, often called an Artificial General Intelligence (AGI) to distinguish from less ambitious AI projects. As yet, researchers have devoted little attention to AGI, with some claiming that intelligence is too complex to be completely replicated in the near term. Some small groups of computer scientists are doing AGI research, however. Organizations pursuing AGI include the Adaptive AI, Artificial General Intelligence Research Institute (AGIRI) and the Singularity Institute for Artificial Intelligence. One recent addition is Numenta, a project based on the theories of Jeff Hawkins, the creator of the Palm Pilot. While Numenta takes a computational approach to general intelligence, Hawkins is also the founder of the RedWood Neuroscience Institute, which explores conscious thought from a biological perspective.
## Simulated human brain model
This is seen by manyTemplate:Who as the quickest means of achieving Strong AI, as it doesn't require complete understanding of how intelligence works. Basically, a very powerful computer would simulate a human brain, often in the form of a network of neurons. For example, given a map of all (or most) of the neurons in a functional human brain, and a good understanding of how a single neuron works, it would be possible for a computer program to simulate the working brain over time. Given some method of communication, this simulated brain might then be shown to be fully intelligent. The exact form of the simulation varies: instead of neurons, a simulation might use groups of neurons, or alternatively, individual molecules might be simulated. It's also unclear which portions of the human brain would need to be modeled: humans can still function while missing portions of their brains, and areas of the brain are associated with activities (such as breathing) that might not be necessary to think.
This approach would require three things:
- Hardware. An extremely powerful computer would be required for such a model. Futurist Ray Kurzweil estimates 10 million MIPS, or ten petaflops. At least one special-purpose petaflops computer has already been built (the Riken MDGRAPE-3) and there are nine current computing projects (such as BlueGene/P) to build more general purpose petaflops computers all of which should be completed by 2008, if not sooner. Most other attempted estimates of the brain's computational power equivalent have been rather higher, ranging from 100 million MIPS to 100 billion MIPS. Furthermore, the overhead introduced by the modeling of the biological details of neural behaviour might require a simulator to have access to computational power much greater than that of the brain itself.
- Software. Software to simulate the function of a brain would be required. This assumes that the human mind is the central nervous system and is governed by physical laws. Constructing the simulation would require a great deal of knowledge about the physical and functional operation of the human brain, and might require detailed information about a particular human brain's structure. Information would be required both of the function of different types of neurons, and of how they are connected. Note that the particular form of the software dictates the hardware necessary to run it. For example, an extremely detailed simulation including molecules or small groups of molecules would require enormously more processing power than a simulation that models neurons using a simple equation, and a more accurate model of a neuron would be expected to be much more expensive computationally than a simple model. The more neurons in the simulation, the more processing power it would require.
- Understanding. Finally, it requires sufficient understanding thereof to be able to model it mathematically. This could be done either by understanding the central nervous system, or by mapping and copying it. Neuroimaging technologies are improving rapidly, and Kurzweil predicts that a map of sufficient quality will become available on a similar timescale to the required computing power. However, the simulation would also have to capture the detailed cellular behaviour of neurons and glial cells, presently only understood in the broadest of outlines.
Once such a model is built, it will be easily altered and thus open to trial and error experimentation. This is likely to lead to huge advances in understanding, allowing the model's intelligence to be improved/motivations altered.
The Blue Brain project aims to use one of the fastest supercomputer architectures in the world, IBM's Blue Gene platform, to simulate a single neocortical column consisting of approximately 60,000 neurons and 5km of interconnecting synapses. The eventual goal of the project is to use supercomputers to simulate an entire brain.
The brain gets its power from performing many parallel operations, a standard computer from performing operations very quickly.
The human brain has roughly 100 billion neurons operating simultaneously, connected by roughly 100 trillion synapses. By comparison, a modern computer microprocessor uses only 1.7 billion transistors. Although estimates of the brain's processing power put it at around 1014 neuron updates per second, it is expected that the first unoptimized simulations of a human brain will require a computer capable of 1018 FLOPS. By comparison a general purpose CPU (circa 2006) operates at a few GFLOPS (109 FLOPS). (each FLOP may require as many as 20,000 logic operations).
However, a neuron is estimated to spike 200 times per second (this giving an upper limit on the number of operations). Signals between them are transmitted at a maximum speed of 150 meters per second. A modern 2GHz processor operates at 2 billion cycles per second, or 10,000,000 times faster than a human neuron, and signals in electronic computers travel at roughly half the speed of light; faster than signals in human by a factor of 1,000,000. The brain consumes about 20W of power where supercomputers may use as much as 1MW or an order of 100,000 more (note: Landauer limit is 3.5x1020 op/sec/watt at room temperature)
Neuro-silicon interfaces have also been proposed .
Critics of this approachTemplate:Who believe it's possible to achieve AI directly without imitating nature and often use the analogy that early attempts to construct flying machines modeled them after birds, but modern aircraft do not look like birds.
## Artificial consciousness research
## Emergence
SomeTemplate:Who have suggested that intelligence can arise as an emergent quality from the convergence of random, man-made technologies. Human sentience—or any other biological and naturally occurring intelligence—arises out of the natural process of species evolution and an individual's experiences. Discussion of this eventuality is currently limited to fiction and theory.OR | Strong AI
Template:Portalpar
Strong AI is a term used by futurists, science fiction writers and forward looking researchers to describe artificial intelligence that matches or exceeds human intelligence.[1] Strong AI is also referred to as the ability to perform "general intelligent action",[2] or as "artificial general intelligence",[3] "artificial consciousness", "sentience", "sapience", "self-awareness" or "consciousness"[4] (although there are subtle differences in the use of each of these terms).
Some references classify artificial intelligence research into "strong AI, applied AI and cognitive simulation."[5] Applied AI (also called "narrow AI"[1] or "weak AI"[6]) refers to the use of software to study or accomplish specific problem solving or reasoning tasks that do not encompass (or in some cases, are completely outside of) the full range of human cognitive abilities.
# History
## Origin of the term
The term "strong AI" was adopted from the name of an argument in the philosophy of artificial intelligence first identified by John Searle in 1980.[7] He wanted to distinguish between two different hypotheses about artificial intelligence:[8]
- An artificial intelligence system can think and have a mind.[9]
- An artificial intelligence system can (only) act like it thinks and has a mind.
The first one is called "the strong AI hypothesis" and the second is "the weak AI hypothesis" because the first one makes the stronger statement: it assumes something special has happened to the machine that goes beyond all its abilities that we can test. Searle referred to the "strong AI hypothesis" as "strong AI". This usage, which is fundamentally different than the subject of this article, is common in academic AI research and textbooks.[10]
The term "strong AI" is now used to describe any artificial intelligence system that acts like it has a mind,[1] regardless of whether a philosopher would be able to determine if it actually has a mind or not. As Russell and Norvig write: "Most AI researchers take the weak AI hypothesis for granted, and don't care about the strong AI hypothesis."[11]
AI researchers are interested in a related statement (that some sources confusingly call "the strong AI hypothesis"):[12]
- An artificial intelligence system can think (or act like it thinks) as well or better than people do.
This assertion, which hinges on the breadth and power of machine intelligence, is the subject of this article.
## Strong AI research
Modern AI research began in the middle 50s.[13] The first generation of AI researchers were convinced that strong AI was possible and that it would exist in just a few decades. As AI pioneer Herbert Simon wrote in 1965: "machines will be capable, within twenty years, of doing any work a man can do."[14] Their predictions were the inspiration for Stanley Kubrick and Arthur C. Clarke's character HAL 9000, who accurately embodied what AI researchers believed they could create.
However, in the early 70s, became obvious that researchers had grossly underestimated the difficulty of the project. The agencies that funded AI became skeptical of strong AI and put researchers under increasing pressure to produce useful technology, or "applied AI". By 1974, funding for AI projects was hard find.[15]
As the eighties began, Japan's fifth generation computer project revived interest in strong AI, setting out a ten year timeline that included strong AI goals like "carry on a casual conversation".[16] In response to this and the success of expert systems, both industry and government pumped money back into the field.[17] However, the market for AI spectacularly collapsed in the late 80s and the goals of the fifth generation computer project were never fulfilled.[18] For the second time in 20 years, AI researchers who had predicted the immanent arrival of strong AI had been shown to fundamentally mistaken about what they could accomplish.
By the 1990s, AI researchers had gained a reputation for making promises they could not keep. Many AI researchers today are reluctant to make any kind of prediction at all[19] and avoid any mention of "human level" artificial intelligence, for fear of being labeled a "wild-eyed dreamer."[20] For the most part, researchers today choose to focus on specific sub-problems where they can produce verifiable results and commercial applications, such as neural nets, computer vision or data mining,[21] and most believe that these sub-problems must be solved before machines with strong AI can exist.[22] Interest in direct research into strong AI tends to come from outside the field, from internet entrepreneurs (such as Jeff Hawkins) or from futurists such as Ray Kurzweil.
# Defining strong AI
Template:Expand-section
Template:Expert
A computer enters the framework of strong AI if a machine approaches or supersedes human intelligence, if it can do typically human tasks, if it can apply a wide range of background knowledge and has some degree of self-consciousness. John McCarthy stated in his work What is AI? that we still do not have a solid definition of intelligence. Human-bound definitions of measurable intelligence, like IQ, cannot easily be applied to machine intelligence.
The most famous definition of AI was the operational one proposed by Alan Turing in his "Turing test" proposal. There have been very few attempts to create such definition since (some of them are in the AI Project)
A proposal to define a more easily quantifiable measure of artificial intelligence is:
Intelligence is the possession of a model of reality and the ability to use this model to conceive and plan actions and to predict their outcomes. The higher the complexity and precision of the model, the plans, and the predictions, and the less time needed, the higher is the intelligence.[1]
# Research approaches
## Artificial general intelligence
Artificial General Intelligence research aims to create AI that can replicate human-level intelligence completely, often called an Artificial General Intelligence (AGI) to distinguish from less ambitious AI projects. As yet, researchers have devoted little attention to AGI, with some claiming that intelligence is too complex to be completely replicated in the near term. Some small groups of computer scientists are doing AGI research, however. Organizations pursuing AGI include the Adaptive AI, Artificial General Intelligence Research Institute (AGIRI) and the Singularity Institute for Artificial Intelligence. One recent addition is Numenta, a project based on the theories of Jeff Hawkins, the creator of the Palm Pilot. While Numenta takes a computational approach to general intelligence, Hawkins is also the founder of the RedWood Neuroscience Institute, which explores conscious thought from a biological perspective.
## Simulated human brain model
This is seen by manyTemplate:Who as the quickest means of achieving Strong AI, as it doesn't require complete understanding of how intelligence works. Basically, a very powerful computer would simulate a human brain, often in the form of a network of neurons. For example, given a map of all (or most) of the neurons in a functional human brain, and a good understanding of how a single neuron works, it would be possible for a computer program to simulate the working brain over time. Given some method of communication, this simulated brain might then be shown to be fully intelligent. The exact form of the simulation varies: instead of neurons, a simulation might use groups of neurons, or alternatively, individual molecules might be simulated. It's also unclear which portions of the human brain would need to be modeled: humans can still function while missing portions of their brains, and areas of the brain are associated with activities (such as breathing) that might not be necessary to think.[citation needed]
This approach would require three things:
- Hardware. An extremely powerful computer would be required for such a model. Futurist Ray Kurzweil estimates 10 million MIPS, or ten petaflops. At least one special-purpose petaflops computer has already been built (the Riken MDGRAPE-3) and there are nine current computing projects (such as BlueGene/P) to build more general purpose petaflops computers all of which should be completed by 2008, if not sooner.[2] Most other attempted estimates of the brain's computational power equivalent have been rather higher, ranging from 100 million MIPS to 100 billion MIPS. Furthermore, the overhead introduced by the modeling of the biological details of neural behaviour might require a simulator to have access to computational power much greater than that of the brain itself.
- Software. Software to simulate the function of a brain would be required. This assumes that the human mind is the central nervous system and is governed by physical laws. Constructing the simulation would require a great deal of knowledge about the physical and functional operation of the human brain, and might require detailed information about a particular human brain's structure. Information would be required both of the function of different types of neurons, and of how they are connected. Note that the particular form of the software dictates the hardware necessary to run it. For example, an extremely detailed simulation including molecules or small groups of molecules would require enormously more processing power than a simulation that models neurons using a simple equation, and a more accurate model of a neuron would be expected to be much more expensive computationally than a simple model. The more neurons in the simulation, the more processing power it would require.
- Understanding. Finally, it requires sufficient understanding thereof to be able to model it mathematically. This could be done either by understanding the central nervous system, or by mapping and copying it. Neuroimaging technologies are improving rapidly, and Kurzweil predicts that a map of sufficient quality will become available on a similar timescale to the required computing power. However, the simulation would also have to capture the detailed cellular behaviour of neurons and glial cells, presently only understood in the broadest of outlines.
Once such a model is built, it will be easily altered and thus open to trial and error experimentation. This is likely to lead to huge advances in understanding, allowing the model's intelligence to be improved/motivations altered.[dubious – discuss]
The Blue Brain project aims to use one of the fastest supercomputer architectures in the world, IBM's Blue Gene platform, to simulate a single neocortical column consisting of approximately 60,000 neurons and 5km of interconnecting synapses. The eventual goal of the project is to use supercomputers to simulate an entire brain.
The brain gets its power from performing many parallel operations, a standard computer from performing operations very quickly.
The human brain has roughly 100 billion neurons operating simultaneously, connected by roughly 100 trillion synapses[23]. By comparison, a modern computer microprocessor uses only 1.7 billion transistors[3]. Although estimates of the brain's processing power put it at around 1014 neuron updates per second,[24] it is expected that the first unoptimized simulations of a human brain will require a computer capable of 1018 FLOPS. By comparison a general purpose CPU (circa 2006) operates at a few GFLOPS (109 FLOPS). (each FLOP may require as many as 20,000 logic operations).
However, a neuron is estimated to spike 200 times per second (this giving an upper limit on the number of operations).[citation needed] Signals between them are transmitted at a maximum speed of 150 meters per second. A modern 2GHz processor operates at 2 billion cycles per second, or 10,000,000 times faster than a human neuron, and signals in electronic computers travel at roughly half the speed of light; faster than signals in human by a factor of 1,000,000.[citation needed] The brain consumes about 20W of power where supercomputers may use as much as 1MW or an order of 100,000 more (note: Landauer limit is 3.5x1020 op/sec/watt at room temperature)
Neuro-silicon interfaces have also been proposed [4] [5].
Critics of this approachTemplate:Who believe it's possible to achieve AI directly without imitating nature and often use the analogy that early attempts to construct flying machines modeled them after birds, but modern aircraft do not look like birds.[citation needed]
## Artificial consciousness research
Template:Expand
## Emergence
SomeTemplate:Who have suggested that intelligence can arise as an emergent quality from the convergence of random, man-made technologies. Human sentience—or any other biological and naturally occurring intelligence—arises out of the natural process of species evolution and an individual's experiences. Discussion of this eventuality is currently limited to fiction and theory.[citation needed]OR | https://www.wikidoc.org/index.php/Strong_AI | |
461e84b5786e3142d31f3eb140dd4d06ed99af03 | wikidoc | Submucosa | Submucosa
# Overview
In the gastrointestinal tract, the submucosa is the layer of loose connective tissue that supports the mucosa, as well as joins the mucosa to the bulk of underlying smooth muscle (fibers running circularly within layer of longitudinal muscle).
# Contents
Blood vessels, lymphatic vessels, and nerves (all supplying the mucosa) will run through here.
Tiny parasympathetic ganglia are scattered around forming the submucosal plexus (or "Meissner's plexus") where preganglionic parasympathetic neurons synapse with postganglionic nerve fibers that supply the muscularis mucosae.
# The submucosa in endoscopy
Identification of the submucosa plays an important role in diagnostic and therapeutic endoscopy, where special fibre-optic cameras are used to perform procedures on the gastrointestinal tract. Abnormalities of the submucosa, such as gastrointestinal stromal tumors, usually show integrity of the mucosal surface.
The submucosa is also identified in endoscopic ultrasound to identify the depth of tumours and to identify other abnormalities. An injection of dye, saline, or epinephrine into the submucosa is imperative in the safe removal of certain polyps.
Endoscopic mucosal resection involves removal of the mucosal layer, and in order to be done safely, a submucosal injection of dye is performed to ensure integrity at the beginning of the procedure. | Submucosa
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Infobox Anatomy
In the gastrointestinal tract, the submucosa is the layer of loose connective tissue that supports the mucosa, as well as joins the mucosa to the bulk of underlying smooth muscle (fibers running circularly within layer of longitudinal muscle).
# Contents
Blood vessels, lymphatic vessels, and nerves (all supplying the mucosa) will run through here.
Tiny parasympathetic ganglia are scattered around forming the submucosal plexus (or "Meissner's plexus") where preganglionic parasympathetic neurons synapse with postganglionic nerve fibers that supply the muscularis mucosae.
# The submucosa in endoscopy
Identification of the submucosa plays an important role in diagnostic and therapeutic endoscopy, where special fibre-optic cameras are used to perform procedures on the gastrointestinal tract. Abnormalities of the submucosa, such as gastrointestinal stromal tumors, usually show integrity of the mucosal surface.
The submucosa is also identified in endoscopic ultrasound to identify the depth of tumours and to identify other abnormalities. An injection of dye, saline, or epinephrine into the submucosa is imperative in the safe removal of certain polyps.
Endoscopic mucosal resection involves removal of the mucosal layer, and in order to be done safely, a submucosal injection of dye is performed to ensure integrity at the beginning of the procedure. | https://www.wikidoc.org/index.php/Submucosa | |
de6f6fc56358018602e9380349e03e675df547e9 | wikidoc | Subphylum | Subphylum
In life, a subphylum is a taxonomic rank intermediate between phylum and superclass. The rank of subdivision in plants and fungi is equivalent to subphylum.
Not all phyla are divided into subphyla. Those that are include:
- Arthropoda: divided into subphyla Trilobitomorpha, Chelicerata, Myriapoda, Hexapoda and Crustacea,
- Brachiopoda: divided into subphyla Linguliformea, Craniformea and Rhychonelliformea,
- Chordata: divided into Urochordata, Cephalochordata, and its largest subphylum Vertebrata.
ca:Subfílum
cs:Podkmen
cy:Is-ffylwm
it:Subphylum
lt:Potipis
hu:Altörzs (rendszertan)
nl:Onderstam (biologie)
fi:Alajakso
th:ไฟลัมย่อย | Subphylum
In life, a subphylum is a taxonomic rank intermediate between phylum and superclass. The rank of subdivision in plants and fungi is equivalent to subphylum.
Not all phyla are divided into subphyla. Those that are include:
- Arthropoda: divided into subphyla Trilobitomorpha, Chelicerata, Myriapoda, Hexapoda and Crustacea,
- Brachiopoda: divided into subphyla Linguliformea, Craniformea and Rhychonelliformea,
- Chordata: divided into Urochordata, Cephalochordata, and its largest subphylum Vertebrata.
Template:Taxanomic ranks
ca:Subfílum
cs:Podkmen
cy:Is-ffylwm
it:Subphylum
lt:Potipis
hu:Altörzs (rendszertan)
nl:Onderstam (biologie)
fi:Alajakso
th:ไฟลัมย่อย
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Subphylum | |
fb9ef356a88501a2f4e88a3e60622cb72ccf504f | wikidoc | Substrate | Substrate
Substrate may mean:
- Substrate (biochemistry), a molecule that is acted upon by an enzyme
- Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached
- Substrate (chemistry), the catalytic material upon which chemical species react
Substrate may also refer to:
- Wafer (electronics), material upon which semiconductor devices are fabricated
- Printed circuit board (electronics), or the electrically insulating portion of a PCB structure | Substrate
Substrate may mean:
- Substrate (biochemistry), a molecule that is acted upon by an enzyme
- Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached
- Substrate (chemistry), the catalytic material upon which chemical species react
Substrate may also refer to:
- Wafer (electronics), material upon which semiconductor devices are fabricated
- Printed circuit board (electronics), or the electrically insulating portion of a PCB structure | https://www.wikidoc.org/index.php/Substrate | |
42ddc04664c79a7979a556af7c5cf00f250f9092 | wikidoc | Sulfatase | Sulfatase
Sulfatases EC 3.1.6. are esterase enzymes which remove sulfate from a variety of substrates by hydrolyzing various sulphate esters.
The following sulphatases were shown to be structurally related based on their sequence homology,,
- cerebroside-sulfatase
- steryl-sulfatase
- arylsulphatase A EC 3.1.6.8 (ASA), a lysosomal enzyme which hydrolyzes cerebroside sulphate;
- arylsulphatase B EC 3.1.6.12 (ASB) which hydrolyzes the sulphate ester group from N-acetylgalactosamine 4-sulphate residues of dermatan sulphate;
- arylsulphatase C (ASD) and E (ASE); steryl-sulphatase EC 3.1.6.2 (STS), a membrane bound enzyme which hydrolyzes 3-beta-hydroxy steroid sulphates;
- iduronate 2-sulphatase EC 3.1.6.13 (IDS), a lysosomal enzyme that hydrolyzes the 2-sulphate groups from iduronic acids in dermatan sulphate and heparan sulphate;
- N-acetylgalactosamine-6-sulphatase EC 3.1.6.4, which hydrolyzes the 6-sulphate groups of the N-acetyl-D-galactosamine of chondroitin sulphate and D-galactose 6-sulphate units of keratan sulphate;
- N-sulphoglucosamine sulphohydrolase EC 3.10.1.1, the lysosomal enzyme that hydrolyses N-sulpho-D-glucosamine into glucosamine and sulphate;
- glucosamine-6-sulphatase EC 3.1.6.14 (G6S), which hydrolyzes the N-acetyl-D-glucosamine 6-sulphate units of heparan sulphate and keratan sulphate;
- N-sulphoglucosamine sulphohydrolase EC 3.10.1.1, the lysosomal enzyme that hydrolyses N-sulpho-D-glucosamine into glucosamine and sulphate;
- sea urchin embryo arylsulphatase EC 3.1.6.1;
- green algae arylsulphatase EC 3.1.6.1, which plays a role in the mineralization of sulphates; and
- arylsulphatase EC 3.1.6.1 from Escherichia coli, Klebsiella aerogenes and Pseudomonas aeruginosa.
# Human proteins containing this domain
ARSA; ARSB; ARSD; ARSE; ARSF; ARSG; ARSH; ARSI;
ARSJ; ARSK; GALNS; GNS; IDS; PIGG; SGSH; STS;
SULF1; SULF2; | Sulfatase
Sulfatases EC 3.1.6. are esterase enzymes which remove sulfate from a variety of substrates by hydrolyzing various sulphate esters.
The following sulphatases were shown to be structurally related based on their sequence homology[1][2],[3],
- cerebroside-sulfatase
- steryl-sulfatase
- arylsulphatase A EC 3.1.6.8 (ASA), a lysosomal enzyme which hydrolyzes cerebroside sulphate;
- arylsulphatase B EC 3.1.6.12 (ASB) which hydrolyzes the sulphate ester group from N-acetylgalactosamine 4-sulphate residues of dermatan sulphate;
- arylsulphatase C (ASD) and E (ASE); steryl-sulphatase EC 3.1.6.2 (STS), a membrane bound enzyme which hydrolyzes 3-beta-hydroxy steroid sulphates;
- iduronate 2-sulphatase EC 3.1.6.13 (IDS), a lysosomal enzyme that hydrolyzes the 2-sulphate groups from iduronic acids in dermatan sulphate and heparan sulphate;
- N-acetylgalactosamine-6-sulphatase EC 3.1.6.4, which hydrolyzes the 6-sulphate groups of the N-acetyl-D-galactosamine of chondroitin sulphate and D-galactose 6-sulphate units of keratan sulphate;
- N-sulphoglucosamine sulphohydrolase EC 3.10.1.1, the lysosomal enzyme that hydrolyses N-sulpho-D-glucosamine into glucosamine and sulphate;
- glucosamine-6-sulphatase EC 3.1.6.14 (G6S), which hydrolyzes the N-acetyl-D-glucosamine 6-sulphate units of heparan sulphate and keratan sulphate;
- N-sulphoglucosamine sulphohydrolase EC 3.10.1.1, the lysosomal enzyme that hydrolyses N-sulpho-D-glucosamine into glucosamine and sulphate;
- sea urchin embryo arylsulphatase EC 3.1.6.1;
- green algae arylsulphatase EC 3.1.6.1, which plays a role in the mineralization of sulphates; and
- arylsulphatase EC 3.1.6.1 from Escherichia coli, Klebsiella aerogenes and Pseudomonas aeruginosa.
# Human proteins containing this domain
ARSA; ARSB; ARSD; ARSE; ARSF; ARSG; ARSH; ARSI;
ARSJ; ARSK; GALNS; GNS; IDS; PIGG; SGSH; STS;
SULF1; SULF2; | https://www.wikidoc.org/index.php/Sulfatase | |
da1bbdb3c96b5ed3d424ca36ee9a245b83a3c659 | wikidoc | Sulpiride | Sulpiride
Sulpiride (brand names Dogmatil (HK, SG, PH), Dolmatil (IE, UK), Eglonyl (RU, ZA), Espiride (ZA), Modal (IL), Sulpor (UK) and others) is an atypical antipsychotic drug (although some texts have referred to it as a typical antipsychotic) of the benzamide class used mainly in the treatment of psychosis associated with schizophrenia and major depressive disorder, and sometimes used in low dosage to treat anxiety and mild depression. Sulpiride is commonly used in Europe, Russia and Japan. Levosulpiride is its purified levo-isomer and is sold in India for similar purpose. So far it has not been approved in the United States, Canada and Australia. The drug is chemically and clinically similar to amisulpride.
# Medical uses
Sulpiride's primary use in medicine is in the management of the symptoms of schizophrenia. It has been used as both a monotherapy and adjunctive therapy (in case of treatment-resistance) in schizophrenia. It has also been used in the treatment of dysthymia. Augmentation with sulpiride has also been tried as a strategy for accelerating antidepressant response in patients with major depressive disorder. There is also evidence of its efficacy in treating panic disorder.
## Pregnancy and lactation
- Pregnancy: Animal studies did not reveal any embryotoxicity or fetotoxicity, nor did limited human experience. Due to insufficient human data, pregnant women should be treated with sulpiride only if strictly indicated. Additionally, the newborns of treated women should be monitored, because isolated cases of extrapyramidal side effects have been reported.
- Lactation: Sulpiride is found in the milk of lactating women. Since the consequences are unclear, women should not breastfeed during treatment.
# Adverse effects
Sulpiride is usually well-tolerated, producing few adverse effects. Their incidences are as follows:
- Dizziness
- Headache
- Extrapyramidal side effects
- Somnolence (not a very prominent adverse effect considering its lack of alpha-1 adrenergic, histamine and muscarinic acetylcholine receptor affinity)
- Insomnia
- Weight gain or loss
- Hyperprolactinaemia (elevated plasma levels of the hormone, prolactin which can, in turn lead to sexual dysfunction, galactorrhoea, amenorrhoea, gynaecomastia, etc.)
- Nausea
- Vomiting
- Nasal congestion
- Anticholinergic adverse effects such as:
- Restlessness
- Impaired concentration
- Tardive dyskinesia — a rare, often permanent movement disorder that, more often than not, results from prolonged treatment with antidopaminergic agents such as antipsychotics. It presents with slow (hence tardive), involuntary, repetitive and purposeless movements that most often affect the facial muscles.
- Neuroleptic malignant syndrome — a rare, life-threatening complication that results from the use of antidopaminergic agents. Its incidence increases with concomitant use of lithium (medication) salts.
- Blood dyscrasias — rare, sometimes life-threatening complications of the use of a number of different antipsychotics (most notably clozapine) which involves abnormalities in the composition of a person's blood (e.g. having too few white blood cells per unit volume of blood. Examples include:
- Seizures
- Torsades de Pointes
- QTc interval prolongation which can lead to potentially fatal arrhythmias.
- Cholestatic jaundice
- Elevated liver enzymes
- Primary biliary cirrhosis
- Allergic reactions
- Photosensitivity — sensitivity to light.
- Skin rashes
- Depression
- Catatonia
- Palpitations
- Agitation
- Diaphoresis — sweating without a precipitating factor (e.g. increased ambient temperature).
- Hypotension — low blood pressure.
- Hypertension — high blood pressure.
- Venous thromboembolism (probably rare)
## Contraindications and cautions
Contraindications
- Hypersensitivity to sulpiride
- Pre-existing breast cancer or other prolactin-dependent tumors
- Phaeochromocytoma
- Intoxication with other centrally active drugs
- Concomitant use of levodopa
- Acute porphyria
- Comatose state or CNS depression
- Bone-marrow suppression
Cautions
- Pre-existing Parkinson's Disease
- Patients below 18 years of age (insufficient clinical data)
- Pre-existing severe heart disease/bradycardia, or hypokalemia (predisposing to long QT syndrome and severe arrhythmias)
- Patients with pre-existing epilepsy. Anticonvulsant therapy should be maintained.
- Lithium use — increased risk of neurological side effects of both drugs
## Overdose
Sulpiride has a relatively low order of acute toxicity. Substantial amounts may cause severe but reversible dystonic crises with torticollis, protrusion of the tongue, and/or trismus. In some cases all the classical symptoms typical of severe Parkinson's Disease may be noted; in others, over-sedation/coma may occur. The treatment is largely symptomatic. Some or all extrapyramidal reactions may respond to the application of anticholinergic drugs such as biperiden or benztropine. All patients should be closely monitored for signs of long-QT syndrome and severe arrhythmias.
# Synthesis
Sulpiride can be synthesized from 5-aminosulfosalicylic acid. Methylating this with dimethylsulfate gives 2-methoxy-5-aminosulfonylbenzoic acid, which is transformed into an amide using 2-aminomethyl-1-ethylpyrrolidine as the amine component and carbonyldiimidazole (CDI) as a condensing agent.
# Pharmacology
Sulpiride is a selective antagonist at dopamine D2 and D3 receptors. This action dominates in doses exceeding 600 mg daily. In doses of 600 to 1,600 mg sulpiride shows mild sedating and antipsychotic activity. Its antipsychotic potency compared to chlorpromazine is only 0.2 (1/5). In low doses (in particular 50 to 200 mg daily) its prominent feature is antagonism of presynaptic inhibitory dopamine receptors accounting for some antidepressant activity and a stimulating effect. Therefore, it is in these doses used as a second line antidepressant. Additionally, it alleviates vertigo.
The benzamide neuroleptics (including sulpiride, amisulpride, and sultopride) have been shown to activate the endogenous gamma-hydroxybutyrate receptor in vivo at therapeutic concentrations. Sulpiride was found in one study in rats to upregulate GHB receptors. GHB has neuroleptic properties and it is believed binding to this receptor may contribute to the effects of these neuroleptics.
Sulpiride, along with clozapine, has been found to activate DNA demethylation in the brain. | Sulpiride
Sulpiride (brand names Dogmatil (HK, SG, PH), Dolmatil (IE, UK), Eglonyl (RU, ZA), Espiride (ZA), Modal (IL), Sulpor (UK) and others) is an atypical antipsychotic drug (although some texts have referred to it as a typical antipsychotic[4]) of the benzamide class used mainly in the treatment of psychosis associated with schizophrenia and major depressive disorder, and sometimes used in low dosage to treat anxiety and mild depression. Sulpiride is commonly used in Europe, Russia and Japan. Levosulpiride is its purified levo-isomer and is sold in India for similar purpose. So far it has not been approved in the United States, Canada and Australia. The drug is chemically and clinically similar to amisulpride.
# Medical uses
Sulpiride's primary use in medicine is in the management of the symptoms of schizophrenia.[2] It has been used as both a monotherapy and adjunctive therapy (in case of treatment-resistance) in schizophrenia.[2][5][6][7][8][9] It has also been used in the treatment of dysthymia.[10] Augmentation with sulpiride has also been tried as a strategy for accelerating antidepressant response in patients with major depressive disorder.[11] There is also evidence of its efficacy in treating panic disorder.[12][13]
## Pregnancy and lactation
- Pregnancy: Animal studies did not reveal any embryotoxicity or fetotoxicity, nor did limited human experience. Due to insufficient human data, pregnant women should be treated with sulpiride only if strictly indicated. Additionally, the newborns of treated women should be monitored, because isolated cases of extrapyramidal side effects have been reported.[2]
- Lactation: Sulpiride is found in the milk of lactating women. Since the consequences are unclear, women should not breastfeed during treatment.[2]
# Adverse effects
Sulpiride is usually well-tolerated, producing few adverse effects. Their incidences are as follows:[2][5][14][15][16][17][18][19][20]
- Dizziness
- Headache
- Extrapyramidal side effects
- Somnolence (not a very prominent adverse effect considering its lack of alpha-1 adrenergic, histamine and muscarinic acetylcholine receptor affinity)
- Insomnia
- Weight gain or loss
- Hyperprolactinaemia (elevated plasma levels of the hormone, prolactin which can, in turn lead to sexual dysfunction, galactorrhoea, amenorrhoea, gynaecomastia, etc.)
- Nausea
- Vomiting
- Nasal congestion
- Anticholinergic adverse effects such as:
- Restlessness
- Impaired concentration
- Tardive dyskinesia — a rare, often permanent movement disorder that, more often than not, results from prolonged treatment with antidopaminergic agents such as antipsychotics. It presents with slow (hence tardive), involuntary, repetitive and purposeless movements that most often affect the facial muscles.
- Neuroleptic malignant syndrome — a rare, life-threatening complication that results from the use of antidopaminergic agents. Its incidence increases with concomitant use of lithium (medication) salts.
- Blood dyscrasias — rare, sometimes life-threatening complications of the use of a number of different antipsychotics (most notably clozapine) which involves abnormalities in the composition of a person's blood (e.g. having too few white blood cells per unit volume of blood. Examples include:
- Seizures
- Torsades de Pointes
- QTc interval prolongation which can lead to potentially fatal arrhythmias.
- Cholestatic jaundice[22]
- Elevated liver enzymes
- Primary biliary cirrhosis[23]
- Allergic reactions
- Photosensitivity — sensitivity to light.
- Skin rashes
- Depression
- Catatonia
- Palpitations
- Agitation
- Diaphoresis — sweating without a precipitating factor (e.g. increased ambient temperature).
- Hypotension — low blood pressure.
- Hypertension — high blood pressure.
- Venous thromboembolism (probably rare)
## Contraindications and cautions
Contraindications[2]
- Hypersensitivity to sulpiride
- Pre-existing breast cancer or other prolactin-dependent tumors
- Phaeochromocytoma
- Intoxication with other centrally active drugs
- Concomitant use of levodopa
- Acute porphyria
- Comatose state or CNS depression
- Bone-marrow suppression
Cautions[2]
- Pre-existing Parkinson's Disease
- Patients below 18 years of age (insufficient clinical data)
- Pre-existing severe heart disease/bradycardia, or hypokalemia (predisposing to long QT syndrome and severe arrhythmias)
- Patients with pre-existing epilepsy. Anticonvulsant therapy should be maintained.
- Lithium use — increased risk of neurological side effects of both drugs
## Overdose
Sulpiride has a relatively low order of acute toxicity. Substantial amounts may cause severe but reversible dystonic crises with torticollis, protrusion of the tongue, and/or trismus. In some cases all the classical symptoms typical of severe Parkinson's Disease may be noted; in others, over-sedation/coma may occur. The treatment is largely symptomatic. Some or all extrapyramidal reactions may respond to the application of anticholinergic drugs such as biperiden or benztropine. All patients should be closely monitored for signs of long-QT syndrome and severe arrhythmias.
# Synthesis
Sulpiride can be synthesized from 5-aminosulfosalicylic acid. Methylating this with dimethylsulfate gives 2-methoxy-5-aminosulfonylbenzoic acid, which is transformed into an amide using 2-aminomethyl-1-ethylpyrrolidine as the amine component and carbonyldiimidazole (CDI) as a condensing agent.
# Pharmacology
Sulpiride is a selective antagonist at dopamine D2 and D3 receptors. This action dominates in doses exceeding 600 mg daily. In doses of 600 to 1,600 mg sulpiride shows mild sedating and antipsychotic activity. Its antipsychotic potency compared to chlorpromazine is only 0.2 (1/5). In low doses (in particular 50 to 200 mg daily) its prominent feature is antagonism of presynaptic inhibitory dopamine receptors accounting for some antidepressant activity and a stimulating effect. Therefore, it is in these doses used as a second line antidepressant. Additionally, it alleviates vertigo.
The benzamide neuroleptics (including sulpiride, amisulpride, and sultopride) have been shown to activate the endogenous gamma-hydroxybutyrate receptor in vivo at therapeutic concentrations.[24] Sulpiride was found in one study in rats to upregulate GHB receptors.[25] GHB has neuroleptic properties and it is believed binding to this receptor may contribute to the effects of these neuroleptics.
Sulpiride, along with clozapine, has been found to activate DNA demethylation in the brain.[26] | https://www.wikidoc.org/index.php/Sulpiride | |
fb50ebe78521a7d8989d9a116e9127e80331703b | wikidoc | Suma root | Suma root
Suma also called Brazilian ginseng (Pfaffia paniculata syn. Hebanthe paniculata, Gomphrena paniculata, Gomphrena eriantha, Iresine erianthos, Iresine paniculata, Iresine tenuis, Pfaffia eriantha, Xeraea paniculata ) is the root of a rambling ground vine found in South America used traditionally as a medicine and tonic. Nicknamed "para todo" which means "for all," suma is an herbal medicine with adaptogenic qualities that serve to normalize and enhance body systems, increase resistance to stress, and boost overall functioning. It has been used for a variety of ailments with good efficacy, hence the name "para todo."
# Pharmacology and mode of action
Suma is said to support hormonal balance, reduce inflammation, inhibit cancer and leukemia cells, enhance immunity, increase libido, and a provide a number of normalizing and rejuvenating effects. One of the reason for its myriad effects may be its ability to increase oxygenation and energy efficiency at the cellular level. Suma contains germanium, beta-ecdysterone, allantoin, and a group of novel phytochemical saponins called pfaffosides.
# History
The ethnomedicine reveals that Iresine celosia, Tlantcuayin, was used by the Maya-Quiché civilization circa 2000 years.
The species appears in famous 1552 manuscript on Precolombian medicine: "Libellus de Medicinalibus Indorum Herbis".
In modern times, during the 1960’s till 1986, Efraín Contreras (1898-1986), a well-known naturopath, discovered the anti-tumoral properties of Iresine celosia, (Amaranthacea Gomphrenoidea), an herb native to Central America. During the decades of the 70s and 80s, he obtained an approval to administer Iresine celosia as a liquid as well as a dry herbal extract to hospital patients at Hospital El Retiro and Hospital Bertha Calderón in Managua, Nicaragua. The evaluation of the Scientific Commission of the Ministry of Health of Nicaragua (1983) concluded that : “ Codin VII (Iresine celosia) herbal extract was given to patients with tumors in the digestive system - prior to surgery, and also, post-surgery. These patients had various carcinomas of the stomach and regional ganglia. The post-surgery doses invariably reduced the size of the tumor as well as other treated cases. During surgery of the carcinomas of the mammary gland and metastasis in situ and at a distance, metastasis in situ disappeared within 12 to 15 days of treatment, and those at a distance were also reduced. In all cases where Codin VI was employed, health improvement was distinctly obvious. General well-being improved, hemorrages, vaginal discharges and pain disappeared. No toxicity or side effects were observed”. In the decade of the 90’s, Iresine celosia was given to patients suffering from prostate problems, sexual impotency with promising results. Important research studies have been carried out by Pierre Crabbé, P.R. Leeming and Carl Djerassi as a contribution from the Department of Chemistry of Wayne State University, USA. (The Structure of the Isoflavone Tlatlancuayin).
Iresine celosia was introduced in Europe for the first time some 15 years ago. In 1994, Ms. Edda Contreras, Efraín Contreras' daughter, collaborated for the first time with the European Institute of Tropical Phytotherapy. From 1994-1998, Iresine celosia was presented at the De Natura Rerum Forum in Cannes, Sophia Antipolis, Biarritz, Lyon and Paris (France). Tradition records that Iresine celosia was used for tumoral pathologies such as prostate, mammary glands, ovaries, brain, intestin, etc. Iresine celosia is also used for activiting the libido, psychiatrique pathologies and for immune system depressions.
Active principle: Iresine celosia contains 2.50% natural glucid steroids. Mechanism of Action : Clinical studies in Nicaragua have shown that Iresine celosia affected the permeability of the pathological cell, and changed the bio-electric potential of the cancerous membrane (Dindail et al). | Suma root
Template:ToLCleanup
Suma also called Brazilian ginseng (Pfaffia paniculata syn. Hebanthe paniculata, Gomphrena paniculata, Gomphrena eriantha, Iresine erianthos, Iresine paniculata, Iresine tenuis, Pfaffia eriantha, Xeraea paniculata [1]) is the root of a rambling ground vine found in South America used traditionally as a medicine and tonic. Nicknamed "para todo" which means "for all," suma is an herbal medicine with adaptogenic qualities that serve to normalize and enhance body systems, increase resistance to stress, and boost overall functioning. It has been used for a variety of ailments with good efficacy[citation needed], hence the name "para todo."
# Pharmacology and mode of action
Suma is said to support hormonal balance, reduce inflammation, inhibit cancer and leukemia cells, enhance immunity, increase libido, and a provide a number of normalizing and rejuvenating effects. One of the reason for its myriad effects may be its ability to increase oxygenation and energy efficiency at the cellular level. Suma contains germanium, beta-ecdysterone, allantoin, and a group of novel phytochemical saponins called pfaffosides.
# History
The ethnomedicine reveals that Iresine celosia, Tlantcuayin, was used by the Maya-Quiché civilization circa 2000 years.
The species appears in famous 1552 manuscript on Precolombian medicine: "Libellus de Medicinalibus Indorum Herbis".
In modern times, during the 1960’s till 1986, Efraín Contreras (1898-1986), a well-known naturopath, discovered the anti-tumoral properties of Iresine celosia, (Amaranthacea Gomphrenoidea), an herb native to Central America. During the decades of the 70s and 80s, he obtained an approval to administer Iresine celosia as a liquid as well as a dry herbal extract to hospital patients at Hospital El Retiro and Hospital Bertha Calderón in Managua, Nicaragua. The evaluation of the Scientific Commission of the Ministry of Health of Nicaragua (1983) concluded that : “ Codin VII (Iresine celosia) herbal extract was given to patients with tumors in the digestive system - prior to surgery, and also, post-surgery. These patients had various carcinomas of the stomach and regional ganglia. The post-surgery doses invariably reduced the size of the tumor as well as other treated cases. During surgery of the carcinomas of the mammary gland and metastasis in situ and at a distance, metastasis in situ disappeared within 12 to 15 days of treatment, and those at a distance were also reduced. In all cases where Codin VI was employed, health improvement was distinctly obvious. General well-being improved, hemorrages, vaginal discharges and pain disappeared. No toxicity or side effects were observed”. In the decade of the 90’s, Iresine celosia was given to patients suffering from prostate problems, sexual impotency with promising results. Important research studies have been carried out by Pierre Crabbé, P.R. Leeming and Carl Djerassi as a contribution from the Department of Chemistry of Wayne State University, USA. (The Structure of the Isoflavone Tlatlancuayin).
Iresine celosia was introduced in Europe for the first time some 15 years ago. In 1994, Ms. Edda Contreras, Efraín Contreras' daughter, collaborated for the first time with the European Institute of Tropical Phytotherapy. From 1994-1998, Iresine celosia was presented at the De Natura Rerum Forum in Cannes, Sophia Antipolis, Biarritz, Lyon and Paris (France). Tradition records that Iresine celosia was used for tumoral pathologies such as prostate, mammary glands, ovaries, brain, intestin, etc. Iresine celosia is also used for activiting the libido, psychiatrique pathologies and for immune system depressions.
Active principle: Iresine celosia contains 2.50% natural glucid steroids. Mechanism of Action : Clinical studies in Nicaragua have shown that Iresine celosia affected the permeability of the pathological cell, and changed the bio-electric potential of the cancerous membrane (Dindail et al). | https://www.wikidoc.org/index.php/Suma_root | |
0273e2259000b339b7191222a2a952f2bc4a1a9d | wikidoc | Sunscreen | Sunscreen
# Overview
Sunscreen (also known as sunblock, suntan lotion) is a lotion, spray or other topical product that helps protect the skin from the sun's ultraviolet (UV) radiation, and which reduces sunburn and other skin damage, with the goal of lowering the risk of skin cancer. However in the United States, the term suntan lotion usually means the opposite of sunscreen, and instead refers to lotion designed to moisturize and maximize UV exposure and tanning rather than block it. These are commonly called indoor tanning lotions when designed for use with tanning beds or just suntan lotion if designed for outdoor use and may or may not have SPF protection in them.
The most effective sunscreens protect against both UVB (ultraviolet radiation with wavelength between 290 and 320 nanometers), which can cause sunburn, and UVA (between 320 and 400 nanometers), which damages the skin with more long-term effects, such as premature skin aging. Most sunscreens work by containing either an organic chemical compound that absorbs ultraviolet light (such as oxybenzone) or an opaque material that reflects light (such as titanium dioxide, zinc oxide), or a combination of both. Typically, absorptive materials are referred to as chemical blocks, whereas opaque materials are mineral or physical blocks.
# Dosing
Dosing for sunscreen can be calculated using the formula for body surface area and subsequently subtracting the area covered by clothing that provides effective UV protection. The dose used in FDA sunscreen testing is 2 mg/cm². Provided one assumes an "average" adult build of height 5 ft 4 in (163 cm) and weight 150 lb (68 kg) with a 32 in (82 cm) waist, that adult wearing a bathing suit covering the groin area should apply 29 g (approximately 1 oz) evenly to the uncovered body area. Considering only the face, this translates to about 1/4 to 1/3 of a teaspoon for the average adult face.
Contrary to the common advice that sunscreen should be reapplied every 2–3 hours, some research has shown that the best protection is achieved by application 15–30 minutes before exposure, followed by one reapplication 15–30 minutes after the sun exposure begins. Further reapplication is only necessary after activities such as swimming, sweating, and rubbing.
However, more recent research at the University of California, Riverside indicates that sunscreen needs to be reapplied within 2 hours in order to remain effective. Not reapplying could even cause more cell damage than not using sunscreen at all, due to the release of extra free radicals from absorbed chemicals.
# History
The first effective sunscreen may have been developed by chemist Franz Greiter in 1938. The product, called Gletscher Crème (Glacier Cream), subsequently became the basis for the company Piz Buin (named in honor of the place Greiter allegedly obtained the sunburn that inspired his concoction), which today is a well-known marketer of sunscreen products. Some internet articles suggest that Gletscher Crème had a sun protection factor of 2, although a research citation is not readily available online.
The first widely used sunscreen was produced by Benjamin Greene, an airman and later a pharmacist, in 1944. The product, Red Vet Pet (for red veterinary petrolatum), had limited effectiveness, working as a physical blocker of ultraviolet radiation. It was a disagreeable red, sticky substance similar to petroleum jelly. This product was developed during the height of World War II, when it was likely that the hazards of sun overexposure were becoming apparent to soldiers in the Pacific and to their families at home.
Franz Greiter is credited with introducing the concept of Sun Protection Factor (SPF) in 1962, which has become a worldwide standard for measuring the effectiveness of sunscreen when applied at an even rate of 2 milligrams per square centimeter (mg/cm²). Some controversy exists over the usefulness of SPF measurements, especially whether the 2 mg/cm² application rate is an accurate reflection of people’s actual use.
Newer sunscreens have been developed with the ability to withstand contact with water and sweat.
# Measurements of sunscreen protection
## Sun protection factor
The SPF of a sunscreen is a laboratory measure of the effectiveness of sunscreen; the higher the SPF, the more protection a sunscreen offers against UV-B (the ultraviolet radiation that causes sunburn). The SPF indicates the time a person can be exposed to sunlight before getting sunburn with a sunscreen applied relative to the time they can be exposed without sunscreen. For example, someone who would burn after 12 minutes in the sun would expect to burn after 2 hours (120 min) if protected by a sunscreen with SPF 10. In practice, the protection from a particular sunscreen depends on factors such as:
- The skin type of the user.
- The amount applied and frequency of re-application.
- Activities in which one engages (for example, swimming leads to a loss of sunscreen from the skin).
- Amount of sunscreen the skin has absorbed.
The SPF is an imperfect measure of skin damage because invisible damage and skin aging is also caused by the very common ultraviolet type A, which does not cause reddening or pain. Conventional sunscreen does not block UVA as effectively as it does UVB, and an SPF rating of 30+ may translate to significantly lower levels of UVA protection according to a 2003 study. According to a 2004 study, UVA also causes DNA damage to cells deep within the skin, increasing the risk of malignant melanomas. Even some products labeled "broad-spectrum UVA/UVB protection" do not provide good protection against UVA rays. The best UVA protection is provided by products that contain zinc oxide, avobenzone, and ecamsule. Titanium dioxide probably gives good protection, but does not completely cover the entire UV-A spectrum.
Due to consumer confusion over the real degree and duration of protection offered, labeling restrictions are in force in several countries. In the United States in 1999, the Food and Drug Administration (FDA) decided to institute the labelling of SPF 30+ for sunscreens offering more protection, and a similar restriction applies in Australia. This was done to discourage companies from making unrealistic claims about the level of protection offered (such as "all day protection"), and because an SPF over 30 does not provide significantly better protection. In the EU sunscreens are limited to SPF 50+, indicating an SPF of 60 or higher.
The SPF can be measured by applying sunscreen to the skin of a volunteer and measuring how long it takes before sunburn occurs when exposed to an artificial sunlight source. In the US, such an in vivo test is required by the FDA. It can also be measured in vitro with the help of a specially designed spectrometer. In this case, the actual transmittance of the sunscreen is measured, along with the degradation of the product due to being exposed to sunlight. In this case, the transmittance of the sunscreen must be measured over all wavelengths in the UV-B range (290–350 nm), along with a table of how effective various wavelengths are in causing sunburn (the erythemal action spectrum) and the actual intensity spectrum of sunlight (see the figure). Such in vitro measurements agree very well with in vivo measurements.
Mathematically, the SPF is calculated from measured data as
where E(\lambda) is the solar irradiance spectrum, A(\lambda) the erythemal action spectrum, and \mathrm{MPF}(\lambda) the monochromatic protection factor, all functions of the wavelength \lambda. The MPF is roughly the inverse of the transmittance at a given wavelength.
The above means that the SPF is not simply the inverse of the transmittance in the UV-B region. If that were true, then applying two layers of SPF 5 sunscreen would be equivalent to SPF 25 (5 times 5). The actual combined SPF is always lower than the square of the single-layer SPF.
## Measurements of UVA protection
Persistent Pigment Darkening (PPD), Immediate Pigment Darkening (IPD), Boots Star System, Japanese PA system.
The Persistent Pigment Darkening (PPD) method is a method of measuring UVA protection, similar to the SPF method of measuring UVB light protection. Theoretically, a sunscreen with a PPD rating of 10 should allow you to endure 10 times as much UVA as you would without protection.
The PPD is used as part of guidelines for EU sunscreens to provide the consumer with a minimum of UVA protection in relation to the SPF. The PPD should be at least 1/3 of the SPF to carry the UVA seal. The implementation of this seal is in its fase-in period, so a sunscreen without may already offer this protection.
## Star rating system
In the UK and Ireland, a star rating system is used to describe the ratio of UVA to UVB protection offered by sun screen creams and sprays. Invented by Dr Diffey of the Boots Company in Nottingham UK, it has been adopted by most companies marketing these products in the UK. It should not be confused with SPF which is measured with reference to burning and UVB. One star products provide the least ratio of UVA protection, five star products are the best.
# Active ingredients
The principal ingredients in sunscreens are usually aromatic molecules conjugated with carbonyl groups. This general structure allows the molecule to absorb high-energy ultraviolet rays and release the energy as lower-energy rays, thereby preventing the skin-damaging ultraviolet rays from reaching the skin. So, upon exposure to UV light, most of the ingredients (with the notable exception of avobenzone) do not undergo significant chemical change, allowing these ingredients to retain the UV-absorbing potency without significant photo-degradation.
The following are the FDA allowable active ingredients in sunscreens:
- p-Aminobenzoic acid (PABA) up to 15 %.
- Avobenzone up to 3%.
- Cinoxate up to 3%.
- Dioxybenzone up to 3%.
- Homosalate up to 15%.
- Methyl anthranilate up to 5%.
- Octocrylene up to 10%.
- Octyl methoxycinnamate (Octinoxate) up to 7.5%.
- Octyl salicylate (Octisalate) up to 5%.
- Oxybenzone up to 6%.
- Padimate O up to 8%.
- Phenylbenzimidazole sulfonic acid (Ensulizole) up to 4%.
- Sulisobenzone up to 10%.
- Titanium dioxide up to 25%.
- Trolamine salicylate up to 12 %.
- Zinc oxide up to 25%.
Recently FDA approved:
- Mexoryl® SX (USAN Ecamsule, INCI Terephthalylidene Dicamphor Sulfonic Acid) - UVA absorber used in combination with other ingredients for UVB
Others approved within the EU and other parts of the world include:
- 4-Methylbenzylidene camphor ((INCI), USAN Enzacamene)
- Tinosorb® M (USAN Bisoctrizole, INCI Methylene Bis-Benzotriazolyl Tetramethylbutylphenol)
- Tinosorb® S (USAN Bemotrizinol, INCI Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine)
- Mexoryl® XL (INCI Drometrizole Trisiloxane)
- Neo Heliopan® AP (USAN Bisdisulizole Disodium, INCI Disodium Phenyl Dibenzimidazole Tetrasulfonate)
- Uvinul® A Plus (INCI Diethylamino Hydroxybenzoyl Hexyl Benzoate)
- Uvinul® T 150 (USAN Octyl Triazone, INCI Ethylhexyl Triazone)
- Uvasorb® HEB (USAN Iscotrizinol, INCI Diethylhexyl Butamido Triazone)
- Parsol® SLX (INCI Polysilicone-15)
- Amiloxate ((USAN), INCI Isoamyl p-Methoxycinnamate)
A lot of the ingredients not approved by the FDA are relatively new and developed to absorb UVA.
# Melanin
The hormone alpha-melanocyte stimulating hormone is made when the body is exposed to sunlight and is responsible for the development of the pigment melanin. Research is being done to create stable artificial forms of the hormone. A promising candidate, melanotan, might be useful in the prevention of skin cancer, by causing tanning without the need for exposure to dangerous levels of UV.
# Possible adverse effects
Some individuals can have mild to moderate allergic reactions to certain ingredients in sunscreen, particularly the chemical benzophenone, which is also known as phenyl ketone, diphenyl ketone, or benzoylbenzene. It is not clear how much of benzophenone is absorbed into the bloodstream, but trace amounts can be found in urinalysis after use.
Sunscreens are effective in reducing sunburn, but not necessarily the risk of cancer. A study published in April 1992, entitled "Could sunscreens increase melanoma risk?" reported that the greatest increase in melanoma occurred in those regions where sunscreen use is most prevalent. The authors point out that "the SPF of sunscreens concerns
solely their ability to absorb ultraviolet B (UV-B) light. Even sunscreens with high SPF factors can be completely transparent
to ultraviolet A (UV-A), which includes 90 to 95% of ultraviolet light. UV-A blocking ingredients, which have commonly been added to most sunscreens since 1989, block only half the UV-A spectrum and provide a protection factor against delayed UV-A induced erythema of only 1.7 at usual concentrations. Both UV-A and UV-B have been shown to mutate DNA and promote skin cancers in animals. UV-A also penetrates deeper into the skin than UV-B... two studies suggest that sunscreens may not be effective in preventing skin cancer. A large case-control study showed higher risks of melanoma in men who used sunscreens, and a large prospective study showed a higher incidence of basal cell carcinoma in women who used sunscreens."
Recently, there has been increased attention to the possibility of adverse health effects associated with the synthetic compounds in most sunscreens. Recent studies found that some sunscreens generate harmful compounds that might promote skin cancer. The three commonly used ultraviolet (UV) filters -- octylmethoxycinnamate, benzophenone 3, and octocrylene -- eventually soak into the deeper layers of the skin after their application, leaving the top skin layers vulnerable to sun damage. UV rays absorbed by the skin can generate harmful compounds called reactive oxygen species (ROS), which can cause skin cancer and premature aging. The researchers found that once the filters in sunscreen soak into the lower layers of skin, the filters react with UV light to create more damaging ROS. To reduce ROS generation and damage, the researchers recommend reapplying the sunscreen often, which will replenish the sunscreen which has penetrated the skin. Future possibilities may include the development of sunscreens which stay at the surface of the skin, or mixing sunscreens with antioxidants that can neutralize ROS.
A significant reduction in sun exposure inhibits the production of vitamin D. The use of sunscreen with a sun protection factor (SPF) of 8 inhibits more than 95% of vitamin D production in the skin. However, excessive sun exposure has been conclusively linked to some forms of skin cancer and signs of premature aging. Season, geographic latitude, time of day, cloud cover, smog, skin type, and sunscreen all have an effect on vitamin D production in the skin. Fifteen minutes per day of direct exposure to the sun (i.e. without sunscreen) is a generally accepted guideline to follow for optimum vitamin D production. | Sunscreen
# Overview
Sunscreen (also known as sunblock, suntan lotion) is a lotion, spray or other topical product that helps protect the skin from the sun's ultraviolet (UV) radiation, and which reduces sunburn and other skin damage, with the goal of lowering the risk of skin cancer. However in the United States, the term suntan lotion usually means the opposite of sunscreen, and instead refers to lotion designed to moisturize and maximize UV exposure and tanning rather than block it. These are commonly called indoor tanning lotions when designed for use with tanning beds or just suntan lotion if designed for outdoor use and may or may not have SPF protection in them.
The most effective sunscreens protect against both UVB (ultraviolet radiation with wavelength between 290 and 320 nanometers), which can cause sunburn, and UVA (between 320 and 400 nanometers), which damages the skin with more long-term effects, such as premature skin aging. Most sunscreens work by containing either an organic chemical compound that absorbs ultraviolet light (such as oxybenzone) or an opaque material that reflects light (such as titanium dioxide, zinc oxide), or a combination of both. Typically, absorptive materials are referred to as chemical blocks, whereas opaque materials are mineral or physical blocks.
# Dosing
Dosing for sunscreen can be calculated using the formula for body surface area and subsequently subtracting the area covered by clothing that provides effective UV protection. The dose used in FDA sunscreen testing is 2 mg/cm².[1] Provided one assumes an "average" adult build of height 5 ft 4 in (163 cm) and weight 150 lb (68 kg) with a 32 in (82 cm) waist, that adult wearing a bathing suit covering the groin area should apply 29 g (approximately 1 oz) evenly to the uncovered body area. Considering only the face, this translates to about 1/4 to 1/3 of a teaspoon for the average adult face.
Contrary to the common advice that sunscreen should be reapplied every 2–3 hours, some research has shown that the best protection is achieved by application 15–30 minutes before exposure, followed by one reapplication 15–30 minutes after the sun exposure begins. Further reapplication is only necessary after activities such as swimming, sweating, and rubbing.[2]
However, more recent research at the University of California, Riverside indicates that sunscreen needs to be reapplied within 2 hours in order to remain effective. Not reapplying could even cause more cell damage than not using sunscreen at all, due to the release of extra free radicals from absorbed chemicals.[3]
# History
The first effective sunscreen may have been developed by chemist Franz Greiter in 1938. The product, called Gletscher Crème (Glacier Cream), subsequently became the basis for the company Piz Buin (named in honor of the place Greiter allegedly obtained the sunburn that inspired his concoction), which today is a well-known marketer of sunscreen products. Some internet articles suggest that Gletscher Crème had a sun protection factor of 2, although a research citation is not readily available online.
The first widely used sunscreen was produced by Benjamin Greene, an airman and later a pharmacist, in 1944. The product, Red Vet Pet (for red veterinary petrolatum), had limited effectiveness, working as a physical blocker of ultraviolet radiation. It was a disagreeable red, sticky substance similar to petroleum jelly. This product was developed during the height of World War II, when it was likely that the hazards of sun overexposure were becoming apparent to soldiers in the Pacific and to their families at home.
Franz Greiter is credited with introducing the concept of Sun Protection Factor (SPF) in 1962, which has become a worldwide standard for measuring the effectiveness of sunscreen when applied at an even rate of 2 milligrams per square centimeter (mg/cm²). Some controversy exists over the usefulness of SPF measurements, especially whether the 2 mg/cm² application rate is an accurate reflection of people’s actual use.
Newer sunscreens have been developed with the ability to withstand contact with water and sweat.
# Measurements of sunscreen protection
## Sun protection factor
The SPF of a sunscreen is a laboratory measure of the effectiveness of sunscreen; the higher the SPF, the more protection a sunscreen offers against UV-B (the ultraviolet radiation that causes sunburn). The SPF indicates the time a person can be exposed to sunlight before getting sunburn with a sunscreen applied relative to the time they can be exposed without sunscreen. For example, someone who would burn after 12 minutes in the sun would expect to burn after 2 hours (120 min) if protected by a sunscreen with SPF 10. In practice, the protection from a particular sunscreen depends on factors such as:
- The skin type of the user.
- The amount applied and frequency of re-application.
- Activities in which one engages (for example, swimming leads to a loss of sunscreen from the skin).
- Amount of sunscreen the skin has absorbed.
The SPF is an imperfect measure of skin damage because invisible damage and skin aging is also caused by the very common ultraviolet type A, which does not cause reddening or pain. Conventional sunscreen does not block UVA as effectively as it does UVB, and an SPF rating of 30+ may translate to significantly lower levels of UVA protection according to a 2003 study. According to a 2004 study, UVA also causes DNA damage to cells deep within the skin, increasing the risk of malignant melanomas.[4] Even some products labeled "broad-spectrum UVA/UVB protection" do not provide good protection against UVA rays.[5] The best UVA protection is provided by products that contain zinc oxide, avobenzone, and ecamsule. Titanium dioxide probably gives good protection, but does not completely cover the entire UV-A spectrum.[6]
Due to consumer confusion over the real degree and duration of protection offered, labeling restrictions are in force in several countries. In the United States in 1999, the Food and Drug Administration (FDA) decided to institute the labelling of SPF 30+ for sunscreens offering more protection, and a similar restriction applies in Australia. This was done to discourage companies from making unrealistic claims about the level of protection offered (such as "all day protection"),[7] and because an SPF over 30 does not provide significantly better protection. In the EU sunscreens are limited to SPF 50+, indicating an SPF of 60 or higher.[8]
The SPF can be measured by applying sunscreen to the skin of a volunteer and measuring how long it takes before sunburn occurs when exposed to an artificial sunlight source. In the US, such an in vivo test is required by the FDA. It can also be measured in vitro with the help of a specially designed spectrometer. In this case, the actual transmittance of the sunscreen is measured, along with the degradation of the product due to being exposed to sunlight. In this case, the transmittance of the sunscreen must be measured over all wavelengths in the UV-B range (290–350 nm), along with a table of how effective various wavelengths are in causing sunburn (the erythemal action spectrum) and the actual intensity spectrum of sunlight (see the figure). Such in vitro measurements agree very well with in vivo measurements.[9]
Mathematically, the SPF is calculated from measured data as
where <math>E(\lambda)</math> is the solar irradiance spectrum, <math>A(\lambda)</math> the erythemal action spectrum, and <math>\mathrm{MPF}(\lambda)</math> the monochromatic protection factor, all functions of the wavelength <math>\lambda</math>. The MPF is roughly the inverse of the transmittance at a given wavelength.
The above means that the SPF is not simply the inverse of the transmittance in the UV-B region. If that were true, then applying two layers of SPF 5 sunscreen would be equivalent to SPF 25 (5 times 5). The actual combined SPF is always lower than the square of the single-layer SPF.
## Measurements of UVA protection
Persistent Pigment Darkening (PPD), Immediate Pigment Darkening (IPD), Boots Star System, Japanese PA system.
The Persistent Pigment Darkening (PPD) method is a method of measuring UVA protection, similar to the SPF method of measuring UVB light protection. Theoretically, a sunscreen with a PPD rating of 10 should allow you to endure 10 times as much UVA as you would without protection.
The PPD is used as part of guidelines for EU sunscreens to provide the consumer with a minimum of UVA protection in relation to the SPF. The PPD should be at least 1/3 of the SPF to carry the UVA seal. The implementation of this seal is in its fase-in period, so a sunscreen without may already offer this protection. [10]
## Star rating system
In the UK and Ireland, a star rating system is used to describe the ratio of UVA to UVB protection offered by sun screen creams and sprays. Invented by Dr Diffey of the Boots Company in Nottingham UK, it has been adopted by most companies marketing these products in the UK. It should not be confused with SPF which is measured with reference to burning and UVB. One star products provide the least ratio of UVA protection, five star products are the best.
# Active ingredients
The principal ingredients in sunscreens are usually aromatic molecules conjugated with carbonyl groups. This general structure allows the molecule to absorb high-energy ultraviolet rays and release the energy as lower-energy rays, thereby preventing the skin-damaging ultraviolet rays from reaching the skin. So, upon exposure to UV light, most of the ingredients (with the notable exception of avobenzone) do not undergo significant chemical change, allowing these ingredients to retain the UV-absorbing potency without significant photo-degradation.[1]
The following are the FDA allowable active ingredients in sunscreens:
- p-Aminobenzoic acid (PABA) up to 15 %.
- Avobenzone up to 3%.
- Cinoxate up to 3%.
- Dioxybenzone up to 3%.
- Homosalate up to 15%.
- Methyl anthranilate up to 5%.
- Octocrylene up to 10%.
- Octyl methoxycinnamate (Octinoxate) up to 7.5%.
- Octyl salicylate (Octisalate) up to 5%.
- Oxybenzone up to 6%.
- Padimate O up to 8%.
- Phenylbenzimidazole sulfonic acid (Ensulizole) up to 4%.
- Sulisobenzone up to 10%.
- Titanium dioxide up to 25%.
- Trolamine salicylate up to 12 %.
- Zinc oxide up to 25%.
Recently FDA approved:
- Mexoryl® SX (USAN Ecamsule, INCI Terephthalylidene Dicamphor Sulfonic Acid) - UVA absorber used in combination with other ingredients for UVB
Others approved within the EU[11] and other parts of the world[12] include:
- 4-Methylbenzylidene camphor ((INCI), USAN Enzacamene)
- Tinosorb® M (USAN Bisoctrizole, INCI Methylene Bis-Benzotriazolyl Tetramethylbutylphenol)
- Tinosorb® S (USAN Bemotrizinol, INCI Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine)
- Mexoryl® XL (INCI Drometrizole Trisiloxane)
- Neo Heliopan® AP (USAN Bisdisulizole Disodium, INCI Disodium Phenyl Dibenzimidazole Tetrasulfonate)
- Uvinul® A Plus (INCI Diethylamino Hydroxybenzoyl Hexyl Benzoate)
- Uvinul® T 150 (USAN Octyl Triazone, INCI Ethylhexyl Triazone)
- Uvasorb® HEB (USAN Iscotrizinol, INCI Diethylhexyl Butamido Triazone)
- Parsol® SLX (INCI Polysilicone-15)
- Amiloxate ((USAN), INCI Isoamyl p-Methoxycinnamate)
A lot of the ingredients not approved by the FDA are relatively new and developed to absorb UVA.[13]
# Melanin
The hormone alpha-melanocyte stimulating hormone is made when the body is exposed to sunlight and is responsible for the development of the pigment melanin. Research is being done to create stable artificial forms of the hormone. A promising candidate, melanotan, might be useful in the prevention of skin cancer, by causing tanning without the need for exposure to dangerous levels of UV.
# Possible adverse effects
Some individuals can have mild to moderate allergic reactions to certain ingredients in sunscreen, particularly the chemical benzophenone, which is also known as phenyl ketone, diphenyl ketone, or benzoylbenzene. It is not clear how much of benzophenone is absorbed into the bloodstream, but trace amounts can be found in urinalysis after use.
Sunscreens are effective in reducing sunburn, but not necessarily the risk of cancer. A study published in April 1992, entitled "Could sunscreens increase melanoma risk?" reported that the greatest increase in melanoma occurred in those regions where sunscreen use is most prevalent.[14] The authors point out that "the SPF of sunscreens concerns
solely their ability to absorb ultraviolet B (UV-B) light. Even sunscreens with high SPF factors can be completely transparent
to ultraviolet A (UV-A), which includes 90 to 95% of ultraviolet light. UV-A blocking ingredients, which have commonly been added to most sunscreens since 1989, block only half the UV-A spectrum and provide a protection factor against delayed UV-A induced erythema of only 1.7 at usual concentrations. Both UV-A and UV-B have been shown to mutate DNA and promote skin cancers in animals. UV-A also penetrates deeper into the skin than UV-B... two studies suggest that sunscreens may not be effective in preventing skin cancer. A large case-control study showed higher risks of melanoma in men who used sunscreens, and a large prospective study showed a higher incidence of basal cell carcinoma in women who used sunscreens."
Recently, there has been increased attention to the possibility of adverse health effects associated with the synthetic compounds in most sunscreens.[15] Recent studies found that some sunscreens generate harmful compounds that might promote skin cancer. The three commonly used ultraviolet (UV) filters -- octylmethoxycinnamate, benzophenone 3, and octocrylene -- eventually soak into the deeper layers of the skin after their application, leaving the top skin layers vulnerable to sun damage. UV rays absorbed by the skin can generate harmful compounds called reactive oxygen species (ROS), which can cause skin cancer and premature aging. The researchers found that once the filters in sunscreen soak into the lower layers of skin, the filters react with UV light to create more damaging ROS.[3] To reduce ROS generation and damage, the researchers recommend reapplying the sunscreen often, which will replenish the sunscreen which has penetrated the skin. Future possibilities may include the development of sunscreens which stay at the surface of the skin, or mixing sunscreens with antioxidants that can neutralize ROS.[16]
A significant reduction in sun exposure inhibits the production of vitamin D. The use of sunscreen with a sun protection factor (SPF) of 8 inhibits more than 95% of vitamin D production in the skin.[17] However, excessive sun exposure has been conclusively linked to some forms of skin cancer and signs of premature aging. Season, geographic latitude, time of day, cloud cover, smog, skin type, and sunscreen all have an effect on vitamin D production in the skin.[18] Fifteen minutes per day of direct exposure to the sun (i.e. without sunscreen) is a generally accepted guideline to follow for optimum vitamin D production.[19] | https://www.wikidoc.org/index.php/Sun_Protection_Factor | |
ba40966ddb2c60341b75e64ab4c9ee2f326de120 | wikidoc | Sunflower | Sunflower
The sunflower (Helianthus annuus) is an annual plant native to the Americas in the family Asteraceae, with a large flowering head (inflorescence). The stem of the flower can grow as high as 3 metres tall, with the flower head reaching up to 30 cm in diameter with the "large" seeds. The term "sunflower" is also used to refer to all plants of the genus Helianthus, many of which are perennial plants.
# Description
What is usually called the flower is actually a head (formally composite flower) of numerous flowers (florets) crowded together. The outer flowers are the ray florets and can be yellow, maroon, orange, or other colors, and are sterile. The florets inside the circular head are called disc florets. The disc florets mature into what are traditionally called "sunflower seeds", but are actually the fruit (an achene) of the plant. The true seeds are encased in an inedible husk.
The florets within this cluster are arranged spirally. Typically each floret is oriented toward the next by approximately the golden angle, producing a pattern of interconnecting spirals where the number of left spirals and the number of right spirals are successive Fibonacci numbers. Typically, there are 34 spirals in 1 direction and 55 in the other; on a very large sunflower you may see 89 in one direction and 144 in the other.
# Heliotropism
Sunflowers in the bud stage exhibit heliotropism. At sunrise, the faces of most sunflowers are turned towards the east. Over the course of the day, they move to track the sun from east to west, while at night they return to an eastward orientation. This motion is performed by motor cells in the pulvinus, a flexible segment of the stem just below the bud. As the bud stage ends, the stem stiffens and the blooming stage is reached.
Sunflowers in the blooming stage are not heliotropic anymore. The stem has frozen, typically in an eastward orientation. The stem and leaves lose their green color.
The wild sunflower typically does not turn toward the sun; its flowering heads may face many directions when mature. However, the leaves typically exhibit some heliotropism.
# Cultivation and uses
Sunflowers are native to the Americas. There is some debate about where the sunflower was first domesticated. The earliest known examples of a fully domesticated sunflower were found at the Hayes site in Tennessee and date back to around 2300 B.C. There were also other remains found at the Olmec site of San Andrés dating some time before 2100 B.C. The Incas used the sunflower as an image of their sun god. Gold images of the flower, as well as seeds, were taken back to Europe early in the 16th century.
To grow well, sunflowers need full sun. They grow best in fertile, moist, well-drained soil with a lot of mulch. In commercial planting, seeds are planted 45 cm (1.5') apart and 2.5 cm (1") deep.
Sunflower "whole seed" (fruit) are sold as a snack food after roasting within heated ovens with or without salt added. Sunflowers can be processed into a peanut butter alternative, Sunbutter, especially in China, Russia, the United States, the Middle East and Europe.
It is also sold as food for birds and can be used directly in cooking and salads.
Sunflower oil, extracted from the seeds, is used for cooking, as a carrier oil and to produce biodiesel, for which it is less expensive than the olive product. A range of sunflower varieties exist with differing fatty acid compositions; some 'high oleic' types contain a higher level of healthy monounsaturated fats in their oil than even olive oil.
During the 18th Century, the use of sunflower oil became very popular in Europe, particularly with members of the Russian Orthodox Church because sunflower oil was one of the few oils that was not prohibited during Lent.
The cake remaining after the seeds have been processed for oil is used as a livestock feed. Some recently developed cultivars have drooping heads. These cultivars are less attractive to gardeners growing the flowers as ornamental plants, but appeal to farmers, because they reduce bird damage and losses from some plant diseases. Sunflowers also produce latex and are the subject of experiments to improve their suitability as an alternative crop for producing hypoallergenic rubber.
For farmers growing other crops, the sunflower is considered a weed. The wild variety will grow unwanted in corn and soybean fields and can have a negative impact on yields.
# Mathematical model
A model for the pattern of florets in the head of a sunflower was proposed by H Vogel. This is expressed in polar coordinates
where θ is the angle, r is the radius or distance from the center, and n is the index number of the floret and c is a constant scaling factor. It is a form of Fermat's spiral. The angle 137.5° is related to the golden ratio and gives a close packing of florets. This model has been used to produce computer graphics representations of sunflowers.
# Size
Sunflowers most commonly grow to heights between 2.5 and 3.5 m (8 - 12'). Scientific literature reports, from 1567, that a 12 m (40'), traditional, single-head, sunflower plant was grown in Padua. The same seed lot grew almost 8 m (24') at other times and places (e.g. Madrid). Much more recent feats (past score years) of over 8 m (25') have been achieved in both Netherlands and Ontario, Canada.
# Cultural usage
- The sunflower is the state flower of the U.S. state of Kansas, and one of the city flowers of Kitakyushu, Japan.
- The sunflower is often used as a symbol of green ideology, much as the red rose is a symbol of socialism or social democracy. The sunflower is also the symbol of the Vegan Society.
# Other species
- The Jerusalem artichoke (Helianthus tuberosa) is related to the sunflower.
- The Mexican sunflower is Tithonia rotundifolia.
- False sunflower refers to plants of the genus Heliopsis.
# Flower formation
- 1. The first stage of the flower formation
1. The first stage of the flower formation
- 2. The flower is still covered, but faces the sun
2. The flower is still covered, but faces the sun
- 3. The flower is nearly completely exposed
3. The flower is nearly completely exposed
- 4. The flower is completely exposed
4. The flower is completely exposed
# Gallery
- Sunflowers in Wilkesboro, North Carolina
Sunflowers in Wilkesboro, North Carolina
- Sunflowers in Manila, Philippines
Sunflowers in Manila, Philippines
- Bumble bee sampling Sunflower nectar
Bumble bee sampling Sunflower nectar
- Sunflowers growing near Fargo, North Dakota
Sunflowers growing near Fargo, North Dakota
- Lone sunflower about 2 m (6 ft, 6') tall
Lone sunflower about 2 m (6 ft, 6') tall
- Sunflower seedlings, just three days after germination
Sunflower seedlings, just three days after germination
- Large Russian Sunflower
Large Russian Sunflower
- Fruiting head
Fruiting head
- Sunflower seeds in many variations and sizes.
Sunflower seeds in many variations and sizes.
- Red sunflowers.
Red sunflowers.
- Small Sunflower
Small Sunflower
- Sunflower Macro
Sunflower Macro
- Sunflower farm, near Behshahr, Iran
Sunflower farm, near Behshahr, Iran
- Extreme close-up of sunflower head in Istanbul, Turkey
Extreme close-up of sunflower head in Istanbul, Turkey | Sunflower
The sunflower (Helianthus annuus) is an annual plant native to the Americas in the family Asteraceae, with a large flowering head (inflorescence). The stem of the flower can grow as high as 3 metres tall, with the flower head reaching up to 30 cm in diameter with the "large" seeds. The term "sunflower" is also used to refer to all plants of the genus Helianthus, many of which are perennial plants.
# Description
What is usually called the flower is actually a head (formally composite flower) of numerous flowers (florets) crowded together. The outer flowers are the ray florets and can be yellow, maroon, orange, or other colors, and are sterile. The florets inside the circular head are called disc florets. The disc florets mature into what are traditionally called "sunflower seeds", but are actually the fruit (an achene) of the plant. The true seeds are encased in an inedible husk.
The florets within this cluster are arranged spirally. Typically each floret is oriented toward the next by approximately the golden angle, producing a pattern of interconnecting spirals where the number of left spirals and the number of right spirals are successive Fibonacci numbers. Typically, there are 34 spirals in 1 direction and 55 in the other; on a very large sunflower you may see 89 in one direction and 144 in the other.
# Heliotropism
Sunflowers in the bud stage exhibit heliotropism. At sunrise, the faces of most sunflowers are turned towards the east. Over the course of the day, they move to track the sun from east to west, while at night they return to an eastward orientation. This motion is performed by motor cells in the pulvinus, a flexible segment of the stem just below the bud. As the bud stage ends, the stem stiffens and the blooming stage is reached.
Sunflowers in the blooming stage are not heliotropic anymore. The stem has frozen, typically in an eastward orientation. The stem and leaves lose their green color.
The wild sunflower typically does not turn toward the sun; its flowering heads may face many directions when mature. However, the leaves typically exhibit some heliotropism.
# Cultivation and uses
Sunflowers are native to the Americas. There is some debate about where the sunflower was first domesticated. The earliest known examples of a fully domesticated sunflower were found at the Hayes site in Tennessee and date back to around 2300 B.C. There were also other remains found at the Olmec site of San Andrés dating some time before 2100 B.C. The Incas used the sunflower as an image of their sun god. Gold images of the flower, as well as seeds, were taken back to Europe early in the 16th century.
To grow well, sunflowers need full sun. They grow best in fertile, moist, well-drained soil with a lot of mulch. In commercial planting, seeds are planted 45 cm (1.5') apart and 2.5 cm (1") deep.
Sunflower "whole seed" (fruit) are sold as a snack food after roasting within heated ovens with or without salt added. Sunflowers can be processed into a peanut butter alternative, Sunbutter, especially in China, Russia, the United States, the Middle East and Europe.
It is also sold as food for birds and can be used directly in cooking and salads.
Sunflower oil, extracted from the seeds, is used for cooking, as a carrier oil and to produce biodiesel, for which it is less expensive than the olive product. A range of sunflower varieties exist with differing fatty acid compositions; some 'high oleic' types contain a higher level of healthy monounsaturated fats in their oil than even olive oil.
During the 18th Century, the use of sunflower oil became very popular in Europe, particularly with members of the Russian Orthodox Church because sunflower oil was one of the few oils that was not prohibited during Lent.
The cake remaining after the seeds have been processed for oil is used as a livestock feed. Some recently developed cultivars have drooping heads. These cultivars are less attractive to gardeners growing the flowers as ornamental plants, but appeal to farmers, because they reduce bird damage and losses from some plant diseases. Sunflowers also produce latex and are the subject of experiments to improve their suitability as an alternative crop for producing hypoallergenic rubber.
For farmers growing other crops, the sunflower is considered a weed. The wild variety will grow unwanted in corn and soybean fields and can have a negative impact on yields.
# Mathematical model
A model for the pattern of florets in the head of a sunflower was proposed by H Vogel. This is expressed in polar coordinates
where θ is the angle, r is the radius or distance from the center, and n is the index number of the floret and c is a constant scaling factor. It is a form of Fermat's spiral. The angle 137.5° is related to the golden ratio and gives a close packing of florets. This model has been used to produce computer graphics representations of sunflowers. [1]
# Size
Sunflowers most commonly grow to heights between 2.5 and 3.5 m (8 - 12'). Scientific literature reports, from 1567, that a 12 m (40'), traditional, single-head, sunflower plant was grown in Padua. The same seed lot grew almost 8 m (24') at other times and places (e.g. Madrid). Much more recent feats (past score years) of over 8 m (25') have been achieved in both Netherlands and Ontario, Canada.
# Cultural usage
- The sunflower is the state flower of the U.S. state of Kansas, and one of the city flowers of Kitakyushu, Japan.
- The sunflower is often used as a symbol of green ideology, much as the red rose is a symbol of socialism or social democracy. The sunflower is also the symbol of the Vegan Society.
# Other species
- The Jerusalem artichoke (Helianthus tuberosa) is related to the sunflower.
- The Mexican sunflower is Tithonia rotundifolia.
- False sunflower refers to plants of the genus Heliopsis.
# Flower formation
- 1. The first stage of the flower formation
1. The first stage of the flower formation
- 2. The flower is still covered, but faces the sun
2. The flower is still covered, but faces the sun
- 3. The flower is nearly completely exposed
3. The flower is nearly completely exposed
- 4. The flower is completely exposed
4. The flower is completely exposed
Template:Video
# Gallery
- Sunflowers in Wilkesboro, North Carolina
Sunflowers in Wilkesboro, North Carolina
- Sunflowers in Manila, Philippines
Sunflowers in Manila, Philippines
- Bumble bee sampling Sunflower nectar
Bumble bee sampling Sunflower nectar
- Sunflowers growing near Fargo, North Dakota
Sunflowers growing near Fargo, North Dakota
- Lone sunflower about 2 m (6 ft, 6') tall
Lone sunflower about 2 m (6 ft, 6') tall
- Sunflower seedlings, just three days after germination
Sunflower seedlings, just three days after germination
- Large Russian Sunflower
Large Russian Sunflower
- Fruiting head
Fruiting head
- Sunflower seeds in many variations and sizes.
Sunflower seeds in many variations and sizes.
- Red sunflowers.
Red sunflowers.
- Small Sunflower
Small Sunflower
- Sunflower Macro
Sunflower Macro
- Sunflower farm, near Behshahr, Iran
Sunflower farm, near Behshahr, Iran
- Extreme close-up of sunflower head in Istanbul, Turkey
Extreme close-up of sunflower head in Istanbul, Turkey | https://www.wikidoc.org/index.php/Sunflower | |
e538b59efd0168f2ff305992e430f7ff05557eb2 | wikidoc | Superatom | Superatom
Superatoms are clusters of atoms which seem to exhibit some of the properties of elemental atoms.
Sodium atoms when cooled from vapor, naturally condense into clusters, more so into clusters of 2, 8, 20, 40, 58 or 92 atoms (the magic numbers), than into the other numbers. The first two of these can be recognized as the numbers of electrons needed to fill s and p orbitals, respectively. The superatom suggestion is that free electrons in the cluster occupy a new set of orbitals that are defined by the entire group of atoms, i.e. cluster, rather than each individual atom separately (non-spherical or doped clusters show deviations in the number of electrons that form a closed shell as the potential is defined by the shape of the positive nuclei.) Superatoms tend to behave chemically in a way that will allow them to have a closed shell of electrons, in this new counting scheme. Therefore, a superatom with one more electron than a full shell should give up that electron very easily, similar to an alkali metal, and a cluster with one electron short of full shell should have a large electron affinity, such as a halogen.
# Aluminum clusters
Certain aluminium clusters have superatom properties. These aluminium clusters are generated as anions (Aln- with n = 1,2,3...) in helium gas and reacted with a gas containing iodine. When analyzed by mass spectrometry one main reaction product turns out to be Al13I-. These clusters of 13 aluminium atoms with an extra electron added do not appear to react with oxygen when it is introduced in the same gas stream. Assuming each atom liberates its 3 valence electrons, this means that there are 40 electrons present, which is one of the magic numbers noted above for sodium, and implies that these numbers are a reflection of the noble gases. Calculations show that the additional electron is located in the aluminium cluster at the location directly opposite from the iodine atom. The cluster must therefore have a higher electron affinity for the electron than iodine and therefore the aluminium cluster is called a superhalogen. The cluster component in Al13I- ion is similar to an iodine ion or better still a bromine atom. The related Al13I2- cluster is expected to behave chemically like the triiodide ion.
Similarly it has been noted that Al14 clusters with 42 electrons (2 more than the magic numbers) appear to exhibit the properties of an alkaline earth metal which typically adopt +2 valence states. This is only known to occur when there are at least 3 iodine atoms attached to an Al14- cluster, Al14I3-. The anionic cluster has a total of 43 itinerant electrons, but the three Iodine atoms each remove one of the itinerant electrons to leave 40 electrons in the jellium shell.
It is particularly easy and reliable to study atomic clusters of inert gas atoms by computer simulation because interaction between two atoms can be approximated very well by the Lennard-Jones potential. Other methods are readily available and it has been established that the magic numbers are 13, 19, 23, 26, 29, 32, 34, 43, 46, 49, 55, etc.
# Three-dimensional periodic table
With more discovered superatoms that act similar to a particular atom, a new branch is starting to form on the periodic table. | Superatom
Template:Wikify
Superatoms are clusters of atoms which seem to exhibit some of the properties of elemental atoms.
Sodium atoms when cooled from vapor, naturally condense into clusters, more so into clusters of 2, 8, 20, 40, 58 or 92 atoms (the magic numbers), than into the other numbers. The first two of these can be recognized as the numbers of electrons needed to fill s and p orbitals, respectively. The superatom suggestion is that free electrons in the cluster occupy a new set of orbitals that are defined by the entire group of atoms, i.e. cluster, rather than each individual atom separately (non-spherical or doped clusters show deviations in the number of electrons that form a closed shell as the potential is defined by the shape of the positive nuclei.) Superatoms tend to behave chemically in a way that will allow them to have a closed shell of electrons, in this new counting scheme. Therefore, a superatom with one more electron than a full shell should give up that electron very easily, similar to an alkali metal, and a cluster with one electron short of full shell should have a large electron affinity, such as a halogen.
# Aluminum clusters
Certain aluminium clusters have superatom properties. These aluminium clusters are generated as anions (Aln- with n = 1,2,3...) in helium gas and reacted with a gas containing iodine. When analyzed by mass spectrometry one main reaction product turns out to be Al13I-.[1] These clusters of 13 aluminium atoms with an extra electron added do not appear to react with oxygen when it is introduced in the same gas stream. Assuming each atom liberates its 3 valence electrons, this means that there are 40 electrons present, which is one of the magic numbers noted above for sodium, and implies that these numbers are a reflection of the noble gases. Calculations show that the additional electron is located in the aluminium cluster at the location directly opposite from the iodine atom. The cluster must therefore have a higher electron affinity for the electron than iodine and therefore the aluminium cluster is called a superhalogen. The cluster component in Al13I- ion is similar to an iodine ion or better still a bromine atom. The related Al13I2- cluster is expected to behave chemically like the triiodide ion.
Similarly it has been noted that Al14 clusters with 42 electrons (2 more than the magic numbers) appear to exhibit the properties of an alkaline earth metal which typically adopt +2 valence states. This is only known to occur when there are at least 3 iodine atoms attached to an Al14- cluster, Al14I3-. The anionic cluster has a total of 43 itinerant electrons, but the three Iodine atoms each remove one of the itinerant electrons to leave 40 electrons in the jellium shell.[2][3]
It is particularly easy and reliable to study atomic clusters of inert gas atoms by computer simulation because interaction between two atoms can be approximated very well by the Lennard-Jones potential. Other methods are readily available and it has been established that the magic numbers are 13, 19, 23, 26, 29, 32, 34, 43, 46, 49, 55, etc. [I. A. Harris et al. Phys. Rev. Lett. Vol. 53, 2391-94 (1984).]
# Three-dimensional periodic table
With more discovered superatoms that act similar to a particular atom, a new branch is starting to form on the periodic table. | https://www.wikidoc.org/index.php/Superatom | |
e8739cbb364158bc303f4f1e362d3b2daa71bc39 | wikidoc | Superbase | Superbase
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
In chemistry, a superbase is an extremely strong base. There is no commonly accepted definition for what qualifies as a superbase, but most chemists would accept sodium hydroxide as a 'benchmark' base just as sulfuric acid is a 'benchmark' acid (see superacid). The hydroxide ion is a good benchmark because it is the strongest base that can exist in a water solution. Stronger bases are neutralized by water acting as an acid, to produce a corresponding hydroxide (and protonated superbase). Another use that can define superbase is stoichiometric α-deprotonation of a carbonyl compound into an enolate, something that cannot be done by "regular bases". Despite this, the term still doesn't have a standard chemical definition, so for example Proton Sponge may be called "superbase".
There are three main classes of superbases: organic, organometallic, and inorganic.
Organometallic compounds of reactive metals are usually superbases, for example organolithium and organomagnesiums (Grignard reagents). Another type of organic superbase has a reactive metal exchanged for a hydrogen on a heteroatom, such as oxygen (unstabilized alkoxides) or nitrogen (lithium diisopropylamide).
Reactions involving superbases are usually water-sensitive, conducted under an inert atmosphere and at a low temperature. A desirable property in many cases is low nucleophilic reactivity, i.e. a non-nucleophilic base. Unhindered alkyllithiums, for example, cannot be used with electrophiles such as carbonyl groups, because they attack the electrophiles as nucleophiles.
In organic synthesis, the Schlosser base (or Lochmann-Schlosser base), i.e. the combination of n-butyllithium and potassium tert-butoxide, is a commonly used superbase. Butyllithium exists as four-, or six-membered clusters, which are kinetically slow to react. The tertiary alcoholate (butoxide) serves to complex the lithium ion, which breaks the butyllithium clusters. This makes the butyllithium kinetically more reactive.
Inorganic superbases are typically salts with highly charged, small negative ions, e.g. lithium nitride, which has extreme negative charge density and so is highly attracted to acids, like the aqueous hydronium ion. Alkali and earth alkali metal hydrides (sodium hydride, calcium hydride) are superbases. | Superbase
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
In chemistry, a superbase is an extremely strong base. There is no commonly accepted definition for what qualifies as a superbase, but most chemists would accept sodium hydroxide as a 'benchmark' base just as sulfuric acid is a 'benchmark' acid (see superacid). The hydroxide ion is a good benchmark because it is the strongest base that can exist in a water solution. Stronger bases are neutralized by water acting as an acid, to produce a corresponding hydroxide (and protonated superbase). Another use that can define superbase is stoichiometric α-deprotonation of a carbonyl compound into an enolate, something that cannot be done by "regular bases". Despite this, the term still doesn't have a standard chemical definition, so for example Proton Sponge may be called "superbase".
There are three main classes of superbases: organic, organometallic, and inorganic.
Organometallic compounds of reactive metals are usually superbases, for example organolithium and organomagnesiums (Grignard reagents). Another type of organic superbase has a reactive metal exchanged for a hydrogen on a heteroatom, such as oxygen (unstabilized alkoxides) or nitrogen (lithium diisopropylamide).
Reactions involving superbases are usually water-sensitive, conducted under an inert atmosphere and at a low temperature. A desirable property in many cases is low nucleophilic reactivity, i.e. a non-nucleophilic base. Unhindered alkyllithiums, for example, cannot be used with electrophiles such as carbonyl groups, because they attack the electrophiles as nucleophiles.
In organic synthesis, the Schlosser base (or Lochmann-Schlosser base), i.e. the combination of n-butyllithium and potassium tert-butoxide, is a commonly used superbase. Butyllithium exists as four-, or six-membered clusters, which are kinetically slow to react. The tertiary alcoholate (butoxide) serves to complex the lithium ion, which breaks the butyllithium clusters. This makes the butyllithium kinetically more reactive.
Inorganic superbases are typically salts with highly charged, small negative ions, e.g. lithium nitride, which has extreme negative charge density and so is highly attracted to acids, like the aqueous hydronium ion. Alkali and earth alkali metal hydrides (sodium hydride, calcium hydride) are superbases. | https://www.wikidoc.org/index.php/Superbase | |
998031e4463c32dc2cd0b44abd6a875a33a5ee97 | wikidoc | SureSmile | SureSmile
# Overview
SureSmile is an orthodontic technique that allows the orthodontist to treat cases using traditional orthodontic braces and roboticly created wires. The orthodontist submits records including precise orthodontic models and scans of the patient's teeth with braces in place. The scans can be produced on a light scanner or by cone beam computerized tomography, a radiographic study similar to a CAT scan. The records are processed and made available online to the orthodontist to produce a virtual treatment objective, the teeth as they should look and work when the case is complete.
The orthodontist then specifies a wire of particular dimension and strength. A wire is roboticly produced to be placed by the orthodontist in the patient's mouth. The orthodontist then monitors the changes over time. A new wire can then be designed, changing the size, strength and shape of the wire to refine the results.
The technique is reported to reduce the time required to complete orthodontic treatment and increase the precision of the results. The negatives include increased costs, the time for taken for the scans, and the x-ray exposure when using the cone beam scans. The advantages include shorter treatment times, more precise results. | SureSmile
Editor in Chief: Berna Zorkun DMD [1]
# Overview
SureSmile is an orthodontic technique that allows the orthodontist to treat cases using traditional orthodontic braces and roboticly created wires. The orthodontist submits records including precise orthodontic models and scans of the patient's teeth with braces in place. The scans can be produced on a light scanner or by cone beam computerized tomography, a radiographic study similar to a CAT scan. The records are processed and made available online to the orthodontist to produce a virtual treatment objective, the teeth as they should look and work when the case is complete.
The orthodontist then specifies a wire of particular dimension and strength. A wire is roboticly produced to be placed by the orthodontist in the patient's mouth. The orthodontist then monitors the changes over time. A new wire can then be designed, changing the size, strength and shape of the wire to refine the results.
The technique is reported to reduce the time required to complete orthodontic treatment and increase the precision of the results. The negatives include increased costs, the time for taken for the scans, and the x-ray exposure when using the cone beam scans. The advantages include shorter treatment times, more precise results. | https://www.wikidoc.org/index.php/SureSmile | |
e29038a4d3c92fedd1d43a23bc8edfa638725e79 | wikidoc | Surfactin | Surfactin
Surfactin is a very powerful surfactant commonly used as an antibiotic. It is a bacterial cyclic lipopeptide, largely prominent for its exceptional surfactant power. Its amphiphilic properties help this substance to survive in both hydrophilic and hydrophobic environment. It is one of the 24 types of antibiotics produced by the Gram-positive endospore-forming bacteria Bacillus subtilis. In the course of various studies of its properties, surfactin was found to exhibit effective characteristics like anti-bacterial, anti-viral, anti-fungal, anti-mycoplasma and hemolytic activities.
# Structure and Synthesis
Surfactin's structure consists of a peptide loop of seven amino acids (L-asparagine, L-leucine, glycine, L-leucine, L-valine and two D-leucines), and a hydrophobic fatty acid chain thirteen to fifteen carbons long which allows its ability to penetrate cellular membranes. Glycine and asparagine residues at positions 1 and 6 respectively, constituting a minor polar domain. On the opposite side, valine residue at position 4 extends down facing the fatty acid chain, making up a major hydrophobic domain. Below critical micellar concentrations (CMCs) the fatty acid tail can extend freely into solution, and then participate in hydrophobic interactions within micelles. This antibiotic is synthesized by a linear nonribosomal peptide synthetase, surfactin synthetase, and has, in solution, a characteristic "horse saddle" conformation that explains its large spectrum of biological activity.
# Physical properties
## Surface tension
Surfactin, like other surfactants, affects the surface tension of liquids in which it is dissolved. It can lower the water's surface tension from 72 mN/m to 27 mN/m at a concentration as low as 20 µM. Surfactin accomplishes this effect as it occupies the intermolecular space between water molecules, decreasing the attractive forces between adjacent water molecules, mainly hydrogen bonds, creating a more fluid solution that can go into tighter regions of space increasing water’s wetting ability. Overall, this property is significant not only for surfactin but for surfactants as a whole, as they are primarily used as detergents and soaps.
## Molecular mechanisms
There are three prevailing hypotheses for how surfactin works. These are described below.
### Cation-carrier effect
The cation-carrier effect is characterized by surfactin’s ability to drive monovalent and divalent cations through an organic barrier. The two acidic residues asparagine and glycine form a "claw" of sorts which easily stabilizes divalent cations. Calcium ions make for the best-fitting cations stabilizing the surfactin conformation and functioning as an assembly template for the formation of micelles. When surfactin penetrates the outer sheet, its fatty acid chain interacts with the acyl chains of the phospholipids, with its headgroup in proximity to the phospholipids polar heads. Attachment of a cation to causes the complex to cross the bilipidic layer undergoing a flip-flop. The headgroup aligns itself with the phospholipids of the inner sheet and the fatty acid chain interacts with the phospholipids acyl chains. The cation is then delivered into the intracellular medium.
### Pore-forming effect
The pore-forming (ion channel) effect is characterized by the formation of cationic channels. It would require surfactin to self-associate inside the membrane, since it cannot span across the cellular membrane. Supramolecular-like structures by successive self-association could then form a channel. This hypothesis for the most part applies only to uncharged membranes where there is a minimal energy barrier between outer and inner membrane leaflets.
### Detergent effect
The detergent effect draws on surfactin's ability to insert its fatty acid chain into the bilipidic layer causing disorganization leading to membrane permeability. Insertion of several surfactin molecules into the membrane can lead to the formation of mixed micelles by self-association and bilayer influenced by fatty chain hydrophobicity ultimately leading to bilayer solubilization.
# Biological properties
Surfactin has a nonspecific mode of action, which originates both benefits and disadvantages. It’s advantageous in the sense that surfactin can act on many kinds of cell membranes, both Gram-positive and Gram-negative. Its non-specificity also has bearing on its tendency to not produce resistant strains of bacteria. Consequently, this efficient mode of cell destruction is indiscriminate, and attacks red blood cells with deadly efficiency.
## Antibacterial and antiviral properties
Surfactin, true to its antibiotic nature, has a very significant antibacterial property, as it is capable of penetrating the cell membranes of all types of bacteria. There are two main types of bacteria and they are Gram-negative and Gram-positive. The two bacteria types differ in the composition of their membrane. The Gram-negative bacteria have an outer lipopolysaccharide membrane and a thin peptidoglycan layer followed by a phospholipids bilayer, whereas the Gram-positive bacteria lack the outer membrane and carry a thicker peptidoglycan layer as well as a phospholipids bilayer. This is an essential factor that contributes to surfactin’s detergent-like activity as it is able to create a permeable environment for the lipid bilayer and causes disruption that solubilizes the membrane.
For surfactin to carry out its antibacterial property successfully, the bacterium needs to be treated with a high concentration. In fact, surfactin needs to be in concentrations between 12–50 µg/ml in order for it to carry out minimal antibacterial effects. This is also known as the minimum inhibitory concentration (MIC).
The antiviral effects of surfactin distinguish this antibiotic from others. This property is such because surfactin has been found to disintegrate enveloped viruses. Surfactin not only disintegrates the viral lipid envelop, but also the capsid of the virus through ion channel formations. This process has been proven through test on several envelop viruses such as HIV and HSV. Also, the isoforms of the fatty acid chain containing 14 or 15 carbon atoms exhibited an improvement in inactivation of the viral envelops. Unfortunately, surfactin only affected cell-free viruses and those that had penetrated the cell were unaffected. Concurrently, if surfactin were exposed to a high medium of protein or lipid concentrations, its antiviral activity would be limited. This is also known as the buffer effect and is a significant drawback in surfactin’s antiviral activity.
## Toxicity
Surfactin has only one drawback: its non specific cytotoxicity. This is seen as surfactin has the ability to lyse a cell. The hemolytic effect has been the result of surfactin having the ability to lyse red blood cells that is enough to warrant caution if used intravascularly. Fortunately, these results were seen at high concentrations of about 40 µM to 60 µM. These concentrations also exhibited the effect of proliferating cells in vitro though it also was the LD50 for this type of cells. At concentrations below 25 µM, toxicity effects of surfactin are not significant. | Surfactin
Surfactin is a very powerful surfactant commonly used as an antibiotic. It is a bacterial cyclic lipopeptide, largely prominent for its exceptional surfactant power. [1] Its amphiphilic properties help this substance to survive in both hydrophilic and hydrophobic environment. It is one of the 24 types of antibiotics produced by the Gram-positive endospore-forming bacteria Bacillus subtilis.[2] In the course of various studies of its properties, surfactin was found to exhibit effective characteristics like anti-bacterial, anti-viral, anti-fungal, anti-mycoplasma and hemolytic activities.[3]
# Structure and Synthesis
Surfactin's structure consists of a peptide loop of seven amino acids (L-asparagine, L-leucine, glycine, L-leucine, L-valine and two D-leucines), and a hydrophobic fatty acid chain thirteen to fifteen carbons long which allows its ability to penetrate cellular membranes. Glycine and asparagine residues at positions 1 and 6 respectively, constituting a minor polar domain. On the opposite side, valine residue at position 4 extends down facing the fatty acid chain, making up a major hydrophobic domain. Below critical micellar concentrations (CMCs) the fatty acid tail can extend freely into solution, and then participate in hydrophobic interactions within micelles.[4] This antibiotic is synthesized by a linear nonribosomal peptide synthetase, surfactin synthetase, and has, in solution, a characteristic "horse saddle" conformation that explains its large spectrum of biological activity.[5]
# Physical properties
## Surface tension
Surfactin, like other surfactants, affects the surface tension of liquids in which it is dissolved. It can lower the water's surface tension from 72 mN/m to 27 mN/m at a concentration as low as 20 µM.[6] Surfactin accomplishes this effect as it occupies the intermolecular space between water molecules, decreasing the attractive forces between adjacent water molecules, mainly hydrogen bonds, creating a more fluid solution that can go into tighter regions of space increasing water’s wetting ability.[7] Overall, this property is significant not only for surfactin but for surfactants as a whole, as they are primarily used as detergents and soaps.
## Molecular mechanisms
There are three prevailing hypotheses for how surfactin works.[8] These are described below.
### Cation-carrier effect
The cation-carrier effect is characterized by surfactin’s ability to drive monovalent and divalent cations through an organic barrier. The two acidic residues asparagine and glycine form a "claw" of sorts which easily stabilizes divalent cations. Calcium ions make for the best-fitting cations stabilizing the surfactin conformation and functioning as an assembly template for the formation of micelles. When surfactin penetrates the outer sheet, its fatty acid chain interacts with the acyl chains of the phospholipids, with its headgroup in proximity to the phospholipids polar heads. Attachment of a cation to causes the complex to cross the bilipidic layer undergoing a flip-flop. The headgroup aligns itself with the phospholipids of the inner sheet and the fatty acid chain interacts with the phospholipids acyl chains.[9] The cation is then delivered into the intracellular medium.
### Pore-forming effect
The pore-forming (ion channel) effect is characterized by the formation of cationic channels. It would require surfactin to self-associate inside the membrane, since it cannot span across the cellular membrane. Supramolecular-like structures by successive self-association could then form a channel. This hypothesis for the most part applies only to uncharged membranes where there is a minimal energy barrier between outer and inner membrane leaflets.[10]
### Detergent effect
The detergent effect draws on surfactin's ability to insert its fatty acid chain into the bilipidic layer causing disorganization leading to membrane permeability.[11] Insertion of several surfactin molecules into the membrane can lead to the formation of mixed micelles by self-association and bilayer influenced by fatty chain hydrophobicity ultimately leading to bilayer solubilization.[12]
# Biological properties
Surfactin has a nonspecific mode of action, which originates both benefits and disadvantages. It’s advantageous in the sense that surfactin can act on many kinds of cell membranes, both Gram-positive and Gram-negative. Its non-specificity also has bearing on its tendency to not produce resistant strains of bacteria. Consequently, this efficient mode of cell destruction is indiscriminate, and attacks red blood cells with deadly efficiency.
## Antibacterial and antiviral properties
Surfactin, true to its antibiotic nature, has a very significant antibacterial property, as it is capable of penetrating the cell membranes of all types of bacteria. There are two main types of bacteria and they are Gram-negative and Gram-positive. The two bacteria types differ in the composition of their membrane. The Gram-negative bacteria have an outer lipopolysaccharide membrane and a thin peptidoglycan layer followed by a phospholipids bilayer, whereas the Gram-positive bacteria lack the outer membrane and carry a thicker peptidoglycan layer as well as a phospholipids bilayer.[13] This is an essential factor that contributes to surfactin’s detergent-like activity as it is able to create a permeable environment for the lipid bilayer and causes disruption that solubilizes the membrane.
For surfactin to carry out its antibacterial property successfully, the bacterium needs to be treated with a high concentration. In fact, surfactin needs to be in concentrations between 12–50 µg/ml in order for it to carry out minimal antibacterial effects.[14] This is also known as the minimum inhibitory concentration (MIC).
The antiviral effects of surfactin distinguish this antibiotic from others. This property is such because surfactin has been found to disintegrate enveloped viruses. Surfactin not only disintegrates the viral lipid envelop, but also the capsid of the virus through ion channel formations. This process has been proven through test on several envelop viruses such as HIV and HSV.[15] Also, the isoforms of the fatty acid chain containing 14 or 15 carbon atoms exhibited an improvement in inactivation of the viral envelops. Unfortunately, surfactin only affected cell-free viruses and those that had penetrated the cell were unaffected. Concurrently, if surfactin were exposed to a high medium of protein or lipid concentrations, its antiviral activity would be limited. This is also known as the buffer effect and is a significant drawback in surfactin’s antiviral activity.
## Toxicity
Surfactin has only one drawback: its non specific cytotoxicity. This is seen as surfactin has the ability to lyse a cell. The hemolytic effect has been the result of surfactin having the ability to lyse red blood cells that is enough to warrant caution if used intravascularly. Fortunately, these results were seen at high concentrations of about 40 µM to 60 µM. These concentrations also exhibited the effect of proliferating cells in vitro though it also was the LD50 for this type of cells.[16] At concentrations below 25 µM, toxicity effects of surfactin are not significant. | https://www.wikidoc.org/index.php/Surfactin | |
3e466ed43a017502e1ca6d7e783f2956676970a7 | wikidoc | Sweetness | Sweetness
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Sweet is one of the five basic tastes and is almost universally regarded as a pleasurable experience. Foods rich in simple carbohydrates such as sugar are those most commonly associated with sweetness, although there are other natural and artificial compounds that are much sweeter, some of which have been used as sugar substitutes for those with a sweet tooth. Other compounds may alter perception of sweetness itself.
The chemosensory basis for detecting sweetness, which varies among both individuals and species, has only been teased apart in recent years. The current theoretical model is the multipoint attachment theory, which involves multiple binding sites between sweetness receptor and the sweet substance itself.
# Examples of sweet substances
A great diversity of chemical compounds, such as aldehydes and ketones are sweet. Among common biological substances, all of the simple carbohydrates are sweet to at least some degree. Sucrose (table sugar) is the prototypical example of a sweet substance, although another sugar, fructose, is somewhat sweeter. Some of the amino acids are mildly sweet: alanine, glycine, and serine are the sweetest. Some other amino acids are perceived as both sweet and bitter.
A number of plant species produce glycosides that are many times sweeter than sugar. The most well-known example is glycyrrhizin, the sweet component of licorice root, which is about 30 times sweeter than sucrose. Another commercially important example is stevioside, from the South American shrub Stevia rebaudiana. It is roughly 250 times sweeter than sucrose. Another class of potent natural sweeteners are the sweet proteins such as thaumatin, found in the West African katemfe fruit. Hen egg lysozyme, an antibiotic protein found in chicken eggs, is also sweet.
Even some inorganic compounds are sweet, including beryllium chloride and lead acetate. The latter may have contributed to lead poisoning among the ancient Roman aristocracy: the Roman delicacy sapa was prepared by boiling soured wine (containing acetic acid) in lead pots.
Hundreds of synthetic organic compounds are known to be sweet. The number of these that are legally permitted as food additives is, however, much smaller. For example, chloroform, nitrobenzene, and Ethylene glycol are sweet, but also toxic. As of 2005, seven artificial sweeteners are in widespread use: saccharin, cyclamate, aspartame, acesulfame potassium, sucralose, alitame, and neotame. Cyclamate was banned for a short period in the US, and a similar situation occurred in Canada with saccharin.
# Sweetness modifiers
A few substances alter the way sweet taste is perceived. One class of these inhibits the perception of sweet tastes, whether from sugars or from highly potent sweeteners. Commercially, the most important of these is lactisole, a compound produced by Domino Sugar. It is used in some jellies and other fruit preserves to bring out their fruit flavors by suppressing their otherwise strong sweetness.
Two natural products have been documented to have similar sweetness-inhibiting properties: gymnemic acid, extracted from the leaves of the Indian vine Gymnema sylvestre and ziziphin, from the leaves of the Chinese jujube (Ziziphus jujuba). Gymnemic acid has been widely promoted within herbal medicine as a treatment for sugar cravings and diabetes mellitus.
On the other hand, two plant proteins, miraculin and curculin, cause sour foods to taste sweet. Once the tongue has been exposed to either of these proteins, sourness is perceived as sweetness for up to an hour afterwards. While curculin has some innate sweet taste of its own, miraculin is by itself quite tasteless.
# The sweetness receptor
Despite the wide variety of chemical substances known to be sweet, and knowledge that the ability to perceive sweet taste must reside in taste buds on the tongue, the biomolecular mechanism of sweet taste was sufficiently elusive that as recently as the 1990s, there was some doubt whether any single "sweetness receptor" actually exists.
The breakthrough for the present understanding of sweetness occurred in 2001, when experiments with laboratory mice showed that mice possessing different versions of the gene T1R3 prefer sweet foods to different extents. Subsequent research has shown that the T1R3 protein forms a complex with a related protein, called T1R2, to form a G-protein coupled receptor that is the sweetness receptor in mammals.
Sweetness perception may differ between species significantly. For example, even amongst the primates sweetness is quite variable. New World monkeys do not find aspartame sweet, while Old World monkeys, apes and humans all do. Felidae like cats cannot perceive sweetness at all.
# Historical theories of sweetness
The development of organic chemistry in the 19th century introduced many new chemical compounds and the means to determine their molecular structures. Early organic chemists tasted many of their products, either intentionally (as a means of characterization) or accidentally (due to poor laboratory hygiene). One of the first attempts to draw systematic correlations between molecules' structures and their tastes was made by a German chemist, Georg Cohn, in 1914. He advanced the hypothesis that in order to evoke a certain taste, a molecule must contain some structural motif (called a sapophore) that produced that taste. With regard to sweetness, he noted that molecules containing multiple hydroxyl groups and those containing chlorine atoms are often sweet, and that among a series of structurally similar compounds, those with smaller molecular weights were often sweeter than the larger compounds.
In 1919, Oertly and Myers proposed a more elaborate theory based on a then-current theory of color in synthetic dyes. They hypothesized that in order to be sweet, a compound must contain one each of two classes of structural motif, a glucophore and an auxogluc. Based on those compounds known to be sweet at the time, they proposed a list of six candidate glucophores and nine auxoglucs.
From these beginnings in the early 20th century, the theory of sweetness enjoyed little further academic attention until 1963, when Robert Shallenberger and Terry Acree proposed the AH-B theory of sweetness. Simply put, they proposed that in order to be sweet, a compound must contain a hydrogen bond donor (AH) and a Lewis base (B) separated by about 0.3 nanometres. According to this theory, the AH-B unit of a sweetener binds with a corresponding AH-B unit on the biological sweetness receptor to produce the sensation of sweetness.
A later refinement of this theory was the AH-B-X theory proposed by Lemont Kier in 1972. While previous researchers had noted that among some groups of compounds, there seemed to be a correlation between hydrophobicity and sweetness, this theory formalized these observations by proposing that in order to be sweet, a compound must have a third binding site (labeled X) that could interact with a hydrophobic site on the sweetness receptor via London dispersion forces. Later researchers have statistically analyzed the distances between the presumed AH, B, and X sites in several families of sweet substances to estimate the distances between these interaction sites on the sweetness receptor.
The most elaborate theory of sweetness to date is the multipoint attachment theory (MPA) proposed by Jean-Marie Tinti and Claude Nofre in 1991. This theory involves a total of eight interaction sites between a sweetener and the sweetness receptor, although not all sweeteners interact with all eight sites. This model has successfully directed efforts aimed at finding highly potent sweeteners, including the most potent family of sweeteners known to date, the guanidine sweeteners. The most potent of these, lugduname, is about 225,000 times sweeter than sucrose. | Sweetness
Lua error in Module:Redirect at line 65: could not parse redirect on page "Sweet".
Sweet is one of the five basic tastes and is almost universally regarded as a pleasurable experience. Foods rich in simple carbohydrates such as sugar are those most commonly associated with sweetness, although there are other natural and artificial compounds that are much sweeter, some of which have been used as sugar substitutes for those with a sweet tooth. Other compounds may alter perception of sweetness itself.
The chemosensory basis for detecting sweetness, which varies among both individuals and species, has only been teased apart in recent years. The current theoretical model is the multipoint attachment theory, which involves multiple binding sites between sweetness receptor and the sweet substance itself.
# Examples of sweet substances
A great diversity of chemical compounds, such as aldehydes and ketones are sweet. Among common biological substances, all of the simple carbohydrates are sweet to at least some degree. Sucrose (table sugar) is the prototypical example of a sweet substance, although another sugar, fructose, is somewhat sweeter. Some of the amino acids are mildly sweet: alanine, glycine, and serine are the sweetest. Some other amino acids are perceived as both sweet and bitter.
A number of plant species produce glycosides that are many times sweeter than sugar. The most well-known example is glycyrrhizin, the sweet component of licorice root, which is about 30 times sweeter than sucrose. Another commercially important example is stevioside, from the South American shrub Stevia rebaudiana. It is roughly 250 times sweeter than sucrose. Another class of potent natural sweeteners are the sweet proteins such as thaumatin, found in the West African katemfe fruit. Hen egg lysozyme, an antibiotic protein found in chicken eggs, is also sweet.
Even some inorganic compounds are sweet, including beryllium chloride and lead acetate. The latter may have contributed to lead poisoning among the ancient Roman aristocracy: the Roman delicacy sapa was prepared by boiling soured wine (containing acetic acid) in lead pots.
Hundreds of synthetic organic compounds are known to be sweet. The number of these that are legally permitted as food additives is, however, much smaller. For example, chloroform, nitrobenzene, and Ethylene glycol are sweet, but also toxic. As of 2005, seven artificial sweeteners are in widespread use: saccharin, cyclamate, aspartame, acesulfame potassium, sucralose, alitame, and neotame. Cyclamate was banned for a short period in the US, and a similar situation occurred in Canada with saccharin.[1]
# Sweetness modifiers
A few substances alter the way sweet taste is perceived. One class of these inhibits the perception of sweet tastes, whether from sugars or from highly potent sweeteners. Commercially, the most important of these is lactisole[3], a compound produced by Domino Sugar. It is used in some jellies and other fruit preserves to bring out their fruit flavors by suppressing their otherwise strong sweetness.
Two natural products have been documented to have similar sweetness-inhibiting properties: gymnemic acid, extracted from the leaves of the Indian vine Gymnema sylvestre and ziziphin, from the leaves of the Chinese jujube (Ziziphus jujuba).[4] Gymnemic acid has been widely promoted within herbal medicine as a treatment for sugar cravings and diabetes mellitus.
On the other hand, two plant proteins, miraculin[5] and curculin[6], cause sour foods to taste sweet. Once the tongue has been exposed to either of these proteins, sourness is perceived as sweetness for up to an hour afterwards. While curculin has some innate sweet taste of its own, miraculin is by itself quite tasteless.
# The sweetness receptor
Despite the wide variety of chemical substances known to be sweet, and knowledge that the ability to perceive sweet taste must reside in taste buds on the tongue, the biomolecular mechanism of sweet taste was sufficiently elusive that as recently as the 1990s, there was some doubt whether any single "sweetness receptor" actually exists.
The breakthrough for the present understanding of sweetness occurred in 2001, when experiments with laboratory mice showed that mice possessing different versions of the gene T1R3 prefer sweet foods to different extents. Subsequent research has shown that the T1R3 protein forms a complex with a related protein, called T1R2, to form a G-protein coupled receptor that is the sweetness receptor in mammals.[7]
Sweetness perception may differ between species significantly. For example, even amongst the primates sweetness is quite variable. New World monkeys do not find aspartame sweet, while Old World monkeys, apes and humans all do.[8] Felidae like cats cannot perceive sweetness at all.
# Historical theories of sweetness
The development of organic chemistry in the 19th century introduced many new chemical compounds and the means to determine their molecular structures. Early organic chemists tasted many of their products, either intentionally (as a means of characterization) or accidentally (due to poor laboratory hygiene). One of the first attempts to draw systematic correlations between molecules' structures and their tastes was made by a German chemist, Georg Cohn, in 1914. He advanced the hypothesis that in order to evoke a certain taste, a molecule must contain some structural motif (called a sapophore) that produced that taste. With regard to sweetness, he noted that molecules containing multiple hydroxyl groups and those containing chlorine atoms are often sweet, and that among a series of structurally similar compounds, those with smaller molecular weights were often sweeter than the larger compounds.
In 1919, Oertly and Myers proposed a more elaborate theory based on a then-current theory of color in synthetic dyes. They hypothesized that in order to be sweet, a compound must contain one each of two classes of structural motif, a glucophore and an auxogluc. Based on those compounds known to be sweet at the time, they proposed a list of six candidate glucophores and nine auxoglucs.
From these beginnings in the early 20th century, the theory of sweetness enjoyed little further academic attention until 1963, when Robert Shallenberger and Terry Acree proposed the AH-B theory of sweetness. Simply put, they proposed that in order to be sweet, a compound must contain a hydrogen bond donor (AH) and a Lewis base (B) separated by about 0.3 nanometres. According to this theory, the AH-B unit of a sweetener binds with a corresponding AH-B unit on the biological sweetness receptor to produce the sensation of sweetness.
A later refinement of this theory was the AH-B-X theory proposed by Lemont Kier in 1972. While previous researchers had noted that among some groups of compounds, there seemed to be a correlation between hydrophobicity and sweetness, this theory formalized these observations by proposing that in order to be sweet, a compound must have a third binding site (labeled X) that could interact with a hydrophobic site on the sweetness receptor via London dispersion forces. Later researchers have statistically analyzed the distances between the presumed AH, B, and X sites in several families of sweet substances to estimate the distances between these interaction sites on the sweetness receptor.
The most elaborate theory of sweetness to date is the multipoint attachment theory (MPA) proposed by Jean-Marie Tinti and Claude Nofre in 1991. This theory involves a total of eight interaction sites between a sweetener and the sweetness receptor, although not all sweeteners interact with all eight sites.[citation needed] This model has successfully directed efforts aimed at finding highly potent sweeteners, including the most potent family of sweeteners known to date, the guanidine sweeteners. The most potent of these, lugduname, is about 225,000 times sweeter than sucrose. | https://www.wikidoc.org/index.php/Sweet | |
f8cafa8132ac5142bd50216ad8467248d3a57278 | wikidoc | Sweet pea | Sweet pea
Sweet Pea (Lathyrus odoratus) is a flowering plant in the genus Lathyrus in the family Fabaceae (legumes), native to the eastern Mediterranean region from Sicily east to Crete.
It is an annual climbing plant, growing to a height of 1-2 m where suitable support is available. The leaves are pinnate with two leaflets and a terminal tendril, this twining round supporting plants to help it climb. The flowers are purple, 2-3.5 cm broad, in the wild plant, larger and very variable in colour in the many cultivars. Unlike most peas, the seeds of the sweet pea are poisonous as they contain a neurotoxin, and should not be eaten. The illness caused by the ingestion of sweet peas is known as odoratism, or sweet pea lathyrism.
Sweet peas have been cultivated since the 17th century and a vast number of cultivars are commercially available. They are often grown by gardeners for their bright colours and the sweet fragrance that gives them their name.
# Horticultural development
Henry Eckford (died 1906), a nurseryman of Scottish descent, cross-bred and developed the sweet pea, turning it from a rather insignificant, if sweetly scented flower, into the floral sensation of the late Victorian era.
His initial success and recognition came while serving as head gardener for the Earl of Radnor, raising new cultivars of pelargoniums and dahlias. In 1870 he went to work for one Dr Sankey of Sandywell near Gloucester. A member of the Royal Horticultural Society, he was awarded a First Class Certificate (the top award) in 1882 for introducing the sweet pea cultivar 'Bronze Prince', marking the start of association with the flower.
In 1888 he set up his development and trial fields for Sweet Peas in the North Shropshire market town of Wem. By 1901, he had introduced a total of 115 cultivars, out of total 264 cultivars grown at the time . Eckford was presented with the Royal Horticultural Society's Victoria Medal of Honour for his work. He died in 1906 but his work was continued, for a time at least, by his son John Eckford.
More lately, the association between the sweet pea, the Eckfords and Wem has been highlighted again. In the late 1980s, the Sweet Pea Society of Wem started an annual Sweet Pea show and the town has again taken the flower to its heart. Many of the street signs now carry a sweet pea motif and an area of the town is known as Eckford Park.
# Genetics
Gregor Mendel is today recognized as the "Father of Modern Genetics" for his work with the cross breeding of pea plants (Pisum sativum) with different characteristics, and sweet pea has been used in a similar way. The Sweet Pea is thus a model organism being used in early experimentations in genetics, particularly by the pioneer geneticist Reginald Punnett. It is highly suitable as a genetic subject because of its ability to self-pollinate and its easily observed Mendelian traits such as color, height and petal form. Many genetical principles were discovered or confirmed in sweet pea. It was used by Punnett in early studies of genetic linkage . Complementary factor inheritance was also elucidated in sweet pea, from the cross of two pure-breeding white strains which gave rise to a blue hybrid, the blue colour requiring two genes, derived independently from the two white parents Like the blue rose, the yellow sweet pea remains elusive, and a true yellow is unlikely to ever be achieved without genetic engineering.
# Notes
- ↑ Graham Rice, The Sweet Pea Book, Batsford 2002, p.9
- ↑ Punnett, R.C. (1923). Linkage in the sweet pea (Lathyrus odoratus). Journal of Genetics 13: 101–123
- ↑ Bateson, W., Saunders, E.R. and Punnett, R.C. (1906). Experimental studies in the physiology of heredity. Reports to the Evolution Committee, Royal Society of London: 3.
de:Duftende Platterbse
lt:Kvapusis pelėžirnis
nl:Welriekende lathyrus
fi:Hajuherne
sv:Luktärt | Sweet pea
Template:Cleanup
Sweet Pea (Lathyrus odoratus) is a flowering plant in the genus Lathyrus in the family Fabaceae (legumes), native to the eastern Mediterranean region from Sicily east to Crete.
It is an annual climbing plant, growing to a height of 1-2 m where suitable support is available. The leaves are pinnate with two leaflets and a terminal tendril, this twining round supporting plants to help it climb. The flowers are purple, 2-3.5 cm broad, in the wild plant, larger and very variable in colour in the many cultivars. Unlike most peas, the seeds of the sweet pea are poisonous as they contain a neurotoxin, and should not be eaten. The illness caused by the ingestion of sweet peas is known as odoratism, or sweet pea lathyrism.
Sweet peas have been cultivated since the 17th century and a vast number of cultivars are commercially available. They are often grown by gardeners for their bright colours and the sweet fragrance that gives them their name.
# Horticultural development
Henry Eckford (died 1906), a nurseryman of Scottish descent, cross-bred and developed the sweet pea, turning it from a rather insignificant, if sweetly scented flower, into the floral sensation of the late Victorian era.
His initial success and recognition came while serving as head gardener for the Earl of Radnor, raising new cultivars of pelargoniums and dahlias. In 1870 he went to work for one Dr Sankey of Sandywell near Gloucester. A member of the Royal Horticultural Society, he was awarded a First Class Certificate (the top award) in 1882 for introducing the sweet pea cultivar 'Bronze Prince', marking the start of association with the flower.
In 1888 he set up his development and trial fields for Sweet Peas in the North Shropshire market town of Wem. By 1901, he had introduced a total of 115 cultivars, out of total 264 cultivars grown at the time [1]. Eckford was presented with the Royal Horticultural Society's Victoria Medal of Honour for his work. He died in 1906 but his work was continued, for a time at least, by his son John Eckford.
More lately, the association between the sweet pea, the Eckfords and Wem has been highlighted again. In the late 1980s, the Sweet Pea Society of Wem started an annual Sweet Pea show and the town has again taken the flower to its heart. Many of the street signs now carry a sweet pea motif and an area of the town is known as Eckford Park.
# Genetics
Gregor Mendel is today recognized as the "Father of Modern Genetics" for his work with the cross breeding of pea plants (Pisum sativum) with different characteristics, and sweet pea has been used in a similar way. The Sweet Pea is thus a model organism being used in early experimentations in genetics, particularly by the pioneer geneticist Reginald Punnett. It is highly suitable as a genetic subject because of its ability to self-pollinate and its easily observed Mendelian traits such as color, height and petal form. Many genetical principles were discovered or confirmed in sweet pea. It was used by Punnett in early studies of genetic linkage [2]. Complementary factor inheritance was also elucidated in sweet pea, from the cross of two pure-breeding white strains which gave rise to a blue hybrid, the blue colour requiring two genes, derived independently from the two white parents [3] Like the blue rose, the yellow sweet pea remains elusive, and a true yellow is unlikely to ever be achieved without genetic engineering.
# Notes
- ↑ Graham Rice, The Sweet Pea Book, Batsford 2002, p.9
- ↑ Punnett, R.C. (1923). Linkage in the sweet pea (Lathyrus odoratus). Journal of Genetics 13: 101–123
- ↑ Bateson, W., Saunders, E.R. and Punnett, R.C. (1906). Experimental studies in the physiology of heredity. Reports to the Evolution Committee, Royal Society of London: 3.
Template:Wikispecies
Template:Faboideae-stub
de:Duftende Platterbse
lt:Kvapusis pelėžirnis
nl:Welriekende lathyrus
fi:Hajuherne
sv:Luktärt | https://www.wikidoc.org/index.php/Sweet_pea | |
ba07fae43d696a5df0e12559dd3e7a9999f5355c | wikidoc | Sybr Safe | Sybr Safe
Sybr Safe can replace the toxic Ethidium Bromide as a nucleic acid stain for gel electrophoresis.
See the product page for more information.
Syber Safe excitation and emission spectra (does not show the lower absorption peak).
# Notes
- BC 14:11, 4 May 2007 (EDT): Users of SynGene gel imagers should be able to detect DNA stained with SybrSafe using the transilluminator, the short band pass emission filter and a counting time of 1s. (Tested on 1μg of NEB 2-Log DNA Ladder). | Sybr Safe
Sybr Safe can replace the toxic Ethidium Bromide as a nucleic acid stain for gel electrophoresis.
See the product page for more information.
Syber Safe excitation and emission spectra (does not show the lower absorption peak).
# Notes
- BC 14:11, 4 May 2007 (EDT): Users of SynGene gel imagers should be able to detect DNA stained with SybrSafe using the transilluminator, the short band pass emission filter and a counting time of 1s. (Tested on 1μg of NEB 2-Log DNA Ladder). | https://www.wikidoc.org/index.php/Sybr_Safe | |
a8b51bf0ac53f9b2917787fd6697b814a94b82af | wikidoc | Syncoilin | Syncoilin
Syncoilin is a muscle-specific intermediate filament, first isolated as a binding partner to α-dystrobrevin, as determined by a yeast two-hybrid assay.
Later, a yeast two-hybrid method was used to demonstrate that syncoilin is a binding partner of desmin. These binding partners suggest that syncoilin acts as a mechanical "linker" between the sarcomere Z-disk (where desmin is localized) and the dystrophin-associated protein complex (where α-dystrobrevin is localized). However, the specific in vivo functions of syncoilin have not yet been determined.
Abnormally high levels of syncoilin have been shown to be a characteristic of neuromuscular wasting diseases such as desminopathy and muscular dystrophy. Therefore, syncoilin is being explored as a promising marker of neuromuscular disease. | Syncoilin
Syncoilin is a muscle-specific intermediate filament, first isolated as a binding partner to α-dystrobrevin, as determined by a yeast two-hybrid assay.[1]
Later, a yeast two-hybrid method was used to demonstrate that syncoilin is a binding partner of desmin.[2] These binding partners suggest that syncoilin acts as a mechanical "linker" between the sarcomere Z-disk (where desmin is localized) and the dystrophin-associated protein complex (where α-dystrobrevin is localized). However, the specific in vivo functions of syncoilin have not yet been determined.
Abnormally high levels of syncoilin have been shown to be a characteristic of neuromuscular wasting diseases such as desminopathy[3] and muscular dystrophy.[4] Therefore, syncoilin is being explored as a promising marker of neuromuscular disease. | https://www.wikidoc.org/index.php/Syncoilin | |
5fc887c3aa04c8591a9c27479992da6cc51582c1 | wikidoc | Syndecans | Syndecans
Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. These core proteins carry three to five heparan sulfate and chondroitin sulfate chains which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin-C.
# Family members
The syndecan protein family is comprised of four members. Syndecans 1 and 3 and syndecans 2 and 4 making up separate subfamilies having arisen by gene duplication and divergent evolution from a single ancestral gene.
The syndecan numbers reflect the order in which the cDNAs for each family member were cloned. All syndecans have an N-terminal signal peptide, an ectodomain, a single hydrophobic transmembrane domain, and a short C-terminal cytoplasmic domain.
The ectodomains show the least amount of amino acid sequence conservation, not more than 10-20%, in contrast the transmembrane and cytoplasmic domains share around 60-70% amino acid sequence identity.
The transmembrane domains contain an unusual alanine/glycine sequence motif while the cytoplasmic domain is essentially composed of two regions of conserved amino acid sequence (C1 and C2), separated by a central variable sequence of amino acids that is distinct for each family member (V). | Syndecans
Syndecans are single transmembrane domain proteins that are thought to act as coreceptors, especially for G protein-coupled receptors. These core proteins carry three to five heparan sulfate and chondroitin sulfate chains which allow for interaction with a large variety of ligands including fibroblast growth factors, vascular endothelial growth factor, transforming growth factor-beta, fibronectin and antithrombin-1. Interactions between fibronectin and some syndecans can be modulated by the extracellular matrix protein tenascin-C.
# Family members
The syndecan protein family is comprised of four members. Syndecans 1 and 3 and syndecans 2 and 4 making up separate subfamilies having arisen by gene duplication and divergent evolution from a single ancestral gene.[1]
The syndecan numbers reflect the order in which the cDNAs for each family member were cloned. All syndecans have an N-terminal signal peptide, an ectodomain, a single hydrophobic transmembrane domain, and a short C-terminal cytoplasmic domain.[2]
The ectodomains show the least amount of amino acid sequence conservation, not more than 10-20%, in contrast the transmembrane and cytoplasmic domains share around 60-70% amino acid sequence identity.[3]
The transmembrane domains contain an unusual alanine/glycine sequence motif while the cytoplasmic domain is essentially composed of two regions of conserved amino acid sequence (C1 and C2), separated by a central variable sequence of amino acids that is distinct for each family member (V). | https://www.wikidoc.org/index.php/Syndecans | |
da70129888866e3014574c5d2ba09d28ac335205 | wikidoc | Synovitis | Synovitis
Synonyms and keywords: Synovial inflammation
# Overview
Synovitis is the medical term for inflammation of a synovial membrane, which line those joints which possess cavities, namely synovial joints. The condition is usually painful, particularly when the joint is moved. The joint usually swells due to fluid collection.
Synovitis is present in several forms of arthritis as well as lupus, gout, and other conditions. The long term presence of synovitis can result in degeneration of the joint.
# Causes
## In Alphabetical Order
- Chondrocalcinosis
- Haemophilia type A
- Lupus
- Pigmented villonodular synovitis
- Polymyalgia Rheumatica
- Rheumatoid arthritis
- SAPHO syndrome
- Systemic sclerosis
# Treatment
Symptoms of synovitis can be treated by a doctor with anti-inflammatory drugs such as NSAIDs. Specific treatment depends on the determining cause of the synovitis.
# Related Chapters
- Tenosynovitis | Synovitis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Synovial inflammation
# Overview
Synovitis is the medical term for inflammation of a synovial membrane, which line those joints which possess cavities, namely synovial joints. The condition is usually painful, particularly when the joint is moved. The joint usually swells due to fluid collection.
Synovitis is present in several forms of arthritis as well as lupus, gout, and other conditions. The long term presence of synovitis can result in degeneration of the joint.
# Causes
## In Alphabetical Order
- Chondrocalcinosis
- Haemophilia type A
- Lupus
- Pigmented villonodular synovitis
- Polymyalgia Rheumatica
- Rheumatoid arthritis
- SAPHO syndrome
- Systemic sclerosis
# Treatment
Symptoms of synovitis can be treated by a doctor with anti-inflammatory drugs such as NSAIDs. Specific treatment depends on the determining cause of the synovitis.
# Related Chapters
- Tenosynovitis
Template:Diseases of the musculoskeletal system and connective tissue
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Synovial_inflammation | |
27e073b8dc8daf7d01fc7e7492f6db94b0a1a85f | wikidoc | Thyroxine | Thyroxine
# Overview
Thyroxine, or 3:5,3':5' tetraiodothyronine (often abbreviated as T4) is the major hormone secreted by the follicular cells of the thyroid gland.
T4 is transported in blood, with 99.95% of the secreted T4 being protein bound, principally to thyroxine binding globulin (TBG) and to a lesser extent to transthyretin and serum albumin.
T4 is involved in controlling the rate of metabolic processes in the body and influencing physical development.
Note: Thyroxine is a prohormone and a reservoir for the active thyroid hormone triiodothyronine (T3), T4 being converted as required in the tissues by deiodinases.
Type II deiodinase converts T4 into T3.
The "D" isomer is called "Dextrothyroxine" and is used as a lipid modifying agent.
The half life of thyroxine once released into the blood circulatory system is about 1 week
# Reactions | Thyroxine
Template:Chembox new
Template:Seealso
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Thyroxine, or 3:5,3':5' tetraiodothyronine (often abbreviated as T4) is the major hormone secreted by the follicular cells of the thyroid gland.
T4 is transported in blood, with 99.95% of the secreted T4 being protein bound, principally to thyroxine binding globulin (TBG) and to a lesser extent to transthyretin and serum albumin.
T4 is involved in controlling the rate of metabolic processes in the body and influencing physical development.
Note: Thyroxine is a prohormone and a reservoir for the active thyroid hormone triiodothyronine (T3), T4 being converted as required in the tissues by deiodinases.
Type II deiodinase converts T4 into T3.
The "D" isomer is called "Dextrothyroxine"[1] and is used as a lipid modifying agent.[2]
The half life of thyroxine once released into the blood circulatory system is about 1 week
# Reactions | https://www.wikidoc.org/index.php/T4 | |
8cafd4c53526ce4f92012a77571969eedcd870e2 | wikidoc | TGF alpha | TGF alpha
Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene. As a member of the epidermal growth factor (EGF) family, TGF-α is a mitogenic polypeptide. The protein becomes activated when binding to receptors capable of protein kinase activity for cellular signaling.
TGF-α is a transforming growth factor that is a ligand for the epidermal growth factor receptor, which activates a signaling pathway for cell proliferation, differentiation and development. This protein may act as either a transmembrane-bound ligand or a soluble ligand. This gene has been associated with many types of cancers, and it may also be involved in some cases of cleft lip/palate.
# Synthesis
TGF-α is synthesized internally as part of a 160 (human) or 159 (rat) amino acid transmembrane precursor. The precursor is composed of an extracellular domain containing a hydrophobic transmembrane domain, 50 amino acids of TGF-α, and a 35-residue-long cytoplasmic domain. In its smallest form TGF-α has six cysteines linked together via three disulfide bridges. Collectively all members of the EGF/TGF-α family share this structure. The protein, however, is not directly related to TGF-β.
In the stomach, TGF-α is manufactured within the normal gastric mucosa. TGF-α has been shown to inhibit gastric acid secretion.
Limited success has resulted from attempts to synthesize of a reductant molecule to TGF-α that displays a similar biological profile.
## Synthesis in the stomach
In the stomach, TGF-α is manufactured within the normal gastric mucosa. TGF-α has been shown to inhibit gastric acid secretion.
# Function
TGF-α can be produced in macrophages, brain cells, and keratinocytes. TGF-α induces epithelial development. Considering that TGF-α is a member of the EGF family, the biological actions of TGF-α and EGF are similar. For instance, TGF-α and EGF bind to the same receptor. When TGF-α binds to EGFR it can initiate multiple cell proliferation events. Cell proliferation events that involve TGF-α bound to EGFR include wound healing and embryogenesis. TGF-α is also involved in tumerogenesis and believed to promote angiogenesis.
TGFα has also been shown to stimulate neural cell proliferation in the adult injured brain.
# Receptor
A 170-kDa glycosylated protein known as the EGF receptor binds to TGF-α allowing the polypeptide to function in various signaling pathways. The EGF receptor is characterized by having an extracellular domain that has numerous amino acid motifs. EGFR is essential for a single transmembrane domain, an intracellular domain (containing tyrosine kinase activity), and ligand recognition. As a membrane anchored-growth factor, TGF-α can be cleaved from an integral membrane glycoprotein via a protease. Soluble forms of TGF-α resulting from the cleavage have the capacity to activate EGFR. EGFR can be activated from a membrane-anchored growth factor as well.
When TGF-α binds to EGFR it dimerizes triggering phosphorylation of a protein-tyrosine kinase. The activity of protein-tyrosine kinase causes an autophosphorylation to occur among several tyrosine residues within EGFR, influencing activation and signaling of other proteins that interact in many signal transduction pathways.
# Animal studies
In an animal model of Parkinson's disease where dopaminergic neurons have been damaged by 6-hydroxydopamine, infusion of TGF-α into the brain caused an increase in the number of neuronal precursor cells. However TGF-α treatment did not result in neurogenesis dopaminergic neurons.
# Human studies
## Neuroendocrine system
The EGF/TGF-α family has been shown to regulate luteinizing hormone-releasing hormone (LHRH) through a glial-neuronal interactive process. Produced in hypothalamic astrocytes, TGF-α indirectly stimulates LHRH release through various intermediates. As a result, TGF-α is a physiological component essential to the initiation process of female puberty.
## Suprachiasmatic nucleus
TGF-α has also been observed to be highly expressed in the suprachiasmatic nucleus (SCN) (5). This finding suggests a role for EGFR signaling in the regulation of CLOCK and circadian rhythms within the SCN. Similar studies have shown that when injected into the third ventricle TGF-α can suppress circadian locomotor behavior along with drinking or eating activities.
## Tumors
Its potential use as a prognostic biomarker in various tumors, like gastric carcinoma. or melanoma has been suggested. Elevated TGF-α is associated with Menetrier's disease, a precancerous condition of the stomach.
# Interactions
TGF alpha has been shown to interact with GORASP1 and GORASP2. | TGF alpha
Transforming growth factor alpha (TGF-α) is a protein that in humans is encoded by the TGFA gene.[1] As a member of the epidermal growth factor (EGF) family, TGF-α is a mitogenic polypeptide.[2] The protein becomes activated when binding to receptors capable of protein kinase activity for cellular signaling.
TGF-α is a transforming growth factor that is a ligand for the epidermal growth factor receptor, which activates a signaling pathway for cell proliferation, differentiation and development. This protein may act as either a transmembrane-bound ligand or a soluble ligand. This gene has been associated with many types of cancers, and it may also be involved in some cases of cleft lip/palate.[1]
# Synthesis
TGF-α is synthesized internally as part of a 160 (human) or 159 (rat) amino acid transmembrane precursor.[3] The precursor is composed of an extracellular domain containing a hydrophobic transmembrane domain, 50 amino acids of TGF-α, and a 35-residue-long cytoplasmic domain.[3] In its smallest form TGF-α has six cysteines linked together via three disulfide bridges. Collectively all members of the EGF/TGF-α family share this structure. The protein, however, is not directly related to TGF-β.
In the stomach, TGF-α is manufactured within the normal gastric mucosa.[4] TGF-α has been shown to inhibit gastric acid secretion.[4]
Limited success has resulted from attempts to synthesize of a reductant molecule to TGF-α that displays a similar biological profile.[5]
## Synthesis in the stomach
In the stomach, TGF-α is manufactured within the normal gastric mucosa.[4] TGF-α has been shown to inhibit gastric acid secretion.[4]
# Function
TGF-α can be produced in macrophages, brain cells, and keratinocytes. TGF-α induces epithelial development. Considering that TGF-α is a member of the EGF family, the biological actions of TGF-α and EGF are similar. For instance, TGF-α and EGF bind to the same receptor. When TGF-α binds to EGFR it can initiate multiple cell proliferation events.[5] Cell proliferation events that involve TGF-α bound to EGFR include wound healing and embryogenesis. TGF-α is also involved in tumerogenesis and believed to promote angiogenesis.[3]
TGFα has also been shown to stimulate neural cell proliferation in the adult injured brain.[6]
# Receptor
A 170-kDa glycosylated protein known as the EGF receptor binds to TGF-α allowing the polypeptide to function in various signaling pathways.[2] The EGF receptor is characterized by having an extracellular domain that has numerous amino acid motifs. EGFR is essential for a single transmembrane domain, an intracellular domain (containing tyrosine kinase activity), and ligand recognition.[2] As a membrane anchored-growth factor, TGF-α can be cleaved from an integral membrane glycoprotein via a protease.[3] Soluble forms of TGF-α resulting from the cleavage have the capacity to activate EGFR. EGFR can be activated from a membrane-anchored growth factor as well.
When TGF-α binds to EGFR it dimerizes triggering phosphorylation of a protein-tyrosine kinase. The activity of protein-tyrosine kinase causes an autophosphorylation to occur among several tyrosine residues within EGFR, influencing activation and signaling of other proteins that interact in many signal transduction pathways.
# Animal studies
In an animal model of Parkinson's disease where dopaminergic neurons have been damaged by 6-hydroxydopamine, infusion of TGF-α into the brain caused an increase in the number of neuronal precursor cells.[6] However TGF-α treatment did not result in neurogenesis dopaminergic neurons.[7]
# Human studies
## Neuroendocrine system
The EGF/TGF-α family has been shown to regulate luteinizing hormone-releasing hormone (LHRH) through a glial-neuronal interactive process.[2] Produced in hypothalamic astrocytes, TGF-α indirectly stimulates LHRH release through various intermediates. As a result, TGF-α is a physiological component essential to the initiation process of female puberty.[2]
## Suprachiasmatic nucleus
TGF-α has also been observed to be highly expressed in the suprachiasmatic nucleus (SCN) (5). This finding suggests a role for EGFR signaling in the regulation of CLOCK and circadian rhythms within the SCN.[8] Similar studies have shown that when injected into the third ventricle TGF-α can suppress circadian locomotor behavior along with drinking or eating activities.[8]
## Tumors
Its potential use as a prognostic biomarker in various tumors, like gastric carcinoma.[9] or melanoma has been suggested.[10] Elevated TGF-α is associated with Menetrier's disease, a precancerous condition of the stomach.[11]
# Interactions
TGF alpha has been shown to interact with GORASP1[12] and GORASP2.[12] | https://www.wikidoc.org/index.php/TGF_alpha | |
95b9dd79381d19bfa0a8a7ea65714916058d84a8 | wikidoc | TNFAIP8L2 | TNFAIP8L2
TNF alpha induced protein 8 like 2 (TNFAIP8L2), also known as TIPE2, is a protein that in humans is encoded by the TNFAIP8L2 gene. It is preferentially expressed in human myeloid cell types and serves as an immune checkpoint regulator of inflammation and metabolism.
# Function
TNFAIP8L2 is a member of the TNFAIP8 (tumor necrosis factor-α-induced protein 8, or TIPE) family that function as transfer proteins for the second messenger lipids PIP2 and PIP3. The other three family members are TNFAIP8, TNFAIP8L1 and TNFAIP8L3.
# Structure
The crystal structure of TIPE2 reveals that it contains a large, hydrophobic central cavity that is poised for cofactor binding.
# Clinical significance
TIPE2 acts as a negative regulator of the immune system. It is down-regulated in patients with infectious and autoimmune diseases and also acts as a tumor suppressor in several types of cancer. Its knockout leads to leukocytosis and systemic inflammatory disorders in mice. | TNFAIP8L2
TNF alpha induced protein 8 like 2 (TNFAIP8L2), also known as TIPE2, is a protein that in humans is encoded by the TNFAIP8L2 gene. It is preferentially expressed in human myeloid cell types and serves as an immune checkpoint regulator of inflammation and metabolism.[1]
# Function
TNFAIP8L2 is a member of the TNFAIP8 (tumor necrosis factor-α-induced protein 8, or TIPE) family that function as transfer proteins for the second messenger lipids PIP2 and PIP3. The other three family members are TNFAIP8, TNFAIP8L1 and TNFAIP8L3.[2]
# Structure
The crystal structure of TIPE2 reveals that it contains a large, hydrophobic central cavity that is poised for cofactor binding.[3]
# Clinical significance
TIPE2 acts as a negative regulator of the immune system[1][4]. It is down-regulated in patients with infectious and autoimmune diseases and also acts as a tumor suppressor in several types of cancer.[5] Its knockout leads to leukocytosis and systemic inflammatory disorders in mice.[2][6] | https://www.wikidoc.org/index.php/TNFAIP8L2 | |
a292256b7e446a64cbc987c4731b48faca0dd696 | wikidoc | TNT Trial | TNT Trial
# Objective
To compare the efficacy of 10 mg and 80 mg daily dose of atorvastatin in patients with stable CAD and baseline LDL-C between 130 mg/dL and 250 mg/dL.
# Methods
The Treating to New Targets (TNT) trial was a randomized trial that enrolled 10,001 patients with stable coronary artery disease to treatment with atorvastatin, 80 or 10 mg/dL, and followed them up for a median period of 4.9 years. The primary end point was a composite of cardiovascular death, myocardial infarction, resuscitated cardiac arrest, and stroke.
# Results
Compared to low dose, high dose atorvastatin was associated with:
- A significantly lower mean serum LDL-C concentration (77 vs 101 mg/dL)
- Significant reductions in the rate of the primary end point (8.7 vs 10.9 percent)
- No reduction in all-cause mortality. Higher doses of atorvastatin, although reduced mortality due to cardiac events, were associated with higher mortality rate due to noncardiovascular events.
# Conclusion
Wider use of the 80-mg dose of atorvastatin in patients with stable coronary disease is safe, cost-effective, and provides an incremental reduction in coronary events. | TNT Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Objective
To compare the efficacy of 10 mg and 80 mg daily dose of atorvastatin in patients with stable CAD and baseline LDL-C between 130 mg/dL and 250 mg/dL.
# Methods
The Treating to New Targets (TNT) trial was a randomized trial that enrolled 10,001 patients with stable coronary artery disease to treatment with atorvastatin, 80 or 10 mg/dL, and followed them up for a median period of 4.9 years. The primary end point was a composite of cardiovascular death, myocardial infarction, resuscitated cardiac arrest, and stroke.
# Results
Compared to low dose, high dose atorvastatin was associated with:
- A significantly lower mean serum LDL-C concentration (77 vs 101 mg/dL)
- Significant reductions in the rate of the primary end point (8.7 vs 10.9 percent)
- No reduction in all-cause mortality. Higher doses of atorvastatin, although reduced mortality due to cardiac events, were associated with higher mortality rate due to noncardiovascular events.
# Conclusion
Wider use of the 80-mg dose of atorvastatin in patients with stable coronary disease is safe, cost-effective, and provides an incremental reduction in coronary events.[1] | https://www.wikidoc.org/index.php/TNT_Trial | |
dba406a0f07c37b9211d5aed14bbdd18fa79125d | wikidoc | TSI slant | TSI slant
The Triple Sugar Iron or TSI test is a microbiological test roughly named for its ability to test microorganism's ability to ferment sugars and to utilize iron to produce hydrogen sulfide. It is often used in the selective identification of enteric bacteria including but not limited to Salmonella and Shigella.
# Composition
The TSI slant is a test tube which contains agar, a pH-sensitive dye (phenol red), high concentrations of lactose and sucrose, and a low concentration of glucose as well as sodium thiosulfate and ferric citrate. All of these ingredients are mixed together and allowed to solidify in the test tube at a slanted angle. The slanted shape of this medium provides an array of surfaces that are either exposed to oxygen-containing air in varying degrees (an aerobic environment) or not exposed to air (an anaerobic environment). TSI agar medium was developed based on Kligler's iron agar, which had been used for the determination of lactose fermentative bacteria, by addition of sucrose to be able to detect also sucrose fermentative bacteria.
# Interpretation of results
Bacteria which ferment any of the three sugars in the medium will produce byproducts. These byproducts are usually acids, which will change the color of the red pH-sensitive dye (phenol red) to a yellow color. Position of the color change distinguishes the acid production associated with glucose fermentation from the acidic byproducts of lactose or sucrose fermentation. Many bacteria that can ferment sugars in the anaerobic butt of the tube are enterobacteria.
Some bacteria are among those that can reduce the thiosulfate anion to sulfide, using the thiosulfate as an electron acceptor to create an iron sulfide precipitate, which appears black. Salmonella is one sulfide-producing bacteria.
Under anaerobic conditions (as occur toward the bottom of the tube) some bacteria use H+ as an electron acceptor and reduce it to hydrogen gas. This is not very soluble and may accumulate as bubbles along the inoculation track, between the agar and the glass, or in the fluid which accumulates at the bottom of the slant. Hydrogen production may lift the agar from the butt of the tube or fracture the agar. Carbon dioxide, if produced, may not manifest as bubbles because it is far more soluble in the medium. | TSI slant
The Triple Sugar Iron or TSI test is a microbiological test roughly named for its ability to test microorganism's ability to ferment sugars and to utilize iron to produce hydrogen sulfide. It is often used in the selective identification of enteric bacteria including but not limited to Salmonella and Shigella.
# Composition
The TSI slant is a test tube which contains agar, a pH-sensitive dye (phenol red), high concentrations of lactose and sucrose, and a low concentration of glucose as well as sodium thiosulfate and ferric citrate. All of these ingredients are mixed together and allowed to solidify in the test tube at a slanted angle. The slanted shape of this medium provides an array of surfaces that are either exposed to oxygen-containing air in varying degrees (an aerobic environment) or not exposed to air (an anaerobic environment). TSI agar medium was developed based on Kligler's iron agar, which had been used for the determination of lactose fermentative bacteria, by addition of sucrose to be able to detect also sucrose fermentative bacteria.
# Interpretation of results
Bacteria which ferment any of the three sugars in the medium will produce byproducts. These byproducts are usually acids, which will change the color of the red pH-sensitive dye (phenol red) to a yellow color. Position of the color change distinguishes the acid production associated with glucose fermentation from the acidic byproducts of lactose or sucrose fermentation. Many bacteria that can ferment sugars in the anaerobic butt of the tube are enterobacteria.
Some bacteria are among those that can reduce the thiosulfate anion to sulfide, using the thiosulfate as an electron acceptor to create an iron sulfide precipitate, which appears black. Salmonella is one sulfide-producing bacteria.
Under anaerobic conditions (as occur toward the bottom of the tube) some bacteria use H+ as an electron acceptor and reduce it to hydrogen gas. This is not very soluble and may accumulate as bubbles along the inoculation track, between the agar and the glass, or in the fluid which accumulates at the bottom of the slant. Hydrogen production may lift the agar from the butt of the tube or fracture the agar. Carbon dioxide, if produced, may not manifest as bubbles because it is far more soluble in the medium.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/TSI | |
3bbb57717f2c9360e63784cf16a6c973e8a4412e | wikidoc | Tacticity | Tacticity
Tacticity (from Greek 'taktikos': of or relating to arrangement or order) is the relative stereochemistry of adjacent chiral centers within a macromolecule . The practical significance of tacticity rests in the link between tacticity and the physical properties of the polymer. The regularity of the macromolecular structure influences the degree to which it has rigid, crystalline long range order or flexible, amorphous long range disorder. Precise knowledge of tacticity of a polymer also helps understanding at what temperature a polymer melts, how soluble it is in a solvent and its mechanical properties.
A tactic macromolecule in the IUPAC definition is a macromolecule in which essentially all the configurational (repeating) units are identical. Tacticity is particularly significant in vinyl polymers of the type -H2C-CH(R)- where each repeating unit with a substituent R on one side of the polymer backbone is followed by the next repeating unit with the substituent on the same side as the previous one, the other side as the previous one or positioned randomly with respect to the previous one. In a hydrocarbon macromolecule with all carbon atoms making up the backbone in a tetrahedral molecular geometry, the zigzag backbone is in the paper plane with the substituents either sticking out of the paper or retreating into the paper. This projection is called the Natta projection after Giulio Natta. Monotactic macromolecules have one stereoisomeric atom per repeat unit, ditactic to n-tactic macromolecules have more than one stereoisomeric atom per unit.
# Describing tacticity
## Diads
Two adjacent structural units in a polymer molecule constitute a diad. If the diad consists of two identically oriented units, the diad is called a meso diad reflecting similar features as a meso compound. If the diad consists of units oriented in opposition, the diad is called a racemo diad as in a racemic compound. In the case of vinyl polymer molecules, a meso diad is one in which the substituent carbon chains are oriented on the same side of the polymer backbone.
## Triads
The stereochemistry of macromolecules can be defined even more precisely with the introduction of triads. An isotactic triad (mm) is made up of two adjacent meso diads, a syndiotactic triad (rr) consists of two adjacent racemo diads and a heterotactic triad (rm) is composed of a meso diad adjacent to a racemo diad. The mass fraction of isotactic (mm) triads is a common quantitative measure of tacticity.
When the stereochemistry of a macromolecule is considered to be a Bernoulli process, triad composition can be calculated from the probability of finding meso diads (Pm). When this probability is 0.25 then the probability of finding:
- an isotactic triad is Pm2 or 0.0625
- an heterotactic triad is 2Pm(1-Pm) or 0.375
- a syndiotactic triad is (1-Pm)2 or 0.5625
with a total probability of 1. Similar relationships with diads exist for tetrads.
## Tetrads, Pentads, etc.
The definition of tetrads and pentads introduce further sophistication and precision to defining tacticity, especially when information on long-range ordering is desirable. Tacticity measurements obtained by Carbon-13 NMR are typically expressed in terms of the relative abundance of various pentads within the polymer molecule, e.g. mmmm, mrrm.
## Other conventions for quantifying tacticity
The primary convention for expressing tacticity is in terms of the relative weight fraction of triad or higher-order components, as described above. An alternative expression for tacticity is the average length of meso and racemo sequences within the polymer molecule. The average meso sequence length may be approximated from the relative abundance of pentads as follows:
MSL = \frac{mmmm+ \tfrac{3}{2} mrrr + 2 rmmr + \tfrac{1}{2} rmrm + \tfrac{1}{2} rmrr}{\tfrac{1}{2} mmmr + rmmr + \tfrac{1}{2}rmrm + \tfrac{1}{2}rmrr}
# Isotactic Polymers
Isotactic polymers are composed of isotactic macromolecules (IUPAC definition). In isotactic macromolecules all the substituents are located on the same side of the macromolecular backbone. An isotactic macromolecule consists of 100% meso diads. Polypropylene formed by Ziegler-Natta catalysis is an isotactic polymer. Isotactic polymers are usually semicrystalline and often form a helix configuration.
# Syndiotactic polymers
In syndiotactic or syntactic macromolecules the substituents have alternate positions along the chain. The macromolecule consists 100% of racemo diads. Syndiotactic polystyrene, made by metallocene catalysis polymerisation, is crystalline with a melting point of 270 °C.
# Atactic polymers
In atactic macromolecules the substituents are placed randomly along the chain. The percentage of meso diads is between 1 and 99%. With the aid of spectroscopic techniques such as NMR it is possible to pinpoint the composition of a polymer in terms of the percentages for each triad.
Polymers that are formed by free-radical mechanisms such as polyvinylchloride are usually atactic. Due to their random nature atactic polymers are usually amorphous. In hemiisotactic macromolecules every other repeat unit has a random substituent.
# Head/tail configuration
In vinyl polymers the complete configuration can be further described by defining polymer head/tail configuration. In a regular macromolecule all monomer units are normally linked in a head to tail configuration so that all β-substituents are separated by three carbon atoms. In head to head configuration this separation is only by 2 carbon atoms and the separation with tail to tail configuration is by 4 atoms. Head/tail configurations are not part of polymer tacticity but should be taken into account when considering polymer defects.
# Techniques for measuring tacticity
Tacticity may be measured directly using proton and carbon-13 nuclear magnetic resonance, especially two-dimensional techniques. NMR techniques enable a quantitative assignment of degree of tacticity by quantifying the relative abundance of diad, triad, and higher order polymer subunits (%rr, %mm, %mrm etc.). Other techniques sensitive to tacticity include x-ray powder diffraction, secondary ion mass spectroscopy (SIMS) and vibrational spectroscopy. Tacticity may also be inferred by measuring another physical property, such as melting temperature, when the relationship between tacticity and that property is well-established. | Tacticity
Tacticity (from Greek 'taktikos': of or relating to arrangement or order) is the relative stereochemistry of adjacent chiral centers within a macromolecule [1]. The practical significance of tacticity rests in the link between tacticity and the physical properties of the polymer. The regularity of the macromolecular structure influences the degree to which it has rigid, crystalline long range order or flexible, amorphous long range disorder. Precise knowledge of tacticity of a polymer also helps understanding at what temperature a polymer melts, how soluble it is in a solvent and its mechanical properties.
A tactic macromolecule in the IUPAC definition is a macromolecule in which essentially all the configurational (repeating) units are identical. Tacticity is particularly significant in vinyl polymers of the type -H2C-CH(R)- where each repeating unit with a substituent R on one side of the polymer backbone is followed by the next repeating unit with the substituent on the same side as the previous one, the other side as the previous one or positioned randomly with respect to the previous one. In a hydrocarbon macromolecule with all carbon atoms making up the backbone in a tetrahedral molecular geometry, the zigzag backbone is in the paper plane with the substituents either sticking out of the paper or retreating into the paper. This projection is called the Natta projection after Giulio Natta. Monotactic macromolecules have one stereoisomeric atom per repeat unit, ditactic to n-tactic macromolecules have more than one stereoisomeric atom per unit.
# Describing tacticity
## Diads
Two adjacent structural units in a polymer molecule constitute a diad. If the diad consists of two identically oriented units, the diad is called a meso diad reflecting similar features as a meso compound. If the diad consists of units oriented in opposition, the diad is called a racemo diad as in a racemic compound. In the case of vinyl polymer molecules, a meso diad is one in which the substituent carbon chains are oriented on the same side of the polymer backbone.
## Triads
The stereochemistry of macromolecules can be defined even more precisely with the introduction of triads. An isotactic triad (mm) is made up of two adjacent meso diads, a syndiotactic triad (rr) consists of two adjacent racemo diads and a heterotactic triad (rm) is composed of a meso diad adjacent to a racemo diad. The mass fraction of isotactic (mm) triads is a common quantitative measure of tacticity.
When the stereochemistry of a macromolecule is considered to be a Bernoulli process, triad composition can be calculated from the probability of finding meso diads (Pm). When this probability is 0.25 then the probability of finding:
- an isotactic triad is Pm2 or 0.0625
- an heterotactic triad is 2Pm(1-Pm) or 0.375
- a syndiotactic triad is (1-Pm)2 or 0.5625
with a total probability of 1. Similar relationships with diads exist for tetrads.
## Tetrads, Pentads, etc.
The definition of tetrads and pentads introduce further sophistication and precision to defining tacticity, especially when information on long-range ordering is desirable. Tacticity measurements obtained by Carbon-13 NMR are typically expressed in terms of the relative abundance of various pentads within the polymer molecule, e.g. mmmm, mrrm.
## Other conventions for quantifying tacticity
The primary convention for expressing tacticity is in terms of the relative weight fraction of triad or higher-order components, as described above. An alternative expression for tacticity is the average length of meso and racemo sequences within the polymer molecule. The average meso sequence length may be approximated from the relative abundance of pentads as follows:[2]
<math>MSL = \frac{mmmm+ \tfrac{3}{2} mrrr + 2 rmmr + \tfrac{1}{2} rmrm + \tfrac{1}{2} rmrr}{\tfrac{1}{2} mmmr + rmmr + \tfrac{1}{2}rmrm + \tfrac{1}{2}rmrr}</math>
# Isotactic Polymers
Isotactic polymers are composed of isotactic macromolecules (IUPAC definition). In isotactic macromolecules all the substituents are located on the same side of the macromolecular backbone. An isotactic macromolecule consists of 100% meso diads. Polypropylene formed by Ziegler-Natta catalysis is an isotactic polymer.[citation needed] Isotactic polymers are usually semicrystalline and often form a helix configuration.
# Syndiotactic polymers
In syndiotactic or syntactic macromolecules the substituents have alternate positions along the chain. The macromolecule consists 100% of racemo diads. Syndiotactic polystyrene, made by metallocene catalysis polymerisation, is crystalline with a melting point of 270 °C.[citation needed]
# Atactic polymers
In atactic macromolecules the substituents are placed randomly along the chain. The percentage of meso diads is between 1 and 99%. With the aid of spectroscopic techniques such as NMR it is possible to pinpoint the composition of a polymer in terms of the percentages for each triad.[citation needed]
Polymers that are formed by free-radical mechanisms such as polyvinylchloride are usually atactic. Due to their random nature atactic polymers are usually amorphous. In hemiisotactic macromolecules every other repeat unit has a random substituent.
# Head/tail configuration
In vinyl polymers the complete configuration can be further described by defining polymer head/tail configuration. In a regular macromolecule all monomer units are normally linked in a head to tail configuration so that all β-substituents are separated by three carbon atoms. In head to head configuration this separation is only by 2 carbon atoms and the separation with tail to tail configuration is by 4 atoms. Head/tail configurations are not part of polymer tacticity but should be taken into account when considering polymer defects.
# Techniques for measuring tacticity
Tacticity may be measured directly using proton and carbon-13 nuclear magnetic resonance, especially two-dimensional techniques.[3] NMR techniques enable a quantitative assignment of degree of tacticity by quantifying the relative abundance of diad, triad, and higher order polymer subunits (%rr, %mm, %mrm etc.). Other techniques sensitive to tacticity include x-ray powder diffraction, secondary ion mass spectroscopy (SIMS)[4] and vibrational spectroscopy. Tacticity may also be inferred by measuring another physical property, such as melting temperature, when the relationship between tacticity and that property is well-established.
# External links
- Tacticity @ Ecole Polytechnique Fédérale de Lausanne [1] [2]
- IUPAC macromolecular glossary [3]
- Application of spectroscopy in polymer charactisation & UCLA Los Angeles [4] | https://www.wikidoc.org/index.php/Tacticity | |
edbf24b834590cfdc998c7ea228b0014e81a862d | wikidoc | Tafamidis | Tafamidis
# Overview
Tafamidis (INN, or Fx-1006A, trade name Vyndaqel) is a drug for the amelioration of transthyretin-related hereditary amyloidosis (also familial amyloid polyneuropathy, or FAP), a rare but deadly neurodegenerative disease. The drug was approved by the European Medicines Agency in November 2011 and by the Japanese Pharmaceuticals and Medical Devices Agency in September 2013.
The marketed drug, a meglumine salt, has completed an 18 month placebo controlled phase II/III clinical trial, and an 12 month extension study which provides evidence that tafamidis slows progression of Familial amyloid polyneuropathy. Tafamidis (20 mg once daily) is used in adult patients with an early stage (stage 1) of familial amyloidotic polyneuropathy.
Tafamidis was discovered in the Jeffery W. Kelly Laboratory at The Scripps Research Institute using a structure-based drug design strategy and was developed at FoldRx pharmaceuticals, a biotechnology company Kelly co-founded with Susan Lindquist. FoldRx was led by Richard Labaudiniere when it was acquired by Pfizer in 2010.
Tafamidis functions by kinetic stabilization of the correctly folded tetrameric form of the transthyretin (TTR) protein. In patients with FAP, this protein dissociates in a process that is rate limiting for aggregation including amyloid fibril formation, causing failure of the autonomic nervous system and/or the peripheral nervous system (neurodegeneration) initially and later failure of the heart. Kinetic Stabilization of tetrameric transthyretin in familial amyloid polyneuropathy patients provides the first pharmacologic evidence that the process of amyloid fibril formation causes this disease, as treatment with tafamidis dramatically slows the process of amyloid fibril formation and the degeneration of post-mitotic tissue. Sixty % of the patients enrolled in the initial clinical trial have the same or an improved neurologic impairment score after six years of taking tafamidis, whereas 30% of the patients progress at a rate ≤ 1/5 of that predicted by the natural history. Importantly, all of the V30M FAP patients remain stage 1 patients after 6 years on tafamidis out of four stages of disease progression.
The process of wild type transthyretin amyloidogenesis also appears to cause senile systemic amyloidosis leading to cardiomyopathy as the prominent phenotype Some mutants of transthyretin, including V122I primarily found in individuals of African descent, are destabilizing enabling heterotetramer dissociation, monomer misfolding, and subsequent misassembly of transthyretin into a variety of aggregate structures including amyloid fibrils leading to familial amyloid cardiomyopathy. While there is clinical evidence from a small number of patients that tafamidis slows the progression of the transthyretin cardiomyopathies, this has yet to be demonstrated in a placebo controlled clinical trial. Pfizer is currently enrolling a placebo-controlled clinical trial to evaluate the ability of tafamidis to slow the progression of familial amyloid cardiomyopathy (mutant and wild type TTR aggregation) and senile systemic amyloidosis, a cardiomyopathy caused by the aggregation of wild type TTR (ClinicalTrials.gov identifier: NCT01994889).
# Regulatory Process
Tafamidis was approved for use in Europe by the European Medicines Agency in November 2011, specifically for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). In September 2013 Tafamidis was approved for use in Japan by the Pharmaceuticals and Medical Devices Agency, specifically for the treatment of transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). Tafamidis is also approved for use in Argentina and Mexico by the relevant authorities. It is currently being considered for approval by the United States Food and Drug Administration (FDA) for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP.
In June 2012, the FDA Peripheral and Central Nervous System Drugs Advisory Committee voted “yes” (13-4 favorable vote) when asked if the findings of the pivotal clinical
study with tafamidis were “sufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefit”. The Advisory Committee voted "no" 4-13 to reject the drug–both primary endpoints were met in the efficacy evaluable population (n=87) and were just missed in the intent to treat population (n=125), apparently because more patients than expected in the intent to treat population were selected for liver transplantation during the course of the trial, not owing to treatment failure, but because their name rose to the top of the transplant list. However, these patients were classified as treatment failures in the conservative analysis used. | Tafamidis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tafamidis (INN, or Fx-1006A,[1] trade name Vyndaqel) is a drug for the amelioration of transthyretin-related hereditary amyloidosis (also familial amyloid polyneuropathy, or FAP), a rare but deadly neurodegenerative disease.[2][3] The drug was approved by the European Medicines Agency in November 2011 and by the Japanese Pharmaceuticals and Medical Devices Agency in September 2013.[4]
The marketed drug, a meglumine salt, has completed an 18 month placebo controlled phase II/III clinical trial,[5][6] and an 12 month extension study which provides evidence that tafamidis slows progression of Familial amyloid polyneuropathy.[7] Tafamidis (20 mg once daily) is used in adult patients with an early stage (stage 1) of familial amyloidotic polyneuropathy.[8][9]
Tafamidis was discovered in the Jeffery W. Kelly Laboratory at The Scripps Research Institute[10] using a structure-based drug design strategy[11] and was developed at FoldRx pharmaceuticals, a biotechnology company Kelly co-founded with Susan Lindquist. FoldRx was led by Richard Labaudiniere when it was acquired by Pfizer in 2010.
Tafamidis functions by kinetic stabilization of the correctly folded tetrameric form of the transthyretin (TTR) protein.[12] In patients with FAP, this protein dissociates in a process that is rate limiting for aggregation including amyloid fibril formation, causing failure of the autonomic nervous system and/or the peripheral nervous system (neurodegeneration) initially and later failure of the heart. Kinetic Stabilization of tetrameric transthyretin in familial amyloid polyneuropathy patients provides the first pharmacologic evidence that the process of amyloid fibril formation causes this disease, as treatment with tafamidis dramatically slows the process of amyloid fibril formation and the degeneration of post-mitotic tissue. Sixty % of the patients enrolled in the initial clinical trial have the same or an improved neurologic impairment score after six years of taking tafamidis, whereas 30% of the patients progress at a rate ≤ 1/5 of that predicted by the natural history. Importantly, all of the V30M FAP patients remain stage 1 patients after 6 years on tafamidis out of four stages of disease progression. [Data presented orally by Professor Coelho in Brazil in 2013][7]
The process of wild type transthyretin amyloidogenesis also appears to cause senile systemic amyloidosis leading to cardiomyopathy as the prominent phenotype [13] Some mutants of transthyretin, including V122I primarily found in individuals of African descent, are destabilizing enabling heterotetramer dissociation, monomer misfolding, and subsequent misassembly of transthyretin into a variety of aggregate structures [14] including amyloid fibrils[15] leading to familial amyloid cardiomyopathy.[16] While there is clinical evidence from a small number of patients that tafamidis slows the progression of the transthyretin cardiomyopathies, this has yet to be demonstrated in a placebo controlled clinical trial. Pfizer is currently enrolling a placebo-controlled clinical trial to evaluate the ability of tafamidis to slow the progression of familial amyloid cardiomyopathy (mutant and wild type TTR aggregation) and senile systemic amyloidosis, a cardiomyopathy caused by the aggregation of wild type TTR (ClinicalTrials.gov identifier: NCT01994889).
# Regulatory Process
Tafamidis was approved for use in Europe by the European Medicines Agency in November 2011, specifically for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). In September 2013 Tafamidis was approved for use in Japan by the Pharmaceuticals and Medical Devices Agency, specifically for the treatment of transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). Tafamidis is also approved for use in Argentina and Mexico by the relevant authorities. It is currently being considered for approval by the United States Food and Drug Administration (FDA) for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP.
In June 2012, the FDA Peripheral and Central Nervous System Drugs Advisory Committee voted “yes” (13-4 favorable vote) when asked if the findings of the pivotal clinical
study with tafamidis were “sufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefit”. The Advisory Committee voted "no" 4-13 to reject the drug–both primary endpoints were met in the efficacy evaluable population (n=87) and were just missed in the intent to treat population (n=125), apparently because more patients than expected in the intent to treat population were selected for liver transplantation during the course of the trial, not owing to treatment failure, but because their name rose to the top of the transplant list. However, these patients were classified as treatment failures in the conservative analysis used. | https://www.wikidoc.org/index.php/Tafamidis | |
465f6ba136a6271245db378192d3c9d52ef0f267 | wikidoc | Talk page | Talk page
JUPITER Crestor 20mg Versus Placebo in Prevention of Cardiovascular (CV) Events
Purpose
The purpose of this study is to determine the safety and effectiveness of long-term therapy with rosuvastatin compared with a placebo, and to evaluate whether treatment with rosuvastatin might be effective in reducing the risk of major cardiovascular events.
Condition
Elevated hs C-Reactive Protein
Intervention
Drug: Rosuvastatin
Phase
III
Study Type: Interventional
Study Design: Prevention, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study
Primary Outcome Measures:
Investigate whether long-term treatment with rosuvastatin compared with placebo will decrease the rate of major cardiovascular events
Secondary Outcome Measures:
Investigate the safety of long-term treatment with rosuvastatin compared with placebo through comparisons of total mortality, noncardiovascular mortality, & adverse events
Investigate whether therapy with rosuvastatin reduces the incidence of diabetes mellitus, venous thromboembolic events, & the incidence of bone fractures.
Estimated Enrollment: 15000
Study Start Date: February 2003
Study Completion Date: August 2008
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Detailed Description:
AstraZeneca announced it has decided to stop the CRESTOR JUPITER clinical study early based on a recommendation from an Independent Data Monitoring Board and the JUPITER Steering Committee, which met on March 29, 2008. The study will be stopped early because there is unequivocal evidence of a reduction in cardiovascular morbidity and mortality amongst patients who received CRESTOR when compared to placebo.
Eligibility
Ages Eligible for Study: 50 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Men 50 years or older, women 60 years or older
Low to normal levels of low density lipoprotein (LDL) cholesterol (< 130mg/dL)
Elevated levels of C-Reactive Protein (CRP) > 2.0 mg/L
Exclusion Criteria:
History of cardiovascular or cerebrovascular events
Active liver disease
Diabetes mellitus
Uncontrolled hypertension or hypothyroidism
History of certain malignancies
Chronic inflammatory conditions
History of alcohol or drug abuse
Methods We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.
Results The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval , 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.
Conclusions In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681 .) | Talk page
JUPITER Crestor 20mg Versus Placebo in Prevention of Cardiovascular (CV) Events
Purpose
The purpose of this study is to determine the safety and effectiveness of long-term therapy with rosuvastatin compared with a placebo, and to evaluate whether treatment with rosuvastatin might be effective in reducing the risk of major cardiovascular events.
Condition
Elevated hs C-Reactive Protein
Intervention
Drug: Rosuvastatin
Phase
III
Study Type: Interventional
Study Design: Prevention, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study
Primary Outcome Measures:
Investigate whether long-term treatment with rosuvastatin compared with placebo will decrease the rate of major cardiovascular events
Secondary Outcome Measures:
Investigate the safety of long-term treatment with rosuvastatin compared with placebo through comparisons of total mortality, noncardiovascular mortality, & adverse events
Investigate whether therapy with rosuvastatin reduces the incidence of diabetes mellitus, venous thromboembolic events, & the incidence of bone fractures.
Estimated Enrollment: 15000
Study Start Date: February 2003
Study Completion Date: August 2008
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Detailed Description:
AstraZeneca announced it has decided to stop the CRESTOR JUPITER clinical study early based on a recommendation from an Independent Data Monitoring Board and the JUPITER Steering Committee, which met on March 29, 2008. The study will be stopped early because there is unequivocal evidence of a reduction in cardiovascular morbidity and mortality amongst patients who received CRESTOR when compared to placebo.
Eligibility
Ages Eligible for Study: 50 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Men 50 years or older, women 60 years or older
Low to normal levels of low density lipoprotein (LDL) cholesterol (< 130mg/dL)
Elevated levels of C-Reactive Protein (CRP) > 2.0 mg/L
Exclusion Criteria:
History of cardiovascular or cerebrovascular events
Active liver disease
Diabetes mellitus
Uncontrolled hypertension or hypothyroidism
History of certain malignancies
Chronic inflammatory conditions
History of alcohol or drug abuse
Methods We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.
Results The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.
Conclusions In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681 [ClinicalTrials.gov] .) | https://www.wikidoc.org/index.php/Talk_page | |
61f87d8515c5fd3745bc9e984cbb9b43a9760223 | wikidoc | Tao Brush | Tao Brush
The Tao Brush is a medical instrument used to perform an alternative method of endometrial biopsy.
The traditional method of endometrial biopsies uses a specialized catheter (the Pipelle) to suction away a portion of the uterine lining. The Tao Brush method instead uses a small, flexible brush to gently brush the entire inside of the uterus. Thus, the Tao Brush is able to gather a more complete sampling of the uterus lining, removes less tissue, and is less painful than the traditional method.
# Early Detection
According to the American Cancer Society, endometrial cancer is the most common cancer of the female reproductive system. In 2007 there will be approximately 39,080 new cases. About 7,400 women in the United States will die of uterine cancer.
The vast majority of the cases (70%) were diagnosed in women between the ages of 45 and 74, with the highest number between 55 and 64. The proportion of women who will be diagnosed with endometrial cancer is 1 in 40. As with all cancers, those diagnosed at an early stage have a much higher survival rate. The Tao Brush biopsy is able to detect endometrial adenocarcinoma, which accounts for 97% of all endometrial cancers. Because the Tao Brush biopsy method is able to collect samples from the entire uterus without discomfort to the patient, it is an excellent method of early detection. Currently, it is the only available method.
# Procedure
The procedure for the Tao Brush biopsy is:
1. The patient will be asked to lay on the table will their feet in the stirrups as for a routine pelvic exam.
2. The brush will be inserted into the uterus. The covering sheath will protect the brush from collecting any contaminating tissue from the cervix.
3. Once the brush is in place, the sheath is removed.
4. The brush is then rotated 4-5 times, collecting tissue from the entire uterine lining.
5. The sheath is then replaced, ensuring that the tissue samples are trapped on the brush.
6. The brush is removed and placed directly in the fixative solution.
The entire procedure takes approximately 30 seconds and can be completed at the same time as a routine Pap Smear.
The sample will be ready for processing in about 30 minutes and can be stored for several weeks, allowing it to be transported to an offsite laboratory. Bostwick Laboratories, currently the only laboratory which processes Tao Brush biopsies, called the TruTest, usually reports the results of the test within 3 business days.
Along with early detection of endometrial cancer, the TruTest also test for Chlamydia, Gonorrhea and HPV. | Tao Brush
The Tao Brush is a medical instrument used to perform an alternative method of endometrial biopsy.
The traditional method of endometrial biopsies uses a specialized catheter (the Pipelle) to suction away a portion of the uterine lining. The Tao Brush method instead uses a small, flexible brush to gently brush the entire inside of the uterus. Thus, the Tao Brush is able to gather a more complete sampling of the uterus lining, removes less tissue, and is less painful than the traditional method.
# Early Detection
According to the American Cancer Society, endometrial cancer is the most common cancer of the female reproductive system. In 2007 there will be approximately 39,080 new cases. About 7,400 women in the United States will die of uterine cancer.
The vast majority of the cases (70%) were diagnosed in women between the ages of 45 and 74, with the highest number between 55 and 64. The proportion of women who will be diagnosed with endometrial cancer is 1 in 40. As with all cancers, those diagnosed at an early stage have a much higher survival rate. The Tao Brush biopsy is able to detect endometrial adenocarcinoma, which accounts for 97% of all endometrial cancers. [1] Because the Tao Brush biopsy method is able to collect samples from the entire uterus without discomfort to the patient, it is an excellent method of early detection. Currently, it is the only available method. [2]
# Procedure
The procedure for the Tao Brush biopsy is:
1. The patient will be asked to lay on the table will their feet in the stirrups as for a routine pelvic exam.
2. The brush will be inserted into the uterus. The covering sheath will protect the brush from collecting any contaminating tissue from the cervix.
3. Once the brush is in place, the sheath is removed.
4. The brush is then rotated 4-5 times, collecting tissue from the entire uterine lining.
5. The sheath is then replaced, ensuring that the tissue samples are trapped on the brush.
6. The brush is removed and placed directly in the fixative solution.
The entire procedure takes approximately 30 seconds and can be completed at the same time as a routine Pap Smear.
The sample will be ready for processing in about 30 minutes and can be stored for several weeks, allowing it to be transported to an offsite laboratory. Bostwick Laboratories, currently the only laboratory which processes Tao Brush biopsies, called the TruTest, usually reports the results of the test within 3 business days. [3]
Along with early detection of endometrial cancer, the TruTest also test for Chlamydia, Gonorrhea and HPV. | https://www.wikidoc.org/index.php/Tao_Brush | |
dee2a6811294caf0c9fbab7310a2920b494ed583 | wikidoc | Tolcapone | Tolcapone
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# Black Box Warning
# Overview
Tolcapone is a Catechol-O-Methyltransferase Inhibitor that is FDA approved for the treatment of signs and symptoms of idiopathic Parkinson's disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Dyskinesia, Nausea, Sleep Disorder , Anorexia , Diarrhea , urine discoloration, somnolence, hallucination, dystonia, and sweating.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- TASMAR is indicated as an adjunct to levodopa and carbidopa for the treatment of the signs and symptoms of idiopathic Parkinson's disease. Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies. Because of the risk of liver injury and because TASMAR, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR.
- The effectiveness of TASMAR was demonstrated in randomized controlled trials in patients receiving concomitant levodopa therapy with carbidopa or another aromatic amino acid decarboxylase inhibitor who experienced end of dose wearing-off phenomena as well as in patients who did not experience such phenomena
### Dosage
- Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies .
- BECAUSE OF THE RISK OF LIVER INJURY AND BECAUSE TASMAR WHEN IT IS EFFECTIVE PROVIDES AN OBSERVABLE SYMPTOMATIC BENEFIT, THE PATIENT WHO FAILS TO SHOW SUBSTANTIAL CLINICAL BENEFIT WITHIN 3 WEEKS OF INITIATION OF TREATMENT, SHOULD BE WITHDRAWN FROM TASMAR.
- TASMAR therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution.
- Patients who develop evidence of hepatocellular injury while on TASMAR and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR is reintroduced. These patients should not ordinarily be considered for retreatment with TASMAR.
- Only prescribe TASMAR for patients taking concomitant carbidopa levodopa therapy. The initial dose of TASMAR is always 100 mg three times per day. The recommended daily dose of TASMAR is also 100 mg tid. In clinical trials, elevations in ALT occurred more frequently at the dose of 200 mg tid. While it is unknown whether the risk of acute fulminant liver failure is increased at the 200-mg dose, it would be prudent to use 200 mg only if the anticipated incremental clinical benefit is justified. If a patient fails to show the expected incremental benefit on the 200-mg dose after a total of 3 weeks of treatment (regardless of dose), TASMAR should be discontinued.
- In clinical trials, the first dose of the day of TASMAR was always taken together with the first dose of the day of levodopa/carbidopa, and the subsequent doses of TASMAR were given approximately 6 and 12 hours later.
- In clinical trials, the majority of patients required a decrease in their daily levodopa dose if their daily dose of levodopa was >600 mg or if patients had moderate or severe dyskinesias before beginning treatment.
- To optimize an individual patient's response, reductions in daily levodopa dose may be necessary. In clinical trials, the average reduction in daily levodopa dose was about 30% in those patients requiring a levodopa dose reduction. (Greater than 70% of patients with levodopa doses above 600 mg daily required such a reduction.)
- TASMAR can be combined with both the immediate and sustained release formulations of levodopa/carbidopa.
- TASMAR may be taken with or without food .
- TASMAR therapy should not be initiated if any patient with liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal.
- No dose adjustment of TASMAR is recommended for patients with mild to moderate renal impairment. However, patients with severe renal impairment should be treated with caution. The safety of tolcapone has not been examined in subjects who had creatinine clearance less than 25 mL/min.
- As with any dopaminergic drug, withdrawal or abrupt reduction in the TASMAR dose may lead to emergence of signs and symptoms of Parkinson's disease or Hyperpyrexia and Confusion, a syndrome complex resembling the neuroleptic malignant syndrome. If a decision is made to discontinue treatment with TASMAR, then it is recommended to closely monitor the patient and adjust other dopaminergic treatments as needed. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. Tapering TASMAR has not been systematically evaluated. As the duration of COMT inhibition with TASMAR is generally 5 to 6 hours on average, decreasing the frequency of dosage to twice or once a day may not in itself prevent withdrawal effects.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tolcapone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolcapone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tolcapone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tolcapone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolcapone in pediatric patients.
# Contraindications
- TASMAR tablets are contraindicated in patients with liver disease, in patients who were withdrawn from TASMAR because of evidence of TASMAR-induced hepatocellular injury or who have demonstrated hypersensitivity to the drug or its ingredients.
TASMAR is also contraindicated in patients with a history of nontraumatic rhabdomyolysis or hyperpyrexia and confusion possibly related to medication
# Warnings
- Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies (see INDICATIONS and DOSAGE AND ADMINISTRATION sections).
- Because of the risk of liver injury and because TASMAR, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR.
- TASMAR therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution.
- Patients who develop evidence of hepatocellular injury while on TASMAR and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR is reintroduced. Accordingly, such patients should not ordinarily be considered for retreatment.
- In controlled Phase 3 trials, increases to more than 3 times the upper limit of normal in ALT or AST occurred in approximately 1% of patients at 100 mg tid and 3% of patients at 200 mg tid. Females were more likely than males to have an increase in liver enzymes (approximately 5% vs 2%). Approximately one third of patients with elevated enzymes had diarrhea. Increases to more than 8 times the upper limit of normal in liver enzymes occurred in 0.3% at 100 mg tid and 0.7% at 200 mg tid. Elevated enzymes led to discontinuation in 0.3% and 1.7% of patients treated with 100 mg tid and 200 mg tid, respectively. Elevations usually occurred within 6 weeks to 6 months of starting treatment. In about half the cases with elevated liver enzymes, enzyme levels returned to baseline values within 1 to 3 months while patients continued TASMAR treatment. When treatment was discontinued, enzymes generally declined within 2 to 3 weeks but in some cases took as long as 1 to 2 months to return to normal.
- Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of TASMAR and a non-selective MAO inhibitor (eg, phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. For this reason, patients should ordinarily not be treated concomitantly with TASMAR and a non-selective MAO inhibitor.
- Tolcapone can be taken concomitantly with a selective MAO-B inhibitor (eg, selegiline).
- Tolcapone (TASMAR) increases plasma levels of levodopa in patients taking concomitant carbidopa levodopa products. Patients taking carbidopa levodopa products alone or with other dopaminergic medications have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes the operation of motor vehicles). Some of these episodes resulted in automobile accidents. Although many of these patients reported somnolence while on TASMAR, some did perceive that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some patients reported these events one year after the initiation of treatment.
- The risk for somnolence was increased with TASMAR treatment (TASMAR 100 mg-18 %, 200 mg-14%, vs placebo-13%) compared to placebo treatment. In clinical trials, discontinuation due to somnolence occurred in 1% of patients treated with 200 mg TASMAR and 0% of patients treated with 100 mg TASMAR or placebo. Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre-existing somnolence, although some patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with TASMAR.
- Before initiating treatment with TASMAR, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with TASMAR such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing TASMAR in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with TASMAR continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
### Precautions
- Dopaminergic therapy in Parkinson's disease patients has been associated with orthostatic hypotension. Tolcapone enhances levodopa bioavailability and, therefore, may increase the occurrence of orthostatic hypotension. In TASMAR clinical trials, orthostatic hypotension was documented at least once in 8%, 14% and 13% of the patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively. A total of 2%, 5% and 4% of the patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively, reported orthostatic symptoms at some time during their treatment and also had at least one episode of orthostatic hypotension documented (however, the episode of orthostatic symptoms itself was invariably not accompanied by vital sign measurements). Patients with orthostasis at baseline were more likely than patients without symptoms to have orthostatic hypotension during the study, irrespective of treatment group. In addition, the effect was greater in tolcapone-treated patients than in placebo-treated patients. Baseline treatment with dopamine agonists or selegiline did not appear to increase the likelihood of experiencing orthostatic hypotension when treated with TASMAR. Approximately 0.7% of the patients treated with TASMAR (5% of patients who were documented to have had at least one episode of orthostatic hypotension) eventually withdrew from treatment due to adverse events presumably related to hypotension.
- In controlled Phase 3 trials, approximately 5%, 4% and 3% of tolcapone 200 mg tid, 100 mg tid and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in all three treatment groups who had an episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement) compared to patients who did not have any episodes of documented hypotension.
- In clinical trials, diarrhea developed in approximately 8%, 16% and 18% of patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively. While diarrhea was generally regarded as mild to moderate in severity, approximately 3% to 4% of patients on tolcapone had diarrhea which was regarded as severe. Diarrhea was the adverse event which most commonly led to discontinuation, with approximately 1%, 5% and 6% of patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively, withdrawing from the trials prematurely. Discontinuing TASMAR for diarrhea was related to the severity of the symptom. Diarrhea resulted in withdrawal in approximately 8%, 40% and 70% of patients with mild, moderate and severe diarrhea, respectively. Although diarrhea generally resolved after discontinuation of TASMAR, it led to hospitalization in 0.3%, 0.7% and 1.7% of patients in the placebo, 100 mg and 200 mg TASMAR tid groups.
- Typically, diarrhea presents 6 to 12 weeks after tolcapone is started, but it may appear as early as 2 weeks and as late as many months after the initiation of treatment. Clinical trial data suggested that diarrhea associated with tolcapone use may sometimes be associated with anorexia (decreased appetite).
- No consistent description of tolcapone-induced diarrhea has been derived from clinical trial data, and the mechanism of action is currently unknown.
- It is recommended that all cases of persistent diarrhea should be followed up with an appropriate work-up (including occult blood samples).
- In clinical trials, hallucinations developed in approximately 5% of patients treated with placebo, compared to 8% and 10% of patients treated with 100 mg or 200 mg three times per day, respectively. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.3% of patients treated with placebo, compared to 1.4% and 1.0% of patients treated with TASMAR 100 mg or 200 mg TASMAR three times per day, respectively. Hallucinations led to hospitalization in 0.0% of patients in the placebo group, compared to 1.7% and 0.0% of patients treated with 100 mg or 200 mg TASMAR three times per day, respectively.
- In general, hallucinations present shortly after the initiation of therapy with tolcapone (typically within the first 2 weeks). Clinical trial data suggest that hallucinations associated with tolcapone use may be responsive to levodopa dose reduction. Patients whose hallucinations resolved had a mean levodopa dose reduction of 175 mg to 200 mg (20% to 25%) after the onset of the hallucinations. Hallucinations were commonly accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming. The incidence of hallucination may be increased in elderly patients over 75 years treated with TASMAR.
- Post-marketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during TASMAR treatment or after starting or increasing the dose of TASMAR. Other drugs prescribed to improve the symptoms of Parkinson’s disease may have similar effects on thinking and behavior. This abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
- Ordinarily, patients with a major psychotic disorder should not be treated with TASMAR because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of TASMAR.
- TASMAR may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. Dyskinesia was the most common adverse reaction observed in controlled trials and developed in approximately 20% of patients treated with placebo, compared to 42% and 51% of patients treated with TASMAR 100 mg or 200 mg three times daily, respectively. The rates of withdrawal for dyskinesia were 0.0% in the placebo group, compared to 0.3% and 1.0% in the groups receiving TASMAR 100 mg or 200 mg three times a day, respectively.
- Reports suggest that patients may experience an intense urge to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges. These reports are associated with patients taking TASMAR in conjunction with carbidopa/levodopa, as well as other medications that increase central dopaminergic tone and that are used to treat patients with Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with TASMAR. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking TASMAR .
- Cases of severe rhabdomyolysis, with one case of multiorgan system failure rapidly progressing to death, have been reported. The complicated nature of these cases makes it impossible to determine what role, if any, TASMAR played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. Some cases, however, included fever, alteration of consciousness and muscular rigidity. It is possible, therefore, that the rhabdomyolysis may be a result of the syndrome described in Hyperpyrexia and Confusion.
- No dosage adjustment is needed in patients with mild to moderate renal impairment, however, patients with severe renal impairment should be treated with caution.
- When rats were dosed daily for 1 or 2 years (exposures 6 times the human exposure or greater) there was a high incidence of proximal tubule cell damage consisting of degeneration, single cell necrosis, hyperplasia, karyocytomegaly and atypical nuclei. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although it has been speculated that these toxicities may occur as the result of a species-specific mechanism, experiments which would confirm that theory have not been conducted.
- Because of the risk of liver injury, TASMAR therapy should not be initiated in any patient with liver disease. For similar reasons, treatment should not be initiated in patients who have two SGPT/ALT or SGOT/AST values greater than the upper limit of normal or any other evidence of hepatocellular dysfunction.
- The rates of hematuria in placebo-controlled trials were approximately 2%, 4% and 5% in placebo, 100 mg and 200 mg TASMAR tid, respectively. The etiology of the increase with TASMAR has not always been explained (for example, by urinary tract infection or coumadin therapy). In placebo-controlled trials in the United States (N=593) rates of microscopically confirmed hematuria were approximately 3%, 2% and 2% in placebo, 100 mg and 200 mg TASMAR tid, respectively.
- The events listed below are known to be associated with the use of drugs that increase dopaminergic activity, although they are most often associated with the use of direct dopamine agonists. While cases of Hyperpyrexia and Confusion have been reported in association with tolcapone withdrawal (see paragraph below), the expected incidence of fibrotic complications is so low that even if tolcapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that even a single example would have been detected in a cohort of the size exposed to tolcapone.
- In clinical trials, four cases of a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, and altered consciousness), similar to that reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs, have been reported in association with the abrupt withdrawal or lowering of the dose of tolcapone. In 3 of these cases, CPK was elevated as well. One patient died, and the other 3 patients recovered over periods of approximately 2, 4 and 6 weeks. Rare cases of this symptom complex have been reported during marketed use. It is difficult to determine if TASMAR played a role in the pathogenesis of these events because these patients received several concomitant medications affecting the central nervous system such as monoaminergic (i.e., MAO-I, tricyclic and selective serotonin reuptake inhibitors) and anticholinergic agents.
- Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived drugs (eg, tolcapone) that increase dopaminergic activity can cause them is unknown.
- Three cases of pleural effusion, one with pulmonary fibrosis, occurred during clinical trials. These patients were also on concomitant dopamine agonists (pergolide or bromocriptine) and had a prior history of cardiac disease or pulmonary pathology (nonmalignant lung lesion).
- Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using TASMAR for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).
# Adverse Reactions
## Clinical Trials Experience
- Cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in postmarketing use. As of May 2005, 3 cases of fatal fulminant hepatic failure have been reported from more than 40,000 patient years of worldwide use. This incidence may be 10- to 100-fold higher than the background incidence in the general population. All 3 cases were reported within the first six months of initiation of treatment with TASMAR. Analysis of the laboratory monitoring data in over 3,400 TASMAR-treated patients participating in clinical trials indicated that increases in SGPT/ALT or SGOT/AST, when present, generally occurred within the first 6 months of treatment with TASMAR.
- The imprecision of the estimated increase is due to uncertainties about the base rate and the actual number of cases occurring in association with TASMAR. The incidence of idiopathic potentially fatal fulminant hepatic failure (ie, not due to viral hepatitis or alcohol) is low. One estimate, based upon transplant registry data, is approximately 3/1,000,000 patients per year in the United States. Whether this estimate is an appropriate basis for estimating the increased risk of liver failure among TASMAR users is uncertain. TASMAR users, for example, differ in age and general health status from candidates for liver transplantation. Similarly, underreporting of cases may lead to significant underestimation of the increased risk associated with the use of TASMAR.
- During the premarketing development of tolcapone, two distinct patient populations were studied, patients with end-of-dose wearing-off phenomena and patients with stable responses to levodopa therapy. All patients received concomitant treatment with levodopa preparations, however, and were similar in other clinical aspects. Adverse events are, therefore, shown for these two populations combined.
- The most commonly observed adverse reactions in the double-blind, placebo-controlled trials (N=892), with a difference in incidence (TASMAR minus Placebo) of at least 5 % or greater in the 100 mg or 200 mg TASMAR- treated groups compared to placebo, were dyskinesia, nausea, diarrhea, anorexia, sleep disorder, vomiting, urine discoloration, somnolence, hallucination, dystonia, and sweating.
- Approximately 16% of the 592 patients who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse reactions compared to 10% of the 298 patients who received placebo. Diarrhea was by far the most frequent cause of discontinuation (approximately 6% in tolcapone patients vs. 1% on placebo).
- Table 4 lists treatment emergent adverse reactions that occurred in at least 1% of patients treated with tolcapone participating in the double-blind, placebo-controlled studies and were numerically more common in at least one of the tolcapone groups. In these studies, either tolcapone or placebo was added to levodopa/carbidopa (or benserazide).
- The prescriber should be aware that these figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence rate in the population studied.
- Female patients may be more likely to develop somnolence than males.
- During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of adverse events were grouped into a smaller number of standardized categories using COSTART dictionary terminology.These categories are used in the listing below.
- All reported events that occurred at least twice (or once for serious or potentially serious events), except those already listed above, trivial events and terms too vague to be meaningful are included, without regard to determination of a causal relationship to TASMAR.
- Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are defined as those occurring in between 1/100 and 1/1000 patients; and rare adverse events are defined as those occurring in fewer than 1/1000 patients.
- frequent: depression, hypesthesia, tremor, speech disorder, vertigo, emotional lability; infrequent: neuralgia, amnesia, extrapyramidal syndrome, hostility, libido increased, manic reaction, nervousness, paranoid reaction, cerebral ischemia, cerebrovascular accident, delusions, libido decreased, neuropathy, apathy, choreoathetosis, myoclonus, psychosis, abnormal thinking, twitching; rare: antisocial reaction, delirium, encephalopathy, hemiplegia, meningitis.
- frequent: tooth disorder; infrequent: dysphagia, gastrointestinal hemorrhage, gastroenteritis, mouth ulceration, increased salivation, abnormal stools, esophagitis, cholelithiasis, colitis, tongue disorder, rectal disorder; rare: cholecystitis, duodenal ulcer, gastrointestinal carcinoma, stomach atony.
- frequent: flank pain, accidental injury, abdominal pain, infection; infrequent: hernia, pain, allergic reaction, cellulitis, fungal infection, viral infection, carcinoma, chills, bacterial infection, neoplasm, abscess, face edema; rare: death.
- frequent: palpitation; infrequent: hypertension, vasodilation, angina pectoris, heart failure, atrial fibrillation, tachycardia, migraine, aortic stenosis, arrhythmia, arteriospasm, bradycardia, cerebral hemorrhage, coronary artery disorder, heart arrest, myocardial infarct, myocardial ischemia, pulmonary embolus; rare: arteriosclerosis, cardiovascular disorder, pericardial effusion, thrombosis.
- frequent: myalgia; infrequent: tenosynovitis, arthrosis, joint disorder.
- frequent: urinary incontinence, impotence; infrequent: prostatic disorder, dysuria, nocturia, polyuria, urinary retention, urinary tract disorder, hematuria, kidney calculus, prostatic carcinoma, breast neoplasm, oliguria, uterine atony, uterine disorder, vaginitis; rare: bladder calculus, ovarian carcinoma, uterine hemorrhage.
- frequent: bronchitis, pharyngitis; infrequent: increased cough , rhinitis, asthma, epistaxis, hyperventilation, laryngitis, hiccup; rare: apnea, hypoxia, lung edema.
- frequent: rash; infrequent: herpes zoster, pruritus, seborrhea, skin discoloration, eczema, erythema multiforme, skin disorder, furunculosis, herpes simplex, urticaria.
- frequent: tinnitus; infrequent: diplopia, ear pain, eye hemorrhage, eye pain, lacrimation disorder, otitis media, parosmia; rare: glaucoma.
- infrequent: edema, hypercholesteremia, thirst, dehydration.
- infrequent: anemia; rare: leukemia, thrombocytopenia.
- infrequent: diabetes mellitus.
- infrequent: surgical procedure
- Tolcapone is not a controlled substance.
- Studies conducted in rats and monkeys did not reveal any potential for physical or psychological dependence. Although clinical trials have not revealed any evidence of the potential for abuse, tolerance or physical dependence, systematic studies in humans designed to evaluate these effects have not been performed.
- Although a program of frequent laboratory monitoring for evidence of hepatocellular injury is deemed essential, it is not clear that periodic monitoring of liver enzymes will prevent the occurrence of fulminant liver failure. However, it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. Accordingly, the following liver monitoring program is recommended.
- Before starting treatment with TASMAR, the physician should conduct appropriate tests to exclude the presence of liver disease. In patients determined to be appropriate candidates for treatment with TASMAR, serum glutamic-pyruvic transaminase (SGPT/ALT) and serum glutamic-oxaloacetic transaminase (SGOT/AST) levels should be determined at baseline and periodically (i.e. every 2 to 4 weeks) for the first 6 months of therapy. After the first six months, periodic monitoring is recommended at intervals deemed clinically relevant. Although more frequent monitoring increases the chances of early detection, the precise schedule for monitoring is a matter of clinical judgement.
- If the dose is increased to 200 mg tid, liver enzyme monitoring should take place before increasing the dose and then be conducted every 2 to 4 weeks for the following 6 months of therapy. After six months, periodic monitoring is recommended at intervals deemed clinically relevant.
- Discontinue TASMAR if SGPT/ALT or SGOT/AST levels exceed 2 times the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic dysfunction (e.g., persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness).
## Postmarketing Experience
- Cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in postmarketing use.
# Drug Interactions
- Although tolcapone is highly protein bound, in vitro studies have shown that tolcapone at a concentration of 50 µg/mL did not displace other highly protein-bound drugs from their binding sites at therapeutic concentrations. The experiments included warfarin (0.5 to 7.2 µg/mL), phenytoin (4.0 to 38.7 µg/mL), tolbutamide (24.5 to 96.1 µg/mL) and digitoxin (9.0 to 27.0 µg/mL).
- Tolcapone may influence the pharmacokinetics of drugs metabolized by COMT. However, no effects were seen on the pharmacokinetics of the COMT substrate carbidopa. The effect of tolcapone on the pharmacokinetics of other drugs of this class such as α-methyldopa, dobutamine, apomorphine, and isoproterenol has not been evaluated. A dose reduction of such compounds should be considered when they are coadministered with tolcapone.
- In vitro experiments have been performed to assess the potential of tolcapone to interact with isoenzymes of cytochrome P450 (CYP). No relevant interactions with substrates for CYP 2A6 (warfarin), CYP 1A2 (caffeine), CYP 3A4 (midazolam, terfenadine, cyclosporine), CYP 2C19 (S-mephenytoin) and CYP 2D6 (desipramine) were observed in vitro. The absence of an interaction with desipramine, a drug metabolized by cytochrome P450 2D6, was also confirmed in an in vivo study where tolcapone did not change the pharmacokinetics of desipramine.
- Due to its affinity to cytochrome P450 2C9 in vitro, tolcapone may interfere with drugs, whose clearance is dependent on this metabolic pathway, such as tolbutamide and warfarin. However, in an in vivo interaction study, tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions involving cytochrome P450 2C9 appear unlikely. Similarly, tolcapone did not affect the pharmacokinetics of desipramine, a drug metabolized by cytochrome P450 2D6, indicating that interactions with drugs metabolized by that enzyme are unlikely. Since clinical information is limited regarding the combination of warfarin and tolcapone, coagulation parameters should be monitored when these two drugs are coadministered.
- Tolcapone did not influence the effect of ephedrine, an indirect sympathomimetic, on hemodynamic parameters or plasma catecholamine levels, either at rest or during exercise. Since tolcapone did not alter the tolerability of ephedrine, these drugs can be coadministered.
- When TASMAR was given together with levodopa/carbidopa and desipramine, there was no significant change in blood pressure, pulse rate and plasma concentrations of desipramine. Overall, the frequency of adverse events increased slightly. These adverse events were predictable based on the known adverse reactions to each of the three drugs individually. Therefore, caution should be exercised when desipramine is administered to Parkinson's disease patients being treated with TASMAR and levodopa/carbidopa.
- In clinical trials, patients receiving TASMAR/levodopa preparations reported a similar adverse event profile independent of whether or not they were also concomitantly administered selegiline (a selective MAO-B inhibitor).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Tolcapone, when administered alone during organogenesis, was not teratogenic at doses of up to 300 mg/kg/day in rats or up to 400 mg/kg/day in rabbits (5.7 times and 15 times the recommended daily clinical dose of 600 mg, on a mg/m2 basis, respectively). In rabbits, however, an increased rate of abortion occurred at a dose of 100 mg/kg/day (3.7 times the daily clinical dose on a mg/m2 basis) or greater. Evidence of maternal toxicity (decreased weight gain, death) was observed at 300 mg/kg in rats and 400 mg/kg in rabbits. When tolcapone was administered to female rats during the last part of gestation and throughout lactation, decreased litter size and impaired growth and learning performance in female pups were observed at a dose of 250/150 mg/kg/day (dose reduced from 250 to 150 mg/kg/day during late gestation due to high rate of maternal mortality; equivalent to 4.8/2.9 times the clinical dose on a mg/m2 basis).
- Tolcapone is always given concomitantly with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in rabbits. The combination of tolcapone (100 mg/kg/day) with levodopa/carbidopa (80/20 mg/kg/day) produced an increased incidence of fetal malformations (primarily external and skeletal digit defects) compared to levodopa/carbidopa alone when pregnant rabbits were treated throughout organogenesis. Plasma exposures to tolcapone (based on AUC) were 0.5 times the expected human exposure, and plasma exposures to levodopa were 6 times higher than those in humans under therapeutic conditions. In a combination embryo-fetal development study in rats, fetal body weights were reduced by the combination of tolcapone (10, 30 and 50 mg/kg/day) and levodopa/carbidopa (120/30 mg/kg/day) and by levodopa/carbidopa alone. Tolcapone exposures were 0.5 times expected human exposure or greater: levodopa exposures were 21 times the expected human exposure or greater. The high dose of 50 mg/kg/day of tolcapone given alone was not associated with reduced fetal body weight (plasma exposures of 1.4 times the expected human exposure).
- There is no experience from clinical studies regarding the use of TASMAR in pregnant women. Therefore, TASMAR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolcapone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tolcapone during labor and delivery.
### Nursing Mothers
- In animal studies, tolcapone was excreted into maternal rat milk.
- It is not known whether tolcapone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tolcapone is administered to a nursing woman.
### Pediatric Use
- There is no identified potential use of tolcapone in pediatric patients.
### Geriatic Use
- Parkinson’s disease is primarily an affliction of the elderly. Consequently, the mean age of patients in tolcapone clinical trials was 60 to 65 years. To investigate safety as it relates to advancing age, three subgroups were identified: less than 65 years, 65 to 75 years, and greater than 75 years. There were generally no consistent age-related trends in safety parameters. However, patients greater than 75 years of age may be more likely to develop hallucinations than patients less than 75 years of age, while patients over 75 may be less likely to develop dystonia. In tolcapone clinical trials, measures of therapeutic efficacy (effects on “Off” time, levodopa dose, and effects on Activities of Daily Living) were not affected by age. Tolcapone pharmacokinetics have not been found to be affected by age
### Gender
There is no FDA guidance on the use of Tolcapone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tolcapone with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is needed in patients with mild to moderate renal impairment, however, patients with severe renal impairment should be treated with caution
### Hepatic Impairment
- Because of the risk of liver injury, TASMAR therapy should not be initiated in any patient with liver disease. For similar reasons, treatment should not be initiated in patients who have two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (see BOXED WARNING) or any other evidence of hepatocellular dysfunction.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tolcapone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tolcapone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- In patients determined to be appropriate candidates for treatment with TASMAR, serum glutamic-pyruvic transaminase (SGPT/ALT) and serum glutamic-oxaloacetic transaminase (SGOT/AST) levels should be determined at baseline and periodically (i.e. every 2 to 4 weeks) for the first 6 months of therapy. After the first six months, periodic monitoring is recommended at intervals deemed clinically relevant.
# IV Compatibility
There is limited information regarding IV Compatibility of Tolcapone in the drug label.
# Overdosage
- The highest dose of tolcapone administered to humans was 800 mg tid, with and without levodopa/carbidopa coadministration. This was in a 1-week study in elderly, healthy volunteers. The peak plasma concentrations of tolcapone at this dose were on average 30 µg/mL (compared to 3 µg/mL and 6 µg/mL with 100 mg and 200 mg tolcapone, respectively). Nausea, vomiting and dizziness were observed, particularly in combination with levodopa/carbidopa.
- The threshold for the lethal plasma concentration for tolcapone based on animal data is >100 µg/mL. Respiratory difficulties were observed in rats at high oral (gavage) and intravenous doses and in dogs with rapidly injected intravenous doses.
- Hospitalization is advised. General supportive care is indicated. Based on the physicochemical properties of the compound, hemodialysis is unlikely to be of benefit.
# Pharmacology
## Mechanism of Action
- Tolcapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).
- In mammals, COMT is distributed throughout various organs. The highest activities are in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.
- The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. Tolcapone enters the CNS to a minimal extent, but has been shown to inhibit central COMT activity in animals.
## Structure
- TASMAR® is available as tablets containing 100 mg tolcapone.
- Tolcapone, an inhibitor of catechol-O-methyltransferase (COMT), is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa therapy. It is a yellow, odorless, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25. The chemical name of tolcapone is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. Its empirical formula is C14H11NO5 and its structural formula is:
- Inactive ingredients: Core: lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone K-30, sodium starch glycolate, talc and magnesium stearate. Film coating: hydroxypropyl methylcellulose, titanium dioxide, talc, ethylcellulose, triacetin and sodium lauryl sulfate, with the following dye system: 100 mg — yellow and red iron oxide.
## Pharmacodynamics
- Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte catechol-O-methyltransferase (COMT) activity after oral administration. The inhibition is closely related to plasma tolcapone concentrations. With a 200-mg single dose of tolcapone, maximum inhibition of erythrocyte COMT activity is on average greater than 80%. During multiple dosing with tolcapone (200 mg tid), erythrocyte COMT inhibition at trough tolcapone blood concentrations is 30% to 45%.
## Pharmacokinetics
- When tolcapone is administered together with levodopa/carbidopa, it increases the relative bioavailability (AUC) of levodopa by approximately twofold. This is due to a decrease in levodopa clearance resulting in a prolongation of the terminal elimination half-life of levodopa (from approximately 2 hours to 3.5 hours). In general, the average peak levodopa plasma concentration (Cmax) and the time of its occurrence (Tmax) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in healthy volunteers and Parkinson's disease patients have confirmed that the maximal effect occurs with 100 mg to 200 mg tolcapone. Plasma levels of 3-OMD are markedly and dose-dependently decreased by tolcapone when given with levodopa/carbidopa.
- Population pharmacokinetic analyses in patients with Parkinson's disease have shown the same effects of tolcapone on levodopa plasma concentrations that occur in healthy volunteers.
- Tolcapone pharmacokinetics are linear over the dose range of 50 mg to 400 mg, independent of levodopa/carbidopa coadministration. The elimination half-life of tolcapone is 2 to 3 hours and there is no significant accumulation. With tid dosing of 100 mg or 200 mg, Cmax is approximately 3 µg/mL and 6 µg/mL, respectively.
- Tolcapone is rapidly absorbed, with a Tmax of approximately 2 hours. The absolute bioavailability following oral administration is about 65%. Food given within 1 hour before and 2 hours after dosing of tolcapone decreases the relative bioavailability by 10% to 20%.
- The steady-state volume of distribution of tolcapone is small (9 L). Tolcapone does not distribute widely into tissues due to its high plasma protein binding. The plasma protein binding of tolcapone is >99.9% over the concentration range of 0.32 to 210 µg/mL. In vitro experiments have shown that tolcapone binds mainly to serum albumin.
- Tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. The main metabolic pathway of tolcapone is glucuronidation; the glucuronide conjugate is inactive. In addition, the compound is methylated by COMT to 3-O-methyl-tolcapone. Tolcapone is metabolized to a primary alcohol (hydroxylation of the methyl group), which is subsequently oxidized to the carboxylic acid. In vitro experiments suggest that the oxidation may be catalyzed by cytochrome P450 3A4 and P450 2A6. The reduction to an amine and subsequent N-acetylation occur to a minor extent. After oral administration of a 14C-labeled dose of tolcapone, 60% of labeled material is excreted in urine and 40% in feces. Tolcapone is a low-extraction-ratio drug (extraction ratio = 0.15) with a moderate systemic clearance of about 7 L/h.
- Tolcapone pharmacokinetics are independent of sex, age, body weight, and race (Japanese, Black and Caucasian). Polymorphic metabolism is unlikely based on the metabolic pathways involved.
- A study in patients with hepatic impairment has shown that moderate non-cirrhotic liver disease had no impact on the pharmacokinetics of tolcapone. In patients with moderate cirrhotic liver disease (Child-Pugh Class B), however, clearance and volume of distribution of unbound tolcapone was reduced by almost 50%. This reduction may increase the average concentration of unbound drug by twofold. TASMAR therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal.
- The pharmacokinetics of tolcapone have not been investigated in a specific renal impairment study. However, the relationship of renal function and tolcapone pharmacokinetics has been investigated using population pharmacokinetics during clinical trials. The data of more than 400 patients have confirmed that over a wide range of creatinine clearance values (30 mL/min to 130 mL/min) the pharmacokinetics of tolcapone are unaffected by renal function. This could be explained by the fact that only a negligible amount of unchanged tolcapone (0.5%) is excreted in the urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile. Accumulation of this stable and inactive metabolite should not present a risk in renally impaired patients with creatinine clearance above 25 mL/min. Given the very high protein binding of tolcapone, no significant removal of the drug by hemodialysis would be expected.
- The effectiveness of TASMAR as an adjunct to levodopa in the treatment of Parkinson's disease was established in three multicenter randomized controlled trials of 13 to 26 weeks' duration, supported by four 6-week trials whose results were consistent with those of the longer trials. In two of the longer trials, tolcapone was evaluated in patients whose Parkinson's disease was characterized by deterioration in their response to levodopa at the end of a dosing interval (so-called fluctuating patients with wearing-off phenomena). In the remaining trial, tolcapone was evaluated in patients whose response to levodopa was relatively stable (so-called non-fluctuators).
- In two 3-month trials, patients with documented episodes of wearing-off phenomena, despite optimum levodopa therapy, were randomized to receive placebo, tolcapone 100 mg tid or 200 mg tid. The formal double-blind portion of the trial was 3 months long, and the primary outcome was a comparison between treatments in the change from baseline in the amount of time spent "On" (a period of relatively good functioning) and "Off" (a period of relatively poor functioning). Patients recorded periodically, throughout the duration of the trial, the time spent in each of these states.
- In addition to the primary outcome, patients were also assessed using sub-parts of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Parts V and VI); an Investigator's Global Assessment of Change (IGA), a subjective scale designed to assess global functioning in 5 areas of Parkinson's disease; the Sickness Impact Profile (SIP), a multi-item scale in 12 domains designed to assess the patient's functioning in multiple areas; and the change in daily levodopa/carbidopa dose.
- In one of the studies, 202 patients were randomized in 11 centers in the United States and Canada. In this trial, all patients were receiving concomitant levodopa and carbidopa. In the second trial, 177 patients were randomized in 24 centers in Europe. In this trial, all patients were receiving concomitant levodopa and benserazide.
- The following tables display the results of these 2 trials:
- In this study, 298 patients with idiopathic Parkinson's disease on stable doses of levodopa/carbidopa who were not experiencing wearing-off phenomena were randomized to placebo, tolcapone 100 mg tid, or tolcapone 200 mg tid for 6 months at 20 centers in the United States and Canada. The primary measure of effectiveness was the Activities of Daily Living portion (Subscale II) of the UPDRS. In addition, the change in daily levodopa dose, other subscales of the UPDRS, and the SIP were assessed as secondary measures. The results are displayed in the following table:
## Nonclinical Toxicology
- Carcinogenicity studies in which tolcapone was administered in the diet were conducted in mice and rats. Mice were treated for 80 (female) or 95 (male) weeks with doses of 100, 300 and 800 mg/kg/day, equivalent to 0.8, 1.6 and 4 times human exposure (AUC = 80 ug∙hr/mL) at the recommended daily clinical dose of 600 mg. Rats were treated for 104 weeks with doses of 50, 250 and 450 mg/kg/day. Tolcapone exposures were 1, 6.3 and 13 times the human exposure in male rats and 1.7, 11.8 and 26.4 times the human exposure in female rats. There was an increased incidence of uterine adenocarcinomas in female rats at exposure equivalent to 26.4 times the human exposure. There was evidence of renal tubular injury and renal tubular tumor formation in rats. A low incidence of renal tubular cell adenomas occurred in middle- and high-dose female rats; tubular cell carcinomas occurred in middle- and high-dose male and high-dose female rats, with a statistically significant increase in high-dose males. Exposures were equivalent to 6.3 (males) or 11.8 (females) times the human exposure or greater; no renal tumors were observed at exposures of 1 (males) or 1.7 (females) times the human exposure. Minimal-to-marked damage to the renal tubules, consisting of proximal tubule cell degeneration, single cell necrosis, hyperplasia and karyocytomegaly, occurred at the doses associated with renal tumors. Renal tubule damage, characterized by proximal tubule cell degeneration and the presence of atypical nuclei, as well as one adenocarcinoma in a high-dose male, were observed in a 1-year study in rats receiving doses of tolcapone of 150 and 450 mg/kg/day. These histopathological changes suggest the possibility that renal tumor formation might be secondary to chronic cell damage and sustained repair, but this relationship has not been established, and the relevance of these findings to humans is not known. There was no evidence of carcinogenic effects in the long-term mouse study. The carcinogenic potential of tolcapone in combination with levodopa/carbidopa has not been examined.
- Tolcapone was clastogenic in the in vitro mouse lymphoma/thymidine kinase assay in the presence of metabolic activation. Tolcapone was not mutagenic in the Ames test, the in vitro V79/HPRT gene mutation assay, or the unscheduled DNA synthesis assay. It was not clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes, or in an in vivo micronucleus assay in mice.
- Tolcapone did not affect fertility and general reproductive performance in rats at doses up to 300 mg/kg/day (5.7 times the human dose on a mg/m2 basis).
# Clinical Studies
There is limited information regarding Clinical Studies of Tolcapone in the drug label.
# How Supplied
- TASMAR is supplied as 100 mg film-coated tablets. The 100 mg tablets are beige, hexagonal and biconvex. Debossed on one side of the 100 mg tablet is TASMAR and the tablet strength (100), and on the other side is a V.
- TASMAR 100 mg Tablets: bottles of 90 (NDC 0187-0938-01).
## Storage
- Store in tight containers at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C-30°C (59°F-86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 100 MG TABLET BOTTLE LABEL
NDC 0187-0938-01
Rx Only
Tasmar ®
(tolcapone)
100 mg
Each tablet
contains
100 mg tolcapone
90 Tablets
### Ingredients And Appearance
# Patient Counseling Information
- Patients should be instructed to take TASMAR only as prescribed.
- TASMAR should not be used by patients until there has been a complete discussion of the risks and the patient has provided written acknowledgement that the risks have been explained.
- Inform patients about clinical signs and symptoms that suggest the onset of hepatic injury (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness). If symptoms of hepatic failure occur, patients should be advised to contact their physician immediately.
- Inform patients of the need to have regular blood tests to monitor liver enzymes.
- Advise patients that sleepiness or drowsiness may occur and that they should not drive a car or operate other complex machinery until they have gained sufficient experience on TASMAR to gauge whether or not it adversely affects their mental and/or motor performance. Advise patients to exercise caution while driving, operating machines, or working at heights during treatment with TASMAR. Because of the possible additive sedative effects, caution should also be used when patients are taking other CNS depressants in combination with TASMAR. Inform patients that nausea may occur, especially at the initiation of treatment with TASMAR.
- Inform patients that hallucinations and other psychotic-like behavior may occur.
- Advise patients about the possibility of developing or worsening of existing dyskinesia and/or dystonia after starting TASMAR.
- Advise patients that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Advise patients to rise slowly, especially after long periods of sitting or lying down. Hypotension may be more likely when patients first start treatment with TASMAR.
- Instruct patients and caregivers to report intense urges to gamble, increased sexual urges, increase in spending money, binge eating, and other intense urges as well as the inability to control these urges to the prescriber while taking TASMAR.
- Although TASMAR has not been shown to be teratogenic in animals, it is always given in conjunction with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in the rabbit. Accordingly, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy.
- Tolcapone is excreted into maternal milk in rats. Because of the possibility that tolcapone may be excreted into human milk, advise patients to notify their physicians if they intend to breastfeed or are breastfeeding an infant.
# Precautions with Alcohol
- Alcohol-Tolcapone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tasmar®
# Look-Alike Drug Names
There is limited information regarding Tolcapone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tolcapone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Black Box Warning
# Overview
Tolcapone is a Catechol-O-Methyltransferase Inhibitor that is FDA approved for the treatment of signs and symptoms of idiopathic Parkinson's disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Dyskinesia, Nausea, Sleep Disorder , Anorexia , Diarrhea , urine discoloration, somnolence, hallucination, dystonia, and sweating.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- TASMAR is indicated as an adjunct to levodopa and carbidopa for the treatment of the signs and symptoms of idiopathic Parkinson's disease. Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies. Because of the risk of liver injury and because TASMAR, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR.
- The effectiveness of TASMAR was demonstrated in randomized controlled trials in patients receiving concomitant levodopa therapy with carbidopa or another aromatic amino acid decarboxylase inhibitor who experienced end of dose wearing-off phenomena as well as in patients who did not experience such phenomena
### Dosage
- Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies .
- BECAUSE OF THE RISK OF LIVER INJURY AND BECAUSE TASMAR WHEN IT IS EFFECTIVE PROVIDES AN OBSERVABLE SYMPTOMATIC BENEFIT, THE PATIENT WHO FAILS TO SHOW SUBSTANTIAL CLINICAL BENEFIT WITHIN 3 WEEKS OF INITIATION OF TREATMENT, SHOULD BE WITHDRAWN FROM TASMAR.
- TASMAR therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution.
- Patients who develop evidence of hepatocellular injury while on TASMAR and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR is reintroduced. These patients should not ordinarily be considered for retreatment with TASMAR.
- Only prescribe TASMAR for patients taking concomitant carbidopa levodopa therapy. The initial dose of TASMAR is always 100 mg three times per day. The recommended daily dose of TASMAR is also 100 mg tid. In clinical trials, elevations in ALT occurred more frequently at the dose of 200 mg tid. While it is unknown whether the risk of acute fulminant liver failure is increased at the 200-mg dose, it would be prudent to use 200 mg only if the anticipated incremental clinical benefit is justified. If a patient fails to show the expected incremental benefit on the 200-mg dose after a total of 3 weeks of treatment (regardless of dose), TASMAR should be discontinued.
- In clinical trials, the first dose of the day of TASMAR was always taken together with the first dose of the day of levodopa/carbidopa, and the subsequent doses of TASMAR were given approximately 6 and 12 hours later.
- In clinical trials, the majority of patients required a decrease in their daily levodopa dose if their daily dose of levodopa was >600 mg or if patients had moderate or severe dyskinesias before beginning treatment.
- To optimize an individual patient's response, reductions in daily levodopa dose may be necessary. In clinical trials, the average reduction in daily levodopa dose was about 30% in those patients requiring a levodopa dose reduction. (Greater than 70% of patients with levodopa doses above 600 mg daily required such a reduction.)
- TASMAR can be combined with both the immediate and sustained release formulations of levodopa/carbidopa.
- TASMAR may be taken with or without food .
- TASMAR therapy should not be initiated if any patient with liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal.
- No dose adjustment of TASMAR is recommended for patients with mild to moderate renal impairment. However, patients with severe renal impairment should be treated with caution. The safety of tolcapone has not been examined in subjects who had creatinine clearance less than 25 mL/min.
- As with any dopaminergic drug, withdrawal or abrupt reduction in the TASMAR dose may lead to emergence of signs and symptoms of Parkinson's disease or Hyperpyrexia and Confusion, a syndrome complex resembling the neuroleptic malignant syndrome. If a decision is made to discontinue treatment with TASMAR, then it is recommended to closely monitor the patient and adjust other dopaminergic treatments as needed. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. Tapering TASMAR has not been systematically evaluated. As the duration of COMT inhibition with TASMAR is generally 5 to 6 hours on average, decreasing the frequency of dosage to twice or once a day may not in itself prevent withdrawal effects.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tolcapone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolcapone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tolcapone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tolcapone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolcapone in pediatric patients.
# Contraindications
- TASMAR tablets are contraindicated in patients with liver disease, in patients who were withdrawn from TASMAR because of evidence of TASMAR-induced hepatocellular injury or who have demonstrated hypersensitivity to the drug or its ingredients.
TASMAR is also contraindicated in patients with a history of nontraumatic rhabdomyolysis or hyperpyrexia and confusion possibly related to medication
# Warnings
- Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies (see INDICATIONS and DOSAGE AND ADMINISTRATION sections).
- Because of the risk of liver injury and because TASMAR, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR.
- TASMAR therapy should not be initiated if the patient exhibits clinical evidence of liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal. Patients with severe dyskinesia or dystonia should be treated with caution.
- Patients who develop evidence of hepatocellular injury while on TASMAR and are withdrawn from the drug for any reason may be at increased risk for liver injury if TASMAR is reintroduced. Accordingly, such patients should not ordinarily be considered for retreatment.
- In controlled Phase 3 trials, increases to more than 3 times the upper limit of normal in ALT or AST occurred in approximately 1% of patients at 100 mg tid and 3% of patients at 200 mg tid. Females were more likely than males to have an increase in liver enzymes (approximately 5% vs 2%). Approximately one third of patients with elevated enzymes had diarrhea. Increases to more than 8 times the upper limit of normal in liver enzymes occurred in 0.3% at 100 mg tid and 0.7% at 200 mg tid. Elevated enzymes led to discontinuation in 0.3% and 1.7% of patients treated with 100 mg tid and 200 mg tid, respectively. Elevations usually occurred within 6 weeks to 6 months of starting treatment. In about half the cases with elevated liver enzymes, enzyme levels returned to baseline values within 1 to 3 months while patients continued TASMAR treatment. When treatment was discontinued, enzymes generally declined within 2 to 3 weeks but in some cases took as long as 1 to 2 months to return to normal.
- Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of TASMAR and a non-selective MAO inhibitor (eg, phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. For this reason, patients should ordinarily not be treated concomitantly with TASMAR and a non-selective MAO inhibitor.
- Tolcapone can be taken concomitantly with a selective MAO-B inhibitor (eg, selegiline).
- Tolcapone (TASMAR) increases plasma levels of levodopa in patients taking concomitant carbidopa levodopa products. Patients taking carbidopa levodopa products alone or with other dopaminergic medications have reported suddenly falling asleep without prior warning of sleepiness while engaged in activities of daily living (includes the operation of motor vehicles). Some of these episodes resulted in automobile accidents. Although many of these patients reported somnolence while on TASMAR, some did perceive that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some patients reported these events one year after the initiation of treatment.
- The risk for somnolence was increased with TASMAR treatment (TASMAR 100 mg-18 %, 200 mg-14%, vs placebo-13%) compared to placebo treatment. In clinical trials, discontinuation due to somnolence occurred in 1% of patients treated with 200 mg TASMAR and 0% of patients treated with 100 mg TASMAR or placebo. Falling asleep while engaged in activities of daily living usually occurs in patients experiencing pre-existing somnolence, although some patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Prescribers should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients who have already experienced somnolence or an episode of sudden sleep onset should not participate in these activities during treatment with TASMAR.
- Before initiating treatment with TASMAR, advise patients about the potential to develop drowsiness and ask specifically about factors that may increase the risk for somnolence with TASMAR such as the use of concomitant sedating medications and the presence of sleep disorders. Consider discontinuing TASMAR in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with TASMAR continues, patients should be advised not to drive and to avoid other potentially dangerous activities that might result in harm if patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
### Precautions
- Dopaminergic therapy in Parkinson's disease patients has been associated with orthostatic hypotension. Tolcapone enhances levodopa bioavailability and, therefore, may increase the occurrence of orthostatic hypotension. In TASMAR clinical trials, orthostatic hypotension was documented at least once in 8%, 14% and 13% of the patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively. A total of 2%, 5% and 4% of the patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively, reported orthostatic symptoms at some time during their treatment and also had at least one episode of orthostatic hypotension documented (however, the episode of orthostatic symptoms itself was invariably not accompanied by vital sign measurements). Patients with orthostasis at baseline were more likely than patients without symptoms to have orthostatic hypotension during the study, irrespective of treatment group. In addition, the effect was greater in tolcapone-treated patients than in placebo-treated patients. Baseline treatment with dopamine agonists or selegiline did not appear to increase the likelihood of experiencing orthostatic hypotension when treated with TASMAR. Approximately 0.7% of the patients treated with TASMAR (5% of patients who were documented to have had at least one episode of orthostatic hypotension) eventually withdrew from treatment due to adverse events presumably related to hypotension.
- In controlled Phase 3 trials, approximately 5%, 4% and 3% of tolcapone 200 mg tid, 100 mg tid and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in all three treatment groups who had an episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement) compared to patients who did not have any episodes of documented hypotension.
- In clinical trials, diarrhea developed in approximately 8%, 16% and 18% of patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively. While diarrhea was generally regarded as mild to moderate in severity, approximately 3% to 4% of patients on tolcapone had diarrhea which was regarded as severe. Diarrhea was the adverse event which most commonly led to discontinuation, with approximately 1%, 5% and 6% of patients treated with placebo, 100 mg and 200 mg TASMAR tid, respectively, withdrawing from the trials prematurely. Discontinuing TASMAR for diarrhea was related to the severity of the symptom. Diarrhea resulted in withdrawal in approximately 8%, 40% and 70% of patients with mild, moderate and severe diarrhea, respectively. Although diarrhea generally resolved after discontinuation of TASMAR, it led to hospitalization in 0.3%, 0.7% and 1.7% of patients in the placebo, 100 mg and 200 mg TASMAR tid groups.
- Typically, diarrhea presents 6 to 12 weeks after tolcapone is started, but it may appear as early as 2 weeks and as late as many months after the initiation of treatment. Clinical trial data suggested that diarrhea associated with tolcapone use may sometimes be associated with anorexia (decreased appetite).
- No consistent description of tolcapone-induced diarrhea has been derived from clinical trial data, and the mechanism of action is currently unknown.
- It is recommended that all cases of persistent diarrhea should be followed up with an appropriate work-up (including occult blood samples).
- In clinical trials, hallucinations developed in approximately 5% of patients treated with placebo, compared to 8% and 10% of patients treated with 100 mg or 200 mg three times per day, respectively. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.3% of patients treated with placebo, compared to 1.4% and 1.0% of patients treated with TASMAR 100 mg or 200 mg TASMAR three times per day, respectively. Hallucinations led to hospitalization in 0.0% of patients in the placebo group, compared to 1.7% and 0.0% of patients treated with 100 mg or 200 mg TASMAR three times per day, respectively.
- In general, hallucinations present shortly after the initiation of therapy with tolcapone (typically within the first 2 weeks). Clinical trial data suggest that hallucinations associated with tolcapone use may be responsive to levodopa dose reduction. Patients whose hallucinations resolved had a mean levodopa dose reduction of 175 mg to 200 mg (20% to 25%) after the onset of the hallucinations. Hallucinations were commonly accompanied by confusion and to a lesser extent sleep disorder (insomnia) and excessive dreaming. The incidence of hallucination may be increased in elderly patients over 75 years treated with TASMAR.
- Post-marketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during TASMAR treatment or after starting or increasing the dose of TASMAR. Other drugs prescribed to improve the symptoms of Parkinson’s disease may have similar effects on thinking and behavior. This abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
- Ordinarily, patients with a major psychotic disorder should not be treated with TASMAR because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of TASMAR.
- TASMAR may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. Dyskinesia was the most common adverse reaction observed in controlled trials and developed in approximately 20% of patients treated with placebo, compared to 42% and 51% of patients treated with TASMAR 100 mg or 200 mg three times daily, respectively. The rates of withdrawal for dyskinesia were 0.0% in the placebo group, compared to 0.3% and 1.0% in the groups receiving TASMAR 100 mg or 200 mg three times a day, respectively.
- Reports suggest that patients may experience an intense urge to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges. These reports are associated with patients taking TASMAR in conjunction with carbidopa/levodopa, as well as other medications that increase central dopaminergic tone and that are used to treat patients with Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with TASMAR. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking TASMAR .
- Cases of severe rhabdomyolysis, with one case of multiorgan system failure rapidly progressing to death, have been reported. The complicated nature of these cases makes it impossible to determine what role, if any, TASMAR played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. Some cases, however, included fever, alteration of consciousness and muscular rigidity. It is possible, therefore, that the rhabdomyolysis may be a result of the syndrome described in Hyperpyrexia and Confusion.
- No dosage adjustment is needed in patients with mild to moderate renal impairment, however, patients with severe renal impairment should be treated with caution.
- When rats were dosed daily for 1 or 2 years (exposures 6 times the human exposure or greater) there was a high incidence of proximal tubule cell damage consisting of degeneration, single cell necrosis, hyperplasia, karyocytomegaly and atypical nuclei. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although it has been speculated that these toxicities may occur as the result of a species-specific mechanism, experiments which would confirm that theory have not been conducted.
- Because of the risk of liver injury, TASMAR therapy should not be initiated in any patient with liver disease. For similar reasons, treatment should not be initiated in patients who have two SGPT/ALT or SGOT/AST values greater than the upper limit of normal or any other evidence of hepatocellular dysfunction.
- The rates of hematuria in placebo-controlled trials were approximately 2%, 4% and 5% in placebo, 100 mg and 200 mg TASMAR tid, respectively. The etiology of the increase with TASMAR has not always been explained (for example, by urinary tract infection or coumadin therapy). In placebo-controlled trials in the United States (N=593) rates of microscopically confirmed hematuria were approximately 3%, 2% and 2% in placebo, 100 mg and 200 mg TASMAR tid, respectively.
- The events listed below are known to be associated with the use of drugs that increase dopaminergic activity, although they are most often associated with the use of direct dopamine agonists. While cases of Hyperpyrexia and Confusion have been reported in association with tolcapone withdrawal (see paragraph below), the expected incidence of fibrotic complications is so low that even if tolcapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that even a single example would have been detected in a cohort of the size exposed to tolcapone.
- In clinical trials, four cases of a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, and altered consciousness), similar to that reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs, have been reported in association with the abrupt withdrawal or lowering of the dose of tolcapone. In 3 of these cases, CPK was elevated as well. One patient died, and the other 3 patients recovered over periods of approximately 2, 4 and 6 weeks. Rare cases of this symptom complex have been reported during marketed use. It is difficult to determine if TASMAR played a role in the pathogenesis of these events because these patients received several concomitant medications affecting the central nervous system such as monoaminergic (i.e., MAO-I, tricyclic and selective serotonin reuptake inhibitors) and anticholinergic agents.
- Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived drugs (eg, tolcapone) that increase dopaminergic activity can cause them is unknown.
- Three cases of pleural effusion, one with pulmonary fibrosis, occurred during clinical trials. These patients were also on concomitant dopamine agonists (pergolide or bromocriptine) and had a prior history of cardiac disease or pulmonary pathology (nonmalignant lung lesion).
- Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using TASMAR for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists).
# Adverse Reactions
## Clinical Trials Experience
- Cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in postmarketing use. As of May 2005, 3 cases of fatal fulminant hepatic failure have been reported from more than 40,000 patient years of worldwide use. This incidence may be 10- to 100-fold higher than the background incidence in the general population. All 3 cases were reported within the first six months of initiation of treatment with TASMAR. Analysis of the laboratory monitoring data in over 3,400 TASMAR-treated patients participating in clinical trials indicated that increases in SGPT/ALT or SGOT/AST, when present, generally occurred within the first 6 months of treatment with TASMAR.
- The imprecision of the estimated increase is due to uncertainties about the base rate and the actual number of cases occurring in association with TASMAR. The incidence of idiopathic potentially fatal fulminant hepatic failure (ie, not due to viral hepatitis or alcohol) is low. One estimate, based upon transplant registry data, is approximately 3/1,000,000 patients per year in the United States. Whether this estimate is an appropriate basis for estimating the increased risk of liver failure among TASMAR users is uncertain. TASMAR users, for example, differ in age and general health status from candidates for liver transplantation. Similarly, underreporting of cases may lead to significant underestimation of the increased risk associated with the use of TASMAR.
- During the premarketing development of tolcapone, two distinct patient populations were studied, patients with end-of-dose wearing-off phenomena and patients with stable responses to levodopa therapy. All patients received concomitant treatment with levodopa preparations, however, and were similar in other clinical aspects. Adverse events are, therefore, shown for these two populations combined.
- The most commonly observed adverse reactions in the double-blind, placebo-controlled trials (N=892), with a difference in incidence (TASMAR minus Placebo) of at least 5 % or greater in the 100 mg or 200 mg TASMAR- treated groups compared to placebo, were dyskinesia, nausea, diarrhea, anorexia, sleep disorder, vomiting, urine discoloration, somnolence, hallucination, dystonia, and sweating.
- Approximately 16% of the 592 patients who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse reactions compared to 10% of the 298 patients who received placebo. Diarrhea was by far the most frequent cause of discontinuation (approximately 6% in tolcapone patients vs. 1% on placebo).
- Table 4 lists treatment emergent adverse reactions that occurred in at least 1% of patients treated with tolcapone participating in the double-blind, placebo-controlled studies and were numerically more common in at least one of the tolcapone groups. In these studies, either tolcapone or placebo was added to levodopa/carbidopa (or benserazide).
- The prescriber should be aware that these figures cannot be used to predict the incidence of adverse reactions in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reactions incidence rate in the population studied.
- Female patients may be more likely to develop somnolence than males.
- During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of adverse events were grouped into a smaller number of standardized categories using COSTART dictionary terminology.These categories are used in the listing below.
- All reported events that occurred at least twice (or once for serious or potentially serious events), except those already listed above, trivial events and terms too vague to be meaningful are included, without regard to determination of a causal relationship to TASMAR.
- Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are defined as those occurring in between 1/100 and 1/1000 patients; and rare adverse events are defined as those occurring in fewer than 1/1000 patients.
- frequent: depression, hypesthesia, tremor, speech disorder, vertigo, emotional lability; infrequent: neuralgia, amnesia, extrapyramidal syndrome, hostility, libido increased, manic reaction, nervousness, paranoid reaction, cerebral ischemia, cerebrovascular accident, delusions, libido decreased, neuropathy, apathy, choreoathetosis, myoclonus, psychosis, abnormal thinking, twitching; rare: antisocial reaction, delirium, encephalopathy, hemiplegia, meningitis.
- frequent: tooth disorder; infrequent: dysphagia, gastrointestinal hemorrhage, gastroenteritis, mouth ulceration, increased salivation, abnormal stools, esophagitis, cholelithiasis, colitis, tongue disorder, rectal disorder; rare: cholecystitis, duodenal ulcer, gastrointestinal carcinoma, stomach atony.
- frequent: flank pain, accidental injury, abdominal pain, infection; infrequent: hernia, pain, allergic reaction, cellulitis, fungal infection, viral infection, carcinoma, chills, bacterial infection, neoplasm, abscess, face edema; rare: death.
- frequent: palpitation; infrequent: hypertension, vasodilation, angina pectoris, heart failure, atrial fibrillation, tachycardia, migraine, aortic stenosis, arrhythmia, arteriospasm, bradycardia, cerebral hemorrhage, coronary artery disorder, heart arrest, myocardial infarct, myocardial ischemia, pulmonary embolus; rare: arteriosclerosis, cardiovascular disorder, pericardial effusion, thrombosis.
- frequent: myalgia; infrequent: tenosynovitis, arthrosis, joint disorder.
- frequent: urinary incontinence, impotence; infrequent: prostatic disorder, dysuria, nocturia, polyuria, urinary retention, urinary tract disorder, hematuria, kidney calculus, prostatic carcinoma, breast neoplasm, oliguria, uterine atony, uterine disorder, vaginitis; rare: bladder calculus, ovarian carcinoma, uterine hemorrhage.
- frequent: bronchitis, pharyngitis; infrequent: increased cough , rhinitis, asthma, epistaxis, hyperventilation, laryngitis, hiccup; rare: apnea, hypoxia, lung edema.
- frequent: rash; infrequent: herpes zoster, pruritus, seborrhea, skin discoloration, eczema, erythema multiforme, skin disorder, furunculosis, herpes simplex, urticaria.
- frequent: tinnitus; infrequent: diplopia, ear pain, eye hemorrhage, eye pain, lacrimation disorder, otitis media, parosmia; rare: glaucoma.
- infrequent: edema, hypercholesteremia, thirst, dehydration.
- infrequent: anemia; rare: leukemia, thrombocytopenia.
- infrequent: diabetes mellitus.
- infrequent: surgical procedure
- Tolcapone is not a controlled substance.
- Studies conducted in rats and monkeys did not reveal any potential for physical or psychological dependence. Although clinical trials have not revealed any evidence of the potential for abuse, tolerance or physical dependence, systematic studies in humans designed to evaluate these effects have not been performed.
- Although a program of frequent laboratory monitoring for evidence of hepatocellular injury is deemed essential, it is not clear that periodic monitoring of liver enzymes will prevent the occurrence of fulminant liver failure. However, it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. Accordingly, the following liver monitoring program is recommended.
- Before starting treatment with TASMAR, the physician should conduct appropriate tests to exclude the presence of liver disease. In patients determined to be appropriate candidates for treatment with TASMAR, serum glutamic-pyruvic transaminase (SGPT/ALT) and serum glutamic-oxaloacetic transaminase (SGOT/AST) levels should be determined at baseline and periodically (i.e. every 2 to 4 weeks) for the first 6 months of therapy. After the first six months, periodic monitoring is recommended at intervals deemed clinically relevant. Although more frequent monitoring increases the chances of early detection, the precise schedule for monitoring is a matter of clinical judgement.
- If the dose is increased to 200 mg tid, liver enzyme monitoring should take place before increasing the dose and then be conducted every 2 to 4 weeks for the following 6 months of therapy. After six months, periodic monitoring is recommended at intervals deemed clinically relevant.
- Discontinue TASMAR if SGPT/ALT or SGOT/AST levels exceed 2 times the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic dysfunction (e.g., persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness).
## Postmarketing Experience
- Cases of severe hepatocellular injury, including fulminant liver failure resulting in death, have been reported in postmarketing use.
# Drug Interactions
- Although tolcapone is highly protein bound, in vitro studies have shown that tolcapone at a concentration of 50 µg/mL did not displace other highly protein-bound drugs from their binding sites at therapeutic concentrations. The experiments included warfarin (0.5 to 7.2 µg/mL), phenytoin (4.0 to 38.7 µg/mL), tolbutamide (24.5 to 96.1 µg/mL) and digitoxin (9.0 to 27.0 µg/mL).
- Tolcapone may influence the pharmacokinetics of drugs metabolized by COMT. However, no effects were seen on the pharmacokinetics of the COMT substrate carbidopa. The effect of tolcapone on the pharmacokinetics of other drugs of this class such as α-methyldopa, dobutamine, apomorphine, and isoproterenol has not been evaluated. A dose reduction of such compounds should be considered when they are coadministered with tolcapone.
- In vitro experiments have been performed to assess the potential of tolcapone to interact with isoenzymes of cytochrome P450 (CYP). No relevant interactions with substrates for CYP 2A6 (warfarin), CYP 1A2 (caffeine), CYP 3A4 (midazolam, terfenadine, cyclosporine), CYP 2C19 (S-mephenytoin) and CYP 2D6 (desipramine) were observed in vitro. The absence of an interaction with desipramine, a drug metabolized by cytochrome P450 2D6, was also confirmed in an in vivo study where tolcapone did not change the pharmacokinetics of desipramine.
- Due to its affinity to cytochrome P450 2C9 in vitro, tolcapone may interfere with drugs, whose clearance is dependent on this metabolic pathway, such as tolbutamide and warfarin. However, in an in vivo interaction study, tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions involving cytochrome P450 2C9 appear unlikely. Similarly, tolcapone did not affect the pharmacokinetics of desipramine, a drug metabolized by cytochrome P450 2D6, indicating that interactions with drugs metabolized by that enzyme are unlikely. Since clinical information is limited regarding the combination of warfarin and tolcapone, coagulation parameters should be monitored when these two drugs are coadministered.
- Tolcapone did not influence the effect of ephedrine, an indirect sympathomimetic, on hemodynamic parameters or plasma catecholamine levels, either at rest or during exercise. Since tolcapone did not alter the tolerability of ephedrine, these drugs can be coadministered.
- When TASMAR was given together with levodopa/carbidopa and desipramine, there was no significant change in blood pressure, pulse rate and plasma concentrations of desipramine. Overall, the frequency of adverse events increased slightly. These adverse events were predictable based on the known adverse reactions to each of the three drugs individually. Therefore, caution should be exercised when desipramine is administered to Parkinson's disease patients being treated with TASMAR and levodopa/carbidopa.
- In clinical trials, patients receiving TASMAR/levodopa preparations reported a similar adverse event profile independent of whether or not they were also concomitantly administered selegiline (a selective MAO-B inhibitor).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Tolcapone, when administered alone during organogenesis, was not teratogenic at doses of up to 300 mg/kg/day in rats or up to 400 mg/kg/day in rabbits (5.7 times and 15 times the recommended daily clinical dose of 600 mg, on a mg/m2 basis, respectively). In rabbits, however, an increased rate of abortion occurred at a dose of 100 mg/kg/day (3.7 times the daily clinical dose on a mg/m2 basis) or greater. Evidence of maternal toxicity (decreased weight gain, death) was observed at 300 mg/kg in rats and 400 mg/kg in rabbits. When tolcapone was administered to female rats during the last part of gestation and throughout lactation, decreased litter size and impaired growth and learning performance in female pups were observed at a dose of 250/150 mg/kg/day (dose reduced from 250 to 150 mg/kg/day during late gestation due to high rate of maternal mortality; equivalent to 4.8/2.9 times the clinical dose on a mg/m2 basis).
- Tolcapone is always given concomitantly with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in rabbits. The combination of tolcapone (100 mg/kg/day) with levodopa/carbidopa (80/20 mg/kg/day) produced an increased incidence of fetal malformations (primarily external and skeletal digit defects) compared to levodopa/carbidopa alone when pregnant rabbits were treated throughout organogenesis. Plasma exposures to tolcapone (based on AUC) were 0.5 times the expected human exposure, and plasma exposures to levodopa were 6 times higher than those in humans under therapeutic conditions. In a combination embryo-fetal development study in rats, fetal body weights were reduced by the combination of tolcapone (10, 30 and 50 mg/kg/day) and levodopa/carbidopa (120/30 mg/kg/day) and by levodopa/carbidopa alone. Tolcapone exposures were 0.5 times expected human exposure or greater: levodopa exposures were 21 times the expected human exposure or greater. The high dose of 50 mg/kg/day of tolcapone given alone was not associated with reduced fetal body weight (plasma exposures of 1.4 times the expected human exposure).
- There is no experience from clinical studies regarding the use of TASMAR in pregnant women. Therefore, TASMAR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolcapone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tolcapone during labor and delivery.
### Nursing Mothers
- In animal studies, tolcapone was excreted into maternal rat milk.
- It is not known whether tolcapone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tolcapone is administered to a nursing woman.
### Pediatric Use
- There is no identified potential use of tolcapone in pediatric patients.
### Geriatic Use
- Parkinson’s disease is primarily an affliction of the elderly. Consequently, the mean age of patients in tolcapone clinical trials was 60 to 65 years. To investigate safety as it relates to advancing age, three subgroups were identified: less than 65 years, 65 to 75 years, and greater than 75 years. There were generally no consistent age-related trends in safety parameters. However, patients greater than 75 years of age may be more likely to develop hallucinations than patients less than 75 years of age, while patients over 75 may be less likely to develop dystonia. In tolcapone clinical trials, measures of therapeutic efficacy (effects on “Off” time, levodopa dose, and effects on Activities of Daily Living) were not affected by age. Tolcapone pharmacokinetics have not been found to be affected by age
### Gender
There is no FDA guidance on the use of Tolcapone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tolcapone with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is needed in patients with mild to moderate renal impairment, however, patients with severe renal impairment should be treated with caution
### Hepatic Impairment
- Because of the risk of liver injury, TASMAR therapy should not be initiated in any patient with liver disease. For similar reasons, treatment should not be initiated in patients who have two SGPT/ALT or SGOT/AST values greater than the upper limit of normal (see BOXED WARNING) or any other evidence of hepatocellular dysfunction.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tolcapone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tolcapone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- In patients determined to be appropriate candidates for treatment with TASMAR, serum glutamic-pyruvic transaminase (SGPT/ALT) and serum glutamic-oxaloacetic transaminase (SGOT/AST) levels should be determined at baseline and periodically (i.e. every 2 to 4 weeks) for the first 6 months of therapy. After the first six months, periodic monitoring is recommended at intervals deemed clinically relevant.
# IV Compatibility
There is limited information regarding IV Compatibility of Tolcapone in the drug label.
# Overdosage
- The highest dose of tolcapone administered to humans was 800 mg tid, with and without levodopa/carbidopa coadministration. This was in a 1-week study in elderly, healthy volunteers. The peak plasma concentrations of tolcapone at this dose were on average 30 µg/mL (compared to 3 µg/mL and 6 µg/mL with 100 mg and 200 mg tolcapone, respectively). Nausea, vomiting and dizziness were observed, particularly in combination with levodopa/carbidopa.
- The threshold for the lethal plasma concentration for tolcapone based on animal data is >100 µg/mL. Respiratory difficulties were observed in rats at high oral (gavage) and intravenous doses and in dogs with rapidly injected intravenous doses.
- Hospitalization is advised. General supportive care is indicated. Based on the physicochemical properties of the compound, hemodialysis is unlikely to be of benefit.
# Pharmacology
## Mechanism of Action
- Tolcapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).
- In mammals, COMT is distributed throughout various organs. The highest activities are in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.
- The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. Tolcapone enters the CNS to a minimal extent, but has been shown to inhibit central COMT activity in animals.
## Structure
- TASMAR® is available as tablets containing 100 mg tolcapone.
- Tolcapone, an inhibitor of catechol-O-methyltransferase (COMT), is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa therapy. It is a yellow, odorless, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25. The chemical name of tolcapone is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. Its empirical formula is C14H11NO5 and its structural formula is:
- Inactive ingredients: Core: lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate anhydrous, povidone K-30, sodium starch glycolate, talc and magnesium stearate. Film coating: hydroxypropyl methylcellulose, titanium dioxide, talc, ethylcellulose, triacetin and sodium lauryl sulfate, with the following dye system: 100 mg — yellow and red iron oxide.
## Pharmacodynamics
- Studies in healthy volunteers have shown that tolcapone reversibly inhibits human erythrocyte catechol-O-methyltransferase (COMT) activity after oral administration. The inhibition is closely related to plasma tolcapone concentrations. With a 200-mg single dose of tolcapone, maximum inhibition of erythrocyte COMT activity is on average greater than 80%. During multiple dosing with tolcapone (200 mg tid), erythrocyte COMT inhibition at trough tolcapone blood concentrations is 30% to 45%.
## Pharmacokinetics
- When tolcapone is administered together with levodopa/carbidopa, it increases the relative bioavailability (AUC) of levodopa by approximately twofold. This is due to a decrease in levodopa clearance resulting in a prolongation of the terminal elimination half-life of levodopa (from approximately 2 hours to 3.5 hours). In general, the average peak levodopa plasma concentration (Cmax) and the time of its occurrence (Tmax) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in healthy volunteers and Parkinson's disease patients have confirmed that the maximal effect occurs with 100 mg to 200 mg tolcapone. Plasma levels of 3-OMD are markedly and dose-dependently decreased by tolcapone when given with levodopa/carbidopa.
- Population pharmacokinetic analyses in patients with Parkinson's disease have shown the same effects of tolcapone on levodopa plasma concentrations that occur in healthy volunteers.
- Tolcapone pharmacokinetics are linear over the dose range of 50 mg to 400 mg, independent of levodopa/carbidopa coadministration. The elimination half-life of tolcapone is 2 to 3 hours and there is no significant accumulation. With tid dosing of 100 mg or 200 mg, Cmax is approximately 3 µg/mL and 6 µg/mL, respectively.
- Tolcapone is rapidly absorbed, with a Tmax of approximately 2 hours. The absolute bioavailability following oral administration is about 65%. Food given within 1 hour before and 2 hours after dosing of tolcapone decreases the relative bioavailability by 10% to 20%.
- The steady-state volume of distribution of tolcapone is small (9 L). Tolcapone does not distribute widely into tissues due to its high plasma protein binding. The plasma protein binding of tolcapone is >99.9% over the concentration range of 0.32 to 210 µg/mL. In vitro experiments have shown that tolcapone binds mainly to serum albumin.
- Tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. The main metabolic pathway of tolcapone is glucuronidation; the glucuronide conjugate is inactive. In addition, the compound is methylated by COMT to 3-O-methyl-tolcapone. Tolcapone is metabolized to a primary alcohol (hydroxylation of the methyl group), which is subsequently oxidized to the carboxylic acid. In vitro experiments suggest that the oxidation may be catalyzed by cytochrome P450 3A4 and P450 2A6. The reduction to an amine and subsequent N-acetylation occur to a minor extent. After oral administration of a 14C-labeled dose of tolcapone, 60% of labeled material is excreted in urine and 40% in feces. Tolcapone is a low-extraction-ratio drug (extraction ratio = 0.15) with a moderate systemic clearance of about 7 L/h.
- Tolcapone pharmacokinetics are independent of sex, age, body weight, and race (Japanese, Black and Caucasian). Polymorphic metabolism is unlikely based on the metabolic pathways involved.
- A study in patients with hepatic impairment has shown that moderate non-cirrhotic liver disease had no impact on the pharmacokinetics of tolcapone. In patients with moderate cirrhotic liver disease (Child-Pugh Class B), however, clearance and volume of distribution of unbound tolcapone was reduced by almost 50%. This reduction may increase the average concentration of unbound drug by twofold. TASMAR therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or two SGPT/ALT or SGOT/AST values greater than the upper limit of normal.
- The pharmacokinetics of tolcapone have not been investigated in a specific renal impairment study. However, the relationship of renal function and tolcapone pharmacokinetics has been investigated using population pharmacokinetics during clinical trials. The data of more than 400 patients have confirmed that over a wide range of creatinine clearance values (30 mL/min to 130 mL/min) the pharmacokinetics of tolcapone are unaffected by renal function. This could be explained by the fact that only a negligible amount of unchanged tolcapone (0.5%) is excreted in the urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile. Accumulation of this stable and inactive metabolite should not present a risk in renally impaired patients with creatinine clearance above 25 mL/min. Given the very high protein binding of tolcapone, no significant removal of the drug by hemodialysis would be expected.
- The effectiveness of TASMAR as an adjunct to levodopa in the treatment of Parkinson's disease was established in three multicenter randomized controlled trials of 13 to 26 weeks' duration, supported by four 6-week trials whose results were consistent with those of the longer trials. In two of the longer trials, tolcapone was evaluated in patients whose Parkinson's disease was characterized by deterioration in their response to levodopa at the end of a dosing interval (so-called fluctuating patients with wearing-off phenomena). In the remaining trial, tolcapone was evaluated in patients whose response to levodopa was relatively stable (so-called non-fluctuators).
- In two 3-month trials, patients with documented episodes of wearing-off phenomena, despite optimum levodopa therapy, were randomized to receive placebo, tolcapone 100 mg tid or 200 mg tid. The formal double-blind portion of the trial was 3 months long, and the primary outcome was a comparison between treatments in the change from baseline in the amount of time spent "On" (a period of relatively good functioning) and "Off" (a period of relatively poor functioning). Patients recorded periodically, throughout the duration of the trial, the time spent in each of these states.
- In addition to the primary outcome, patients were also assessed using sub-parts of the Unified Parkinson's Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Parts V and VI); an Investigator's Global Assessment of Change (IGA), a subjective scale designed to assess global functioning in 5 areas of Parkinson's disease; the Sickness Impact Profile (SIP), a multi-item scale in 12 domains designed to assess the patient's functioning in multiple areas; and the change in daily levodopa/carbidopa dose.
- In one of the studies, 202 patients were randomized in 11 centers in the United States and Canada. In this trial, all patients were receiving concomitant levodopa and carbidopa. In the second trial, 177 patients were randomized in 24 centers in Europe. In this trial, all patients were receiving concomitant levodopa and benserazide.
- The following tables display the results of these 2 trials:
- In this study, 298 patients with idiopathic Parkinson's disease on stable doses of levodopa/carbidopa who were not experiencing wearing-off phenomena were randomized to placebo, tolcapone 100 mg tid, or tolcapone 200 mg tid for 6 months at 20 centers in the United States and Canada. The primary measure of effectiveness was the Activities of Daily Living portion (Subscale II) of the UPDRS. In addition, the change in daily levodopa dose, other subscales of the UPDRS, and the SIP were assessed as secondary measures. The results are displayed in the following table:
## Nonclinical Toxicology
- Carcinogenicity studies in which tolcapone was administered in the diet were conducted in mice and rats. Mice were treated for 80 (female) or 95 (male) weeks with doses of 100, 300 and 800 mg/kg/day, equivalent to 0.8, 1.6 and 4 times human exposure (AUC = 80 ug∙hr/mL) at the recommended daily clinical dose of 600 mg. Rats were treated for 104 weeks with doses of 50, 250 and 450 mg/kg/day. Tolcapone exposures were 1, 6.3 and 13 times the human exposure in male rats and 1.7, 11.8 and 26.4 times the human exposure in female rats. There was an increased incidence of uterine adenocarcinomas in female rats at exposure equivalent to 26.4 times the human exposure. There was evidence of renal tubular injury and renal tubular tumor formation in rats. A low incidence of renal tubular cell adenomas occurred in middle- and high-dose female rats; tubular cell carcinomas occurred in middle- and high-dose male and high-dose female rats, with a statistically significant increase in high-dose males. Exposures were equivalent to 6.3 (males) or 11.8 (females) times the human exposure or greater; no renal tumors were observed at exposures of 1 (males) or 1.7 (females) times the human exposure. Minimal-to-marked damage to the renal tubules, consisting of proximal tubule cell degeneration, single cell necrosis, hyperplasia and karyocytomegaly, occurred at the doses associated with renal tumors. Renal tubule damage, characterized by proximal tubule cell degeneration and the presence of atypical nuclei, as well as one adenocarcinoma in a high-dose male, were observed in a 1-year study in rats receiving doses of tolcapone of 150 and 450 mg/kg/day. These histopathological changes suggest the possibility that renal tumor formation might be secondary to chronic cell damage and sustained repair, but this relationship has not been established, and the relevance of these findings to humans is not known. There was no evidence of carcinogenic effects in the long-term mouse study. The carcinogenic potential of tolcapone in combination with levodopa/carbidopa has not been examined.
- Tolcapone was clastogenic in the in vitro mouse lymphoma/thymidine kinase assay in the presence of metabolic activation. Tolcapone was not mutagenic in the Ames test, the in vitro V79/HPRT gene mutation assay, or the unscheduled DNA synthesis assay. It was not clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes, or in an in vivo micronucleus assay in mice.
- Tolcapone did not affect fertility and general reproductive performance in rats at doses up to 300 mg/kg/day (5.7 times the human dose on a mg/m2 basis).
# Clinical Studies
There is limited information regarding Clinical Studies of Tolcapone in the drug label.
# How Supplied
- TASMAR is supplied as 100 mg film-coated tablets. The 100 mg tablets are beige, hexagonal and biconvex. Debossed on one side of the 100 mg tablet is TASMAR and the tablet strength (100), and on the other side is a V.
- TASMAR 100 mg Tablets: bottles of 90 (NDC 0187-0938-01).
## Storage
- Store in tight containers at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C-30°C (59°F-86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - 100 MG TABLET BOTTLE LABEL
NDC 0187-0938-01
Rx Only
Tasmar ®
(tolcapone)
100 mg
Each tablet
contains
100 mg tolcapone
90 Tablets
### Ingredients And Appearance
# Patient Counseling Information
- Patients should be instructed to take TASMAR only as prescribed.
- TASMAR should not be used by patients until there has been a complete discussion of the risks and the patient has provided written acknowledgement that the risks have been explained.
- Inform patients about clinical signs and symptoms that suggest the onset of hepatic injury (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness). If symptoms of hepatic failure occur, patients should be advised to contact their physician immediately.
- Inform patients of the need to have regular blood tests to monitor liver enzymes.
- Advise patients that sleepiness or drowsiness may occur and that they should not drive a car or operate other complex machinery until they have gained sufficient experience on TASMAR to gauge whether or not it adversely affects their mental and/or motor performance. Advise patients to exercise caution while driving, operating machines, or working at heights during treatment with TASMAR. Because of the possible additive sedative effects, caution should also be used when patients are taking other CNS depressants in combination with TASMAR. Inform patients that nausea may occur, especially at the initiation of treatment with TASMAR.
- Inform patients that hallucinations and other psychotic-like behavior may occur.
- Advise patients about the possibility of developing or worsening of existing dyskinesia and/or dystonia after starting TASMAR.
- Advise patients that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Advise patients to rise slowly, especially after long periods of sitting or lying down. Hypotension may be more likely when patients first start treatment with TASMAR.
- Instruct patients and caregivers to report intense urges to gamble, increased sexual urges, increase in spending money, binge eating, and other intense urges as well as the inability to control these urges to the prescriber while taking TASMAR.
- Although TASMAR has not been shown to be teratogenic in animals, it is always given in conjunction with levodopa/carbidopa, which is known to cause visceral and skeletal malformations in the rabbit. Accordingly, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy.
- Tolcapone is excreted into maternal milk in rats. Because of the possibility that tolcapone may be excreted into human milk, advise patients to notify their physicians if they intend to breastfeed or are breastfeeding an infant.
# Precautions with Alcohol
- Alcohol-Tolcapone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tasmar®[1]
# Look-Alike Drug Names
There is limited information regarding Tolcapone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tasmar | |
f27aee25fcdc0fcdece7118dbcfba130d0d89997 | wikidoc | Tedisamil | Tedisamil
# Overview
Tedisamil (3,7-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo-3,3,1-nonane) is an experimental class III antiarrhythmic agent currently being investigated for the treatment of atrial fibrillation. Tedisamil blocks multiple types of potassium channels in the heart resulting in slowed heart rate. While the effects of tedisamil have been demonstrated in both atrial and ventricular muscle, repolarization is prolonged more efficiently in the atria. Tedisamil is administered intravenously and has a half-life of approximately 8 –13 hours in circulation. Tedisamil is being developed as an alternative to other antiarrhythmics as incidence of additional arrhythmic events is lower compared to other class III agents. Tedisamil also has significant anti-ischemic properties and was initially investigated as a potential treatment for angina until its antiarrhythmic effects were discovered.
Tedisamil is manufactured by Solvay Pharmaceuticals Inc. under the proposed trade name Pulzium and is currently in phase III of clinical testing for atrial fibrillation.
# Molecular Problem
Arrhythmias are broadly defined as abnormal electrical activity in the heart and can affect both the atria and ventricles. Atrial arrhythmias are the most common type of arrhythmia with several subtypes currently described, including atrial fibrillation. In atrial fibrillation, there is continual quivering of the atria as contraction of the muscle is uncoordinated. Under normal conditions, an electrical impulse from the sinoatrial (SA) node is distributed rapidly throughout the atria causing coordinated excitement and inactivation of atrial muscle cell ion channels resulting in uniform contraction and relaxation of the muscle fibres. During fibrillation, other electrical signals overwhelm the SA node and ion channel excitement is no longer uniform throughout the atria. This results in inappropriate activation properties, further preventing uniform contraction and relaxation of the muscle. Subsequent action potentials from the SA node will not be able to uniformly excite the muscle as not all of the channels will be available to open as some will still be held in the inactivation phase. This results in disjointed contraction, or quivering, seen in the atrial muscle during fibrillation.
# Mechanism of Action
Tedisamil acts to restore normal electrical rhythm in the heart by prolonging the inactivation phase of the muscle. Both atrial and ventricular repolarization is lengthened by tedisamil by blocking multiple potassium channels including the transient outward (Ito), the adenosine triphosphate-dependent (IK-ATP), and the delayed rectifier potassium currents (IKr and IKs). Tedisamil action is dose dependent as currents are blocked longer and more effectively at higher concentrations. Tedisamil activity is greatest on Ito and acts by binding to the channel in its open configuration. This produces a blocked state and delays its inactivation. To restore normal function, tedisamil must unbind from the channel so that it can inactivate and eventually reopen. Similar mechanisms have been observed on the IKr and IKs currents. In both Ito and delayed rectifier channels, the tedisamil binding site appears to be internal as both binding and unbinding occur more effectively when tedisamil is applied inside the cell. Tedisamil also appears to provide specific, single channel blocking of IK-ATP at high concentrations. As the potassium channels are responsible for restoring the resting membrane potential during an action potential, lengthening their inactivation will stop the cycle of fibrillation by preventing muscle contraction until all ion channels are available to open. Regular use of tedisamil will prevent further fibrillation and restore normal electrical rhythm.
Tedisamil’s antiarrythmic activity also appears to be supported by inhibiting sodium currents in cardiac muscle. However this is only observed at concentrations above 20μM, concentrations 20-fold higher than required for potassium channel blocks. | Tedisamil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tedisamil (3,7-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo-3,3,1-nonane) is an experimental class III antiarrhythmic agent currently being investigated for the treatment of atrial fibrillation. Tedisamil blocks multiple types of potassium channels in the heart resulting in slowed heart rate. While the effects of tedisamil have been demonstrated in both atrial and ventricular muscle, repolarization is prolonged more efficiently in the atria.[1] Tedisamil is administered intravenously and has a half-life of approximately 8 –13 hours in circulation.[1] Tedisamil is being developed as an alternative to other antiarrhythmics as incidence of additional arrhythmic events is lower compared to other class III agents.[1] Tedisamil also has significant anti-ischemic properties and was initially investigated as a potential treatment for angina until its antiarrhythmic effects were discovered.[2]
Tedisamil is manufactured by Solvay Pharmaceuticals Inc. under the proposed trade name Pulzium and is currently in phase III of clinical testing for atrial fibrillation.[3]
# Molecular Problem
Arrhythmias are broadly defined as abnormal electrical activity in the heart and can affect both the atria and ventricles. Atrial arrhythmias are the most common type of arrhythmia with several subtypes currently described, including atrial fibrillation. In atrial fibrillation, there is continual quivering of the atria as contraction of the muscle is uncoordinated.[4] Under normal conditions, an electrical impulse from the sinoatrial (SA) node is distributed rapidly throughout the atria causing coordinated excitement and inactivation of atrial muscle cell ion channels resulting in uniform contraction and relaxation of the muscle fibres.[4] During fibrillation, other electrical signals overwhelm the SA node and ion channel excitement is no longer uniform throughout the atria.[4] This results in inappropriate activation properties, further preventing uniform contraction and relaxation of the muscle.[4] Subsequent action potentials from the SA node will not be able to uniformly excite the muscle as not all of the channels will be available to open as some will still be held in the inactivation phase.[4] This results in disjointed contraction, or quivering, seen in the atrial muscle during fibrillation.
# Mechanism of Action
Tedisamil acts to restore normal electrical rhythm in the heart by prolonging the inactivation phase of the muscle. Both atrial and ventricular repolarization is lengthened by tedisamil by blocking multiple potassium channels including the transient outward (Ito), the adenosine triphosphate-dependent (IK-ATP), and the delayed rectifier potassium currents (IKr and IKs).[5][6][7] Tedisamil action is dose dependent as currents are blocked longer and more effectively at higher concentrations.[1] Tedisamil activity is greatest on Ito and acts by binding to the channel in its open configuration.[5] This produces a blocked state and delays its inactivation.[5] To restore normal function, tedisamil must unbind from the channel so that it can inactivate and eventually reopen.[5] Similar mechanisms have been observed on the IKr and IKs currents.[6] In both Ito and delayed rectifier channels, the tedisamil binding site appears to be internal as both binding and unbinding occur more effectively when tedisamil is applied inside the cell.[6] Tedisamil also appears to provide specific, single channel blocking of IK-ATP at high concentrations.[7] As the potassium channels are responsible for restoring the resting membrane potential during an action potential, lengthening their inactivation will stop the cycle of fibrillation by preventing muscle contraction until all ion channels are available to open. Regular use of tedisamil will prevent further fibrillation and restore normal electrical rhythm.
Tedisamil’s antiarrythmic activity also appears to be supported by inhibiting sodium currents in cardiac muscle.[5] However this is only observed at concentrations above 20μM, concentrations 20-fold higher than required for potassium channel blocks.[5] | https://www.wikidoc.org/index.php/Tedisamil | |
f7c7e10088a181e125c7aed94c9823c5612351c7 | wikidoc | Tedizolid | Tedizolid
# Disclaimer
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# Overview
Tedizolid is an antibacterial that is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Common adverse reactions include diarrhea, nausea, vomiting, dizziness, aand headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tedizolid phosphate® is an oxazolidinone-class antibacterial indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant ]] and methicillin-susceptible MSSA isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), and Enterococcus faecalis.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of tedizolid phosphate and other antibacterial drugs, tedizolid phosphate should be used only to treat ABSSSI that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- The recommended dosage of tedizolid phosphate is 200 mg administered once daily for six (6) days either orally (with or without food) or as an intravenous (IV) infusion in patients 18 years of age or older.
- The recommended dosage and administration is described in TABLE 1.
- No dose adjustment is necessary when changing from intravenous to oral tedizolid phosphate.
- If patients miss a dose, they should take it as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, wait until their next scheduled dose.
- Tedizolid phosphate is supplied as a sterile, lyophilized powder for injection in single-use vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted only with 0.9% Sodium Chloride Injection, USP.
- Tedizolid phosphate vials contain no antimicrobial preservatives and are intended for single use only.
- The contents of the vial should be reconstituted using aseptic technique as follows:
Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
- Reconstitute the tedizolid phosphate vial with 4 mL of Sterile Water for Injection.
- Gently swirl the contents and let the vial stand until the cake has completely dissolved and any foam disperses.
- Inspect the vial to ensure the solution contains no particulate matter and no cake or powder remains attached to the sides of the vial. If necessary, invert the vial to dissolve any remaining powder and swirl gently to prevent foaming. The reconstituted solution is clear and colorless to pale-yellow in color; the total storage time should not exceed 24 hours at either room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F).
- Tilt the upright vial and insert a syringe with appropriately sized needle into the bottom corner of the vial and remove 4 mL of the reconstituted solution. Do not invert the vial during extraction.
- The reconstituted solution must be further diluted in 250 mL of 0.9% Sodium Chloride Injection, USP. Slowly inject the 4 mL of reconstituted solution into a 250 mL bag of 0.9% Sodium Chloride Injection, USP. Invert the bag gently to mix. Do NOT shake the bag as this may cause foaming.
- Administer as an intravenous infusion only.
- Do not administer as an intravenous push or bolus. Do not mix tedizolid phosphate with other drugs when administering. It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.
- The intravenous bag containing the reconstituted and diluted intravenous solution should be inspected visually for particulate matter prior to administration. Discard if visible particles are observed. The resulting solution is clear and colorless to pale-yellow in color.
- After reconstitution and dilution, tedizolid phosphate is to be administered via intravenous infusion using a total time of 1 hour.
- The total time from reconstitution to administration should not exceed 24 hours at room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F).
- Tedizolid phosphate is compatible with 0.9% Sodium Chloride Injection, USP.
- Tedizolid phosphate for injection is incompatible with any solution containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer's Injection and Hartmann's Solution.
- Limited data are available on the compatibility of tedizolid phosphate for injection with other intravenous substances, additives or other medications and they should not be added to tedizolid phosphate single-use vials or infused simultaneously. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of tedizolid phosphate with 0.9% Sodium Chloride Injection, USP.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tedizolid in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tedizolid in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tedizolid in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tedizolid in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tedizolid in pediatric patients.
# Contraindications
There is limited information regarding Tedizolid Contraindications in the drug label.
# Warnings
- The safety and efficacy of tedizolid phosphate in patients with neutropenia (neutrophil counts <1000 cells/mm3) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of tedizolid phosphate was reduced in the absence of granulocytes. Alternative therapies should be considered when treating patients with neutropenia and acute bacterial skin and skin structure infection.
- Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents including tedizolid phosphate, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
- Prescribing tedizolid phosphate in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice.
- Adverse reactions were evaluated for 1050 patients treated with tedizolid phosphate and 662 patients treated with the comparator antibacterial drug in two Phase 2 and two Phase 3 clinical trials. The median age of patients treated with tedizolid phosphate in the Phase 2 and Phase 3 trials was 42 years, ranging between 17 and 86 years old. Patients treated with tedizolid phosphate were predominantly male (65%) and White (82%).
- Serious adverse reactions occurred in 12/662 (1.8%) of patients treated with tedizolid phosphate and in 13/662 (2.0%) of patients treated with the comparator. tedizolid phosphate was discontinued due to an adverse reaction in 3/662 (0.5%) of patients and the comparator was discontinued due to an adverse reaction in 6/662 (0.9%) of patients.
- The most common adverse reactions in patients treated with tedizolid phosphate were nausea (8%), headache (6%), diarrhea (4%), vomiting (3%), and dizziness (2%). The median time of onset of adverse reactions was 5 days for both tedizolid phosphate and linezolid with 12% occurring on the second day of treatment in both treatment groups.
- TABLE 2 lists selected adverse reactions occurring in at least 2% of patients treated with tedizolid phosphate in clinical trials.
- The following selected adverse reactions were reported in tedizolid phosphate-treated patients at a rate of less than 2% in these clinical trials:
- Blood and Lymphatic System Disorders: anemia
- Cardiovascular: palpitations, tachycardia
- Eye Disorders: asthenopia, vision blurred, visual impairment, vitreous floaters
- General Disorders and Administration Site Conditions: infusion-related reactions
- Immune System Disorders: drug hypersensitivity
- Infections and Infestations: Clostridium difficile colitis, oral candidiasis, vulvovaginal mycotic infection
- Investigations: hepatic transaminases increased, white blood cell count decreased
- Nervous System Disorders: hypoesthesia, paresthesia, VIIth nerve paralysis
- Psychiatric Disorders: insomnia
- (Skin and Subcutaneous Tissue Disorders: pruritus, urticaria, dermatitis
- Vascular Disorders: flushing, hypertension
- Laboratory Parameters
- Hematology laboratory abnormalities that were determined to be potentially clinically significant in the pooled Phase 3 ABSSSI clinical trials are provided in TABLE 3.
- Phase 1 studies conducted in healthy adults exposed to tedizolid phosphate for 21 days showed a possible dose and duration effect on hematologic parameters beyond 6 days of treatment. In the Phase 3 trials, clinically significant changes in these parameters were generally similar for both treatment arms (seeTABLE 3).
- Peripheral and optic neuropathy have been described in patients treated with another member of the oxazolidinone class for longer than 28 days. In Phase 3 trials, reported adverse reactions for peripheral neuropathy and optic nerve disorders were similar between both treatment arms (peripheral neuropathy 1.2% vs. 0.6% for tedizolid phosphate and linezolid, respectively; optic nerve disorders 0.3% vs. 0.2%, respectively). No data are available for patients exposed to tedizolid phosphate for longer than 6 days.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tedizolid in the drug label.
# Drug Interactions
There is limited information regarding Tedizolid Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of tedizolid phosphate in pregnant women. tedizolid phosphate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In embryo-fetal studies, tedizolid phosphate was shown to produce fetal developmental toxicities in mice, rats, and rabbits. Fetal developmental effects occurring in mice in the absence of maternal toxicity included reduced fetal weights and an increased incidence of costal cartilage anomalies at the high dose of 25 mg/kg/day (4-fold the estimated human exposure level based on AUCs). In rats, decreased fetal weights and increased skeletal variations including reduced ossification of the sternabrae, vertebrae, and skull were observed at the high dose of 15 mg/kg/day (6-fold the estimated human exposure based on AUCs) and were associated with maternal toxicity (reduced maternal body weights). In rabbits, reduced fetal weights but no malformations or variations were observed at doses associated with maternal toxicity. The no observed adverse effect levels (NOAELs) for fetal toxicity in mice (5 mg/kg/day), maternal and fetal toxicity in rats (2.5 mg/kg/day), and rabbits (1 mg/kg/day) were associated with tedizolid plasma area under the curve (AUC) values approximately equivalent to (mice and rats) or 0.04-fold (rabbit) the tedizolid AUC value associated with the oral human therapeutic dose.
- In a pre-postnatal study, there were no adverse maternal or offspring effects when female rats were treated during pregnancy and lactation with tedizolid phosphate at the highest tested dose of 3.75 mg/kg/day, with plasma tedizolid exposure (AUC) approximately equivalent to the human plasma AUC exposure at the clinical dose of 200 mg/day.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tedizolid in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tedizolid during labor and delivery.
### Nursing Mothers
- Tedizolid is excreted in the breast milk of rats. It is not known whether tedizolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tedizolid phosphate is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 have not been established.
### Geriatic Use
- Clinical studies of tedizolid phosphate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. No overall differences in pharmacokinetics were observed between elderly subjects and younger subjects.
### Gender
There is no FDA guidance on the use of Tedizolid with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tedizolid with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tedizolid in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tedizolid in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tedizolid in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tedizolid in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Tedizolid in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tedizolid in the drug label.
# Overdosage
- In the event of overdosage, tedizolid phosphate should be discontinued and general supportive treatment given. Hemodialysis does not result in meaningful removal of tedizolid from systemic circulation.
# Pharmacology
## Mechanism of Action
- Tedizolid phosphate is the prodrug of tedizolid, an antibacterial agent Microbiology
- Tedizolid belongs to the oxazolidinone class of antibacterial drugs.
- Mechanism of Action
- The antibacterial activity of tedizolid is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis. Tedizolid inhibits bacterial protein synthesis through a mechanism of action different from that of other non-oxazolidinone class antibacterial drugs; therefore, cross-resistance between tedizolid and other classes of antibacterial drugs is unlikely. The results of in vitro time-kill studies show that tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci.
- Mechanism of Resistance
- Organisms resistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins (L3 and L4) are generally cross-resistant to tedizolid. In the limited number of Staphylococcus aureus strains tested, the presence of the chloramphenicol-florfenicol resistance (cfr) gene did not result in resistance to tedizolid in the absence of chromosomal mutations.
- Frequency of Resistance
- Spontaneous mutations conferring reduced susceptibility to tedizolid occur in vitro at a frequency rate of approximately 10-10.
- Interaction with Other Antimicrobial Drugs
- In vitro drug combination studies with tedizolid and aztreonam, ceftriaxone, ceftazidime, imipenem, rifampin, trimethoprim/sulfamethoxazole, minocycline, clindamycin, ciprofloxacin, daptomycin, vancomycin, gentamicin, amphotericin B, ketoconazole, and terbinafine demonstrate neither synergy nor antagonism.
- Spectrum of Activity
- Tedizolid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections, as described in Indications and Usage (1).
- Aerobic and Facultative Gram-positive Bacteria
- Staphylococcus aureus (including methicillin-resistant and methicillin-susceptible isolates)
- Streptococcus pyogenes
- Streptococcus agalactiae
- Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S. constellatus)
- Enterococcus faecalis
- The following in vitro data are available, but their clinical significance has not been established. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to 0.5 mcg/mL for tedizolid. However, the safety and effectiveness of tedizolid phosphate in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
- Aerobic and Facultative Anaerobic Gram-positive Bacteria
- Staphylococcus epidermidis (including methicillin-susceptible and methicillin-resistant isolates)
- Staphylococcus haemolyticus
- Staphylococcus lugdunensis
- Enterococcus faecium
- Susceptibility Test Methods
- When available, the clinical microbiology laboratory should provide cumulative results of the in vitrosusceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an effective antibacterial drug for treatment.
- Dilution Techniques
- Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MIC values provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC values should be determined using a standardized procedure based on dilution methods (broth, agar, or microdilution) or equivalent using standardized inoculum and concentrations of tedizolid.1, 3The MIC values should be interpreted according to the criteria provided in TABLE 5.
- Diffusion techniques
- Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure requires the use of standardized inoculum concentrations.2, 3 This procedure uses paper disks impregnated with 20 mcg tedizolid to test the susceptibility of microorganisms to tedizolid. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 20 mcg tedizolid disk should be interpreted according to the criteria in TABLE 5.
- A report of "Susceptible" indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative drugs, the test should be repeated. This category implies possible clinical efficacy in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
- Quality Control
- Standardized susceptibility test procedures require the use of laboratory control microorganisms to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1, 2, 3 Standardized tedizolid powder should provide the following range of MIC values noted in TABLE 6. For the diffusion technique using the 20 mcg tedizolid disk, results within the ranges specified in TABLE 6 should be observed.
## Structure
- tedizolid phosphate (tedizolid phosphate), a phosphate prodrug, is converted to tedizolid in the presence of phosphatases.
- Tedizolid phosphate has the chemical name phenyl}-2-oxooxazolidin- 5-yl]methyl hydrogen phosphate.
- Its empirical formula is C17H16FN6O6P and its molecular weight is 450.32. Its structural formula is:
- Tedizolid phosphate is a white to yellow solid and is administered orally or by intravenous infusion.
- The pharmacologically active moiety, tedizolid, is an antibacterial agent of the oxazolidinone class.
- tablets contain 200 mg of tedizolid phosphate, and the following inactive ingredients: microcrystalline cellulose, mannitol, crospovidone, povidone, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc, and yellow iron oxide.
- tedizolid phosphate for injection is a sterile, white to off-white sterile lyophilized powder for injection in single-use vials of 200 mg. The inactive ingredients are mannitol (105 mg), sodium hydroxide, and hydrochloric acid, which is used in minimal quantities for pH adjustment.
## Pharmacodynamics
- The AUC/minimum inhibitory concentration (MIC) was shown to best correlate with tedizolid activity in animal infection models.
- In the mouse thigh infection model of S. aureus, antistaphylococcal killing activity was impacted by the presence of granulocytes. In granulocytopenic mice (neutrophil count <100 cells/mL), bacterial stasis was achieved at a human-equivalent dose of approximately 2000 mg/day; whereas, in non-granulocytopenic animals, stasis was achieved at a human-equivalent dose of approximately 100 mg/day. The safety and efficacy of tedizolid phosphate for the treatment of neutropenic patients (neutrophil counts <1000 cells/mm3) have not been evaluated.
- In a randomized, positive- and placebo-controlled crossover thorough QTc study, 48 enrolled subjects were administered a single oral dose of tedizolid phosphate at a therapeutic dose of 200 mg, tedizolid phosphate at a supratherapeutic dose of 1200 mg, placebo, and a positive control; no significant effects of tedizolid phosphate on heart rate, electrocardiogram morphology, PR, QRS, or QT interval were detected. Therefore, tedizolid phosphate does not affect cardiac repolarization.
## Pharmacokinetics
- Tedizolid phosphate is a prodrug that is converted by phosphatases to tedizolid, the microbiologically active moiety, following oral and intravenous administration. Only the pharmacokinetic profile of tedizolid is discussed further due to negligible systemic exposure of tedizolid phosphate following oral and intravenous administration. Following multiple once-daily oral or intravenous administration, steady-state concentrations are achieved within approximately three days with tedizolid accumulation of approximately 30% (tedizolid half-life of approximately 12 hours). Pharmacokinetic (PK) parameters of tedizolid following oral and intravenous administration of 200 mg once daily tedizolid phosphate are shown in TABLE 4.
- Absorption
- Peak plasma tedizolid concentrations are achieved within approximately 3 hours following oral administration under fasting conditions or at the end of the 1 hour intravenous infusion of tedizolid phosphate. The absolute bioavailability is approximately 91% and no dosage adjustment is necessary between intravenous and oral administration.
- Tedizolid phosphate (oral) may be administered with or without food as total systemic exposure (AUC0-∞) is unchanged between fasted and fed (high-fat, high-calorie) conditions.
- Distribution
- Protein binding of tedizolid to human plasma proteins is approximately 70 to 90%. The mean steady state volume of distribution of tedizolid in healthy adults following a single intravenous dose of tedizolid phosphate 200 mg ranged from 67 to 80 L (approximately twice total body water). Tedizolid penetrates into the interstitial space fluid of adipose and skeletal muscle tissue with exposure similar to free drug exposure in plasma.
- Metabolism
- Other than tedizolid, which accounts for approximately 95% of the total radiocarbon AUC in plasma, there are no other significant circulating metabolites in humans.
- There was no degradation of tedizolid in human liver microsomes indicating tedizolid is unlikely to be a substrate for hepatic CYP450 enzymes.
- Excretion
- Following single oral administration of 14C-labeled tedizolid phosphate under fasted conditions, the majority of elimination occurred via the liver, with 82% of the radioactive dose recovered in feces and 18% in urine, primarily as a non-circulating and microbiologically inactive sulfate conjugate. Most of the elimination of tedizolid (>85%) occurs within 96 hours. Less than 3% of the tedizolid phosphate-administered dose is excreted in feces and urine as unchanged tedizolid.
- Specific Populations
- Based on the population pharmacokinetic analysis, there are no clinically relevant demographic or clinical patient factors (including age, gender, race, ethnicity, weight, body mass index, and measures of renal or liver function) that impact the pharmacokinetics of tedizolid.
- Hepatic Impairment
- Following administration of a single 200 mg oral dose of tedizolid phosphate, no clinically meaningful changes in mean tedizolid Cmax and AUC0-∞ were observed in patients with moderate (n=8) or severe (n=8) hepatic impairment (Child-Pugh Class B and C) compared to 8 matched healthy control subjects. No dose adjustment is necessary for patients with hepatic impairment.
- Renal Impairment
- Following administration of a single 200 mg intravenous dose of tedizolid phosphate to 8 subjects with severe renal impairment defined as eGFR <30 mL/min/1.73 m2, the Cmax was essentially unchanged and AUC0-∞ was decreased by less than 10% compared to 8 matched healthy control subjects. Hemodialysis does not result in meaningful removal of tedizolid from systemic circulation, as assessed in subjects with end-stage renal disease (eGFR <15 mL/min/1.73 m2). No dosage adjustment is necessary in patients with renal impairment or patients on hemodialysis.
- Geriatric Patients
- The pharmacokinetics of tedizolid were evaluated in a Phase 1 study conducted in elderly healthy volunteers (age 65 years and older, with at least 5 subjects at least 75 years old; n=14) compared to younger control subjects (25 to 45 years old; n=14) following administration of a single oral dose of tedizolid phosphate 200 mg. There were no clinically meaningful differences in tedizolid Cmax and AUC0-∞between elderly subjects and younger control subjects. No dosage adjustment of tedizolid phosphate is necessary in elderly patients.
- Gender
- The impact of gender on the pharmacokinetics of tedizolid phosphate was evaluated in clinical trials of healthy males and females and in a population pharmacokinetics analysis. The pharmacokinetics of tedizolid were similar in males and females. No dosage adjustment of tedizolid phosphate is necessary based on gender.
- Drug Interaction Studies
- Drug Metabolizing Enzymes
- Transformation via Phase 1 hepatic oxidative metabolism is not a significant pathway for elimination of tedizolid phosphate.
- Neither tedizolid phosphate nor tedizolid detectably inhibited or induced the metabolism of selected CYP enzyme substrates. No potential drug interactions with tedizolid were identified in in vitro CYP inhibition or induction studies. These results suggest that drug-drug interactions based on oxidative metabolism are unlikely.
- Membrane Transporters
- The potential for tedizolid or tedizolid phosphate to inhibit transport of probe substrates of important drug uptake (OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2) and efflux transporters (P-gp and ABCG2 ) was tested in vitro. No clinically significant inhibition of any transporter was observed at tedizolid circulating plasma concentrations up to the Cmax.
- Monoamine Oxidase Inhibition
- Tedizolid is a reversible inhibitor of monoamine oxidase (MAO) in vitro. The interaction with MAO inhibitors could not be evaluated in Phase 2 and 3 trials, as subjects taking such medications were excluded from the trials.
- Adrenergic Agents
- Two placebo-controlled crossover studies were conducted to assess the potential of 200 mg oral tedizolid phosphate at steady state to enhance pressor responses to pseudoephedrine and tyramine in healthy individuals. No meaningful changes in blood pressure or heart rate were seen with pseudoephedrine. The median tyramine dose required to cause an increase in systolic blood pressure of ≥30 mmHg from pre-dose baseline was 325 mg with tedizolid phosphate compared to 425 mg with placebo. Palpitations were reported in 21/29 (72.4%) subjects exposed to tedizolid phosphate compared to 13/28 (46.4%) exposed to placebo in the tyramine challenge study.
- Serotonergic Agents
- Serotonergic effects at doses of tedizolid phosphate up to 30-fold above the human equivalent dose did not differ from vehicle control in a mouse model that predicts serotonergic activity.
- In Phase 3 trials, subjects taking serotonergic agents including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin 5-hydroxytryptamine (5-HT1) receptor agonists (triptans), meperidine, or buspirone were excluded.
## Nonclinical Toxicology
- Long-term carcinogenicity studies have not been conducted with tedizolid phosphate.
- Tedizolid phosphate was negative for genotoxicity in all in vitro assays (bacterial reverse mutation (Ames), Chinese hamster lung (CHL) cell chromosomal aberration) and in all in vivo tests (mouse bone marrow micronucleus, rat liver unscheduled DNA synthesis). Tedizolid, generated from tedizolid phosphate after metabolic activation (in vitro and in vivo), was also tested for genotoxicity. Tedizolid was positive in an in vitro CHL cell chromosomal aberration assay, but negative for genotoxicity in other in vitro assays (Ames, mouse lymphoma mutagenicity) and in vivo in a mouse bone marrow micronucleus assay.
- In a fertility study, oral tedizolid phosphate had no adverse effects on the fertility or reproductive performance, including spermatogenesis, of male rats at the maximum tested dose (50 mg/kg/day) with a plasma tedizolid AUC approximately 5-fold greater than the plasma AUC value in humans at the oral therapeutic dose. Tedizolid phosphate also had no adverse effects on the fertility or reproductive performance of adult female rats at doses up to the maximum tested (15 mg/kg/day). Plasma tedizolid exposure (AUC) at this NOAEL in female rats was approximately 4-fold higher than that in humans at the oral therapeutic dose.
- Repeated-oral and intravenous dosing of tedizolid phosphate in rats in 1-month and 3-month toxicology studies produced dose- and time-dependent bone marrow hypocellularity (myeloid, erythroid, and megakaryocyte), with associated reduction in circulating RBCs, WBCs, and platelets. These effects showed evidence of reversibility and occurred at plasma tedizolid exposure levels (AUC) ≥6-fold greater than the plasma exposure associated with the human therapeutic dose. In a 1-month immunotoxicology study in rats, repeated oral dosing of tedizolid phosphate was shown to significantly reduce splenic B cells and T cells and reduce plasma IgG titers. These effects occurred at plasma tedizolid exposure levels (AUC) ≥3-fold greater than the expected human plasma exposure associated with the therapeutic dose.
# Clinical Studies
- A total of 1315 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized in two multicenter, multinational, double-blind, non-inferiority trials. Both trials compared tedizolid phosphate 200 mg once daily for 6 days versus linezolid 600 mg every 12 hours for 10 days. In Trial 1, patients were treated with oral therapy, while in Trial 2, patients could receive oral therapy after a minimum of one day of intravenous therapy. Patients with cellulitis/erysipelas, major cutaneous abscess, or wound infection were enrolled in the trials. Patients with wound infections could have received aztreonam and/or metronidazole as adjunctive therapy for gram-negative bacterial coverage, if needed. The intent-to-treat (ITT) patient population included all randomized patients.
- In Trial 1, 332 patients with ABSSSI were randomized to tedizolid phosphate and 335 patients were randomized to linezolid. The majority (91%) of patients treated with tedizolid phosphate in Trial 1 were less than 65 years old with a median age of 43 years (range: 18 to 86 years). Patients treated with tedizolid phosphate were predominantly male (61%) and White (84%); 13% had BMI ≥35 kg/m2, 8% had diabetes mellitus, 35% were current or recent intravenous drug users, and 2% had moderate to severe renal impairment. The overall median surface area of infection was 188 cm2. The types of ABSSSI included were cellulitis/erysipelas (41%), wound infection (29%), and major cutaneous abscess (30%). In addition to local signs and symptoms of infection, patients were also required to have at least one regional or systemic sign of infection at baseline, defined as lymphadenopathy (87% of patients), temperature 38°C or higher (16% of patients), white blood cell count greater than 10,000 cells/mm3 or less than 4000 cells/mm3 (42%), or 10% or more band forms on white blood cell differential (4%).
- The primary endpoint in Trial 1 was early clinical response defined as no increase from baseline lesion area at 48-72 hours after the first dose and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours in the ITT population.
- In Trial 2, 332 patients with ABSSSI were randomized to tedizolid phosphate and 334 patients were randomized to linezolid. The majority (87%) of patients treated with tedizolid phosphate in Trial 2 were less than 65 years old with a median age of 46 years (range: 17 to 86 years). Patients treated with tedizolid phosphate were predominantly male (68%) and White (86%); 16% had BMI ≥35 kg/m2, 10% had diabetes mellitus, 20% were current or recent intravenous drug users, and 4% had moderate to severe renal impairment. The overall median surface area of infection was 231 cm2. The types of ABSSSI included were cellulitis/erysipelas (50%), wound infection (30%), and major cutaneous abscess (20%). In addition to local signs and symptoms of infection, patients were also required to have at least one regional or systemic sign of infection at baseline, defined as lymphadenopathy (71% of patients), temperature 38°C or higher (31% of patients), white blood cell count greater than 10,000 cells/mm3 or less than 4000 cells/mm3 (53%), or 10% or more band forms on white blood cell differential (16%). The primary endpoint in Trial 2 was early clinical response defined as at least a 20% decrease from baseline lesion area at 48-72 hours after the first dose in the ITT population (TABLE 7).
- An investigator assessment of clinical response was made at the post-therapy evaluation (PTE) (7 - 14 days after the end of therapy) in the ITT and CE (Clinically Evaluable) populations. Clinical success was defined as resolution or near resolution of most disease-specific signs and symptoms, absence or near resolution of systemic signs of infection if present at baseline (lymphadenopathy, fever, >10% immature neutrophils, abnormal WBC count), and no new signs, symptoms, or complications attributable to the ABSSSI requiring further treatment of the primary lesion
# How Supplied
- tedizolid phosphate tablets are yellow film-coated oval tablets containing 200 mg of tedizolid phosphate; each tablet is debossed with "TZD" on one side and "200" on the other side.
- They are supplied as follows:
- HDPE bottles of 30 tablets with child-resistant closure (NDC 67919-041-01)
- Unit dose blister packs of 6 tablets (NDC 67919-041-02)
- tedizolid phosphate is supplied as a sterile, lyophilized powder for injection in single-use vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted only with 0.9% Sodium Chloride Injection, USP.
- They are supplied as follows:
- Package of ten 200 mg single-dose vials (NDC 67919-040-01)
## Storage
- tedizolid phosphate tablets and tedizolid phosphate for injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed that tedizolid phosphate tablets may be taken with or without food and without any dietary restrictions .
- Patients should be advised that antibacterial drugs including tedizolid phosphate should only be used to treat bacterial infections. tedizolid phosphate does not treat viral infections (e.g., the common cold). When tedizolid phosphate is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by tedizolid phosphate or other antibacterial drugs in the future.
- Patients should be informed that if they miss a dose, they should take the dose as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remains before the next dose, then they should wait until their next scheduled dose. Patients should take the prescribed number of doses .
- Keep tedizolid phosphate and all medications out of reach of children.
- Patients should be advised that diarrhea is a common problem caused by antibacterial drugs including tedizolid phosphate and usually resolves when the drug is discontinued. Sometimes after starting treatment with antibiotics, patients can develop frequent watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic and may be a sign of a more serious intestinal infection .If this occurs, patients should contact their healthcare provider as soon as possible.
# Precautions with Alcohol
- Alcohol-Tedizolid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SIVEXTRO
# Look-Alike Drug Names
There is limited information regarding Tedizolid Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tedizolid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Overview
Tedizolid is an antibacterial that is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Common adverse reactions include diarrhea, nausea, vomiting, dizziness, aand headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tedizolid phosphate® is an oxazolidinone-class antibacterial indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant [[[MRSA]]] and methicillin-susceptible MSSA isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), and Enterococcus faecalis.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of tedizolid phosphate and other antibacterial drugs, tedizolid phosphate should be used only to treat ABSSSI that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- The recommended dosage of tedizolid phosphate is 200 mg administered once daily for six (6) days either orally (with or without food) or as an intravenous (IV) infusion in patients 18 years of age or older.
- The recommended dosage and administration is described in TABLE 1.
- No dose adjustment is necessary when changing from intravenous to oral tedizolid phosphate.
- If patients miss a dose, they should take it as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remain before the next dose, wait until their next scheduled dose.
- Tedizolid phosphate is supplied as a sterile, lyophilized powder for injection in single-use vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted only with 0.9% Sodium Chloride Injection, USP.
- Tedizolid phosphate vials contain no antimicrobial preservatives and are intended for single use only.
- The contents of the vial should be reconstituted using aseptic technique as follows:
Note: To minimize foaming, AVOID vigorous agitation or shaking of the vial during or after reconstitution.
- Reconstitute the tedizolid phosphate vial with 4 mL of Sterile Water for Injection.
- Gently swirl the contents and let the vial stand until the cake has completely dissolved and any foam disperses.
- Inspect the vial to ensure the solution contains no particulate matter and no cake or powder remains attached to the sides of the vial. If necessary, invert the vial to dissolve any remaining powder and swirl gently to prevent foaming. The reconstituted solution is clear and colorless to pale-yellow in color; the total storage time should not exceed 24 hours at either room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F).
- Tilt the upright vial and insert a syringe with appropriately sized needle into the bottom corner of the vial and remove 4 mL of the reconstituted solution. Do not invert the vial during extraction.
- The reconstituted solution must be further diluted in 250 mL of 0.9% Sodium Chloride Injection, USP. Slowly inject the 4 mL of reconstituted solution into a 250 mL bag of 0.9% Sodium Chloride Injection, USP. Invert the bag gently to mix. Do NOT shake the bag as this may cause foaming.
- Administer as an intravenous infusion only.
- Do not administer as an intravenous push or bolus. Do not mix tedizolid phosphate with other drugs when administering. It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.
- The intravenous bag containing the reconstituted and diluted intravenous solution should be inspected visually for particulate matter prior to administration. Discard if visible particles are observed. The resulting solution is clear and colorless to pale-yellow in color.
- After reconstitution and dilution, tedizolid phosphate is to be administered via intravenous infusion using a total time of 1 hour.
- The total time from reconstitution to administration should not exceed 24 hours at room temperature or under refrigeration at 2°C to 8°C (36°F to 46°F).
- Tedizolid phosphate is compatible with 0.9% Sodium Chloride Injection, USP.
- Tedizolid phosphate for injection is incompatible with any solution containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer's Injection and Hartmann's Solution.
- Limited data are available on the compatibility of tedizolid phosphate for injection with other intravenous substances, additives or other medications and they should not be added to tedizolid phosphate single-use vials or infused simultaneously. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of tedizolid phosphate with 0.9% Sodium Chloride Injection, USP.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tedizolid in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tedizolid in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tedizolid in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tedizolid in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tedizolid in pediatric patients.
# Contraindications
There is limited information regarding Tedizolid Contraindications in the drug label.
# Warnings
- The safety and efficacy of tedizolid phosphate in patients with neutropenia (neutrophil counts <1000 cells/mm3) have not been adequately evaluated. In an animal model of infection, the antibacterial activity of tedizolid phosphate was reduced in the absence of granulocytes. Alternative therapies should be considered when treating patients with neutropenia and acute bacterial skin and skin structure infection.
- Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents including tedizolid phosphate, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
- Prescribing tedizolid phosphate in the absence of a proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice.
- Adverse reactions were evaluated for 1050 patients treated with tedizolid phosphate and 662 patients treated with the comparator antibacterial drug in two Phase 2 and two Phase 3 clinical trials. The median age of patients treated with tedizolid phosphate in the Phase 2 and Phase 3 trials was 42 years, ranging between 17 and 86 years old. Patients treated with tedizolid phosphate were predominantly male (65%) and White (82%).
- Serious adverse reactions occurred in 12/662 (1.8%) of patients treated with tedizolid phosphate and in 13/662 (2.0%) of patients treated with the comparator. tedizolid phosphate was discontinued due to an adverse reaction in 3/662 (0.5%) of patients and the comparator was discontinued due to an adverse reaction in 6/662 (0.9%) of patients.
- The most common adverse reactions in patients treated with tedizolid phosphate were nausea (8%), headache (6%), diarrhea (4%), vomiting (3%), and dizziness (2%). The median time of onset of adverse reactions was 5 days for both tedizolid phosphate and linezolid with 12% occurring on the second day of treatment in both treatment groups.
- TABLE 2 lists selected adverse reactions occurring in at least 2% of patients treated with tedizolid phosphate in clinical trials.
- The following selected adverse reactions were reported in tedizolid phosphate-treated patients at a rate of less than 2% in these clinical trials:
- Blood and Lymphatic System Disorders: anemia
- Cardiovascular: palpitations, tachycardia
- Eye Disorders: asthenopia, vision blurred, visual impairment, vitreous floaters
- General Disorders and Administration Site Conditions: infusion-related reactions
- Immune System Disorders: drug hypersensitivity
- Infections and Infestations: Clostridium difficile colitis, oral candidiasis, vulvovaginal mycotic infection
- Investigations: hepatic transaminases increased, white blood cell count decreased
- Nervous System Disorders: hypoesthesia, paresthesia, VIIth nerve paralysis
- Psychiatric Disorders: insomnia
- (Skin and Subcutaneous Tissue Disorders: pruritus, urticaria, dermatitis
- Vascular Disorders: flushing, hypertension
- Laboratory Parameters
- Hematology laboratory abnormalities that were determined to be potentially clinically significant in the pooled Phase 3 ABSSSI clinical trials are provided in TABLE 3.
- Phase 1 studies conducted in healthy adults exposed to tedizolid phosphate for 21 days showed a possible dose and duration effect on hematologic parameters beyond 6 days of treatment. In the Phase 3 trials, clinically significant changes in these parameters were generally similar for both treatment arms (seeTABLE 3).
- Peripheral and optic neuropathy have been described in patients treated with another member of the oxazolidinone class for longer than 28 days. In Phase 3 trials, reported adverse reactions for peripheral neuropathy and optic nerve disorders were similar between both treatment arms (peripheral neuropathy 1.2% vs. 0.6% for tedizolid phosphate and linezolid, respectively; optic nerve disorders 0.3% vs. 0.2%, respectively). No data are available for patients exposed to tedizolid phosphate for longer than 6 days.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tedizolid in the drug label.
# Drug Interactions
There is limited information regarding Tedizolid Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of tedizolid phosphate in pregnant women. tedizolid phosphate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In embryo-fetal studies, tedizolid phosphate was shown to produce fetal developmental toxicities in mice, rats, and rabbits. Fetal developmental effects occurring in mice in the absence of maternal toxicity included reduced fetal weights and an increased incidence of costal cartilage anomalies at the high dose of 25 mg/kg/day (4-fold the estimated human exposure level based on AUCs). In rats, decreased fetal weights and increased skeletal variations including reduced ossification of the sternabrae, vertebrae, and skull were observed at the high dose of 15 mg/kg/day (6-fold the estimated human exposure based on AUCs) and were associated with maternal toxicity (reduced maternal body weights). In rabbits, reduced fetal weights but no malformations or variations were observed at doses associated with maternal toxicity. The no observed adverse effect levels (NOAELs) for fetal toxicity in mice (5 mg/kg/day), maternal and fetal toxicity in rats (2.5 mg/kg/day), and rabbits (1 mg/kg/day) were associated with tedizolid plasma area under the curve (AUC) values approximately equivalent to (mice and rats) or 0.04-fold (rabbit) the tedizolid AUC value associated with the oral human therapeutic dose.
- In a pre-postnatal study, there were no adverse maternal or offspring effects when female rats were treated during pregnancy and lactation with tedizolid phosphate at the highest tested dose of 3.75 mg/kg/day, with plasma tedizolid exposure (AUC) approximately equivalent to the human plasma AUC exposure at the clinical dose of 200 mg/day.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tedizolid in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tedizolid during labor and delivery.
### Nursing Mothers
- Tedizolid is excreted in the breast milk of rats. It is not known whether tedizolid is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tedizolid phosphate is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 have not been established.
### Geriatic Use
- Clinical studies of tedizolid phosphate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. No overall differences in pharmacokinetics were observed between elderly subjects and younger subjects.
### Gender
There is no FDA guidance on the use of Tedizolid with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tedizolid with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tedizolid in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tedizolid in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tedizolid in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tedizolid in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Tedizolid in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tedizolid in the drug label.
# Overdosage
- In the event of overdosage, tedizolid phosphate should be discontinued and general supportive treatment given. Hemodialysis does not result in meaningful removal of tedizolid from systemic circulation.
# Pharmacology
## Mechanism of Action
- Tedizolid phosphate is the prodrug of tedizolid, an antibacterial agent Microbiology
- Tedizolid belongs to the oxazolidinone class of antibacterial drugs.
- Mechanism of Action
- The antibacterial activity of tedizolid is mediated by binding to the 50S subunit of the bacterial ribosome resulting in inhibition of protein synthesis. Tedizolid inhibits bacterial protein synthesis through a mechanism of action different from that of other non-oxazolidinone class antibacterial drugs; therefore, cross-resistance between tedizolid and other classes of antibacterial drugs is unlikely. The results of in vitro time-kill studies show that tedizolid is bacteriostatic against enterococci, staphylococci, and streptococci.
- Mechanism of Resistance
- Organisms resistant to oxazolidinones via mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins (L3 and L4) are generally cross-resistant to tedizolid. In the limited number of Staphylococcus aureus strains tested, the presence of the chloramphenicol-florfenicol resistance (cfr) gene did not result in resistance to tedizolid in the absence of chromosomal mutations.
- Frequency of Resistance
- Spontaneous mutations conferring reduced susceptibility to tedizolid occur in vitro at a frequency rate of approximately 10-10.
- Interaction with Other Antimicrobial Drugs
- In vitro drug combination studies with tedizolid and aztreonam, ceftriaxone, ceftazidime, imipenem, rifampin, trimethoprim/sulfamethoxazole, minocycline, clindamycin, ciprofloxacin, daptomycin, vancomycin, gentamicin, amphotericin B, ketoconazole, and terbinafine demonstrate neither synergy nor antagonism.
- Spectrum of Activity
- Tedizolid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections, as described in Indications and Usage (1).
- Aerobic and Facultative Gram-positive Bacteria
- Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates)
- Streptococcus pyogenes
- Streptococcus agalactiae
- Streptococcus anginosus Group (including S. anginosus, S. intermedius, and S. constellatus)
- Enterococcus faecalis
- The following in vitro data are available, but their clinical significance has not been established. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to 0.5 mcg/mL for tedizolid. However, the safety and effectiveness of tedizolid phosphate in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
- Aerobic and Facultative Anaerobic Gram-positive Bacteria
- Staphylococcus epidermidis (including methicillin-susceptible and methicillin-resistant isolates)
- Staphylococcus haemolyticus
- Staphylococcus lugdunensis
- Enterococcus faecium
- Susceptibility Test Methods
- When available, the clinical microbiology laboratory should provide cumulative results of the in vitrosusceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an effective antibacterial drug for treatment.
- Dilution Techniques
- Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MIC values provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC values should be determined using a standardized procedure based on dilution methods (broth, agar, or microdilution) or equivalent using standardized inoculum and concentrations of tedizolid.1, 3The MIC values should be interpreted according to the criteria provided in TABLE 5.
- Diffusion techniques
- Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure requires the use of standardized inoculum concentrations.2, 3 This procedure uses paper disks impregnated with 20 mcg tedizolid to test the susceptibility of microorganisms to tedizolid. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 20 mcg tedizolid disk should be interpreted according to the criteria in TABLE 5.
- A report of "Susceptible" indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative drugs, the test should be repeated. This category implies possible clinical efficacy in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
- Quality Control
- Standardized susceptibility test procedures require the use of laboratory control microorganisms to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1, 2, 3 Standardized tedizolid powder should provide the following range of MIC values noted in TABLE 6. For the diffusion technique using the 20 mcg tedizolid disk, results within the ranges specified in TABLE 6 should be observed.
## Structure
- tedizolid phosphate (tedizolid phosphate), a phosphate prodrug, is converted to tedizolid in the presence of phosphatases.
- Tedizolid phosphate has the chemical name [(5R)-(3-{3-Fluoro-4-[6-(2-methyl-2H-tetrazol- 5-yl) pyridin-3-yl]phenyl}-2-oxooxazolidin- 5-yl]methyl hydrogen phosphate.
- Its empirical formula is C17H16FN6O6P and its molecular weight is 450.32. Its structural formula is:
- Tedizolid phosphate is a white to yellow solid and is administered orally or by intravenous infusion.
- The pharmacologically active moiety, tedizolid, is an antibacterial agent of the oxazolidinone class.
- tablets contain 200 mg of tedizolid phosphate, and the following inactive ingredients: microcrystalline cellulose, mannitol, crospovidone, povidone, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc, and yellow iron oxide.
- tedizolid phosphate for injection is a sterile, white to off-white sterile lyophilized powder for injection in single-use vials of 200 mg. The inactive ingredients are mannitol (105 mg), sodium hydroxide, and hydrochloric acid, which is used in minimal quantities for pH adjustment.
## Pharmacodynamics
- The AUC/minimum inhibitory concentration (MIC) was shown to best correlate with tedizolid activity in animal infection models.
- In the mouse thigh infection model of S. aureus, antistaphylococcal killing activity was impacted by the presence of granulocytes. In granulocytopenic mice (neutrophil count <100 cells/mL), bacterial stasis was achieved at a human-equivalent dose of approximately 2000 mg/day; whereas, in non-granulocytopenic animals, stasis was achieved at a human-equivalent dose of approximately 100 mg/day. The safety and efficacy of tedizolid phosphate for the treatment of neutropenic patients (neutrophil counts <1000 cells/mm3) have not been evaluated.
- In a randomized, positive- and placebo-controlled crossover thorough QTc study, 48 enrolled subjects were administered a single oral dose of tedizolid phosphate at a therapeutic dose of 200 mg, tedizolid phosphate at a supratherapeutic dose of 1200 mg, placebo, and a positive control; no significant effects of tedizolid phosphate on heart rate, electrocardiogram morphology, PR, QRS, or QT interval were detected. Therefore, tedizolid phosphate does not affect cardiac repolarization.
## Pharmacokinetics
- Tedizolid phosphate is a prodrug that is converted by phosphatases to tedizolid, the microbiologically active moiety, following oral and intravenous administration. Only the pharmacokinetic profile of tedizolid is discussed further due to negligible systemic exposure of tedizolid phosphate following oral and intravenous administration. Following multiple once-daily oral or intravenous administration, steady-state concentrations are achieved within approximately three days with tedizolid accumulation of approximately 30% (tedizolid half-life of approximately 12 hours). Pharmacokinetic (PK) parameters of tedizolid following oral and intravenous administration of 200 mg once daily tedizolid phosphate are shown in TABLE 4.
- Absorption
- Peak plasma tedizolid concentrations are achieved within approximately 3 hours following oral administration under fasting conditions or at the end of the 1 hour intravenous infusion of tedizolid phosphate. The absolute bioavailability is approximately 91% and no dosage adjustment is necessary between intravenous and oral administration.
- Tedizolid phosphate (oral) may be administered with or without food as total systemic exposure (AUC0-∞) is unchanged between fasted and fed (high-fat, high-calorie) conditions.
- Distribution
- Protein binding of tedizolid to human plasma proteins is approximately 70 to 90%. The mean steady state volume of distribution of tedizolid in healthy adults following a single intravenous dose of tedizolid phosphate 200 mg ranged from 67 to 80 L (approximately twice total body water). Tedizolid penetrates into the interstitial space fluid of adipose and skeletal muscle tissue with exposure similar to free drug exposure in plasma.
- Metabolism
- Other than tedizolid, which accounts for approximately 95% of the total radiocarbon AUC in plasma, there are no other significant circulating metabolites in humans.
- There was no degradation of tedizolid in human liver microsomes indicating tedizolid is unlikely to be a substrate for hepatic CYP450 enzymes.
- Excretion
- Following single oral administration of 14C-labeled tedizolid phosphate under fasted conditions, the majority of elimination occurred via the liver, with 82% of the radioactive dose recovered in feces and 18% in urine, primarily as a non-circulating and microbiologically inactive sulfate conjugate. Most of the elimination of tedizolid (>85%) occurs within 96 hours. Less than 3% of the tedizolid phosphate-administered dose is excreted in feces and urine as unchanged tedizolid.
- Specific Populations
- Based on the population pharmacokinetic analysis, there are no clinically relevant demographic or clinical patient factors (including age, gender, race, ethnicity, weight, body mass index, and measures of renal or liver function) that impact the pharmacokinetics of tedizolid.
- Hepatic Impairment
- Following administration of a single 200 mg oral dose of tedizolid phosphate, no clinically meaningful changes in mean tedizolid Cmax and AUC0-∞ were observed in patients with moderate (n=8) or severe (n=8) hepatic impairment (Child-Pugh Class B and C) compared to 8 matched healthy control subjects. No dose adjustment is necessary for patients with hepatic impairment.
- Renal Impairment
- Following administration of a single 200 mg intravenous dose of tedizolid phosphate to 8 subjects with severe renal impairment defined as eGFR <30 mL/min/1.73 m2, the Cmax was essentially unchanged and AUC0-∞ was decreased by less than 10% compared to 8 matched healthy control subjects. Hemodialysis does not result in meaningful removal of tedizolid from systemic circulation, as assessed in subjects with end-stage renal disease (eGFR <15 mL/min/1.73 m2). No dosage adjustment is necessary in patients with renal impairment or patients on hemodialysis.
- Geriatric Patients
- The pharmacokinetics of tedizolid were evaluated in a Phase 1 study conducted in elderly healthy volunteers (age 65 years and older, with at least 5 subjects at least 75 years old; n=14) compared to younger control subjects (25 to 45 years old; n=14) following administration of a single oral dose of tedizolid phosphate 200 mg. There were no clinically meaningful differences in tedizolid Cmax and AUC0-∞between elderly subjects and younger control subjects. No dosage adjustment of tedizolid phosphate is necessary in elderly patients.
- Gender
- The impact of gender on the pharmacokinetics of tedizolid phosphate was evaluated in clinical trials of healthy males and females and in a population pharmacokinetics analysis. The pharmacokinetics of tedizolid were similar in males and females. No dosage adjustment of tedizolid phosphate is necessary based on gender.
- Drug Interaction Studies
- Drug Metabolizing Enzymes
- Transformation via Phase 1 hepatic oxidative metabolism is not a significant pathway for elimination of tedizolid phosphate.
- Neither tedizolid phosphate nor tedizolid detectably inhibited or induced the metabolism of selected CYP enzyme substrates. No potential drug interactions with tedizolid were identified in in vitro CYP inhibition or induction studies. These results suggest that drug-drug interactions based on oxidative metabolism are unlikely.
- Membrane Transporters
- The potential for tedizolid or tedizolid phosphate to inhibit transport of probe substrates of important drug uptake (OAT1, OAT3, OATP1B1, OATP1B3, OCT1, and OCT2) and efflux transporters (P-gp and ABCG2 [also known as BCRP]) was tested in vitro. No clinically significant inhibition of any transporter was observed at tedizolid circulating plasma concentrations up to the Cmax.
- Monoamine Oxidase Inhibition
- Tedizolid is a reversible inhibitor of monoamine oxidase (MAO) in vitro. The interaction with MAO inhibitors could not be evaluated in Phase 2 and 3 trials, as subjects taking such medications were excluded from the trials.
- Adrenergic Agents
- Two placebo-controlled crossover studies were conducted to assess the potential of 200 mg oral tedizolid phosphate at steady state to enhance pressor responses to pseudoephedrine and tyramine in healthy individuals. No meaningful changes in blood pressure or heart rate were seen with pseudoephedrine. The median tyramine dose required to cause an increase in systolic blood pressure of ≥30 mmHg from pre-dose baseline was 325 mg with tedizolid phosphate compared to 425 mg with placebo. Palpitations were reported in 21/29 (72.4%) subjects exposed to tedizolid phosphate compared to 13/28 (46.4%) exposed to placebo in the tyramine challenge study.
- Serotonergic Agents
- Serotonergic effects at doses of tedizolid phosphate up to 30-fold above the human equivalent dose did not differ from vehicle control in a mouse model that predicts serotonergic activity.
- In Phase 3 trials, subjects taking serotonergic agents including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin 5-hydroxytryptamine (5-HT1) receptor agonists (triptans), meperidine, or buspirone were excluded.
## Nonclinical Toxicology
- Long-term carcinogenicity studies have not been conducted with tedizolid phosphate.
- Tedizolid phosphate was negative for genotoxicity in all in vitro assays (bacterial reverse mutation (Ames), Chinese hamster lung (CHL) cell chromosomal aberration) and in all in vivo tests (mouse bone marrow micronucleus, rat liver unscheduled DNA synthesis). Tedizolid, generated from tedizolid phosphate after metabolic activation (in vitro and in vivo), was also tested for genotoxicity. Tedizolid was positive in an in vitro CHL cell chromosomal aberration assay, but negative for genotoxicity in other in vitro assays (Ames, mouse lymphoma mutagenicity) and in vivo in a mouse bone marrow micronucleus assay.
- In a fertility study, oral tedizolid phosphate had no adverse effects on the fertility or reproductive performance, including spermatogenesis, of male rats at the maximum tested dose (50 mg/kg/day) with a plasma tedizolid AUC approximately 5-fold greater than the plasma AUC value in humans at the oral therapeutic dose. Tedizolid phosphate also had no adverse effects on the fertility or reproductive performance of adult female rats at doses up to the maximum tested (15 mg/kg/day). Plasma tedizolid exposure (AUC) at this NOAEL in female rats was approximately 4-fold higher than that in humans at the oral therapeutic dose.
- Repeated-oral and intravenous dosing of tedizolid phosphate in rats in 1-month and 3-month toxicology studies produced dose- and time-dependent bone marrow hypocellularity (myeloid, erythroid, and megakaryocyte), with associated reduction in circulating RBCs, WBCs, and platelets. These effects showed evidence of reversibility and occurred at plasma tedizolid exposure levels (AUC) ≥6-fold greater than the plasma exposure associated with the human therapeutic dose. In a 1-month immunotoxicology study in rats, repeated oral dosing of tedizolid phosphate was shown to significantly reduce splenic B cells and T cells and reduce plasma IgG titers. These effects occurred at plasma tedizolid exposure levels (AUC) ≥3-fold greater than the expected human plasma exposure associated with the therapeutic dose.
# Clinical Studies
- A total of 1315 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized in two multicenter, multinational, double-blind, non-inferiority trials. Both trials compared tedizolid phosphate 200 mg once daily for 6 days versus linezolid 600 mg every 12 hours for 10 days. In Trial 1, patients were treated with oral therapy, while in Trial 2, patients could receive oral therapy after a minimum of one day of intravenous therapy. Patients with cellulitis/erysipelas, major cutaneous abscess, or wound infection were enrolled in the trials. Patients with wound infections could have received aztreonam and/or metronidazole as adjunctive therapy for gram-negative bacterial coverage, if needed. The intent-to-treat (ITT) patient population included all randomized patients.
- In Trial 1, 332 patients with ABSSSI were randomized to tedizolid phosphate and 335 patients were randomized to linezolid. The majority (91%) of patients treated with tedizolid phosphate in Trial 1 were less than 65 years old with a median age of 43 years (range: 18 to 86 years). Patients treated with tedizolid phosphate were predominantly male (61%) and White (84%); 13% had BMI ≥35 kg/m2, 8% had diabetes mellitus, 35% were current or recent intravenous drug users, and 2% had moderate to severe renal impairment. The overall median surface area of infection was 188 cm2. The types of ABSSSI included were cellulitis/erysipelas (41%), wound infection (29%), and major cutaneous abscess (30%). In addition to local signs and symptoms of infection, patients were also required to have at least one regional or systemic sign of infection at baseline, defined as lymphadenopathy (87% of patients), temperature 38°C or higher (16% of patients), white blood cell count greater than 10,000 cells/mm3 or less than 4000 cells/mm3 (42%), or 10% or more band forms on white blood cell differential (4%).
- The primary endpoint in Trial 1 was early clinical response defined as no increase from baseline lesion area at 48-72 hours after the first dose and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours in the ITT population.
- In Trial 2, 332 patients with ABSSSI were randomized to tedizolid phosphate and 334 patients were randomized to linezolid. The majority (87%) of patients treated with tedizolid phosphate in Trial 2 were less than 65 years old with a median age of 46 years (range: 17 to 86 years). Patients treated with tedizolid phosphate were predominantly male (68%) and White (86%); 16% had BMI ≥35 kg/m2, 10% had diabetes mellitus, 20% were current or recent intravenous drug users, and 4% had moderate to severe renal impairment. The overall median surface area of infection was 231 cm2. The types of ABSSSI included were cellulitis/erysipelas (50%), wound infection (30%), and major cutaneous abscess (20%). In addition to local signs and symptoms of infection, patients were also required to have at least one regional or systemic sign of infection at baseline, defined as lymphadenopathy (71% of patients), temperature 38°C or higher (31% of patients), white blood cell count greater than 10,000 cells/mm3 or less than 4000 cells/mm3 (53%), or 10% or more band forms on white blood cell differential (16%). The primary endpoint in Trial 2 was early clinical response defined as at least a 20% decrease from baseline lesion area at 48-72 hours after the first dose in the ITT population (TABLE 7).
- An investigator assessment of clinical response was made at the post-therapy evaluation (PTE) (7 - 14 days after the end of therapy) in the ITT and CE (Clinically Evaluable) populations. Clinical success was defined as resolution or near resolution of most disease-specific signs and symptoms, absence or near resolution of systemic signs of infection if present at baseline (lymphadenopathy, fever, >10% immature neutrophils, abnormal WBC count), and no new signs, symptoms, or complications attributable to the ABSSSI requiring further treatment of the primary lesion
# How Supplied
- tedizolid phosphate tablets are yellow film-coated oval tablets containing 200 mg of tedizolid phosphate; each tablet is debossed with "TZD" on one side and "200" on the other side.
- They are supplied as follows:
- HDPE bottles of 30 tablets with child-resistant closure (NDC 67919-041-01)
- Unit dose blister packs of 6 tablets (NDC 67919-041-02)
- tedizolid phosphate is supplied as a sterile, lyophilized powder for injection in single-use vials of 200 mg. Each 200 mg vial must be reconstituted with Sterile Water for Injection and subsequently diluted only with 0.9% Sodium Chloride Injection, USP.
- They are supplied as follows:
- Package of ten 200 mg single-dose vials (NDC 67919-040-01)
## Storage
- tedizolid phosphate tablets and tedizolid phosphate for injection should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed that tedizolid phosphate tablets may be taken with or without food and without any dietary restrictions .
- Patients should be advised that antibacterial drugs including tedizolid phosphate should only be used to treat bacterial infections. tedizolid phosphate does not treat viral infections (e.g., the common cold). When tedizolid phosphate is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by tedizolid phosphate or other antibacterial drugs in the future.
- Patients should be informed that if they miss a dose, they should take the dose as soon as possible anytime up to 8 hours prior to their next scheduled dose. If less than 8 hours remains before the next dose, then they should wait until their next scheduled dose. Patients should take the prescribed number of doses .
- Keep tedizolid phosphate and all medications out of reach of children.
- Patients should be advised that diarrhea is a common problem caused by antibacterial drugs including tedizolid phosphate and usually resolves when the drug is discontinued. Sometimes after starting treatment with antibiotics, patients can develop frequent watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic and may be a sign of a more serious intestinal infection .If this occurs, patients should contact their healthcare provider as soon as possible.
# Precautions with Alcohol
- Alcohol-Tedizolid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SIVEXTRO
# Look-Alike Drug Names
There is limited information regarding Tedizolid Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tedizolid | |
8e250a5c74f7baefb92e4292192cbf9041e72b51 | wikidoc | Tegaserod | Tegaserod
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# Overview
Tegaserod is a serotonergic analog that is FDA approved for the treatment of IBS with constipation, chronic idiopathic constipation. Common adverse reactions include abdominal pain, diarrhea, flatulence, nausea, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tegaserod maleate is indicated for the short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation.
- The safety and effectiveness of Zelnorm in men with IBS with constipation have not been established.
- Tegaserod maleate is indicated for the treatment of patients less than 65 years of age with chronic idiopathic constipation. The effectiveness of Zelnorm in patients 65 years or older with chronic idiopathic constipation has not been established.
- The efficacy of tegaserod maleate for the treatment of IBS with constipation or chronic idiopathic constipation has not been studied beyond 12 weeks.
- IBS with Constipation: The recommended dosage of Tegaserod maleate is 6 mg taken twice daily orally before meals for 4-6 weeks. For those women who respond to therapy at 4-6 weeks, an additional 4-6 week course can be considered.
- Chronic Idiopathic Constipation
- The recommended dosage of tegaserod maleate is 6 mg taken twice daily orally before meals. :- Physicians and patients should periodically assess the need for continued therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tegaserod in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tegaserod in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tegaserod in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tegaserod in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tegaserod in pediatric patients.
# Contraindications
- Tegaserod maleate is contraindicated in those patients with:
- Severe renal impairment.
- Moderate or severe hepatic impairment.
- A history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions.
- A known hypersensitivity to the drug or any of its excipients.
# Warnings
- Serious consequences of diarrhea, including hypovolemia, hypotension, and syncope have been reported in the clinical studies and during marketed use of Tegaserod maleate In some cases, these complications have required hospitalization for rehydration. Tegaserod maleate should be discontinued immediately in patients who develop severe diarrhea, hypotension or syncope. tegaserod maleate should not be initiated in patients who are currently experiencing or frequently experience diarrhea.
# Adverse Reactions
## Clinical Trials Experience
- In Phase 3 clinical trials 2,632 female and male patients received Tegaserod maleate 6 mg b.i.d. or placebo. The frequency and type of adverse events for females and males were similar. The following adverse experiences were reported in 1% or more of patients who received tegaserod maleate and occurred more frequently on tegaserod maleate than placebo:
- In Phase 3 clinical trials 2,603 male and female patients received tegaserod maleate 6 mg b.i.d., 2 mg b.i.d. or placebo. The following adverse experiences were reported in 1% or more of patients who received tegaserod maleate and occurred more frequently than in patients who received placebo.
- Tegaserod maleate was not associated with changes in ECG intervals.
- Tegaserod maleate-Induced Diarrhea.
- In the Phase 3 clinical studies, 8.8% of patients receiving tegaserod maleate reported diarrhea as an adverse experience compared to 3.8% of patients receiving placebo. The majority of the tegaserod maleate patients reporting diarrhea had a single episode. In most cases, diarrhea occurred within the first week of treatment. Typically, diarrhea resolved with continued therapy. Overall, the discontinuation rate from the studies due to diarrhea was 1.6% among the tegaserod maleate-treated patients. In clinical studies, a small number of patients (0.04%) experienced clinically significant diarrhea including hospitalization, hypovolemia, hypotension and need for intravenous fluids. Diarrhea can be the pharmacologic response to tegaserod maleate.
- In the two Phase 3 studies, 6.6% of patients treated with tegaserod maleate 6 mg b.i.d. and 4.2% of patients treated with tegaserod maleate 2 mg b.i.d. reported diarrhea as an adverse event, versus 3.0% of patients receiving placebo.
- The diarrhea episodes experienced by patients treated with tegaserod occurred early after initiation of treatment (median of 5.5 days), were of short duration (median of 2.5 days), and occurred only once in the majority of patient.
- Typically, diarrhea resolved with continued therapy; only 0.9% of patients treated with tegaserod maleate 6 mg b.i.d. discontinued the study due to diarrhea (compared to 0.3% in the tegaserod maleate 2 mg b.i.d. group and 0.2% in the placebo group).
- An increase in abdominal surgeries was observed on tegaserod maleate (9/2,965; 0.3%) vs. placebo (3/1,740; 0.2%) in the Phase 3 IBS clinical studies. The increase was primarily due to a numerical imbalance in cholecystectomies reported in patients treated with tegaserod maleate (5/2,965; 0.17%) vs. placebo (1/1,740; 0.06%). In chronic idiopathic constipation clinical trials there was no increase in the frequency of abdominal and pelvic surgeries in active vs. placebo groups: 9/1,752; 0.5% on tegaserod maleate versus 8/861; 0.9% on placebo. A causal relationship between abdominal surgeries and tegaserod maleate has not been established.
- The following list of adverse events includes those from Phase 3 clinical studies (6 mg b.i.d. or 2 mg b.i.d.) which were reported more frequently (>0.2%) in patients on tegaserod maleate than placebo; or which were considered by the investigator to be possibly related to tegaserod maleate and reported more frequently (>0.1%) on tegaserod maleate than placebo; or which lead to discontinuation more frequently (≥0.1% and in more than 1 patient) on tegaserod maleate than placebo. The list also contains those serious adverse events from all clinical trials in patients treated with either 6 mg b.i.d. or 2 mg b.i.d. tegaserod maleate which were either considered by the investigator as possibly drug related, or occurred in at least 2 more patients on tegaserod maleate than on placebo. Although the events reported occurred during treatment with tegaserod maleate, they were not necessarily caused by it.
- Cardiac Disorders.
- Angina pectoris, supraventricular tachycardia, syncope.
- Ear and Labyrinth Disorders.
- Vertigo.
- Eye Disorders.
- Visual disturbance.
- Gastrointestinal Disorders.
- Hemorrhoids, proctalgia, stomach discomfort, fecal incontinence, irritable bowel syndrome, dyspepsia, gastroesophageal reflux, gastritis.
- General Disorders and Administration Site Conditions.
- Chest pain, peripheral edema.
- Hepatobiliary Disorders.
- Cholelithiasis.
- Immune System Disorders.
- Hypersensitivity reactions.
- Investigations.
- Creatinine phosphokinase increased, increased eosinophil count, low neutrophil count.
- Metabolism and Nutrition Disorders.
- Increased appetite.
- Neoplasms Benign, Malignant and Unspecified (including cysts and polyps).
- Breast carcinoma.
- Psychiatric Disorders.
- Depression, sleep disorder, restlessness.
- Respiratory, Thoracic and Mediastinal Disorders.
- Dyspnea, pharyngolaryngeal pain.
- Reproductive System and Breast Disorders.
- Miscarriage, menorrhagia.
- Surgical and Medical Procedures.
- holecystectomy.
- Vascular Disorders.
- Flushing, hypotension.
## Postmarketing Experience
- ischemic colitis, mesenteric ischemia, gangrenous bowel, rectal bleeding,syncope, hypotension, hypovolemia, electrolyte disorders, suspected sphincter of Oddi spasm, bile duct stone, cholecystitis with elevated transaminases, and ypersensitivity reaction including rash, urticaria, pruritus and serious allergic Type I reactions. Because these cases are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. No causal relationship between these events and tegaserod maleate use has been established.
- Post-marketing reports of diarrhea, which can be a pharmacologic response to tegaserod maleate, have also been received.
# Drug Interactions
There is limited information regarding Tegaserod Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats at oral doses up to 100 mg/kg/day (approximately 15 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr) and rabbits at oral doses up to 120 mg/kg/day (approximately 51 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr) and have revealed no evidence of impaired fertility or harm to the fetus due to tegaserod. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tegaserod in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tegaserod during labor and delivery.
### Nursing Mothers
- Tegaserod and its metabolites are excreted in the milk of lactating rats with a high milk to plasma ratio. It is not known whether tegaserod is excreted in human milk. Many drugs, which are excreted in human milk, have potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for tegaserod in the mouse carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Tegaserod with respect to pediatric patients.
### Geriatic Use
- Of 4,035 patients in Phase 3 clinical studies of tegaserod maleate, 290 were at least 65 years of age, while 52 were at least 75 years old. No overall differences in safety were observed between these patients and younger patients with regard to adverse events.
- No dose adjustment is necessary when administering tegaserod maleate to patients with IBS with constipation over 65 years old.
- Of 2,612 patients in Phase 3 clinical studies of tegaserod maleate, 331 were at least 65 years of age. Efficacy in patients 65 years of age or greater showed no significant difference between drug and placebo responses. Patients 65 years of age or greater who received tegaserod maleate experienced a higher incidence of diarrhea and discontinuations due to diarrhea than patients younger than 65.
### Gender
There is no FDA guidance on the use of Tegaserod with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tegaserod with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tegaserod in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tegaserod in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tegaserod in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tegaserod in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral.
### Monitoring
There is limited information regarding Monitoring of Tegaserod in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tegaserod in the drug label.
# Overdosage
- There have been no reports of human overdosage with tegaserod maleate. Single oral doses of 120 mg of tegaserod were administered to 3 healthy volunteers in 1 study. All 3 subjects developed diarrhea and headache. Two of these subjects also reported intermittent abdominal pain, and 1 developed orthostatic hypotension. In 28 healthy subjects exposed to doses of tegaserod of 90 to 180 mg/d for several days, adverse events were diarrhea (100%), headache (57%), abdominal pain (18%), flatulence (18%), nausea (7%) and vomiting (7%).
- Based on the large distribution volume and high protein binding of tegaserod it is unlikely that tegaserod could be removed by dialysis. In cases of overdosage treat symptomatically and institute supportive measures as appropriate.
# Pharmacology
## Mechanism of Action
- Irritable bowel syndrome with constipation and chronic idiopathic constipation are both lower gastrointestinal dysmotility disorders. Clinical investigations have shown that both motor and sensory functions of the gut appear to be altered in patients suffering from irritable bowel syndrome (IBS), while in patients with chronic idiopathic constipation, reduced intestinal motility is the predominant cause of the condition. Both the enteric nervous system, which acts to integrate and process information in the gut, and 5-hydroxytryptamine (5-HT, serotonin) are thought to represent key elements in the etiology of both IBS and idiopathic constipation. Approximately 95% of serotonin is found throughout the gastrointestinal tract, primarily stored in enterochromaffin cells but also in enteric nerves acting as a neurotransmitter. Serotonin has been shown to be involved in regulating motility, visceral sensitivity and intestinal secretion. Investigations suggest an important role of serotonin Type-4 (5-HT4) receptors in the maintenance of gastrointestinal functions in humans. 5-HT4 receptor mRNA has been found throughout the human gastrointestinal tract.
- Tegaserod is a 5-HT4 receptor partial agonist that binds with high affinity at human 5-HT4 receptors, whereas it has no appreciable affinity for 5-HT3 or dopamine receptors. It has moderate affinity for 5-HT1 receptors. Tegaserod, by acting as an agonist at neuronal 5-HT4 receptors, triggers the release of further neurotransmitters such as calcitonin gene-related peptide from sensory neurons.
- The activation of 5-HT4 receptors in the gastrointestinal tract stimulates the peristaltic reflex and intestinal secretion, as well as inhibits visceral sensitivity. In vivo studies showed that tegaserod enhanced basal motor activity and normalized impaired motility throughout the gastrointestinal tract. In addition, studies demonstrated that tegaserod moderated visceral sensitivity during colorectal distension in animals.
## Structure
- Tegaserod maleate tablets contain tegaserod as the hydrogen maleate salt. As the maleate salt, tegaserod is chemically designated as 3-(5-methoxy-1H-indol-3-ylmethylene)-N-pentylcarbazimidamide hydrogen maleate. Its empirical formula is C16H23N5OC4H4O4. The molecular weight is 417.47 and the structural formula is
- Tegaserod as the maleate salt is a white to off-white crystalline powder and is slightly soluble in ethanol and very slightly soluble in water. Each 1.385 mg of tegaserod as the maleate is equivalent to 1 mg of tegaserod. Tegaserod maleate is available for oral use in the following tablet formulations:
- 2-mg and 6-mg tablets (blister packs) containing 2 mg and 6 mg tegaserod, respectively and the following inactive ingredients: crospovidone, glyceryl monostearate, hypromellose, lactose monohydrate, poloxamer 188, and polyethylene glycol 4000
- 6-mg tablets (bottles) containing 6 mg tegaserod and the following inactive ingredients: crospovidone, glyceryl behenate, hypromellose, lactose monohydrate, and colloidal silicon dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tegaserod in the drug label.
## Pharmacokinetics
- Peak plasma concentrations are reached approximately 1 hour after oral dosing. The absolute bioavailability of tegaserod when administered to fasting subjects is approximately 10%. The pharmacokinetics are dose proportional over the 2 mg to 12 mg range given twice daily for 5 days. There was no clinically relevant accumulation of tegaserod in plasma when a 6 mg b.i.d. dose was given for 5 days.
- When the drug is administered with food, the bioavailability of tegaserod is reduced by 40%-65% and Cmax by approximately 20%-40%. Similar reductions in plasma concentration occur when tegaserod is administered to subjects within 30 minutes prior to a meal, or 2.5 hours after a meal. Tmax of tegaserod is prolonged from approximately 1 hour to 2 hours when taken following a meal, but decreased to 0.7 hours when taken 30 minutes prior to a meal.
- Tegaserod is approximately 98% bound to plasma proteins, predominantly alpha-1-acid glycoprotein. Tegaserod exhibits pronounced distribution into tissues following intravenous dosing with a volume of distribution at steady-state of 368 ± 223 L.
- Tegaserod is metabolized mainly via two pathways. The first is a presystemic acid catalyzed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide. The main metabolite has negligible affinity for 5-HT4 receptors in vitro. In humans, systemic exposure to tegaserod was not altered at neutral gastric pH values. The second metabolic pathway of tegaserod is direct glucuronidation which leads to generation of three isomeric N-glucuronides.
- The plasma clearance of tegaserod is 77 ± 15 L/h with an estimated terminal half-life (T1/2) of 11 ± 5 hours following intravenous dosing. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in the feces, with the remaining one-third excreted in the urine, primarily as the main metabolite.
- Patients
- The pharmacokinetics of tegaserod in IBS patients are comparable to those in healthy subjects. The pharmacokinetics of tegaserod in patients with chronic idiopathic constipation have not been studied.
- Reduced Renal Function: No change in the pharmacokinetics of tegaserod was observed in subjects with severe renal impairment requiring hemodialysis (creatinine clearance <15 mL/min/1.73 m2). Cmax and AUC of the main pharmacologically inactive metabolite of tegaserod, 5-methoxy-indole-3-carboxylic acid glucuronide, increased 2- and 10-fold respectively, in subjects with severe renal impairment compared to healthy controls. No dosage adjustment is required in patients with mild-to-moderate renal impairment. Tegaserod is not recommended in patients with severe renal impairment.
- Reduced Hepatic Function
- In subjects with mild hepatic impairment, mean AUC was 31% higher and Cmax 16% higher compared to subjects with normal hepatic function. No dosage adjustment is required in patients with mild impairment, however, caution is recommended when using tegaserod in this patient population. Tegaserod has not adequately been studied in patients with moderate and severe hepatic impairment, and is therefore not recommended in these patients.
- Gender
- Gender has no effect on the pharmacokinetics of tegaserod.
- Race
- Data were inadequate to assess the effect of race on the pharmacokinetics of tegaserod.
- Age
- In a clinical pharmacology study conducted to assess the pharmacokinetics of tegaserod administered to healthy young (18-40 years) and healthy elderly (65-85 years) subjects, peak plasma concentration and exposure were 22% and 40% greater, respectively, in elderly females than young females but still within the variability seen in tegaserod pharmacokinetics in healthy subjects. Based on an analysis across several pharmacokinetic studies in healthy subjects, there is no age effect on the pharmacokinetics of tegaserod when allowing for body weight as a covariate. Therefore, dose adjustment in elderly patients who have IBS with constipation is not necessary.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Tegaserod in the drug label.
# Clinical Studies
- RESULTS IN WOMEN: In three multicenter, double-blind, placebo-controlled studies, 2,470 women (mean age 43 years ; 86% Caucasian, 10% African American) with at least a 3-month history of IBS symptoms prior to the study baseline period that included abdominal pain, bloating and constipation received either tegaserod maleate® (tegaserod maleate) 6 mg b.i.d. or placebo. In all patients, constipation was characterized by at least two of the following three symptoms each occurring ≥25% of the time over a 3-month period:< 3 bowel movements/week, hard or lumpy stools, or straining with a bowel movement. The study design consisted of a 4-week placebo-free baseline period followed by a 12-week double-blind treatment period. Study 1 and 2 evaluated a fixed dose regimen of tegaserod 6 mg b.i.d. while Study 3 utilized a dose-titration design.
- Each week of the 4-week placebo-free baseline period and the 12-week double-blind treatment period, patients were asked the question, “Please consider how you felt this past week in regard to your IBS, in particular your overall well-being, and symptoms of abdominal discomfort, pain and altered bowel habit. Compared to the way you usually felt before entering the study, how would you rate your relief of symptoms during the past week?” The response variable consisted of the following 5 categories: completely relieved, considerably relieved, somewhat relieved, unchanged, or worse. Patients were classified as responders within a month if they were considerably or completely relieved for at least two of the four weeks, or if they were at least somewhat relieved for each of the four weeks.
- Calculated response rates during month 1 and during month 3 as described above are shown in the table below. The differences in response rates vs. placebo were greater at month 1 than month 3.
- Response: ≥ 2 of 4 weeks complete or considerable relief or 4 of 4 weeks with at least somewhat relief.
- The same efficacy variable (i.e., complete relief, considerable relief, somewhat relief, unchanged, worse) was analyzed on a weekly basis. The proportion of female patients with complete, considerable or somewhat relief at weeks 1, 4, 6, 8 and 12 are shown in the figure below.
- In addition, individual symptoms of abdominal pain/discomfort and bloating were assessed daily using a 6 or 7 point intensity scale. A positive response was defined as at least a 1 point reduction in the scale. During the first four weeks in the fixed dose studies, 8 to 11% more Zelnorm-treated patients than placebo patients were responders for abdominal pain/discomfort. Similarly, 9 to 12% more tegaserod maleate-treated patients were responders for bloating. Corresponding differences at month 3 were 1 to 10% for abdominal pain/discomfort and 4 to 11% for bloating. Patients on tegaserod maleate also experienced an increase in median number of stools from 3.8/week at baseline to 6.3/week at month 1 and 6.0/week at month 3, while placebo patients increased from 4.0/week to 5.1/week at month 1 and 5.5/week at month 3.
- RESULTS IN MEN: In two randomized, placebo-controlled, double-blind studies enrolling 288 males, there were no significant differences between placebo and tegaserod maleate response rates in subgroup analyses by gender.
- In two multicenter, double-blind, placebo-controlled studies, 2,612 patients with chronic constipation were randomized to receive either tegaserod maleate 6 mg b.i.d., 2 mg b.i.d., or placebo.
- RESULTS IN PATIENTS UNDER AGE 65: A total of 2,281 patients were less than 65 years of age. Patients (91% female, mean age 43 , 90% Caucasian, 4.3% African American) had constipation defined as less than 3 complete spontaneous bowel movements per week and at least one of the following symptoms for at least 25% of defecations: straining, hard/very hard stools, incomplete evacuation. A bowel movement was evaluated by the patient as complete if it resulted in a feeling of complete emptying of their bowel. A bowel movement was considered to be spontaneous if no laxatives were taken in the preceding 24 hours. The study population consisted of patients with a 6 month or longer history of constipation symptoms (median 12 years). Patients with constipation known to be due to other known colon diseases, pelvic floor dysfunction, metabolic or neurological disturbances, or concomitant medications were excluded.
- After a 2-week baseline, patients were randomized to a 12-week double-blind treatment with tegaserod maleate 6 mg b.i.d., tegaserod maleate 2 mg b.i.d., or placebo. This treatment period was followed, in Study 1, by an extension period where patients received either 6 mg b.i.d. or 2 mg b.i.d. for an additional 13 months. The drop out rate for lack of efficacy for the additional 13-month period was 19% for 6 mg b.i.d. and 22% for 2 mg b.i.d.. In Study 2, the 12-week treatment period was followed by a 4-week drug-free withdrawal period.
- Patients were classified as responders (primary efficacy variable) if they achieved an average increase of at least one CSBM per week during the first four weeks of treatment compared to baseline, and had at least 7 days of exposure in the study.
- The response rate for the primary efficacy variable in patients under 65 years of age was higher in the tegaserod maleate 6 mg b.i.d. group compared to the placebo group for each of the 2 trials (p <0.0001, Table 2). This difference was statistically significant for CSBM changes averaged over the first 4 weeks of treatment and the full 12 weeks of treatment. The results with tegaserod maleate 2 mg b.i.d. showed significant changes during the first 4 weeks, however, no statistically significant changes were observed over 12 weeks in one study.
- At baseline, the median number of CSBM’s per week was zero and the mean number of CSBM’s per week was 0.5. Regardless of baseline, tegaserod maleate significantly increased the number of complete spontaneous bowel movements compared to placebo at each week (p<0.05).
- Tegaserod maleate also significantly increased the number of SBM’s compared to placebo at each week (p<0.05).
- Patients treated with tegaserod maleate experienced a statistically significant reduction in the individual symptoms of straining, abdominal distension/bloating, and abdominal discomfort/pain, and a statistically significant improvement in stool consistency and frequency compared to placebo when averaged over the 12 weeks (p<0.05). In addition, a global constipation relief score, computed as an average of 4 scores measuring abdominal discomfort/pain, abdominal distension/bloating, bothersomeness of constipation and satisfaction with bowel habits, showed statistically significant improvement for tegaserod maleate compared to placebo when averaged over the 12 weeks (p<0.05).
- RESULTS IN PATIENTS AGE 65 AND OVER: Subgroup analyses of patients 65 and older (n=331) showed no significant treatment effects for tegaserod maleate over placebo.
# How Supplied
- tegaserod maleate® (tegaserod maleate) is available as whitish to slightly yellowish, marbled, circular flat tablets with a bevelled edge containing 2 mg or 6 mg tegaserod as follows:
- 2-mg Tablet - white round engraved with “NVR” and “DL”
- Unit Dose (blister pack)
- Box of 60 (strips of 10)…………………………………………….NDC 0078-0355-80
- 6-mg Tablet - white round engraved with “NVR” and “EH”
- Unit Dose (blister pack)
- Box of 60 (strips of 10) ……………………………………………NDC 0078-0356-80
- Bottle of 60………………………………………………………………...NDC 0078-0426-20
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Tegaserod Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Tegaserod interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zelnorm®
# Look-Alike Drug Names
There is limited information regarding Tegaserod Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tegaserod
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
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# Overview
Tegaserod is a serotonergic analog that is FDA approved for the treatment of IBS with constipation, chronic idiopathic constipation. Common adverse reactions include abdominal pain, diarrhea, flatulence, nausea, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tegaserod maleate is indicated for the short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation.
- The safety and effectiveness of Zelnorm in men with IBS with constipation have not been established.
- Tegaserod maleate is indicated for the treatment of patients less than 65 years of age with chronic idiopathic constipation. The effectiveness of Zelnorm in patients 65 years or older with chronic idiopathic constipation has not been established.
- The efficacy of tegaserod maleate for the treatment of IBS with constipation or chronic idiopathic constipation has not been studied beyond 12 weeks.
- IBS with Constipation: The recommended dosage of Tegaserod maleate is 6 mg taken twice daily orally before meals for 4-6 weeks. For those women who respond to therapy at 4-6 weeks, an additional 4-6 week course can be considered.
- Chronic Idiopathic Constipation
- The recommended dosage of tegaserod maleate is 6 mg taken twice daily orally before meals. :* Physicians and patients should periodically assess the need for continued therapy.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tegaserod in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tegaserod in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tegaserod in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tegaserod in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tegaserod in pediatric patients.
# Contraindications
- Tegaserod maleate is contraindicated in those patients with:
- Severe renal impairment.
- Moderate or severe hepatic impairment.
- A history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions.
- A known hypersensitivity to the drug or any of its excipients.
# Warnings
- Serious consequences of diarrhea, including hypovolemia, hypotension, and syncope have been reported in the clinical studies and during marketed use of Tegaserod maleate In some cases, these complications have required hospitalization for rehydration. Tegaserod maleate should be discontinued immediately in patients who develop severe diarrhea, hypotension or syncope. tegaserod maleate should not be initiated in patients who are currently experiencing or frequently experience diarrhea.
# Adverse Reactions
## Clinical Trials Experience
- In Phase 3 clinical trials 2,632 female and male patients received Tegaserod maleate 6 mg b.i.d. or placebo. The frequency and type of adverse events for females and males were similar. The following adverse experiences were reported in 1% or more of patients who received tegaserod maleate and occurred more frequently on tegaserod maleate than placebo:
- In Phase 3 clinical trials 2,603 male and female patients received tegaserod maleate 6 mg b.i.d., 2 mg b.i.d. or placebo. The following adverse experiences were reported in 1% or more of patients who received tegaserod maleate and occurred more frequently than in patients who received placebo.
- Tegaserod maleate was not associated with changes in ECG intervals.
- Tegaserod maleate-Induced Diarrhea.
- In the Phase 3 clinical studies, 8.8% of patients receiving tegaserod maleate reported diarrhea as an adverse experience compared to 3.8% of patients receiving placebo. The majority of the tegaserod maleate patients reporting diarrhea had a single episode. In most cases, diarrhea occurred within the first week of treatment. Typically, diarrhea resolved with continued therapy. Overall, the discontinuation rate from the studies due to diarrhea was 1.6% among the tegaserod maleate-treated patients. In clinical studies, a small number of patients (0.04%) experienced clinically significant diarrhea including hospitalization, hypovolemia, hypotension and need for intravenous fluids. Diarrhea can be the pharmacologic response to tegaserod maleate.
- In the two Phase 3 studies, 6.6% of patients treated with tegaserod maleate 6 mg b.i.d. and 4.2% of patients treated with tegaserod maleate 2 mg b.i.d. reported diarrhea as an adverse event, versus 3.0% of patients receiving placebo.
- The diarrhea episodes experienced by patients treated with tegaserod occurred early after initiation of treatment (median of 5.5 days), were of short duration (median of 2.5 days), and occurred only once in the majority of patient.
- Typically, diarrhea resolved with continued therapy; only 0.9% of patients treated with tegaserod maleate 6 mg b.i.d. discontinued the study due to diarrhea (compared to 0.3% in the tegaserod maleate 2 mg b.i.d. group and 0.2% in the placebo group).
- An increase in abdominal surgeries was observed on tegaserod maleate (9/2,965; 0.3%) vs. placebo (3/1,740; 0.2%) in the Phase 3 IBS clinical studies. The increase was primarily due to a numerical imbalance in cholecystectomies reported in patients treated with tegaserod maleate (5/2,965; 0.17%) vs. placebo (1/1,740; 0.06%). In chronic idiopathic constipation clinical trials there was no increase in the frequency of abdominal and pelvic surgeries in active vs. placebo groups: 9/1,752; 0.5% on tegaserod maleate versus 8/861; 0.9% on placebo. A causal relationship between abdominal surgeries and tegaserod maleate has not been established.
- The following list of adverse events includes those from Phase 3 clinical studies (6 mg b.i.d. or 2 mg b.i.d.) which were reported more frequently (>0.2%) in patients on tegaserod maleate than placebo; or which were considered by the investigator to be possibly related to tegaserod maleate and reported more frequently (>0.1%) on tegaserod maleate than placebo; or which lead to discontinuation more frequently (≥0.1% and in more than 1 patient) on tegaserod maleate than placebo. The list also contains those serious adverse events from all clinical trials in patients treated with either 6 mg b.i.d. or 2 mg b.i.d. tegaserod maleate which were either considered by the investigator as possibly drug related, or occurred in at least 2 more patients on tegaserod maleate than on placebo. Although the events reported occurred during treatment with tegaserod maleate, they were not necessarily caused by it.
- Cardiac Disorders.
- Angina pectoris, supraventricular tachycardia, syncope.
- Ear and Labyrinth Disorders.
- Vertigo.
- Eye Disorders.
- Visual disturbance.
- Gastrointestinal Disorders.
- Hemorrhoids, proctalgia, stomach discomfort, fecal incontinence, irritable bowel syndrome, dyspepsia, gastroesophageal reflux, gastritis.
- General Disorders and Administration Site Conditions.
- Chest pain, peripheral edema.
- Hepatobiliary Disorders.
- Cholelithiasis.
- Immune System Disorders.
- Hypersensitivity reactions.
- Investigations.
- Creatinine phosphokinase increased, increased eosinophil count, low neutrophil count.
- Metabolism and Nutrition Disorders.
- Increased appetite.
- Neoplasms Benign, Malignant and Unspecified (including cysts and polyps).
- Breast carcinoma.
- Psychiatric Disorders.
- Depression, sleep disorder, restlessness.
- Respiratory, Thoracic and Mediastinal Disorders.
- Dyspnea, pharyngolaryngeal pain.
- Reproductive System and Breast Disorders.
- Miscarriage, menorrhagia.
- Surgical and Medical Procedures.
- holecystectomy.
- Vascular Disorders.
- Flushing, hypotension.
## Postmarketing Experience
- ischemic colitis, mesenteric ischemia, gangrenous bowel, rectal bleeding,syncope, hypotension, hypovolemia, electrolyte disorders, suspected sphincter of Oddi spasm, bile duct stone, cholecystitis with elevated transaminases, and ypersensitivity reaction including rash, urticaria, pruritus and serious allergic Type I reactions. Because these cases are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. No causal relationship between these events and tegaserod maleate use has been established.
- Post-marketing reports of diarrhea, which can be a pharmacologic response to tegaserod maleate, have also been received.
# Drug Interactions
There is limited information regarding Tegaserod Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats at oral doses up to 100 mg/kg/day (approximately 15 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr) and rabbits at oral doses up to 120 mg/kg/day (approximately 51 times the human exposure at 6 mg b.i.d. based on plasma AUC0-24 hr) and have revealed no evidence of impaired fertility or harm to the fetus due to tegaserod. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tegaserod in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tegaserod during labor and delivery.
### Nursing Mothers
- Tegaserod and its metabolites are excreted in the milk of lactating rats with a high milk to plasma ratio. It is not known whether tegaserod is excreted in human milk. Many drugs, which are excreted in human milk, have potential for serious adverse reactions in nursing infants. Based on the potential for tumorigenicity shown for tegaserod in the mouse carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Tegaserod with respect to pediatric patients.
### Geriatic Use
- Of 4,035 patients in Phase 3 clinical studies of tegaserod maleate, 290 were at least 65 years of age, while 52 were at least 75 years old. No overall differences in safety were observed between these patients and younger patients with regard to adverse events.
- No dose adjustment is necessary when administering tegaserod maleate to patients with IBS with constipation over 65 years old.
- Of 2,612 patients in Phase 3 clinical studies of tegaserod maleate, 331 were at least 65 years of age. Efficacy in patients 65 years of age or greater showed no significant difference between drug and placebo responses. Patients 65 years of age or greater who received tegaserod maleate experienced a higher incidence of diarrhea and discontinuations due to diarrhea than patients younger than 65.
### Gender
There is no FDA guidance on the use of Tegaserod with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tegaserod with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tegaserod in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tegaserod in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tegaserod in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tegaserod in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral.
### Monitoring
There is limited information regarding Monitoring of Tegaserod in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tegaserod in the drug label.
# Overdosage
- There have been no reports of human overdosage with tegaserod maleate. Single oral doses of 120 mg of tegaserod were administered to 3 healthy volunteers in 1 study. All 3 subjects developed diarrhea and headache. Two of these subjects also reported intermittent abdominal pain, and 1 developed orthostatic hypotension. In 28 healthy subjects exposed to doses of tegaserod of 90 to 180 mg/d for several days, adverse events were diarrhea (100%), headache (57%), abdominal pain (18%), flatulence (18%), nausea (7%) and vomiting (7%).
- Based on the large distribution volume and high protein binding of tegaserod it is unlikely that tegaserod could be removed by dialysis. In cases of overdosage treat symptomatically and institute supportive measures as appropriate.
# Pharmacology
## Mechanism of Action
- Irritable bowel syndrome with constipation and chronic idiopathic constipation are both lower gastrointestinal dysmotility disorders. Clinical investigations have shown that both motor and sensory functions of the gut appear to be altered in patients suffering from irritable bowel syndrome (IBS), while in patients with chronic idiopathic constipation, reduced intestinal motility is the predominant cause of the condition. Both the enteric nervous system, which acts to integrate and process information in the gut, and 5-hydroxytryptamine (5-HT, serotonin) are thought to represent key elements in the etiology of both IBS and idiopathic constipation. Approximately 95% of serotonin is found throughout the gastrointestinal tract, primarily stored in enterochromaffin cells but also in enteric nerves acting as a neurotransmitter. Serotonin has been shown to be involved in regulating motility, visceral sensitivity and intestinal secretion. Investigations suggest an important role of serotonin Type-4 (5-HT4) receptors in the maintenance of gastrointestinal functions in humans. 5-HT4 receptor mRNA has been found throughout the human gastrointestinal tract.
- Tegaserod is a 5-HT4 receptor partial agonist that binds with high affinity at human 5-HT4 receptors, whereas it has no appreciable affinity for 5-HT3 or dopamine receptors. It has moderate affinity for 5-HT1 receptors. Tegaserod, by acting as an agonist at neuronal 5-HT4 receptors, triggers the release of further neurotransmitters such as calcitonin gene-related peptide from sensory neurons.
- The activation of 5-HT4 receptors in the gastrointestinal tract stimulates the peristaltic reflex and intestinal secretion, as well as inhibits visceral sensitivity. In vivo studies showed that tegaserod enhanced basal motor activity and normalized impaired motility throughout the gastrointestinal tract. In addition, studies demonstrated that tegaserod moderated visceral sensitivity during colorectal distension in animals.
## Structure
- Tegaserod maleate tablets contain tegaserod as the hydrogen maleate salt. As the maleate salt, tegaserod is chemically designated as 3-(5-methoxy-1H-indol-3-ylmethylene)-N-pentylcarbazimidamide hydrogen maleate. Its empirical formula is C16H23N5O•C4H4O4. The molecular weight is 417.47 and the structural formula is
- Tegaserod as the maleate salt is a white to off-white crystalline powder and is slightly soluble in ethanol and very slightly soluble in water. Each 1.385 mg of tegaserod as the maleate is equivalent to 1 mg of tegaserod. Tegaserod maleate is available for oral use in the following tablet formulations:
- 2-mg and 6-mg tablets (blister packs) containing 2 mg and 6 mg tegaserod, respectively and the following inactive ingredients: crospovidone, glyceryl monostearate, hypromellose, lactose monohydrate, poloxamer 188, and polyethylene glycol 4000
- 6-mg tablets (bottles) containing 6 mg tegaserod and the following inactive ingredients: crospovidone, glyceryl behenate, hypromellose, lactose monohydrate, and colloidal silicon dioxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tegaserod in the drug label.
## Pharmacokinetics
- Peak plasma concentrations are reached approximately 1 hour after oral dosing. The absolute bioavailability of tegaserod when administered to fasting subjects is approximately 10%. The pharmacokinetics are dose proportional over the 2 mg to 12 mg range given twice daily for 5 days. There was no clinically relevant accumulation of tegaserod in plasma when a 6 mg b.i.d. dose was given for 5 days.
- When the drug is administered with food, the bioavailability of tegaserod is reduced by 40%-65% and Cmax by approximately 20%-40%. Similar reductions in plasma concentration occur when tegaserod is administered to subjects within 30 minutes prior to a meal, or 2.5 hours after a meal. Tmax of tegaserod is prolonged from approximately 1 hour to 2 hours when taken following a meal, but decreased to 0.7 hours when taken 30 minutes prior to a meal.
- Tegaserod is approximately 98% bound to plasma proteins, predominantly alpha-1-acid glycoprotein. Tegaserod exhibits pronounced distribution into tissues following intravenous dosing with a volume of distribution at steady-state of 368 ± 223 L.
- Tegaserod is metabolized mainly via two pathways. The first is a presystemic acid catalyzed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide. The main metabolite has negligible affinity for 5-HT4 receptors in vitro. In humans, systemic exposure to tegaserod was not altered at neutral gastric pH values. The second metabolic pathway of tegaserod is direct glucuronidation which leads to generation of three isomeric N-glucuronides.
- The plasma clearance of tegaserod is 77 ± 15 L/h with an estimated terminal half-life (T1/2) of 11 ± 5 hours following intravenous dosing. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in the feces, with the remaining one-third excreted in the urine, primarily as the main metabolite.
- Patients
- The pharmacokinetics of tegaserod in IBS patients are comparable to those in healthy subjects. The pharmacokinetics of tegaserod in patients with chronic idiopathic constipation have not been studied.
- Reduced Renal Function: No change in the pharmacokinetics of tegaserod was observed in subjects with severe renal impairment requiring hemodialysis (creatinine clearance <15 mL/min/1.73 m2). Cmax and AUC of the main pharmacologically inactive metabolite of tegaserod, 5-methoxy-indole-3-carboxylic acid glucuronide, increased 2- and 10-fold respectively, in subjects with severe renal impairment compared to healthy controls. No dosage adjustment is required in patients with mild-to-moderate renal impairment. Tegaserod is not recommended in patients with severe renal impairment.
- Reduced Hepatic Function
- In subjects with mild hepatic impairment, mean AUC was 31% higher and Cmax 16% higher compared to subjects with normal hepatic function. No dosage adjustment is required in patients with mild impairment, however, caution is recommended when using tegaserod in this patient population. Tegaserod has not adequately been studied in patients with moderate and severe hepatic impairment, and is therefore not recommended in these patients.
- Gender
- Gender has no effect on the pharmacokinetics of tegaserod.
- Race
- Data were inadequate to assess the effect of race on the pharmacokinetics of tegaserod.
- Age
- In a clinical pharmacology study conducted to assess the pharmacokinetics of tegaserod administered to healthy young (18-40 years) and healthy elderly (65-85 years) subjects, peak plasma concentration and exposure were 22% and 40% greater, respectively, in elderly females than young females but still within the variability seen in tegaserod pharmacokinetics in healthy subjects. Based on an analysis across several pharmacokinetic studies in healthy subjects, there is no age effect on the pharmacokinetics of tegaserod when allowing for body weight as a covariate. Therefore, dose adjustment in elderly patients who have IBS with constipation is not necessary.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Tegaserod in the drug label.
# Clinical Studies
- RESULTS IN WOMEN: In three multicenter, double-blind, placebo-controlled studies, 2,470 women (mean age 43 years [range 17-89 years]; 86% Caucasian, 10% African American) with at least a 3-month history of IBS symptoms prior to the study baseline period that included abdominal pain, bloating and constipation received either tegaserod maleate® (tegaserod maleate) 6 mg b.i.d. or placebo. In all patients, constipation was characterized by at least two of the following three symptoms each occurring ≥25% of the time over a 3-month period:< 3 bowel movements/week, hard or lumpy stools, or straining with a bowel movement. The study design consisted of a 4-week placebo-free baseline period followed by a 12-week double-blind treatment period. Study 1 and 2 evaluated a fixed dose regimen of tegaserod 6 mg b.i.d. while Study 3 utilized a dose-titration design.
- Each week of the 4-week placebo-free baseline period and the 12-week double-blind treatment period, patients were asked the question, “Please consider how you felt this past week in regard to your IBS, in particular your overall well-being, and symptoms of abdominal discomfort, pain and altered bowel habit. Compared to the way you usually felt before entering the study, how would you rate your relief of symptoms during the past week?” The response variable consisted of the following 5 categories: completely relieved, considerably relieved, somewhat relieved, unchanged, or worse. Patients were classified as responders within a month if they were considerably or completely relieved for at least two of the four weeks, or if they were at least somewhat relieved for each of the four weeks.
- Calculated response rates during month 1 and during month 3 as described above are shown in the table below. The differences in response rates vs. placebo were greater at month 1 than month 3.
- Response: ≥ 2 of 4 weeks complete or considerable relief or 4 of 4 weeks with at least somewhat relief.
- The same efficacy variable (i.e., complete relief, considerable relief, somewhat relief, unchanged, worse) was analyzed on a weekly basis. The proportion of female patients with complete, considerable or somewhat relief at weeks 1, 4, 6, 8 and 12 are shown in the figure below.
- In addition, individual symptoms of abdominal pain/discomfort and bloating were assessed daily using a 6 or 7 point intensity scale. A positive response was defined as at least a 1 point reduction in the scale. During the first four weeks in the fixed dose studies, 8 to 11% more Zelnorm-treated patients than placebo patients were responders for abdominal pain/discomfort. Similarly, 9 to 12% more tegaserod maleate-treated patients were responders for bloating. Corresponding differences at month 3 were 1 to 10% for abdominal pain/discomfort and 4 to 11% for bloating. Patients on tegaserod maleate also experienced an increase in median number of stools from 3.8/week at baseline to 6.3/week at month 1 and 6.0/week at month 3, while placebo patients increased from 4.0/week to 5.1/week at month 1 and 5.5/week at month 3.
- RESULTS IN MEN: In two randomized, placebo-controlled, double-blind studies enrolling 288 males, there were no significant differences between placebo and tegaserod maleate response rates in subgroup analyses by gender.
- In two multicenter, double-blind, placebo-controlled studies, 2,612 patients with chronic constipation were randomized to receive either tegaserod maleate 6 mg b.i.d., 2 mg b.i.d., or placebo.
- RESULTS IN PATIENTS UNDER AGE 65: A total of 2,281 patients were less than 65 years of age. Patients (91% female, mean age 43 [range 18-64], 90% Caucasian, 4.3% African American) had constipation defined as less than 3 complete spontaneous bowel movements [CSBM] per week and at least one of the following symptoms for at least 25% of defecations: straining, hard/very hard stools, incomplete evacuation. A bowel movement was evaluated by the patient as complete if it resulted in a feeling of complete emptying of their bowel. A bowel movement was considered to be spontaneous [SBM] if no laxatives were taken in the preceding 24 hours. The study population consisted of patients with a 6 month or longer history of constipation symptoms (median 12 years). Patients with constipation known to be due to other known colon diseases, pelvic floor dysfunction, metabolic or neurological disturbances, or concomitant medications were excluded.
- After a 2-week baseline, patients were randomized to a 12-week double-blind treatment with tegaserod maleate 6 mg b.i.d., tegaserod maleate 2 mg b.i.d., or placebo. This treatment period was followed, in Study 1, by an extension period where patients received either 6 mg b.i.d. or 2 mg b.i.d. for an additional 13 months. The drop out rate for lack of efficacy for the additional 13-month period was 19% for 6 mg b.i.d. and 22% for 2 mg b.i.d.. In Study 2, the 12-week treatment period was followed by a 4-week drug-free withdrawal period.
- Patients were classified as responders (primary efficacy variable) if they achieved an average increase of at least one CSBM per week during the first four weeks of treatment compared to baseline, and had at least 7 days of exposure in the study.
- The response rate for the primary efficacy variable in patients under 65 years of age was higher in the tegaserod maleate 6 mg b.i.d. group compared to the placebo group for each of the 2 trials (p <0.0001, Table 2). This difference was statistically significant for CSBM changes averaged over the first 4 weeks of treatment and the full 12 weeks of treatment. The results with tegaserod maleate 2 mg b.i.d. showed significant changes during the first 4 weeks, however, no statistically significant changes were observed over 12 weeks in one study.
- At baseline, the median number of CSBM’s per week was zero and the mean number of CSBM’s per week was 0.5. Regardless of baseline, tegaserod maleate significantly increased the number of complete spontaneous bowel movements compared to placebo at each week (p<0.05).
- Tegaserod maleate also significantly increased the number of SBM’s compared to placebo at each week (p<0.05).
- Patients treated with tegaserod maleate experienced a statistically significant reduction in the individual symptoms of straining, abdominal distension/bloating, and abdominal discomfort/pain, and a statistically significant improvement in stool consistency and frequency compared to placebo when averaged over the 12 weeks (p<0.05). In addition, a global constipation relief score, computed as an average of 4 scores measuring abdominal discomfort/pain, abdominal distension/bloating, bothersomeness of constipation and satisfaction with bowel habits, showed statistically significant improvement for tegaserod maleate compared to placebo when averaged over the 12 weeks (p<0.05).
- RESULTS IN PATIENTS AGE 65 AND OVER: Subgroup analyses of patients 65 and older (n=331) showed no significant treatment effects for tegaserod maleate over placebo.
# How Supplied
- tegaserod maleate® (tegaserod maleate) is available as whitish to slightly yellowish, marbled, circular flat tablets with a bevelled edge containing 2 mg or 6 mg tegaserod as follows:
- 2-mg Tablet - white round engraved with “NVR” and “DL”
- Unit Dose (blister pack)
- Box of 60 (strips of 10)…………………………………………….NDC 0078-0355-80
- 6-mg Tablet - white round engraved with “NVR” and “EH”
- Unit Dose (blister pack)
- Box of 60 (strips of 10) ……………………………………………NDC 0078-0356-80
- Bottle of 60………………………………………………………………...NDC 0078-0426-20
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Tegaserod Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Tegaserod interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zelnorm®[1]
# Look-Alike Drug Names
There is limited information regarding Tegaserod Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tegaserod | |
9df60515a40124602b6b8436517796e17e922979 | wikidoc | Teleology | Teleology
# Overview
Teleology (Greek: telos: end, purpose) is the philosophical study of design and purpose. A teleological school of thought is one that holds all things to be designed for or directed toward a final result, that there is an inherent purpose or final cause for all that exists.
It is traditionally contrasted with metaphysical naturalism, which views nature as lacking design or purpose. In the first case form is defined by function, in the second function is defined by form. Teleology would say that a person has eyes because he has the need of eyesight, (form follows function), while naturalism would argue that a person has sight simply because he has eyes, or that function follows form (eyesight follows from having eyes).
In European philosophy, teleology may be identified with Aristotelianism and the scholastic tradition. Most theology presupposes a teleology: "intelligent design" is a teleological argument for the existence of God. Aristotle's analysis speaks of a material cause, efficient cause, and formal cause but all these serve a final cause.
Later teleology was fundamental to the speculative philosophy of Hegel and was explored in detail by Immanuel Kant in his Critique of Judgement.
In general it may be said that there are two types of final cause, which may be called intrinsic finality and extrinsic finality.
- Extrinsic finality consists of a being realizing a purpose outside that being, for the utility and welfare of other beings. For instance, minerals are "designed" to be used by plants which are in turn "designed" to be used by animals - and similarly humanity serves some ultimate good beyond itself.
- Intrinsic finality consists of a being realizing a purpose directed toward the perfection of its own nature. In essence, it is what is "good for" a being. Just as physical masses obey universal gravitational tendencies, which did not evolve, but are simply a cosmic "given", so life is intended to behave in certain ways so as to preserve itself from death, disease, and pain.
In bioethics, teleology is used to describe the utilitarian view that an action's ethics is determined by its good or bad consequences.
# Classical Teleology
Plato summarized the teleological position in his dialogue Phaedo, bemoaning those who fail to distinguish between the ultimate Cause and the mere means by which that Cause acts:
Similarly, Aristotle argued that Democritus, proponent of the atomic theory, was wrong to attempt to reduce all things to mere necessity, because such thinking neglects the purpose, order, and "final cause" that causes the necessity:
Hence Plato and Aristotle agreed that all lesser causes were in the service of an ultimate good while Democritus or Lucretius were supporters of what is now often called metaphysical naturalism, or accidentalism:
# Modern and postmodern philosophy
In the various neo-Hegelian schools - proposing a history of our species some consider to be at variance with Darwin, with the dialectical materialism of Karl Marx and Friedrich Engels and with what is now called analytic philosophy — the point of departure is not so much formal logic and scientific fact but 'identity'. (In Hegel's terminology: 'objective spirit'.)
Individual human consciousness, in the process of reaching for autonomy and freedom, has no choice but to deal with an obvious reality: the collective identities (such as the multiplicity of world views, ethnic, cultural and national identities) which divide the human race and which set (and always have set) different groups in violent conflict with each other. Hegel conceived of the 'totality' of mutually antagonistic world-views and life-forms in history as being 'goal-driven', that is, oriented towards an end-point in history. The 'objective contradiction' of 'subject' and 'object' would eventually 'sublate' into a form of life which leaves violent conflict behind. This goal-oriented, 'teleological' notion of the 'historical process as a whole' is present in a variety of 20th Century authors, from Lukács and Jaspers to Horkheimer and Adorno.
In contrast teleology and "grand narratives" are eschewed in the postmodern attitude and teleology may be viewed as reductive, exclusionary and harmful to those whose stories are erased.
Against this, Alasdair MacIntyre has argued that a narrative understanding of oneself, of one's capacity as an independent reasoner, one's dependence on others and on the social practices and traditions in which one participates, all tends towards an ultimate good of liberation. Social practices may themselves be understood as teleologically orientated to internal goods, for example practices of philosophical and scientific enquiry are teleologically ordered to the elaboration of a true understanding of their objects. MacIntyre's book After Virtue famously dismissed the naturalistic teleology of Aristotle's 'metaphysical biology', but he has cautiously moved from that book's account of a sociological teleology toward an exploration of what remains valid in a more traditional teleological naturalism.
# Teleology and Science
Science concerns itself with physical causality and is well able to function within the bounds of naturalism, indeed, it has frequently to counter appeals to undemonstrable modes of causality. Yet teleological ideas still find refuge in the unpenetrated beginnings and endings of things.
## Physics
It has been claimed that within the framework of thermodynamics, the irreversibility of macroscopic processes is explained in a teleological way.
In recent decades a form of teleological reasoning has reappeared in certain quarters of physics and cosmology, under the heading of anthropic principle, a term Brandon Carter coined in 1973. One of the problems the anthropic principle tries to address is this: why has the universe, which began in a very simple state (Big Bang), since grown ever more complex to the extent that it is even more hospitable to human life than is necessary for mere survival but even allows advanced human civilization?
## Chemistry
Teleological arguments in the field of chemistry have once again often centred around the fitness of materials to form the complex molecular bonds of life. For example, Lawrence Joseph Henderson, an American bio-chemist, advanced such a view in the early 20th century.
## Biology
Biology has always been susceptible to teleological thought, even after Darwin proposed survival as the only observable final good. Driesch, for example, presented a modified vitalism in whch an Aristotlean (or Kantian) entelechy drove embryonic development. Contemporary accounts of teleology within biology are heavily influenced by Larry Wright's etiological account, which seeks to supply a definition of "function" that can be applied to natural phenomena as well as human constructions such as a hammer. Most contemporary accounts of teleology follow Wright. (Ruth Millikan for instance). Others, however, such as Godfrey-Smith and Ernst Mayr, object to any such theory, preferring naturalistic accounts of teleology.
## Cybernetics and Teleonomy
Julian Bigelow, Arturo Rosenblueth, and Norbert Wiener have conceived of feedback mechanisms as lending a teleology to machinery. Wiener, a mathematician, coined the term 'cybernetics' to denote the study of "teleological mechanisms," . Cybernetics is the study of the communication and control of regulatory feedback both in living beings and machines, and in combinations of the two.
In recent years, end-driven teleology has become contrasted with "apparent" teleology, i.e teleonomy or process-driven systems.
## Philosophy of science
For a very detailed discussion of the recent resurgence of teleology in natural science, see Barrow and Tipler (1986). Their work includes:
- A review of much of the intellectual history of teleology and design arguments.
- A chapter on the teleological implications of earth science and chemistry, with special reference to the work of Lawrence Joseph Henderson;
- A discussion of the implications of evolutionary biology for teleology, emphasizing the writings of Theodosius Dobzhansky and Ernst Mayr;
- Teleological speculations on the ultimate fate of the universe. | Teleology
# Overview
Teleology (Greek: telos: end, purpose) is the philosophical study of design and purpose. A teleological school of thought is one that holds all things to be designed for or directed toward a final result, that there is an inherent purpose or final cause for all that exists.
It is traditionally contrasted with metaphysical naturalism, which views nature as lacking design or purpose. In the first case form is defined by function, in the second function is defined by form. Teleology would say that a person has eyes because he has the need of eyesight, (form follows function), while naturalism would argue that a person has sight simply because he has eyes, or that function follows form (eyesight follows from having eyes).
In European philosophy, teleology may be identified with Aristotelianism and the scholastic tradition. Most theology presupposes a teleology[1]: "intelligent design" is a teleological argument for the existence of God. Aristotle's analysis speaks of a material cause, efficient cause, and formal cause but all these serve a final cause.
Later teleology was fundamental to the speculative philosophy of Hegel and was explored in detail by Immanuel Kant in his Critique of Judgement.
In general it may be said that there are two types of final cause, which may be called intrinsic finality and extrinsic finality.
- Extrinsic finality consists of a being realizing a purpose outside that being, for the utility and welfare of other beings. For instance, minerals are "designed" to be used by plants which are in turn "designed" to be used by animals - and similarly humanity serves some ultimate good beyond itself.
- Intrinsic finality consists of a being realizing a purpose directed toward the perfection of its own nature. In essence, it is what is "good for" a being. Just as physical masses obey universal gravitational tendencies, which did not evolve, but are simply a cosmic "given", so life is intended to behave in certain ways so as to preserve itself from death, disease, and pain.
In bioethics, teleology is used to describe the utilitarian view that an action's ethics is determined by its good or bad consequences.
# Classical Teleology
Plato summarized the teleological position in his dialogue Phaedo, bemoaning those who fail to distinguish between the ultimate Cause and the mere means by which that Cause acts:
Similarly, Aristotle argued that Democritus, proponent of the atomic theory, was wrong to attempt to reduce all things to mere necessity, because such thinking neglects the purpose, order, and "final cause" that causes the necessity:
Hence Plato and Aristotle agreed that all lesser causes were in the service of an ultimate good while Democritus or Lucretius were supporters of what is now often called metaphysical naturalism, or accidentalism:
# Modern and postmodern philosophy
In the various neo-Hegelian schools - proposing a history of our species some consider to be at variance with Darwin, with the dialectical materialism of Karl Marx and Friedrich Engels and with what is now called analytic philosophy — the point of departure is not so much formal logic and scientific fact but 'identity'. (In Hegel's terminology: 'objective spirit'.)
Individual human consciousness, in the process of reaching for autonomy and freedom, has no choice but to deal with an obvious reality: the collective identities (such as the multiplicity of world views, ethnic, cultural and national identities) which divide the human race and which set (and always have set) different groups in violent conflict with each other. Hegel conceived of the 'totality' of mutually antagonistic world-views and life-forms in history as being 'goal-driven', that is, oriented towards an end-point in history. The 'objective contradiction' of 'subject' and 'object' would eventually 'sublate' into a form of life which leaves violent conflict behind. This goal-oriented, 'teleological' notion of the 'historical process as a whole' is present in a variety of 20th Century authors, from Lukács and Jaspers to Horkheimer and Adorno.
In contrast teleology and "grand narratives" are eschewed in the postmodern attitude [4] and teleology may be viewed as reductive, exclusionary and harmful to those whose stories are erased.[5]
Against this, Alasdair MacIntyre has argued that a narrative understanding of oneself, of one's capacity as an independent reasoner, one's dependence on others and on the social practices and traditions in which one participates, all tends towards an ultimate good of liberation. Social practices may themselves be understood as teleologically orientated to internal goods, for example practices of philosophical and scientific enquiry are teleologically ordered to the elaboration of a true understanding of their objects. MacIntyre's book After Virtue famously dismissed the naturalistic teleology of Aristotle's 'metaphysical biology', but he has cautiously moved from that book's account of a sociological teleology toward an exploration of what remains valid in a more traditional teleological naturalism.
# Teleology and Science
Science concerns itself with physical causality and is well able to function within the bounds of naturalism, indeed, it has frequently to counter appeals to undemonstrable modes of causality. Yet teleological ideas still find refuge in the unpenetrated beginnings and endings of things.
## Physics
It has been claimed that within the framework of thermodynamics, the irreversibility of macroscopic processes is explained in a teleological way.[6]
In recent decades a form of teleological reasoning has reappeared in certain quarters of physics and cosmology, under the heading of anthropic principle, a term Brandon Carter coined in 1973. One of the problems the anthropic principle tries to address is this: why has the universe, which began in a very simple state (Big Bang), since grown ever more complex to the extent that it is even more hospitable to human life than is necessary for mere survival but even allows advanced human civilization?
## Chemistry
Teleological arguments in the field of chemistry have once again often centred around the fitness of materials to form the complex molecular bonds of life. For example, Lawrence Joseph Henderson, an American bio-chemist, advanced such a view in the early 20th century.
## Biology
Biology has always been susceptible to teleological thought, even after Darwin proposed survival as the only observable final good. Driesch, for example, presented a modified vitalism in whch an Aristotlean (or Kantian) entelechy drove embryonic development. Contemporary accounts of teleology within biology are heavily influenced by Larry Wright's etiological account,[7] which seeks to supply a definition of "function" that can be applied to natural phenomena as well as human constructions such as a hammer. Most contemporary accounts of teleology follow Wright. (Ruth Millikan[8] for instance[9]). Others, however, such as Godfrey-Smith[10] and Ernst Mayr,[11] object to any such theory, preferring naturalistic accounts of teleology.
## Cybernetics and Teleonomy
Julian Bigelow, Arturo Rosenblueth, and Norbert Wiener have conceived of feedback mechanisms as lending a teleology to machinery. Wiener, a mathematician, coined the term 'cybernetics' to denote the study of "teleological mechanisms," [12]. Cybernetics is the study of the communication and control of regulatory feedback both in living beings and machines, and in combinations of the two.
In recent years, end-driven teleology has become contrasted with "apparent" teleology, i.e teleonomy or process-driven systems.
## Philosophy of science
For a very detailed discussion of the recent resurgence of teleology in natural science, see Barrow and Tipler (1986). Their work includes:
- A review of much of the intellectual history of teleology and design arguments.
- A chapter on the teleological implications of earth science and chemistry, with special reference to the work of Lawrence Joseph Henderson;
- A discussion of the implications of evolutionary biology for teleology, emphasizing the writings of Theodosius Dobzhansky and Ernst Mayr;
- Teleological speculations on the ultimate fate of the universe. | https://www.wikidoc.org/index.php/Teleological | |
5b39c1a4edb6a2886cf37d3145bdbeccaa9b2100 | wikidoc | Teleostei | Teleostei
Teleostei is one of three infraclasses in class Actinopterygii, the ray-finned fishes. This diverse group, which arose in the Triassic period , includes 20,000 extant species in about 40 orders. The other two infraclasses, Holostei and Chondrostei, are paraphyletic.
On the basis of biomass as well as of species count, teleosts are the typical vertebrates, and all other vertebrates are exceptions to the teleost rule. See Actinopterygii for a complete list of orders.
# Characteristics
Teleosts have a movable maxilla and premaxilla and corresponding modifications in the jaw musculature. These modifications make it possible for teleosts to protrude their jaws outwards from the mouth. The caudal fin is homocercal, meaning the upper and lower lobes are about equal in size. The spine ends at the caudal peduncle, distinguishing this group from those in which the spine extends into the upper lobe of the caudal fin. | Teleostei
Teleostei is one of three infraclasses in class Actinopterygii, the ray-finned fishes. This diverse group, which arose in the Triassic period [1], includes 20,000 extant species in about 40 orders. The other two infraclasses, Holostei and Chondrostei, are paraphyletic.[2]
On the basis of biomass as well as of species count, teleosts are the typical vertebrates, and all other vertebrates are exceptions to the teleost rule. See Actinopterygii for a complete list of orders.
# Characteristics
Teleosts have a movable maxilla and premaxilla and corresponding modifications in the jaw musculature. These modifications make it possible for teleosts to protrude their jaws outwards from the mouth.[2][3] The caudal fin is homocercal, meaning the upper and lower lobes are about equal in size. The spine ends at the caudal peduncle, distinguishing this group from those in which the spine extends into the upper lobe of the caudal fin. [2] | https://www.wikidoc.org/index.php/Teleost_fish | |
9079892824b6333362457618d0fd4e66af9ded0d | wikidoc | Templates | Templates
# What is a template?
A template is a computer program that generates the same content on multiple pages. For example, the help menu that appears at the bottom of the page is a template that appears on all pages. If you edited a page, at the bottom of that page, you would see the code {{WH}}. This tells the software to insert the help menu at the bottom of the page.
# Give an example of how and why I might want to create a template
Using a template can save you time so that you don't have to type the same text over and over again. Say you don't want to type the following text every time you add your name to a page as Editor-in-Chief:
Instead of typing this text every time, you could create a template with a short name like BS. When you type in {{BS}} then
would appear.
# How do I create a template to put my name in on multiple pages?
Create a page named after the abbreviation you want to use. The word Template: must proceed the name of the page. For Bill Smith, this might be:
On this new page called Template:BS type in the text you want to appear:
Save the page.
When you want your name to appear as Editor-In-Chief, insert the template
It will then show up like this: | Templates
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# What is a template?
A template is a computer program that generates the same content on multiple pages. For example, the help menu that appears at the bottom of the page is a template that appears on all pages. If you edited a page, at the bottom of that page, you would see the code {{WH}}. This tells the software to insert the help menu at the bottom of the page.
# Give an example of how and why I might want to create a template
Using a template can save you time so that you don't have to type the same text over and over again. Say you don't want to type the following text every time you add your name to a page as Editor-in-Chief:
Instead of typing this text every time, you could create a template with a short name like BS. When you type in {{BS}} then
Editor-In-Chief: Bill Smith, M.D.; Greater City Hospital, Anytown USA
would appear.
# How do I create a template to put my name in on multiple pages?
Create a page named after the abbreviation you want to use. The word Template: must proceed the name of the page. For Bill Smith, this might be:
Template:BS
On this new page called Template:BS type in the text you want to appear:
Save the page.
When you want your name to appear as Editor-In-Chief, insert the template
It will then show up like this:
Editor-In-Chief: Bill Smith, M.D.; Greater City Hospital, Anytown USA
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Templates | |
5bd33a5f69de6da91a3680638391388824a15c50 | wikidoc | Tenofovir | Tenofovir
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Tenofovir is a nucleotide reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older, chronic hepatitis B in adults and pediatric patients 12 years of age and older. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, diarrhea, headache, pain, depression, asthenia, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The dose is one 300 mg tenofovir tablet once daily taken orally, without regard to food.
- Dosing Information
- The dose is one 300 mg tenofovir tablet once daily taken orally, without regard to food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: The Department of Health and Human Services Panel on Antiretroviral Guidelines and the American Association for the Study of Liver Diseases (AASLD)
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Adult, Category B
- Dosing Information
- Tenofovir 300 mg/day
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tenofovir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Pediatric Patients 12 Years of Age and Older (35 kg or more)
- The dose is one 300 mg tenofovir tablet once daily taken orally, without regard to food.
- For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of tenofovir is 8 mg of tenofovir disoproxil fumarate per kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets.
- Tenofovir oral powder should be measured only with the supplied dosing scoop. One level scoop delivers 1 g of powder which contains 40 mg of tenofovir disoproxil fumarate. Tenofovir oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Do not administer tenofovir oral powder in a liquid as the powder may float on top of the liquid even after stirring. Further patient instructions on how to administer tenofovir oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling (Patient Information).
- Tenofovir is also available as tablets in 150, 200, 250 and 300 mg strengths for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets. The dose is one tablet once daily taken orally, without regard to food.
- Tables 1 and 2 contain dosing recommendations for tenofovir oral powder and tablets based on body weight. Weight should be monitored periodically and the tenofovir dose adjusted accordingly.
- Pediatric Patients 12 Years of Age and Older (35 kg or more)
- The dose is one 300 mg tenofovir tablet once daily taken orally, without regard to food.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tenofovir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tenofovir in pediatric patients.
# Contraindications
- None
# Warnings
### Precautions
- Lactic Acidosis/Severe Hepatomegaly with Steatosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with tenofovir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
- Exacerbation of Hepatitis after Discontinuation of Treatment
- Discontinuation of anti-HBV therapy, including tenofovir, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue tenofovir should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
- New Onset or Worsening Renal Impairment
- Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir.
- It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with tenofovir. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA®, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of tenofovir, and periodically during tenofovir therapy.
- Dosing interval adjustment of tenofovir and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min. No safety or efficacy data are available in patients with renal impairment who received tenofovir using these dosing guidelines, so the potential benefit of tenofovir therapy should be assessed against the potential risk of renal toxicity.
- Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)). Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.
- Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.
- Coadministration with Other Products
- Tenofovir should not be used in combination with the fixed-dose combination products ATRIPLA, COMPLERA, STRIBILD, or TRUVADA since tenofovir disoproxil fumarate is a component of these products.
- Tenofovir should not be administered in combination with HEPSERA (adefovir dipivoxil).
- Patients Coinfected with HIV-1 and HBV
- Due to the risk of development of HIV-1 resistance, tenofovir should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.
- HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with tenofovir. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with tenofovir.
- Bone Effects
- Bone Mineral Density:
In clinical trials in HIV-1 infected adults, tenofovir was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir.
Clinical trials evaluating tenofovir in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected.
The effects of tenofovir-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.
- In clinical trials in HIV-1 infected adults, tenofovir was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir.
- Clinical trials evaluating tenofovir in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected.
- The effects of tenofovir-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.
- Mineralization Defects:
Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF.
- Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF.
- Fat Redistribution
- In HIV-infected patients redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including tenofovir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections , which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Early Virologic Failure
- Clinical trials in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- More than 12,000 subjects have been treated with tenofovir alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access programs. A total of 1,544 subjects have received tenofovir 300 mg once daily in clinical trials; over 11,000 subjects have received tenofovir in expanded access programs.
- The most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.
- Treatment-Naïve Patients
- Study 903 - Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatment-naïve subjects received tenofovir (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness.
- Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 4.
- Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with tenofovir (19% and 1%) respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir and stavudine treatment arms. A summary of Grades 3–4 laboratory abnormalities is provided in Table 5.
- Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve subjects received either tenofovir + EMTRIVA® administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this trial were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve subjects (Table 6).
- Changes in Bone Mineral Density:
- In HIV-1 infected adult subjects in Study 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of tenofovir-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the tenofovir group relative to the stavudine group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range.
- Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 7).
- Treatment-Experienced Patients
- Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment experienced subjects were generally consistent with those seen in treatment naïve subjects including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical trials due to gastrointestinal adverse reactions (Study 907).
- A summary of moderate to severe, treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907 is provided in Table 8.
- Laboratory Abnormalities: Laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir and placebo-treated groups. A summary of Grades 3–4 laboratory abnormalities is provided in Table 9.
- Assessment of adverse reactions is based on two randomized trials (Studies 352 and 321) in 184 HIV-1 infected pediatric subjects (2 to less than 18 years of age) who received treatment with tenofovir (N=93) or placebo/active comparator (N=91) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in subjects who received treatment with tenofovir were consistent with those observed in clinical trials in adults.
- Eighty-nine pediatric subjects (2 to less than 12 years of age) received tenofovir in Study 352 for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score.
- Changes in Bone Mineral Density:
- Clinical trials in HIV-1 infected children and adolescents evaluated BMD changes. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the tenofovir compared to the placebo treatment group. Six tenofovir treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were –0.341 for lumbar spine and –0.458 for total body in the 28 subjects who were treated with tenofovir for 96 weeks. In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the Tenofovir and the d4T or AZT treatment groups. Total body BMD gain was less in the Tenofovir compared to the d4T or AZT treatment groups. One Tenofovir-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z scores were –0.012 for lumbar spine and –0.338 for total body in the 64 subjects who were treated with Tenofovir for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected.
- Treatment-Emergent Adverse Reactions: In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with Tenofovir during the 48-week double-blind period experienced nausea: 9% with Tenofovir versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with Tenofovir included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.
- During the open-label phase of treatment with Tenofovir (weeks 48–240) in Studies 0102 and 0103, less than 1% of subjects (5/585) experienced a confirmed increase in serum creatinine of 0.5 mg/dL from baseline. No significant change in the tolerability profile was observed with continued treatment for up to 240 weeks.
- Laboratory Abnormalities: A summary of Grades 3–4 laboratory abnormalities through Week 48 is provided in Table 10. Grades 3–4 laboratory abnormalities were similar in subjects continuing Tenofovir treatment for up to 240 weeks in these trials.
- The overall incidence of on-treatment ALT flares (defined as serum ALT greater than 2 × baseline and greater than 10 × ULN, with or without associated symptoms) was similar between Tenofovir (2.6%) and HEPSERA (2%). ALT flares generally occurred within the first 4–8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication.
- The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with Tenofovir were consistent with those observed in other hepatitis B clinical trials in adults.
- In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with Tenofovir or other antiviral drugs for up to 48 weeks. Among the 45 subjects receiving Tenofovir, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus less than 2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score greater than or equal to 10 and MELD score greater than or equal to 14 at entry) developed renal failure. Because both Tenofovir and decompensated liver disease may have an impact on renal function, the contribution of Tenofovir to renal impairment in this population is difficult to ascertain.
- One of 45 subjects experienced an on-treatment hepatic flare during the 48 Week trial.
- Assessment of adverse reactions is based on one randomized study (Study GS-US-174-0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with Tenofovir (N = 52) or placebo (N = 54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with Tenofovir were consistent with those observed in clinical trials of Tenofovir in adults.
- In this study, both the Tenofovir and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population. The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in Tenofovir-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively). Three subjects in the Tenofovir group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to Tenofovir were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body. In subjects receiving Tenofovir for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Tenofovir. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Allergic reaction, including angioedema.
- Lactic acidosis, hypokalemia, hypophosphatemia.
- Dyspnea.
- Pancreatitis, increased amylase, abdominal pain.
- Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT).
- Rash.
- Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy.
- Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria.
- Asthenia.
- The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy:
- Rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
# Drug Interactions
- Didanosine
- Coadministration of Tenofovir and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.
- When administered with Tenofovir, Cmax and AUC of didanosine increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving Tenofovir with didanosine 400 mg daily.
- In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with Tenofovir. In patients weighing less than 60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with Tenofovir. When coadministered, Tenofovir and didanosine EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). For additional information on coadministration of Tenofovir and didanosine, please refer to the full prescribing information for didanosine.
- HIV-1 Protease Inhibitors
- Tenofovir decreases the AUC and Cmin of atazanavir. When coadministered with Tenofovir, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Tenofovir should not be coadministered with atazanavir without ritonavir.
- Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is co-administered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving Tenofovir concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for Tenofovir-associated adverse reactions. Tenofovir should be discontinued in patients who develop Tenofovir-associated adverse reactions.
- Drugs Affecting Renal Function
- Since tenofovir is primarily eliminated by the kidneys, coadministration of Tenofovir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs.
- In the treatment of chronic hepatitis B, Tenofovir should not be administered in combination with HEPSERA (adefovir dipivoxil).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Tenofovir should be used during pregnancy only if clearly needed.
- Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Tenofovir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
- Animal Data
- Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tenofovir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tenofovir during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving Tenofovir.
### Pediatric Use
- Pediatric Patients 2 Years of Age and Older with HIV-1 infection
- The safety of Tenofovir in pediatric patients aged 2 to less than 18 years is supported by data from two randomized trials in which Tenofovir was administered to HIV-1 infected treatment-experienced subjects. In addition, the pharmacokinetic profile of tenofovir in patients 2 to less than 18 years of age at the recommended doses was similar to that found to be safe and effective in adult clinical trials.
- In Study 352, 92 treatment-experienced subjects 2 to less than 12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimen were randomized to either replace stavudine or zidovudine with Tenofovir (N = 44) or continue their original regimen (N = 48) for 48 weeks. Five additional subjects over the age of 12 were enrolled and randomized (Tenofovir N=4, original regimen N=1) but are not included in the efficacy analysis. After 48 weeks, all eligible subjects were allowed to continue in the study receiving open-label Tenofovir. At Week 48, 89% of subjects in the Tenofovir treatment group and 90% of subjects in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations less than 400 copies/mL. During the 48 week randomized phase of the study, 1 subject in the Tenofovir group discontinued the study prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the Tenofovir group and 1 subject in the stavudine or zidovudine group) discontinued for other reasons.
- In Study 321, 87 treatment-experienced subjects 12 to less than 18 years of age were treated with Tenofovir (N=45) or placebo (N=42) in combination with an optimized background regimen (OBR) for 48 weeks. The mean baseline CD4 cell count was 374 cells/mm3 and the mean baseline plasma HIV-1 RNA was 4.6 log10 copies/mL. At baseline, 90% of subjects harbored NRTI resistance-associated substitutions in their HIV-1 isolates. Overall, the trial failed to show a difference in virologic response between the Tenofovir and placebo treatment groups. Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to Tenofovir and OBR.
- Although changes in HIV-1 RNA in these highly treatment-experienced subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of Tenofovir in pediatric patients 12 years of age and older who weigh greater than or equal to 35 kg and whose HIV-1 isolate is expected to be sensitive to Tenofovir.
- Safety and effectiveness of Tenofovir in pediatric patients younger than 2 years of age with HIV-1 infection have not been established.
- Pediatric Patients 12 Years of Age and Older with Chronic Hepatitis B
- In Study 115, 106 HBeAg negative (9%) and positive (91%) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with Tenofovir 300 mg (N = 52) or placebo (N = 54) for 72 weeks. At study entry, the mean HBV DNA was 8.1 log10 copies/mL and mean ALT was 101 U/L. Of 52 subjects treated with Tenofovir, 20 subjects were nucleos(t)ide-naïve and 32 subjects were nucleos(t)ide-experienced. Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience. At Week 72, 88% (46/52) of subjects in the Tenofovir group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL. Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving Tenofovir had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group. One Tenofovir-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation.
- Safety and effectiveness of Tenofovir in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.
### Geriatic Use
- Clinical trials of Tenofovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Tenofovir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tenofovir with respect to specific racial populations.
### Renal Impairment
- It is recommended that the dosing interval for Tenofovir be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis.
### Hepatic Impairment
There is no FDA guidance on the use of Tenofovir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tenofovir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tenofovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in patients with mild renal impairment.
- Bone mineral density monitoring should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia.
# IV Compatibility
There is limited information regarding IV Compatibility of Tenofovir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Limited clinical experience at doses higher than the therapeutic dose of Tenofovir 300 mg is available. In Study 901, 600 mg tenofovir disoproxil fumarate was administered to 8 subjects orally for 28 days. No severe adverse reactions were reported. The effects of higher doses are not known.
### Management
- If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
- Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of Tenofovir, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Tenofovir in the drug label.
# Pharmacology
## Mechanism of Action
- Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
## Structure
- Tenofovir is the brand name for tenofovir disoproxil fumarate (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.
- The chemical name of tenofovir disoproxil fumarate is 9-methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P - C4H4O4 and a molecular weight of 635.52. It has the following structural formula:
- Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C.
- Tenofovir is available as tablets or as an oral powder.
- Tenofovir tablets are for oral administration in strengths of 150, 200, 250, and 300 mg of tenofovir disoproxil fumarate, which are equivalent to 123, 163, 204 and 245 mg of tenofovir disoproxil, respectively. Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The 300 mg tablets are coated with Opadry II Y–30–10671–A, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. The 150, 200, and 250 mg tablets are coated with Opadry II 32K-18425, which contains hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.
- Tenofovir oral powder is available for oral administration as white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate per gram of oral powder, which is equivalent to 33 mg of tenofovir disoproxil. The oral powder contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, ethylcellulose, and silicon dioxide.
- In this insert, all dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tenofovir in the drug label.
## Pharmacokinetics
- The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
- Absorption
- Tenofovir is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from Tenofovir in fasted subjects is approximately 25%. Following oral administration of a single dose of Tenofovir 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 0.30 ± 0.09 µg/mL and 2.29 ± 0.69 µg∙hr/mL, respectively.
- The pharmacokinetics of tenofovir are dose proportional over a Tenofovir dose range of 75 to 600 mg and are not affected by repeated dosing.
- In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean Cmax of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.
- Distribution
- In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
- Metabolism and Elimination
- In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes.
- Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of Tenofovir, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of Tenofovir 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
- Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
- Effects of Food on Oral Absorption
- Administration of Tenofovir 300 mg tablets following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0–∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of Tenofovir with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 µg/mL and 3.32 ± 1.37 µg∙hr/mL following multiple doses of Tenofovir 300 mg once daily in the fed state, when meal content was not controlled.
- Special Populations
- Race: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.
- Gender: Tenofovir pharmacokinetics are similar in male and female subjects.
- Pediatric Patients 2 Years of Age and Older: Steady-state pharmacokinetics of tenofovir were evaluated in 31 HIV-1 infected pediatric subjects 2 to less than 18 years (Table 11). Tenofovir exposure achieved in these pediatric subjects receiving oral once daily doses of Tenofovir 300 mg (tablet) or 8 mg/kg of body weight (powder) up to a maximum dose of 300 mg was similar to exposures achieved in adults receiving once-daily doses of Tenofovir 300 mg.
- Tenofovir exposures in 52 HBV-infected pediatric subjects (12 to less than 18 years of age) receiving oral once-daily doses of Tenofovir 300 mg tablet were comparable to exposures achieved in HIV-1-infected adults and adolescents receiving once-daily doses of 300 mg.
- Geriatric Patients: Pharmacokinetic trials have not been performed in the elderly (65 years and older).
- Patients with Impaired Renal Function: The pharmacokinetics of tenofovir are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0–∞ of tenofovir were increased (Table 12). It is recommended that the dosing interval for Tenofovir be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis.
- Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of Tenofovir, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
- Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg single dose of Tenofovir have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in Tenofovir dosing is required in patients with hepatic impairment.
- Assessment of Drug Interactions
- At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP mediated interactions involving tenofovir with other medicinal products is low.
- Tenofovir has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 13 and 14 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of Tenofovir on the pharmacokinetics of coadministered drug. Coadministration of Tenofovir with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of Tenofovir with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with Tenofovir, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 14). The mechanism of this interaction is unknown.
- No clinically significant drug interactions have been observed between Tenofovir and efavirenz, methadone, nelfinavir, oral contraceptives, or ribavirin.
- Mechanism of Action
- Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
- Activity against HIV
- Antiviral Activity
- The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 µM to 8.5 µM. In drug combination studies, tenofovir was not antagonistic with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir). Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 µM to 2.2 µM) and strain specific activity against HIV-2 (EC50 values ranged from 1.6 µM to 5.5 µM).
- Resistance
- HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2–4 fold reduction in susceptibility to tenofovir.
- In Study 903 of treatment-naïve subjects (Tenofovir + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz), genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of efavirenz and lamivudine resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) analyzed patient isolates on the Tenofovir arm and in 2/49 (4%) analyzed patient isolates on the stavudine arm. Of the 8 subjects whose virus developed K65R in the Tenofovir arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and one at Week 96. Other substitutions resulting in resistance to Tenofovir were not identified in this trial.
- In Study 934 of treatment-naïve subjects (Tenofovir + EMTRIVA + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz), genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subject isolates in the Tenofovir + EMTRIVA group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
- Cross-Resistance
- Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R substitution selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with this substitution also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.
- In Studies 902 and 907 conducted in treatment-experienced subjects (Tenofovir + Standard Background Therapy (SBT) compared to Placebo + SBT), 14/304 (5%) of the Tenofovir-treated subjects with virologic failure through Week 96 had greater than 1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution in the HIV-1 reverse transcriptase gene.
- The virologic response to Tenofovir therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Studies 902 and 907. In these clinical trials, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI substitution. Virologic responses for subjects in the genotype substudy were similar to the overall trial results.
- Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of Tenofovir to pre-existing zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. Tenofovir-treated subjects whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution showed reduced responses to Tenofovir therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to Tenofovir therapy. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to Tenofovir. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
- In the protocol defined analyses, virologic response to Tenofovir was not reduced in subjects with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.
- Studies 902 and 907 Phenotypic Analyses
- Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to Tenofovir and response to Tenofovir therapy. Table 15 summarizes the HIV-1 RNA response by baseline Tenofovir susceptibility.
- Activity against HBV
- Antiviral Activity
- The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir ranged from 0.14 to 1.5 µM, with CC50 (50% cytotoxicity concentration) values greater than 100 µM. In cell culture combination antiviral activity studies of tenofovir with the nucleoside HBV reverse transcriptase inhibitors entecavir, lamivudine, and telbivudine, and with the nucleoside HIV-1 reverse transcriptase inhibitor emtricitabine, no antagonistic activity was observed.
- Resistance
- Cumulative Tenofovir genotypic resistance has been evaluated annually for up to 240 weeks in Studies 0102, 0103, 0106, 0108, and 0121 with the paired HBV reverse transcriptase amino acid sequences of the pre-treatment and on-treatment isolates from subjects who received at least 24 weeks of Tenofovir monotherapy and remained viremic with HBV DNA greater than or equal to 400 copies/mL at the end of each study year (or at discontinuation of Tenofovir monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Studies 0102 and 0103, HBeAg-positive subjects had a higher baseline viral load than HBeAg-negative subjects and a significantly higher proportion of the subjects remained viremic at their last time point on Tenofovir monotherapy (15% versus 4%, respectively).
- HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 16); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to Tenofovir (genotypic and phenotypic analyses).
- Cross-Resistance
- Cross-resistance has been observed between HBV nucleoside/nucleotide analogue reverse transcriptase inhibitors.
- In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.
- HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild type virus.
- HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9- to 1.5-fold that of wild type virus.
- One hundred fifty-two subjects initiating Tenofovir therapy in Studies 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV nucleos(t)ide analogue reverse transcriptase inhibitors: 14 with adefovir resistance-associated substitutions (rtA181S/T/V and/or rtN236T), 135 with lamivudine resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and lamivudine resistance-associated substitutions. Following up to 240 weeks of Tenofovir treatment, 11 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with lamivudine-resistant HBV, and 2 of the 3 subjects with both adefovir- and lamivudine-resistant HBV achieved and maintained virologic suppression (HBV DNA less than 400 copies/mL). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.
## Nonclinical Toxicology
- Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.
- Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice.
- There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.
- Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
- Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.
# Clinical Studies
- Treatment-Naïve Adult Patients
- Study 903
- Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter trial comparing Tenofovir (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18–64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm3 (range 3–956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417–5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4+ cell counts <200 cells/mm3. Treatment outcomes through 48 and 144 weeks are presented in Table 17.
- Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4+ cell count (< or ≥200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of subjects in the Tenofovir and stavudine arms, respectively achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm3 for the Tenofovir arm and 283 cells/mm3 for the stavudine arm.
- Through 144 weeks, 11 subjects in the Tenofovir group and 9 subjects in the stavudine group experienced a new CDC Class C event.
- Study 934
- Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + Tenofovir administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + Tenofovir with efavirenz. Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 18.
- Through Week 48, 84% and 73% of subjects in the emtricitabine + Tenofovir group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + Tenofovir group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the EMTRIVA + Tenofovir group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).
- Through 48 weeks, 7 subjects in the emtricitabine + Tenofovir group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
- Treatment-Experienced Adult Patients
- Study 907
- Study 907 was a 24-week, double-blind placebo-controlled multicenter trial of Tenofovir added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects. After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label Tenofovir for an additional 24 weeks. Subjects had a mean baseline CD4+ cell count of 427 cells/mm3 (range 23–1385), median baseline plasma HIV-1 RNA of 2340 (range 50–75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the subjects was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.
- The percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks are summarized in Table 19.
- At 24 weeks of therapy, there was a higher proportion of subjects in the Tenofovir arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4+ cell counts by Week 24 was +11 cells/mm3 for the Tenofovir group and -5 cells/mm3 for the placebo group. Mean change in absolute CD4+ cell counts by Week 48 was +4 cells/mm3 for the Tenofovir group.
- Through Week 24, one subject in the Tenofovir group and no subjects in the placebo arm experienced a new CDC Class C event.
- HBeAg-Negative Chronic Hepatitis B
- Study 0102 was a Phase 3, randomized, double-blind, active-controlled trial of Tenofovir 300 mg compared to HEPSERA 10 mg in 375 HBeAg- (anti-HBe+) subjects with compensated liver function, the majority of whom were nucleoside-naïve. The mean age of subjects was 44 years, 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy and 18% were nucleoside-experienced (16% had prior lamivudine experience). At baseline, subjects had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log10 copies/mL; and mean serum ALT was 140 U/L.
- HBeAg-Positive Chronic Hepatitis B
- Study 0103 was a Phase 3, randomized, double-blind, active-controlled trial of Tenofovir 300 mg compared to HEPSERA 10 mg in 266 HBeAg+ nucleoside-naïve subjects with compensated liver function. The mean age of subjects was 34 years, 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and <5% were nucleoside experienced. At baseline, subjects had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log10 copies /mL; and mean serum ALT was 147 U/L.
- The primary data analysis was conducted after all subjects reached 48 weeks of treatment and results are summarized below.
- The primary efficacy endpoint in both trials was complete response to treatment defined as HBV DNA <400 copies/mL and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 20).
- Treatment Beyond 48 Weeks
- In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to Tenofovir and HEPSERA, respectively) were eligible to roll over to open-label Tenofovir with no interruption in treatment.
- In Study 0102, 304 of 375 subjects (81%) continued in the study through Week 240. Among subjects randomized to Tenofovir followed by open-label treatment with Tenofovir, 82% had HBV DNA < 400 copies/mL, and 69% had ALT normalization at Week 240. Among subjects randomized to HEPSERA followed by open-label treatment with Tenofovir, 88% had HBV DNA < 400 copies/mL and 76% had ALT normalization through Week 240. No subject in either treatment group experienced HBsAg loss/seroconversion through Week 240.
- In Study 0103, 185 of 266 subjects (69%) continued in the study through Week 240. Among subjects randomized to Tenofovir, 63% had HBV DNA < 400 copies/mL, 44% had ALT normalization, and 34% had HBeAg loss (26% seroconversion to anti-HBe antibody) through Week 240. Among subjects randomized to HEPSERA followed by up to 192 weeks of open-label treatment with Tenofovir, 64% had HBV DNA < 400 copies/mL, 54% had ALT normalization, and 34% had HBeAg loss (29% seroconversion to anti-HBe antibody) through Week 240. At Week 240, HBsAg loss was 9% in both treatment groups, and seroconversion to anti-HBs was 7% for the subjects initially randomized to Tenofovir and 9% for subjects initially randomized to HEPSERA.
- Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with Tenofovir monotherapy were available for analysis at baseline, Week 48 and Week 240. There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label Tenofovir without biopsy data that would be expected to affect histological outcomes at Week 240. Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively. In the subjects without cirrhosis at baseline (Ishak fibrosis score 0-4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. In subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points. No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.
- Patients with Lamivudine-Resistant Chronic Hepatitis B
- Study 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of Tenofovir compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥ 1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M). One hundred forty-one adult subjects were randomized to the Tenofovir treatment arm. The mean age of subjects randomized to Tenofovir was 47 years (range 18–73), 74% were male, 59% were Caucasian, and 37% were Asian. At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT. Subjects had a mean HBV DNA of 6.4 log10 copies/mL and mean serum ALT of 71 U/L at baseline.
- After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to Tenofovir had HBV DNA < 400 copies/mL, and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization. Among the HBeAg-positive subjects randomized to Tenofovir, 10 of 65 subjects (15%) experienced HBeAg loss, and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96. The proportion of subjects with HBV DNA concentrations below 400 copies/mL at Week 96 was similar between the Tenofovir monotherapy and the comparator arms.
- Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.
- Patients with Chronic Hepatitis B and Decompensated Liver Disease
- Tenofovir was studied in a small randomized, double-blind, active-controlled trial evaluating the safety of Tenofovir compared to other antiviral drugs in subjects with chronic hepatitis B and decompensated liver disease through 48 weeks (Study 0108).
- Forty-five adult subjects (37 males and 8 females) were randomized to the Tenofovir treatment arm. At baseline, 69% subjects were HBeAg-negative, and 31% were HBeAg-positive. Subjects had a mean Child-Pugh score of 7, a mean MELD score of 12, mean HBV DNA of 5.8 log10 copies/mL and mean serum ALT of 61 U/L at baseline. Trial endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphorus of < 2 mg/dL.
- At 48 weeks, 31/44 (70%) and 12/26 (46%) Tenofovir-treated subjects achieved an HBV DNA < 400 copies/mL, and normalized ALT, respectively. The trial was not designed to evaluate treatment impact on clinical endpoints such as progression of liver disease, need for liver transplantation, or death.
# How Supplied
- Tablets
- Tenofovir tablets, 150 mg, are triangle-shaped, white, film-coated tablets containing 150 mg of tenofovir disoproxil fumarate, which is equivalent to 123 mg of tenofovir disoproxil, are debossed with "GSI" on one side and with "150" on the other side. Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure. (NDC 61958-0404-1)
- Tenofovir tablets, 200 mg, are round-shaped, white, film-coated tablets containing 200 mg of tenofovir disoproxil fumarate, which is equivalent to 163 mg of tenofovir disoproxil, are debossed with "GSI" on one side and with "200" on the other side. Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure. (NDC 61958-0405-1)
- Tenofovir tablets, 250 mg, are capsule-shaped, white, film-coated tablets containing 250 mg of tenofovir disoproxil fumarate, which is equivalent to 204 mg of tenofovir disoproxil, are debossed with "GSI" on one side and with "250" on the other side. Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure. (NDC 61958-0406-1)
- Tenofovir tablets, 300 mg, are almond-shaped, light blue, film-coated tablets containing 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, are debossed with "GILEAD" and "4331" on one side and with "300" on the other side. Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure. (NDC 61958-0401-1)
- Oral Powder
- Tenofovir oral powder consists of white, coated granules containing 40 mg of tenofovir disoproxil fumarate, which is equivalent to 33 mg of tenofovir disoproxil, per gram of powder and is available in multi-use bottles containing 60 grams of oral powder, closed with a child-resistant closure, and co-packaged with a dosing scoop. (NDC 61958-0403-1)
- Store Tenofovir tablets and oral powder at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F).
- Keep the bottle tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.
## Storage
There is limited information regarding Tenofovir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised that:
- Tenofovir is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using Tenofovir.
- Patients should avoid doing things that can spread HIV or HBV to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. Tenofovir is excreted in breast milk and it is not known whether it can harm the baby. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
- The long term effects of Tenofovir are unknown.
- Tenofovir tablets and oral powder are for oral ingestion only.
- Tenofovir should not be discontinued without first informing their physician.
- If you have HIV-1 infection, with or without HBV coinfection, it is important to take Tenofovir with combination therapy.
- It is important to take Tenofovir on a regular dosing schedule and to avoid missing doses.
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with Tenofovir should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness).
- Severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and have discontinued Tenofovir.
- Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs). Dosing interval of Tenofovir may need adjustment in patients with renal impairment.
- Tenofovir should not be coadministered with the fixed-dose combination products ATRIPLA, COMPLERA, STRIBILD, and TRUVADA since it is a component of these products.
- Tenofovir should not be administered in combination with HEPSERA .
- Patients with HIV-1 should be tested for Hepatitis B virus (HBV) before initiating antiretroviral therapy.
- In patients with chronic hepatitis B, it is important to obtain HIV antibody testing prior to initiating Tenofovir.
- Decreases in bone mineral density have been observed with the use of Tenofovir. Bone mineral density monitoring should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia.
- In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. The relationship between response and long-term prevention of outcomes such as hepatocellular carcinoma is not known.
# Precautions with Alcohol
- Alcohol-Tenofovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VIREAD®
# Look-Alike Drug Names
There is limited information regarding Tenofovir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tenofovir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
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# Black Box Warning
# Overview
Tenofovir is a nucleotide reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older, chronic hepatitis B in adults and pediatric patients 12 years of age and older. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, diarrhea, headache, pain, depression, asthenia, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The dose is one 300 mg tenofovir tablet once daily taken orally, without regard to food.
- Dosing Information
- The dose is one 300 mg tenofovir tablet once daily taken orally, without regard to food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: The Department of Health and Human Services Panel on Antiretroviral Guidelines and the American Association for the Study of Liver Diseases (AASLD)
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Adult, Category B
- Dosing Information
- Tenofovir 300 mg/day[1]
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tenofovir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Pediatric Patients 12 Years of Age and Older (35 kg or more)
- The dose is one 300 mg tenofovir tablet once daily taken orally, without regard to food.
- For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of tenofovir is 8 mg of tenofovir disoproxil fumarate per kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets.
- Tenofovir oral powder should be measured only with the supplied dosing scoop. One level scoop delivers 1 g of powder which contains 40 mg of tenofovir disoproxil fumarate. Tenofovir oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Do not administer tenofovir oral powder in a liquid as the powder may float on top of the liquid even after stirring. Further patient instructions on how to administer tenofovir oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling (Patient Information).
- Tenofovir is also available as tablets in 150, 200, 250 and 300 mg strengths for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets. The dose is one tablet once daily taken orally, without regard to food.
- Tables 1 and 2 contain dosing recommendations for tenofovir oral powder and tablets based on body weight. Weight should be monitored periodically and the tenofovir dose adjusted accordingly.
- Pediatric Patients 12 Years of Age and Older (35 kg or more)
- The dose is one 300 mg tenofovir tablet once daily taken orally, without regard to food.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tenofovir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tenofovir in pediatric patients.
# Contraindications
- None
# Warnings
### Precautions
- Lactic Acidosis/Severe Hepatomegaly with Steatosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with tenofovir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
- Exacerbation of Hepatitis after Discontinuation of Treatment
- Discontinuation of anti-HBV therapy, including tenofovir, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue tenofovir should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
- New Onset or Worsening Renal Impairment
- Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir.
- It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with tenofovir. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA®, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of tenofovir, and periodically during tenofovir therapy.
- Dosing interval adjustment of tenofovir and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min. No safety or efficacy data are available in patients with renal impairment who received tenofovir using these dosing guidelines, so the potential benefit of tenofovir therapy should be assessed against the potential risk of renal toxicity.
- Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)). Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.
- Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.
- Coadministration with Other Products
- Tenofovir should not be used in combination with the fixed-dose combination products ATRIPLA, COMPLERA, STRIBILD, or TRUVADA since tenofovir disoproxil fumarate is a component of these products.
- Tenofovir should not be administered in combination with HEPSERA (adefovir dipivoxil).
- Patients Coinfected with HIV-1 and HBV
- Due to the risk of development of HIV-1 resistance, tenofovir should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.
- HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with tenofovir. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with tenofovir.
- Bone Effects
- Bone Mineral Density:
In clinical trials in HIV-1 infected adults, tenofovir was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir.
Clinical trials evaluating tenofovir in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected.
The effects of tenofovir-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.
- In clinical trials in HIV-1 infected adults, tenofovir was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir.
- Clinical trials evaluating tenofovir in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected.
- The effects of tenofovir-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.
- Mineralization Defects:
Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF.
- Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF.
- Fat Redistribution
- In HIV-infected patients redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including tenofovir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Early Virologic Failure
- Clinical trials in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- More than 12,000 subjects have been treated with tenofovir alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access programs. A total of 1,544 subjects have received tenofovir 300 mg once daily in clinical trials; over 11,000 subjects have received tenofovir in expanded access programs.
- The most common adverse reactions (incidence greater than or equal to 10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.
- Treatment-Naïve Patients
- Study 903 - Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatment-naïve subjects received tenofovir (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness.
- Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 4.
- Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with tenofovir (19% and 1%) respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir and stavudine treatment arms. A summary of Grades 3–4 laboratory abnormalities is provided in Table 5.
- Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve subjects received either tenofovir + EMTRIVA® administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse reactions observed in this trial were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve subjects (Table 6).
- Changes in Bone Mineral Density:
- In HIV-1 infected adult subjects in Study 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of tenofovir-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the tenofovir group relative to the stavudine group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range.
- Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 7).
- Treatment-Experienced Patients
- Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment experienced subjects were generally consistent with those seen in treatment naïve subjects including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical trials due to gastrointestinal adverse reactions (Study 907).
- A summary of moderate to severe, treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907 is provided in Table 8.
- Laboratory Abnormalities: Laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir and placebo-treated groups. A summary of Grades 3–4 laboratory abnormalities is provided in Table 9.
- Assessment of adverse reactions is based on two randomized trials (Studies 352 and 321) in 184 HIV-1 infected pediatric subjects (2 to less than 18 years of age) who received treatment with tenofovir (N=93) or placebo/active comparator (N=91) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in subjects who received treatment with tenofovir were consistent with those observed in clinical trials in adults.
- Eighty-nine pediatric subjects (2 to less than 12 years of age) received tenofovir in Study 352 for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score.
- Changes in Bone Mineral Density:
- Clinical trials in HIV-1 infected children and adolescents evaluated BMD changes. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the tenofovir compared to the placebo treatment group. Six tenofovir treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were –0.341 for lumbar spine and –0.458 for total body in the 28 subjects who were treated with tenofovir for 96 weeks. In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the Tenofovir and the d4T or AZT treatment groups. Total body BMD gain was less in the Tenofovir compared to the d4T or AZT treatment groups. One Tenofovir-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z scores were –0.012 for lumbar spine and –0.338 for total body in the 64 subjects who were treated with Tenofovir for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected.
- Treatment-Emergent Adverse Reactions: In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with Tenofovir during the 48-week double-blind period experienced nausea: 9% with Tenofovir versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with Tenofovir included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.
- During the open-label phase of treatment with Tenofovir (weeks 48–240) in Studies 0102 and 0103, less than 1% of subjects (5/585) experienced a confirmed increase in serum creatinine of 0.5 mg/dL from baseline. No significant change in the tolerability profile was observed with continued treatment for up to 240 weeks.
- Laboratory Abnormalities: A summary of Grades 3–4 laboratory abnormalities through Week 48 is provided in Table 10. Grades 3–4 laboratory abnormalities were similar in subjects continuing Tenofovir treatment for up to 240 weeks in these trials.
- The overall incidence of on-treatment ALT flares (defined as serum ALT greater than 2 × baseline and greater than 10 × ULN, with or without associated symptoms) was similar between Tenofovir (2.6%) and HEPSERA (2%). ALT flares generally occurred within the first 4–8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation. ALT flares typically resolved within 4 to 8 weeks without changes in study medication.
- The adverse reactions observed in subjects with chronic hepatitis B and lamivudine resistance who received treatment with Tenofovir were consistent with those observed in other hepatitis B clinical trials in adults.
- In a small randomized, double-blind, active-controlled trial (0108), subjects with CHB and decompensated liver disease received treatment with Tenofovir or other antiviral drugs for up to 48 weeks. Among the 45 subjects receiving Tenofovir, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain (22%), nausea (20%), insomnia (18%), pruritus (16%), vomiting (13%), dizziness (13%), and pyrexia (11%). Two of 45 (4%) subjects died through Week 48 of the trial due to progression of liver disease. Three of 45 (7%) subjects discontinued treatment due to an adverse event. Four of 45 (9%) subjects experienced a confirmed increase in serum creatinine of 0.5 mg/dL (1 subject also had a confirmed serum phosphorus less than 2 mg/dL through Week 48). Three of these subjects (each of whom had a Child-Pugh score greater than or equal to 10 and MELD score greater than or equal to 14 at entry) developed renal failure. Because both Tenofovir and decompensated liver disease may have an impact on renal function, the contribution of Tenofovir to renal impairment in this population is difficult to ascertain.
- One of 45 subjects experienced an on-treatment hepatic flare during the 48 Week trial.
- Assessment of adverse reactions is based on one randomized study (Study GS-US-174-0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with Tenofovir (N = 52) or placebo (N = 54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with Tenofovir were consistent with those observed in clinical trials of Tenofovir in adults.
- In this study, both the Tenofovir and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population. The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in Tenofovir-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively). Three subjects in the Tenofovir group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to Tenofovir were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body. In subjects receiving Tenofovir for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Tenofovir. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Allergic reaction, including angioedema.
- Lactic acidosis, hypokalemia, hypophosphatemia.
- Dyspnea.
- Pancreatitis, increased amylase, abdominal pain.
- Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT).
- Rash.
- Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy.
- Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria.
- Asthenia.
- The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy:
- Rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
# Drug Interactions
- Didanosine
- Coadministration of Tenofovir and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.
- When administered with Tenofovir, Cmax and AUC of didanosine increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving Tenofovir with didanosine 400 mg daily.
- In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with Tenofovir. In patients weighing less than 60 kg, the didanosine dose should be reduced to 200 mg once daily when it is coadministered with Tenofovir. When coadministered, Tenofovir and didanosine EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). For additional information on coadministration of Tenofovir and didanosine, please refer to the full prescribing information for didanosine.
- HIV-1 Protease Inhibitors
- Tenofovir decreases the AUC and Cmin of atazanavir. When coadministered with Tenofovir, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Tenofovir should not be coadministered with atazanavir without ritonavir.
- Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is co-administered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving Tenofovir concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for Tenofovir-associated adverse reactions. Tenofovir should be discontinued in patients who develop Tenofovir-associated adverse reactions.
- Drugs Affecting Renal Function
- Since tenofovir is primarily eliminated by the kidneys, coadministration of Tenofovir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs.
- In the treatment of chronic hepatitis B, Tenofovir should not be administered in combination with HEPSERA (adefovir dipivoxil).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Tenofovir should be used during pregnancy only if clearly needed.
- Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Tenofovir, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
- Animal Data
- Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tenofovir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tenofovir during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving Tenofovir.
### Pediatric Use
- Pediatric Patients 2 Years of Age and Older with HIV-1 infection
- The safety of Tenofovir in pediatric patients aged 2 to less than 18 years is supported by data from two randomized trials in which Tenofovir was administered to HIV-1 infected treatment-experienced subjects. In addition, the pharmacokinetic profile of tenofovir in patients 2 to less than 18 years of age at the recommended doses was similar to that found to be safe and effective in adult clinical trials.
- In Study 352, 92 treatment-experienced subjects 2 to less than 12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimen were randomized to either replace stavudine or zidovudine with Tenofovir (N = 44) or continue their original regimen (N = 48) for 48 weeks. Five additional subjects over the age of 12 were enrolled and randomized (Tenofovir N=4, original regimen N=1) but are not included in the efficacy analysis. After 48 weeks, all eligible subjects were allowed to continue in the study receiving open-label Tenofovir. At Week 48, 89% of subjects in the Tenofovir treatment group and 90% of subjects in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations less than 400 copies/mL. During the 48 week randomized phase of the study, 1 subject in the Tenofovir group discontinued the study prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the Tenofovir group and 1 subject in the stavudine or zidovudine group) discontinued for other reasons.
- In Study 321, 87 treatment-experienced subjects 12 to less than 18 years of age were treated with Tenofovir (N=45) or placebo (N=42) in combination with an optimized background regimen (OBR) for 48 weeks. The mean baseline CD4 cell count was 374 cells/mm3 and the mean baseline plasma HIV-1 RNA was 4.6 log10 copies/mL. At baseline, 90% of subjects harbored NRTI resistance-associated substitutions in their HIV-1 isolates. Overall, the trial failed to show a difference in virologic response between the Tenofovir and placebo treatment groups. Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to Tenofovir and OBR.
- Although changes in HIV-1 RNA in these highly treatment-experienced subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of Tenofovir in pediatric patients 12 years of age and older who weigh greater than or equal to 35 kg and whose HIV-1 isolate is expected to be sensitive to Tenofovir.
- Safety and effectiveness of Tenofovir in pediatric patients younger than 2 years of age with HIV-1 infection have not been established.
- Pediatric Patients 12 Years of Age and Older with Chronic Hepatitis B
- In Study 115, 106 HBeAg negative (9%) and positive (91%) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with Tenofovir 300 mg (N = 52) or placebo (N = 54) for 72 weeks. At study entry, the mean HBV DNA was 8.1 log10 copies/mL and mean ALT was 101 U/L. Of 52 subjects treated with Tenofovir, 20 subjects were nucleos(t)ide-naïve and 32 subjects were nucleos(t)ide-experienced. Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience. At Week 72, 88% (46/52) of subjects in the Tenofovir group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL. Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving Tenofovir had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group. One Tenofovir-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation.
- Safety and effectiveness of Tenofovir in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.
### Geriatic Use
- Clinical trials of Tenofovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Tenofovir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tenofovir with respect to specific racial populations.
### Renal Impairment
- It is recommended that the dosing interval for Tenofovir be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis.
### Hepatic Impairment
There is no FDA guidance on the use of Tenofovir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tenofovir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tenofovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in patients with mild renal impairment.
- Bone mineral density monitoring should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia.
# IV Compatibility
There is limited information regarding IV Compatibility of Tenofovir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Limited clinical experience at doses higher than the therapeutic dose of Tenofovir 300 mg is available. In Study 901, 600 mg tenofovir disoproxil fumarate was administered to 8 subjects orally for 28 days. No severe adverse reactions were reported. The effects of higher doses are not known.
### Management
- If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
- Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of Tenofovir, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Tenofovir in the drug label.
# Pharmacology
## Mechanism of Action
- Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
## Structure
- Tenofovir is the brand name for tenofovir disoproxil fumarate (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.
- The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2-bis(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P • C4H4O4 and a molecular weight of 635.52. It has the following structural formula:
- Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C.
- Tenofovir is available as tablets or as an oral powder.
- Tenofovir tablets are for oral administration in strengths of 150, 200, 250, and 300 mg of tenofovir disoproxil fumarate, which are equivalent to 123, 163, 204 and 245 mg of tenofovir disoproxil, respectively. Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The 300 mg tablets are coated with Opadry II Y–30–10671–A, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. The 150, 200, and 250 mg tablets are coated with Opadry II 32K-18425, which contains hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.
- Tenofovir oral powder is available for oral administration as white, taste-masked, coated granules containing 40 mg of tenofovir disoproxil fumarate per gram of oral powder, which is equivalent to 33 mg of tenofovir disoproxil. The oral powder contains the following inactive ingredients: mannitol, hydroxypropyl cellulose, ethylcellulose, and silicon dioxide.
- In this insert, all dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tenofovir in the drug label.
## Pharmacokinetics
- The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.
- Absorption
- Tenofovir is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from Tenofovir in fasted subjects is approximately 25%. Following oral administration of a single dose of Tenofovir 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 0.30 ± 0.09 µg/mL and 2.29 ± 0.69 µg∙hr/mL, respectively.
- The pharmacokinetics of tenofovir are dose proportional over a Tenofovir dose range of 75 to 600 mg and are not affected by repeated dosing.
- In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean Cmax of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.
- Distribution
- In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 µg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
- Metabolism and Elimination
- In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes.
- Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of Tenofovir, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of Tenofovir 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
- Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.
- Effects of Food on Oral Absorption
- Administration of Tenofovir 300 mg tablets following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0–∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of Tenofovir with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 µg/mL and 3.32 ± 1.37 µg∙hr/mL following multiple doses of Tenofovir 300 mg once daily in the fed state, when meal content was not controlled.
- Special Populations
- Race: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.
- Gender: Tenofovir pharmacokinetics are similar in male and female subjects.
- Pediatric Patients 2 Years of Age and Older: Steady-state pharmacokinetics of tenofovir were evaluated in 31 HIV-1 infected pediatric subjects 2 to less than 18 years (Table 11). Tenofovir exposure achieved in these pediatric subjects receiving oral once daily doses of Tenofovir 300 mg (tablet) or 8 mg/kg of body weight (powder) up to a maximum dose of 300 mg was similar to exposures achieved in adults receiving once-daily doses of Tenofovir 300 mg.
- Tenofovir exposures in 52 HBV-infected pediatric subjects (12 to less than 18 years of age) receiving oral once-daily doses of Tenofovir 300 mg tablet were comparable to exposures achieved in HIV-1-infected adults and adolescents receiving once-daily doses of 300 mg.
- Geriatric Patients: Pharmacokinetic trials have not been performed in the elderly (65 years and older).
- Patients with Impaired Renal Function: The pharmacokinetics of tenofovir are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0–∞ of tenofovir were increased (Table 12). It is recommended that the dosing interval for Tenofovir be modified in patients with estimated creatinine clearance below 50 mL/min or in patients with ESRD who require dialysis.
- Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of Tenofovir, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
- Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg single dose of Tenofovir have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in Tenofovir dosing is required in patients with hepatic impairment.
- Assessment of Drug Interactions
- At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP mediated interactions involving tenofovir with other medicinal products is low.
- Tenofovir has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 13 and 14 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of Tenofovir on the pharmacokinetics of coadministered drug. Coadministration of Tenofovir with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of Tenofovir with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with Tenofovir, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 14). The mechanism of this interaction is unknown.
- No clinically significant drug interactions have been observed between Tenofovir and efavirenz, methadone, nelfinavir, oral contraceptives, or ribavirin.
- Mechanism of Action
- Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
- Activity against HIV
- Antiviral Activity
- The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 µM to 8.5 µM. In drug combination studies, tenofovir was not antagonistic with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir). Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 µM to 2.2 µM) and strain specific activity against HIV-2 (EC50 values ranged from 1.6 µM to 5.5 µM).
- Resistance
- HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2–4 fold reduction in susceptibility to tenofovir.
- In Study 903 of treatment-naïve subjects (Tenofovir + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz), genotypic analyses of isolates from subjects with virologic failure through Week 144 showed development of efavirenz and lamivudine resistance-associated substitutions to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in 8/47 (17%) analyzed patient isolates on the Tenofovir arm and in 2/49 (4%) analyzed patient isolates on the stavudine arm. Of the 8 subjects whose virus developed K65R in the Tenofovir arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and one at Week 96. Other substitutions resulting in resistance to Tenofovir were not identified in this trial.
- In Study 934 of treatment-naïve subjects (Tenofovir + EMTRIVA + efavirenz versus zidovudine (AZT)/lamivudine (3TC) + efavirenz), genotypic analysis performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation showed development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the two treatment arms. The M184V substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subject isolates in the Tenofovir + EMTRIVA group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis.
- Cross-Resistance
- Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R substitution selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with this substitution also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N), showed a 3.1-fold decrease in the susceptibility to tenofovir.
- In Studies 902 and 907 conducted in treatment-experienced subjects (Tenofovir + Standard Background Therapy (SBT) compared to Placebo + SBT), 14/304 (5%) of the Tenofovir-treated subjects with virologic failure through Week 96 had greater than 1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution in the HIV-1 reverse transcriptase gene.
- The virologic response to Tenofovir therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Studies 902 and 907. In these clinical trials, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI substitution. Virologic responses for subjects in the genotype substudy were similar to the overall trial results.
- Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance of Tenofovir to pre-existing zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and appeared to depend on the type and number of specific substitutions. Tenofovir-treated subjects whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution showed reduced responses to Tenofovir therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to Tenofovir therapy. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to Tenofovir. Limited data are available for subjects whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response.
- In the protocol defined analyses, virologic response to Tenofovir was not reduced in subjects with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. HIV-1 RNA responses among these subjects were durable through Week 48.
- Studies 902 and 907 Phenotypic Analyses
- Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation between baseline susceptibility to Tenofovir and response to Tenofovir therapy. Table 15 summarizes the HIV-1 RNA response by baseline Tenofovir susceptibility.
- Activity against HBV
- Antiviral Activity
- The antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC50 values for tenofovir ranged from 0.14 to 1.5 µM, with CC50 (50% cytotoxicity concentration) values greater than 100 µM. In cell culture combination antiviral activity studies of tenofovir with the nucleoside HBV reverse transcriptase inhibitors entecavir, lamivudine, and telbivudine, and with the nucleoside HIV-1 reverse transcriptase inhibitor emtricitabine, no antagonistic activity was observed.
- Resistance
- Cumulative Tenofovir genotypic resistance has been evaluated annually for up to 240 weeks in Studies 0102, 0103, 0106, 0108, and 0121 with the paired HBV reverse transcriptase amino acid sequences of the pre-treatment and on-treatment isolates from subjects who received at least 24 weeks of Tenofovir monotherapy and remained viremic with HBV DNA greater than or equal to 400 copies/mL at the end of each study year (or at discontinuation of Tenofovir monotherapy) using an as-treated analysis. In the nucleotide-naïve population from Studies 0102 and 0103, HBeAg-positive subjects had a higher baseline viral load than HBeAg-negative subjects and a significantly higher proportion of the subjects remained viremic at their last time point on Tenofovir monotherapy (15% versus 4%, respectively).
- HBV isolates from these subjects who remained viremic showed treatment-emergent substitutions (Table 16); however, no specific substitutions occurred at a sufficient frequency to be associated with resistance to Tenofovir (genotypic and phenotypic analyses).
- Cross-Resistance
- Cross-resistance has been observed between HBV nucleoside/nucleotide analogue reverse transcriptase inhibitors.
- In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V substitutions associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild type virus. The rtL180M and rtM204I/V double substitutions conferred 3.4-fold reduced susceptibility to tenofovir.
- HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild type virus.
- HBV strains expressing the adefovir resistance-associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild type virus. Strains containing the rtA181T substitution showed changes in susceptibility to tenofovir ranging from 0.9- to 1.5-fold that of wild type virus.
- One hundred fifty-two subjects initiating Tenofovir therapy in Studies 0102, 0103, 0106, 0108, and 0121 harbored HBV with known resistance substitutions to HBV nucleos(t)ide analogue reverse transcriptase inhibitors: 14 with adefovir resistance-associated substitutions (rtA181S/T/V and/or rtN236T), 135 with lamivudine resistance-associated substitutions (rtM204I/V), and 3 with both adefovir and lamivudine resistance-associated substitutions. Following up to 240 weeks of Tenofovir treatment, 11 of the 14 subjects with adefovir-resistant HBV, 124 of the 135 subjects with lamivudine-resistant HBV, and 2 of the 3 subjects with both adefovir- and lamivudine-resistant HBV achieved and maintained virologic suppression (HBV DNA less than 400 copies/mL). Three of the 5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained viremic.
## Nonclinical Toxicology
- Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.
- Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice.
- There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats.
- Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
- Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.
# Clinical Studies
- Treatment-Naïve Adult Patients
- Study 903
- Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter trial comparing Tenofovir (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18–64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm3 (range 3–956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417–5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4+ cell counts <200 cells/mm3. Treatment outcomes through 48 and 144 weeks are presented in Table 17.
- Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4+ cell count (< or ≥200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of subjects in the Tenofovir and stavudine arms, respectively achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm3 for the Tenofovir arm and 283 cells/mm3 for the stavudine arm.
- Through 144 weeks, 11 subjects in the Tenofovir group and 9 subjects in the stavudine group experienced a new CDC Class C event.
- Study 934
- Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + Tenofovir administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + Tenofovir with efavirenz. Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 18.
- Through Week 48, 84% and 73% of subjects in the emtricitabine + Tenofovir group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + Tenofovir group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the EMTRIVA + Tenofovir group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).
- Through 48 weeks, 7 subjects in the emtricitabine + Tenofovir group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).
- Treatment-Experienced Adult Patients
- Study 907
- Study 907 was a 24-week, double-blind placebo-controlled multicenter trial of Tenofovir added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects. After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label Tenofovir for an additional 24 weeks. Subjects had a mean baseline CD4+ cell count of 427 cells/mm3 (range 23–1385), median baseline plasma HIV-1 RNA of 2340 (range 50–75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the subjects was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.
- The percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks are summarized in Table 19.
- At 24 weeks of therapy, there was a higher proportion of subjects in the Tenofovir arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4+ cell counts by Week 24 was +11 cells/mm3 for the Tenofovir group and -5 cells/mm3 for the placebo group. Mean change in absolute CD4+ cell counts by Week 48 was +4 cells/mm3 for the Tenofovir group.
- Through Week 24, one subject in the Tenofovir group and no subjects in the placebo arm experienced a new CDC Class C event.
- HBeAg-Negative Chronic Hepatitis B
- Study 0102 was a Phase 3, randomized, double-blind, active-controlled trial of Tenofovir 300 mg compared to HEPSERA 10 mg in 375 HBeAg- (anti-HBe+) subjects with compensated liver function, the majority of whom were nucleoside-naïve. The mean age of subjects was 44 years, 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy and 18% were nucleoside-experienced (16% had prior lamivudine experience). At baseline, subjects had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log10 copies/mL; and mean serum ALT was 140 U/L.
- HBeAg-Positive Chronic Hepatitis B
- Study 0103 was a Phase 3, randomized, double-blind, active-controlled trial of Tenofovir 300 mg compared to HEPSERA 10 mg in 266 HBeAg+ nucleoside-naïve subjects with compensated liver function. The mean age of subjects was 34 years, 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and <5% were nucleoside experienced. At baseline, subjects had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log10 copies /mL; and mean serum ALT was 147 U/L.
- The primary data analysis was conducted after all subjects reached 48 weeks of treatment and results are summarized below.
- The primary efficacy endpoint in both trials was complete response to treatment defined as HBV DNA <400 copies/mL and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 20).
- Treatment Beyond 48 Weeks
- In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to Tenofovir and HEPSERA, respectively) were eligible to roll over to open-label Tenofovir with no interruption in treatment.
- In Study 0102, 304 of 375 subjects (81%) continued in the study through Week 240. Among subjects randomized to Tenofovir followed by open-label treatment with Tenofovir, 82% had HBV DNA < 400 copies/mL, and 69% had ALT normalization at Week 240. Among subjects randomized to HEPSERA followed by open-label treatment with Tenofovir, 88% had HBV DNA < 400 copies/mL and 76% had ALT normalization through Week 240. No subject in either treatment group experienced HBsAg loss/seroconversion through Week 240.
- In Study 0103, 185 of 266 subjects (69%) continued in the study through Week 240. Among subjects randomized to Tenofovir, 63% had HBV DNA < 400 copies/mL, 44% had ALT normalization, and 34% had HBeAg loss (26% seroconversion to anti-HBe antibody) through Week 240. Among subjects randomized to HEPSERA followed by up to 192 weeks of open-label treatment with Tenofovir, 64% had HBV DNA < 400 copies/mL, 54% had ALT normalization, and 34% had HBeAg loss (29% seroconversion to anti-HBe antibody) through Week 240. At Week 240, HBsAg loss was 9% in both treatment groups, and seroconversion to anti-HBs was 7% for the subjects initially randomized to Tenofovir and 9% for subjects initially randomized to HEPSERA.
- Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with Tenofovir monotherapy were available for analysis at baseline, Week 48 and Week 240. There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label Tenofovir without biopsy data that would be expected to affect histological outcomes at Week 240. Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively. In the subjects without cirrhosis at baseline (Ishak fibrosis score 0-4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. In subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points. No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.
- Patients with Lamivudine-Resistant Chronic Hepatitis B
- Study 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of Tenofovir compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥ 1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M). One hundred forty-one adult subjects were randomized to the Tenofovir treatment arm. The mean age of subjects randomized to Tenofovir was 47 years (range 18–73), 74% were male, 59% were Caucasian, and 37% were Asian. At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT. Subjects had a mean HBV DNA of 6.4 log10 copies/mL and mean serum ALT of 71 U/L at baseline.
- After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to Tenofovir had HBV DNA < 400 copies/mL, and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization. Among the HBeAg-positive subjects randomized to Tenofovir, 10 of 65 subjects (15%) experienced HBeAg loss, and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96. The proportion of subjects with HBV DNA concentrations below 400 copies/mL at Week 96 was similar between the Tenofovir monotherapy and the comparator arms.
- Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.
- Patients with Chronic Hepatitis B and Decompensated Liver Disease
- Tenofovir was studied in a small randomized, double-blind, active-controlled trial evaluating the safety of Tenofovir compared to other antiviral drugs in subjects with chronic hepatitis B and decompensated liver disease through 48 weeks (Study 0108).
- Forty-five adult subjects (37 males and 8 females) were randomized to the Tenofovir treatment arm. At baseline, 69% subjects were HBeAg-negative, and 31% were HBeAg-positive. Subjects had a mean Child-Pugh score of 7, a mean MELD score of 12, mean HBV DNA of 5.8 log10 copies/mL and mean serum ALT of 61 U/L at baseline. Trial endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥ 0.5 mg/dL or confirmed serum phosphorus of < 2 mg/dL.
- At 48 weeks, 31/44 (70%) and 12/26 (46%) Tenofovir-treated subjects achieved an HBV DNA < 400 copies/mL, and normalized ALT, respectively. The trial was not designed to evaluate treatment impact on clinical endpoints such as progression of liver disease, need for liver transplantation, or death.
# How Supplied
- Tablets
- Tenofovir tablets, 150 mg, are triangle-shaped, white, film-coated tablets containing 150 mg of tenofovir disoproxil fumarate, which is equivalent to 123 mg of tenofovir disoproxil, are debossed with "GSI" on one side and with "150" on the other side. Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure. (NDC 61958-0404-1)
- Tenofovir tablets, 200 mg, are round-shaped, white, film-coated tablets containing 200 mg of tenofovir disoproxil fumarate, which is equivalent to 163 mg of tenofovir disoproxil, are debossed with "GSI" on one side and with "200" on the other side. Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure. (NDC 61958-0405-1)
- Tenofovir tablets, 250 mg, are capsule-shaped, white, film-coated tablets containing 250 mg of tenofovir disoproxil fumarate, which is equivalent to 204 mg of tenofovir disoproxil, are debossed with "GSI" on one side and with "250" on the other side. Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure. (NDC 61958-0406-1)
- Tenofovir tablets, 300 mg, are almond-shaped, light blue, film-coated tablets containing 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, are debossed with "GILEAD" and "4331" on one side and with "300" on the other side. Each bottle contains 30 tablets, a desiccant (silica gel canister or sachet), and closed with a child-resistant closure. (NDC 61958-0401-1)
- Oral Powder
- Tenofovir oral powder consists of white, coated granules containing 40 mg of tenofovir disoproxil fumarate, which is equivalent to 33 mg of tenofovir disoproxil, per gram of powder and is available in multi-use bottles containing 60 grams of oral powder, closed with a child-resistant closure, and co-packaged with a dosing scoop. (NDC 61958-0403-1)
- Store Tenofovir tablets and oral powder at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F).
- Keep the bottle tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.
## Storage
There is limited information regarding Tenofovir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised that:
- Tenofovir is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using Tenofovir.
- Patients should avoid doing things that can spread HIV or HBV to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. Tenofovir is excreted in breast milk and it is not known whether it can harm the baby. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
- The long term effects of Tenofovir are unknown.
- Tenofovir tablets and oral powder are for oral ingestion only.
- Tenofovir should not be discontinued without first informing their physician.
- If you have HIV-1 infection, with or without HBV coinfection, it is important to take Tenofovir with combination therapy.
- It is important to take Tenofovir on a regular dosing schedule and to avoid missing doses.
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with Tenofovir should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness).
- Severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and have discontinued Tenofovir.
- Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs). Dosing interval of Tenofovir may need adjustment in patients with renal impairment.
- Tenofovir should not be coadministered with the fixed-dose combination products ATRIPLA, COMPLERA, STRIBILD, and TRUVADA since it is a component of these products.
- Tenofovir should not be administered in combination with HEPSERA .
- Patients with HIV-1 should be tested for Hepatitis B virus (HBV) before initiating antiretroviral therapy.
- In patients with chronic hepatitis B, it is important to obtain HIV antibody testing prior to initiating Tenofovir.
- Decreases in bone mineral density have been observed with the use of Tenofovir. Bone mineral density monitoring should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia.
- In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. The relationship between response and long-term prevention of outcomes such as hepatocellular carcinoma is not known.
# Precautions with Alcohol
- Alcohol-Tenofovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VIREAD®[2]
# Look-Alike Drug Names
There is limited information regarding Tenofovir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tenofovir | |
4e07775ccf917e916ebef2970e317b2feccf62c5 | wikidoc | Terebinth | Terebinth
Terebinth (Pistacia terebinthus) also called turpentine tree is a species of Pistacia, native to the Mediterranean region from the western regions of Morocco, Portugal and the Canary Islands, to the eastern regions of Turkey and Syria.
It is a small deciduous tree or large shrub growing to 10 m tall. The leaves are compound, 10-20 cm long, odd pinnate with five to eleven opposite glossy oval leaflets, the leaflets 2-6 cm long and 1-3 cm broad. The flowers are reddish-purple, appearing with the new leaves in early spring. The fruit consists of small, globular drupes 5-7 mm long, red to black when ripe. All parts of the plant have a strong resinous smell.
# History
John Chadwick believes that the terebinth is the plant called ki-ta-no in some of the Linear B tablets. He cites the work of a Spanish scholar, J.L. Melena, who had found "an ancient lexicon which showed that kritanos was another name for the turpentine tree, and that the Mycenaean spelling could represent a variant form of this word."
Terebinth is mentioned in the Bible (primarily the Hebrew Scriptures/Tanakh or Old Testament), for example in Isaiah 1:29, where the Hebrew word "el" or "elim" is often translated as oak or terebinth:
Terebinths are also mentioned in three successive chapters of Genesis (12:6, 13:18, 14:13) in reference to the places where Abram (later Abraham) camped.
There are at least a few references in Judges; Ch4 (in reference to Heber, the Kenite, of the children of Hobab), Ch6 (in reference to an angel of the Lord who came to visit Gideon. Most versions use 'oak'), and Ch 9 (in reference to the crowning of Abimelech, by the terebinth of the pillar that was in Shechem. Most versions use 'oak').
Terebinth is also referred to in Virgil's Aeneid, Book 10, line 136 where Ascanius in battle is compared to "ivory skilfully inlaid in Orician terebinth" ("inclusum Oricia terebintho ebur")
# Uses
It is used as a source for turpentine, possibly the earliest known source. The turpentine of the terebinth is now called Chian, Scio, or Cyprian turpentine.
The fruits are used in Cyprus for baking of a specialty village bread. In Crete, where the plant is called tsikoudia, it is used to flavor the local variety of pomace brandy, also called tsikoudia. The plant is rich in tannin and resinous substances and was used for its aromatic and medicinal properties in classical Greece. A mild sweet scented gum can be produced from the bark, and galls often found on the plant are used for tanning leather. Recently an anti-inflammatory triterpene has been extracted from these galls .
# Footnotes
- ↑ John Chadwick, The Mycenaean World (Cambridge: University Press, 1976),p. 120
# External references
- Flora Europaea: Pistacia terebinthus
- Rushforth, K. (1999). Trees of Britain and Europe. HarperCollins ISBN 0-00-220013-9.
- Jewish Encyclopedia: Oak and Terebinth
- Concise Oxford English Dictionary
- Kypros.org
- Giner-Larza EM et al, Anti-inflammatory triterpenes from Pistacia terebinthus galls, Planta Med. 2002 Apr;68(4):311-5.
ca:Terebint
de:Terebinthe
el:Τερέβινθος (φυτό)
eo:Terebintarbo
gl:Escornacabras
it:Pistacia terebinthus
he:אלה ארצישראלית
nl:Terpentijnboom
sv:Terebint | Terebinth
Terebinth (Pistacia terebinthus) also called turpentine tree is a species of Pistacia, native to the Mediterranean region from the western regions of Morocco, Portugal and the Canary Islands, to the eastern regions of Turkey and Syria.
It is a small deciduous tree or large shrub growing to 10 m tall. The leaves are compound, 10-20 cm long, odd pinnate with five to eleven opposite glossy oval leaflets, the leaflets 2-6 cm long and 1-3 cm broad. The flowers are reddish-purple, appearing with the new leaves in early spring. The fruit consists of small, globular drupes 5-7 mm long, red to black when ripe. All parts of the plant have a strong resinous smell.
# History
John Chadwick believes that the terebinth is the plant called ki-ta-no in some of the Linear B tablets. He cites the work of a Spanish scholar, J.L. Melena, who had found "an ancient lexicon which showed that kritanos was another name for the turpentine tree, and that the Mycenaean spelling could represent a variant form of this word."[1]
Terebinth is mentioned in the Bible (primarily the Hebrew Scriptures/Tanakh or Old Testament), for example in Isaiah 1:29, where the Hebrew word "el" or "elim" is often translated as oak or terebinth:
Terebinths are also mentioned in three successive chapters of Genesis (12:6, 13:18, 14:13) in reference to the places where Abram (later Abraham) camped.
There are at least a few references in Judges; Ch4 (in reference to Heber, the Kenite, of the children of Hobab), Ch6 (in reference to an angel of the Lord who came to visit Gideon. Most versions use 'oak'), and Ch 9 (in reference to the crowning of Abimelech, by the terebinth of the pillar that was in Shechem. Most versions use 'oak').
Terebinth is also referred to in Virgil's Aeneid, Book 10, line 136 where Ascanius in battle is compared to "ivory skilfully inlaid in [...] Orician terebinth" ("inclusum[...] Oricia terebintho [...] ebur")
# Uses
It is used as a source for turpentine, possibly the earliest known source. The turpentine of the terebinth is now called Chian, Scio, or Cyprian turpentine.
The fruits are used in Cyprus for baking of a specialty village bread. In Crete, where the plant is called tsikoudia, it is used to flavor the local variety of pomace brandy, also called tsikoudia. The plant is rich in tannin and resinous substances and was used for its aromatic and medicinal properties in classical Greece. A mild sweet scented gum can be produced from the bark, and galls often found on the plant are used for tanning leather. Recently an anti-inflammatory triterpene has been extracted from these galls [1].
# Footnotes
- ↑ John Chadwick, The Mycenaean World (Cambridge: University Press, 1976),p. 120
# External references
- Flora Europaea: Pistacia terebinthus
- Rushforth, K. (1999). Trees of Britain and Europe. HarperCollins ISBN 0-00-220013-9.
- Jewish Encyclopedia: Oak and Terebinth
- Concise Oxford English Dictionary
- Kypros.org
- Giner-Larza EM et al, Anti-inflammatory triterpenes from Pistacia terebinthus galls, Planta Med. 2002 Apr;68(4):311-5.
ca:Terebint
de:Terebinthe
el:Τερέβινθος (φυτό)
eo:Terebintarbo
gl:Escornacabras
it:Pistacia terebinthus
he:אלה ארצישראלית
nl:Terpentijnboom
sv:Terebint
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Terebinth | |
11372b08fc33462baa87fd9e28a8418f1754a60f | wikidoc | Tetrasomy | Tetrasomy
A tetrasomy is a form of aneuploidy with the presence of four copies, instead of the normal two, of a particular chromosome.
# Causes
## Full
Full tetrasomy of an individual occurs due to non-disjunction when the cells are dividing (meiosis I or II) to form egg and sperm cells (gametogenesis). This can result in extra chromosomes in a sperm or egg cell. After fertilization, the resulting fetus has 48 chromosomes instead of the typical 46.
## Autosomal tetrasomies
- Cat eye syndrome where tetrasomy of chromosome 22 is present
- Pallister-Killian syndrome (tetrasomy 12p)
- Tetrasomy 9p
- Tetrasomy 18p
## Sex-chromosome tetrasomies
- 48, XXXX syndrome
- 48, XXYY syndrome
- Klinefelter's syndrome, where XXXY tetrasomy is present | Tetrasomy
A tetrasomy is a form of aneuploidy with the presence of four copies, instead of the normal two, of a particular chromosome.
# Causes
## Full
Full tetrasomy of an individual occurs due to non-disjunction when the cells are dividing (meiosis I or II) to form egg and sperm cells (gametogenesis). This can result in extra chromosomes in a sperm or egg cell. After fertilization, the resulting fetus has 48 chromosomes instead of the typical 46.
## Autosomal tetrasomies
- Cat eye syndrome where tetrasomy of chromosome 22 is present
- Pallister-Killian syndrome (tetrasomy 12p)
- Tetrasomy 9p
- Tetrasomy 18p
## Sex-chromosome tetrasomies
- 48, XXXX syndrome
- 48, XXYY syndrome
- Klinefelter's syndrome, where XXXY tetrasomy is present
Template:Chromosomal abnormalities
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Tetrasomy | |
bd064d4dcedcc95ec47278f7022950ae4fcb0612 | wikidoc | Tetrazine | Tetrazine
Tetrazine is an unstable compound that consists of a six-membered aromatic ring containing four nitrogen atoms with the molecular formula C2H2N4. The name tetrazine is used in the nomenclature of derivatives of this compound. Three core-ring isomers exist: 1,2,3,4-tetrazines, 1,2,3,5-tetrazines and 1,2,4,5-tetrazines
# 1,2,3,4-tetrazines
1,2,3,4-Tetrazines are often isolated fused to an aromatic ring system and are stablized as the dioxide derivatives.
# 1,2,4,5-tetrazine
1,2,4,5-Tetrazines are very well known and myriad 3,6-disubstituted 1,2,4,5-tetrazines are known . These materials are of use in the area of energetic chemistry.
The compound 3,6-di-2-pyridyl-1,2,4,5-tetrazine has two pyridine substituents and is of importance as a reagent in Diels-Alder reactions. It reacts with norbornadiene in a sequence of one DA reactions and two retro-DA reactions to cyclopentadiene and a pyridazine with exchange of an acetylene unit:
With norbornadiene fused to an arene the reaction stops at an intermediary stage | Tetrazine
Tetrazine is an unstable compound that consists of a six-membered aromatic ring containing four nitrogen atoms with the molecular formula C2H2N4. The name tetrazine is used in the nomenclature of derivatives of this compound. Three core-ring isomers exist: 1,2,3,4-tetrazines, 1,2,3,5-tetrazines and 1,2,4,5-tetrazines
# 1,2,3,4-tetrazines
1,2,3,4-Tetrazines are often isolated fused to an aromatic ring system and are stablized as the dioxide derivatives.
# 1,2,4,5-tetrazine
1,2,4,5-Tetrazines are very well known and myriad 3,6-disubstituted 1,2,4,5-tetrazines are known [1]. These materials are of use in the area of energetic chemistry.
The compound 3,6-di-2-pyridyl-1,2,4,5-tetrazine [2] has two pyridine substituents and is of importance as a reagent in Diels-Alder reactions. It reacts with norbornadiene in a sequence of one DA reactions and two retro-DA reactions to cyclopentadiene and a pyridazine with exchange of an acetylene unit:
With norbornadiene fused to an arene the reaction stops at an intermediary stage [3] | https://www.wikidoc.org/index.php/Tetrazine | |
d9f2ea3f229267e3a0ceb78d63196a01c004ec96 | wikidoc | Thioamide | Thioamide
Thioamides (rarely, thionamide) are a group of organic compounds that share a common functional group with the general structure R1-CS-NR2R3. One of the best ways of making thioamides is the reaction of an amide with Lawesson's reagent.
Thioamides are also a class of drugs which are used to control thyrotoxicosis.
Incorporation of thioamides into peptides are used as isosters for the amide bond. Peptide modifications are interesting analogoues of the native peptide, which can reveal the structure-activity-relationship (SAR). Analogoues of peptides can also be used as drugs with an improved oral bioavailability.
# Mechanism of action
They inhibit the enzyme thyroid peroxidase in the thyroid, reducing the synthesis of triiodothyronine (T3) and thyroxine (T4); block uptake of iodotyrosines from the colloid. They also block iodine release from peripheral hormone. Maximum effects occur only after a month since hormone depletion is caused by reduced synthesis, which is a slow process.
# Adverse effects
It penetrates the placental barrier, thus caution is advised when used during pregnancy.
10% of patients report:
- Skin eruptions, such as macules and papules.
- Urticaria
- Dermatitis
- Fever
- Arthralgia
0.03% of all patients develop agranulocytosis, a dangerous side-effect.
# Members of the thioamide group
- Methimazole
- Carbimazole converted in vivo to methimazole
- Propylthiouracil | Thioamide
Thioamides (rarely, thionamide) are a group of organic compounds that share a common functional group with the general structure R1-CS-NR2R3. One of the best ways of making thioamides is the reaction of an amide with Lawesson's reagent.
Thioamides are also a class of drugs which are used to control thyrotoxicosis.
Incorporation of thioamides into peptides are used as isosters for the amide bond. Peptide modifications are interesting analogoues of the native peptide, which can reveal the structure-activity-relationship (SAR). Analogoues of peptides can also be used as drugs with an improved oral bioavailability.
# Mechanism of action
They inhibit the enzyme thyroid peroxidase in the thyroid, reducing the synthesis of triiodothyronine (T3) and thyroxine (T4); block uptake of iodotyrosines from the colloid. They also block iodine release from peripheral hormone. Maximum effects occur only after a month since hormone depletion is caused by reduced synthesis, which is a slow process.
# Adverse effects
It penetrates the placental barrier, thus caution is advised when used during pregnancy.
10% of patients report:
- Skin eruptions, such as macules and papules.
- Urticaria
- Dermatitis
- Fever
- Arthralgia
0.03% of all patients develop agranulocytosis, a dangerous side-effect.
# Members of the thioamide group
- Methimazole
- Carbimazole converted in vivo to methimazole
- Propylthiouracil
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Thioamide | |
778b304e6daa411bc5e06d17619bb74c24df1f8c | wikidoc | Thioester | Thioester
Thioesters are compounds resulting from the bonding of sulfur with an acyl group with the general formula R-S-CO-R'. They are the product of esterification between a carboxylic acid and a thiol (as opposed to an alcohol in regular esters).
# Thioesters and the origin of life
Some biochemists believe that the thioester bond was critical for the origin of life. One Nobel Prize winning scientist, Belgium's Christian de Duve, posits a "Thioester World" which preceded and developed into an "RNA World", itself the immediate precursor to the appearance of entities we would call organisms.
As de Duve explains:
# Examples
- Acetyl-CoA
- Malonyl-CoA
# Thionoesters
Thionoesters are isomeric with thioesters. In a thionoester, sulfur replaces the carbonyl oxygen in an ester. Methylthionobenzoate is C6H5C(S)OCH3. Such compounds are typically prepared by the reaction of the thioacyl chloride with an alcohol, but they can also be made by the reaction of Lawesson's reagent with esters. | Thioester
Thioesters are compounds resulting from the bonding of sulfur with an acyl group with the general formula R-S-CO-R'. They are the product of esterification between a carboxylic acid and a thiol (as opposed to an alcohol in regular esters).
# Thioesters and the origin of life
Some biochemists believe that the thioester bond was critical for the origin of life. One Nobel Prize winning scientist, Belgium's Christian de Duve, posits a "Thioester World" which preceded and developed into an "RNA World", itself the immediate precursor to the appearance of entities we would call organisms.
As de Duve explains:
# Examples
- Acetyl-CoA
- Malonyl-CoA
# Thionoesters
Thionoesters are isomeric with thioesters. In a thionoester, sulfur replaces the carbonyl oxygen in an ester. Methylthionobenzoate is C6H5C(S)OCH3. Such compounds are typically prepared by the reaction of the thioacyl chloride with an alcohol, but they can also be made by the reaction of Lawesson's reagent with esters.[1] | https://www.wikidoc.org/index.php/Thioester | |
85e74574959bc6a1adbc8735caf440718c3eccd7 | wikidoc | Thioether | Thioether
A thioether (similar to sulfide) is a functional group in organic chemistry that has the structure R1-S-R2 as shown on right. Like many other sulfur-containing compounds, volatile thioethers characteristically have foul odors.
A thioether is similar to an ether except that it contains a sulfur atom in place of the oxygen. Because oxygen and sulfur belong to the chalcogens group in the periodic table, the chemical properties of ethers and thioethers share some commonalities. This functional group is important in biology, most notably in the amino acid methionine and the cofactor biotin.
# Preparation
- Thioethers are typically prepared by the alkylation of thiols:
Such reactions are accelerated in the presence of base, which converts the thiol into the more nucleophilic thiolate.
- An alternative method of synthesis includes the addition of a thiol to an alkene, typically catalysed by free radicals:
- Thioethers can also be prepared via the Pummerer rearrangement.
# Reactions
- While ethers are generally stable, thioethers (R-S-R) are easily oxidized to the sulfoxides (R-S(=O)-R), which can themselves be further oxidized to sulfones (R-S(=O)2-R). For example, dimethyl sulfide can be oxidized as follows:
Typical oxidants include peroxides.
- The sulfur-sulfur bond in disulfides is susceptible to cleavage by nucleophiles, and reaction with a carbon nucleophile produces a thioether:
- Trialkysulfonium salts react with nucleophiles with a dialkyl sulfide as a leaving group:
This reaction is exploited in biological systems as a means of transferring an alkyl group. For example, S-adenosylmethionine acts as a methylating agent in biological SN2 reactions.
- Ethers can be alkylated at oxygen only with difficulty to give highly reactive trialkyloxonium salts. In contrast, thioethers are readily alkylated to give stable sulfonium salts, such as trimethylsulfonium:
## Thiophenes
The heterocyclic compound thiophene is formally a thioether. Because of the aromatic character of this heterocycle, the nonbonding electrons on sulfur, normally responsible for the nucleophilicity so characteristic of thioethers, are delocalized into the π-system. Consequently thiophene exhibits few properties expected for a thioether - thiophene is non-nucleophilic at sulfur and, in fact, is sweet-smelling. Upon hydrogenation, thiophene gives tetrahydrothiophene, C4H8S, which indeed does behave as a typical thioether. | Thioether
A thioether (similar to sulfide) is a functional group in organic chemistry that has the structure R1-S-R2 as shown on right. Like many other sulfur-containing compounds, volatile thioethers characteristically have foul odors.[1]
A thioether is similar to an ether except that it contains a sulfur atom in place of the oxygen. Because oxygen and sulfur belong to the chalcogens group in the periodic table, the chemical properties of ethers and thioethers share some commonalities. This functional group is important in biology, most notably in the amino acid methionine and the cofactor biotin.
# Preparation
- Thioethers are typically prepared by the alkylation of thiols:
Such reactions are accelerated in the presence of base, which converts the thiol into the more nucleophilic thiolate.
- An alternative method of synthesis includes the addition of a thiol to an alkene, typically catalysed by free radicals:
- Thioethers can also be prepared via the Pummerer rearrangement.
# Reactions
- While ethers are generally stable, thioethers (R-S-R) are easily oxidized to the sulfoxides (R-S(=O)-R), which can themselves be further oxidized to sulfones (R-S(=O)2-R). For example, dimethyl sulfide can be oxidized as follows:
Typical oxidants include peroxides.
- The sulfur-sulfur bond in disulfides is susceptible to cleavage by nucleophiles, and reaction with a carbon nucleophile produces a thioether:
- Trialkysulfonium salts react with nucleophiles with a dialkyl sulfide as a leaving group:
This reaction is exploited in biological systems as a means of transferring an alkyl group. For example, S-adenosylmethionine acts as a methylating agent in biological SN2 reactions.
- Ethers can be alkylated at oxygen only with difficulty to give highly reactive trialkyloxonium salts. In contrast, thioethers are readily alkylated to give stable sulfonium salts, such as trimethylsulfonium:
## Thiophenes
The heterocyclic compound thiophene is formally a thioether. Because of the aromatic character of this heterocycle, the nonbonding electrons on sulfur, normally responsible for the nucleophilicity so characteristic of thioethers, are delocalized into the π-system. Consequently thiophene exhibits few properties expected for a thioether - thiophene is non-nucleophilic at sulfur and, in fact, is sweet-smelling. Upon hydrogenation, thiophene gives tetrahydrothiophene, C4H8S, which indeed does behave as a typical thioether. | https://www.wikidoc.org/index.php/Thioether | |
eda44104e7b18402814fb755cf8d6aa7e376b578 | wikidoc | Tiopronin | Tiopronin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Tiopronin is a renal-urologic agent that is FDA approved for the treatment of and prevention of cystine (kidney) stone formation in patients with severe homozygous cystinuria. Common adverse reactions include nausea, vomiting, abdominal pain, diarrhea, impairment in taste and smell, rash and pruritis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- THIOLA® is indicated for the prevention of cystine (kidney) stone formation in patients with severe homozygous cystinuria with urinary cystine greater than 500 mg/day, who are resistant to treatment with conservative measures of high fluid intake, alkali and diet modification, or who have adverse reactions to d-penicillamine.
- Cystine stones typically occur in approximately 10,000 persons in the United States who are homozygous for cystinuria. These persons excrete abnormal amounts of cystine in urine of over 250 mg/g creatinine, as well as excessive amounts of other dibasic amino acids (lysine, arginine and ornithine). In addition, they show varying intestinal transport defects for these same amino acids. The stone formation is the result of poor aqueous solubility of cystine.
- Since there are no known inhibitors of the crystallization of cystine, the stone formation is determined primarily by the urinary supersaturation of cystine. Thus, cystine stones could theoretically form whenever urinary cystine concentration exceeds the solubility limit. Cystine solubility in urine is pH-dependent, and ranges from 170-300 mg/liter at pH 5, 190-400 mg/liter at pH 7 and 220-500 mg/liter at pH 7.5.
- The goal of therapy is to reduce urinary cystine concentration below its solubility limit. It may be accomplished by dietary means aimed at reducing cystine synthesis and by a high fluid intake in order to increase urine volume and thereby lower cystine concentration.
- Unfortunately, the above conservative measures alone may be ineffective in controlling cystine stone formation in some homozygous patients with severe cystinuria (urinary cystine exceeding 500 mg/day). In such patients, d-penicillamine has been used as an additional therapy. Like THIOLA™, dpenicillamine undergoes thiol-disulfide exchange with cystine, thereby lowering the amount of sparingly soluble cystine in urine.
- However, d-penicillamine treatment is frequently accompanied by adverse reactions, such as dermatologic complications, hypersensitivity reactions, hematologic abnormalities and renal disturbances. THIOLA® may have a particular therapeutic role in such patients.
### Dosing Information
- It is recommended that a conservative treatment program should be attempted first. At least 3 liters of fluid (10-10 oz. glassfuls) should be provided, including two glasses with each meal and at bedtime. The patients should be expected to awake at night to urinate; they should drink two more glasses of fluids before returning to bed. Additional fluids should be consumed if there is excessive sweating or intestinal fluid loss. A minimum urine output of 2 liters/day on a consistent basis should be sought. A modest amount of alkali should be provided in order to maintain urinary pH at a high normal range (6.5-7.0). Potassium alkali are advantageous over sodium alkali, because they do not cause hypercalciuria and are less likely to cause the complication of calcium stones.
- Excessive alkali therapy is not advisable. When urinary pH increases above 7.0 with alkali therapy, the complication of calcium phosphate nephrolithiasis may ensue because of the enhanced urinary supersaturation of hydroxyapatite in an alkaline environment.
- In patients who continue to form cystine stones on the above conservative program, THIOLA® may be added to the treatment program. THIOLA® may also be substituted for d-penicillamine in patients who have developed toxicity to the latter drug. In both situations, the conservative treatment program should be continued.
- The dose of THIOLA® should not be arbitrary but should be based on that amount required to reduce urinary cystine concentration to below its solubility limit (generally <250 mg/liter). The extent of the decline in cystine excretion is generally dependent on the THIOLA® dosage.
- THIOLA® may be begun at a dosage of 800 mg/day in adult patients with cystine stones. In a multiclinic trial, average dose of THIOLA® was about 1000 mg/day. However, some patients require a smaller dose. In children, initial dosage may be based on 15 mg/kg/day. Urinary cystine should be measured at 1 month after THIOLA® treatment, and every 3 months thereafter. THIOLA® dosage should be readjusted depending on the urinary cystine value. Whenever possible, THIOLA® should be given in divided doses 3 times/day at least one hour before or 2 hours after meals.
- In patients who had shown severe toxicity to d-penicillamine, THIOLA® might be begun at a lower dosage.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tiopronin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiopronin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tiopronin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tiopronin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiopronin in pediatric patients.
# Contraindications
- The use of THIOLA® during pregnancy is contraindicated, except in those with severe cystinuria where the anticipated benefit of inhibited stone formation clearly outweighs possible hazards of treatment (see PRECAUTIONS).
- THIOLA® should not be begun again in patients with a prior history of developing agranulocytosis, aplastic anemia or thrombocytopenia on this medication.
- Mothers maintained on THIOLA® treatment should not nurse their infants.
# Warnings
- Despite apparent lower toxicity of THIOLA™, THIOLA® may potentially cause all the serious adverse reactions reported for d-penicillamine. Thus, although no death has been reported to result directly from THIOLA® treatment, a fatal outcome from THIOLA® is possible, as has been reported with d-penicillamine therapy from such complications as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture’s syndrome or myasthenia gravis.
- Leukopenia of the granulocytic series may develop without eosinophilia. Thrombocytopenia may be immunologic in origin or occur on an idiosyncratic basis. The reduction in peripheral blood white count to less than 3500/cubic mm or in platelet count to below 100,000 cubic mm mandates cessation of therapy. Patients should be instructed to report promptly the occurrence of any symptom or sign of these hematological abnormalities, such as fever, sore throat, chills, bleeding or easy bruisability.
- Proteinuria, sometimes sufficiently severe to cause nephrotic syndrome, may develop from membranous glomerulopathy. A close observation of affected patients is mandatory.
- The following complications, though rare, have been reported during d-penicillamine therapy and could occur during THIOLA® treatment. When there are abnormal urinary findings associated with hemoptysis and pulmonary infiltrates suggestive of Goodpasture’s syndrome, THIOLA® treatment should be stopped. Appearance of myasthenic syndrome or myasthenia gravis requires cessation of treatment. When pemphigus-type reactions develop, THIOLA® therapy should be stopped. Steroid treatment may be necessary.
### PRECAUTIONS
- Patients should be advised of the potential development of complications and to report promptly the occurrence of any symptom or sign of them.
- To help monitor potential complications, the following tests are recommended: peripheral blood counts, direct platelet count, hemoglobin, serum albumin, liver function tests, 24-hour urinary protein and routine urinalysis at 3- 6 month intervals during treatment. In order to assess effect on stone disease, urinary cystine analysis should be monitored frequently during the first 6 months when the optimum dose schedule is being determined, and at 6-month intervals thereafter. Abdominal roentogenogram (KUB) is advised on a yearly basis to monitor the size and appearance/disappearance of stone(s).
# Adverse Reactions
## Clinical Trials Experience
- Some patients may develop drug fever, usually during the first month of therapy. THIOLA® treatment should be discontinued until the fever subsides. It may be reinstated at a small dose, with a gradual increase in dosage until the desired level is achieved.
- A generalized rash (erythematous, maculopapular or morbilliform) accompanied by pruritis may develop during the first few months of treatment. It may be controlled by antihistamine therapy, typically recedes when THIOLA® treatment is discontinued, and seldom recurs when THIOLA® treatment is restarted at a lower dosage. Less commonly, rash may appear late in the course of treatment (of more than 6 months). Located usually in the trunk, the late rash is associated with intense pruritis, recedes slowly after discontinuing treatment, and usually recurs upon resumption of treatment.
- A drug reaction simulating lupus erythematous, manifested by fever, arthralgia and lymphadenopathy may develop. It may be associated with a positive antinuclear antibody test, but not necessarily with nephropathy. It may require discontinuance of THIOLA® treatment.
- A reduction in taste perception may develop. It is believed to be the result of chelation of trace metals by THIOLA™. Hypogeusia is often self-limiting.
- Unlike during d-penicillamine therapy, vitamin B6 deficiency is uncommonly associated with THIOLA® treatment.
- Some patients may complain of wrinkling and friability of skin. This complication usually occurs after long-term treatment, and is believed to result from the effect of THIOLA® on collagen.
- A multiclinic trial involving 66 cystinuric patients in the United States indicated that THIOLA® is associated with fewer or less severe adverse reactions than d-penicillamine. Among those who had to stop taking d-penicillamine due to toxicity, 64.7% could take THIOLA® . In those without prior history of d-penicillamine treatment, only 5.9% developed reactions of sufficient severity to require THIOLA® withdrawal. A review of available literature supports the findings from this trial.
- Despite this apparent reduced toxicity to THIOLA® relative to d-penicillamine, THIOLA® treatment may potentially be associated with all the adverse reactions reported with d-penicillamine. They include:
- Nausea, emesis, diarrhea or soft stools, anorexia, abdominal pain, bloating or flatus) in about 1 in 6 patients, Impairment in taste and smell in about 1 in 25 patients,
- Increased bleeding, anemia, leukopenia, thrombocytopenia, eosinophilia) in about 1 in 25 patients;
- Myasthenic syndrome in about 1 in 50 patients.
- Bronchiolitis, hemoptysis, pulmonary infiltrates, dyspnea in about 1 in 50 patients
- Dermatologic complications (pharyngitis, oral ulcers, rash, ecchymosis, prurites, uritcaria, warts, skin wrinkling, pemphigus, elastosis perforans serpiginosa) in about 1 in 6 patients
- Hypersensitivity reactions (laryngeal edema, dyspnea, respiratory distress, fever, chills, arthralgia, weakness, fatigue, myalgia, adenopathy) in about 1 in 25 patients
- Proteinuria, nephrotic syndrome, hematuria) in about 1 in 20 patients.
- These reactions are more likely to develop during THIOLA® therapy among patients who had previously shown toxicity to d-penicillamine.
- In patients who had previously manifested adverse reactions to d-penicillamine, adverse reactions to THIOLA® are more likely to occur than in patients who took THIOLA® for the first time. A close supervision with a careful monitoring of potential side effects is mandatory during THIOLA® treatment. Patients should be told to report promptly any symptoms suggesting toxicity. The treatment with THIOLA® should be stopped if severe toxicity develops.
- Jaundice and abnormal liver function tests have been reported during THIOLA® therapy for non-cystinuric conditions. A direct cause and effect relationship, based upon these foreign reports, has not been established. Although such complications were not encountered in the small multi-center trials in the United States, patients should be carefully monitored and if any abnormalities are noted, the drug should be discontinued and the patient treated by appropriate measures.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tiopronin in the drug label.
# Drug Interactions
There is limited information regarding Drug Interactions of Tiopronin in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- D-penicillamine has been shown to cause skeletal defects and cleft palates in the fetus when given to pregnant rats at 10 times the dose recommended for human use. A similar teratogenicity might be expected for THIOLA® although no such findings could be related to the drug in studies in mice and rats at doses up to 10 times the highest recommended human dose.
- There are no adequate and well-controlled studies in pregnant women. THIOLA® should be used during pregnancy only if the potential benefit justifies potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tiopronin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tiopronin during labor and delivery.
### Nursing Mothers
- Because THIOLA® may be excreted in milk and because of the potential serious adverse reactions of nursing infants from THIOLA®, mothers taking THIOLA® should not nurse their infants.
### Pediatric Use
- Safety and effectiveness below the age of 9 have not been established.
### Geriatic Use
There is no FDA guidance on the use of Tiopronin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Tiopronin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tiopronin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tiopronin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tiopronin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tiopronin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tiopronin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Tiopronin in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Tiopronin in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Tiopronin in the drug label.
# Pharmacology
There is limited information regarding Tiopronin Pharmacology in the drug label.
## Mechanism of Action
- THIOLA® is an active reducing agent which undergoes thiol-disulfide exchange with cystine to form a mixed disulfide of Thiola-cysteine.
- From this reaction, a water-soluble mixed disulfide is formed and the amount of sparingly soluble cystine is reduced. When THIOLA® is given orally, up to 48% of dose appears in urine during the first 4 hours and up to 78% by 72 hours. Thus, in patients with cystinuria, sufficient amount of THIOLA® or its active metabolites could appear in urine to react with cystine, lowering cystine excretion.
## Structure
- THIOLA® (Tiopronin) is a reducing and complexing thiol compound. Tiopronin is N-(2-Mercaptopropionyl) glycine and has the following structure:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tiopronin in the drug label.
## Pharmacokinetics
- The decrement in urinary cystine produced by THIOLA® is generally proportional to the dose. A reduction in urinary cystine of 250-350 mg/day at a THIOLA® dosage of 1 g/day, and a decline of approximately 500 mg/day at a dosage of 2 g/day, might be expected. THIOLA® causes a sustained reduction in cystine excretion without apparent loss of effectiveness. THIOLA® has a rapid onset and offset of action, showing a fall in cystine excretion on the first day of administration and a rise on the first day of drug withdrawal.
## Nonclinical Toxicology
- Long-term carcino-genicity studies in animals have not been performed. High doses of THIOLA® in experimental animals have been shown to interfere with maintenance of pregnancy and viability of the fetus.
# Clinical Studies
There is limited information regarding Clinical Studies of Tiopronin in the drug label.
# How Supplied
THIOLA® (NDC 0178-0900-01), is available for oral administration as 100 mg. round, white, sugar coated tablets in bottles of 100 tablets each. Each tablet is imprinted in red with “M” on one side and blank on the other side.
C05 Rev 010060
MISSION PHARMACAL COMPANY, San Antonio, TX 78230 1355
## Storage
- Store at 25°C (77°F); excursions permitted to 15- 30°C (59-86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
THIOLA® Label
NDC: 0178-0900-01
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Tiopronin in the drug label.
# Precautions with Alcohol
- Alcohol-Tiopronin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- THIOLA®
# Look-Alike Drug Names
There is limited information regarding Tiopronin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tiopronin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Tiopronin is a renal-urologic agent that is FDA approved for the treatment of and prevention of cystine (kidney) stone formation in patients with severe homozygous cystinuria. Common adverse reactions include nausea, vomiting, abdominal pain, diarrhea, impairment in taste and smell, rash and pruritis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- THIOLA® is indicated for the prevention of cystine (kidney) stone formation in patients with severe homozygous cystinuria with urinary cystine greater than 500 mg/day, who are resistant to treatment with conservative measures of high fluid intake, alkali and diet modification, or who have adverse reactions to d-penicillamine.
- Cystine stones typically occur in approximately 10,000 persons in the United States who are homozygous for cystinuria. These persons excrete abnormal amounts of cystine in urine of over 250 mg/g creatinine, as well as excessive amounts of other dibasic amino acids (lysine, arginine and ornithine). In addition, they show varying intestinal transport defects for these same amino acids. The stone formation is the result of poor aqueous solubility of cystine.
- Since there are no known inhibitors of the crystallization of cystine, the stone formation is determined primarily by the urinary supersaturation of cystine. Thus, cystine stones could theoretically form whenever urinary cystine concentration exceeds the solubility limit. Cystine solubility in urine is pH-dependent, and ranges from 170-300 mg/liter at pH 5, 190-400 mg/liter at pH 7 and 220-500 mg/liter at pH 7.5.
- The goal of therapy is to reduce urinary cystine concentration below its solubility limit. It may be accomplished by dietary means aimed at reducing cystine synthesis and by a high fluid intake in order to increase urine volume and thereby lower cystine concentration.
- Unfortunately, the above conservative measures alone may be ineffective in controlling cystine stone formation in some homozygous patients with severe cystinuria (urinary cystine exceeding 500 mg/day). In such patients, d-penicillamine has been used as an additional therapy. Like THIOLA™, dpenicillamine undergoes thiol-disulfide exchange with cystine, thereby lowering the amount of sparingly soluble cystine in urine.
- However, d-penicillamine treatment is frequently accompanied by adverse reactions, such as dermatologic complications, hypersensitivity reactions, hematologic abnormalities and renal disturbances. THIOLA® may have a particular therapeutic role in such patients.
### Dosing Information
- It is recommended that a conservative treatment program should be attempted first. At least 3 liters of fluid (10-10 oz. glassfuls) should be provided, including two glasses with each meal and at bedtime. The patients should be expected to awake at night to urinate; they should drink two more glasses of fluids before returning to bed. Additional fluids should be consumed if there is excessive sweating or intestinal fluid loss. A minimum urine output of 2 liters/day on a consistent basis should be sought. A modest amount of alkali should be provided in order to maintain urinary pH at a high normal range (6.5-7.0). Potassium alkali are advantageous over sodium alkali, because they do not cause hypercalciuria and are less likely to cause the complication of calcium stones.
- Excessive alkali therapy is not advisable. When urinary pH increases above 7.0 with alkali therapy, the complication of calcium phosphate nephrolithiasis may ensue because of the enhanced urinary supersaturation of hydroxyapatite in an alkaline environment.
- In patients who continue to form cystine stones on the above conservative program, THIOLA® may be added to the treatment program. THIOLA® may also be substituted for d-penicillamine in patients who have developed toxicity to the latter drug. In both situations, the conservative treatment program should be continued.
- The dose of THIOLA® should not be arbitrary but should be based on that amount required to reduce urinary cystine concentration to below its solubility limit (generally <250 mg/liter). The extent of the decline in cystine excretion is generally dependent on the THIOLA® dosage.
- THIOLA® may be begun at a dosage of 800 mg/day in adult patients with cystine stones. In a multiclinic trial, average dose of THIOLA® was about 1000 mg/day. However, some patients require a smaller dose. In children, initial dosage may be based on 15 mg/kg/day. Urinary cystine should be measured at 1 month after THIOLA® treatment, and every 3 months thereafter. THIOLA® dosage should be readjusted depending on the urinary cystine value. Whenever possible, THIOLA® should be given in divided doses 3 times/day at least one hour before or 2 hours after meals.
- In patients who had shown severe toxicity to d-penicillamine, THIOLA® might be begun at a lower dosage.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tiopronin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiopronin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tiopronin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tiopronin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tiopronin in pediatric patients.
# Contraindications
- The use of THIOLA® during pregnancy is contraindicated, except in those with severe cystinuria where the anticipated benefit of inhibited stone formation clearly outweighs possible hazards of treatment (see PRECAUTIONS).
- THIOLA® should not be begun again in patients with a prior history of developing agranulocytosis, aplastic anemia or thrombocytopenia on this medication.
- Mothers maintained on THIOLA® treatment should not nurse their infants.
# Warnings
- Despite apparent lower toxicity of THIOLA™, THIOLA® may potentially cause all the serious adverse reactions reported for d-penicillamine. Thus, although no death has been reported to result directly from THIOLA® treatment, a fatal outcome from THIOLA® is possible, as has been reported with d-penicillamine therapy from such complications as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture’s syndrome or myasthenia gravis.
- Leukopenia of the granulocytic series may develop without eosinophilia. Thrombocytopenia may be immunologic in origin or occur on an idiosyncratic basis. The reduction in peripheral blood white count to less than 3500/cubic mm or in platelet count to below 100,000 cubic mm mandates cessation of therapy. Patients should be instructed to report promptly the occurrence of any symptom or sign of these hematological abnormalities, such as fever, sore throat, chills, bleeding or easy bruisability.
- Proteinuria, sometimes sufficiently severe to cause nephrotic syndrome, may develop from membranous glomerulopathy. A close observation of affected patients is mandatory.
- The following complications, though rare, have been reported during d-penicillamine therapy and could occur during THIOLA® treatment. When there are abnormal urinary findings associated with hemoptysis and pulmonary infiltrates suggestive of Goodpasture’s syndrome, THIOLA® treatment should be stopped. Appearance of myasthenic syndrome or myasthenia gravis requires cessation of treatment. When pemphigus-type reactions develop, THIOLA® therapy should be stopped. Steroid treatment may be necessary.
### PRECAUTIONS
- Patients should be advised of the potential development of complications and to report promptly the occurrence of any symptom or sign of them.
- To help monitor potential complications, the following tests are recommended: peripheral blood counts, direct platelet count, hemoglobin, serum albumin, liver function tests, 24-hour urinary protein and routine urinalysis at 3- 6 month intervals during treatment. In order to assess effect on stone disease, urinary cystine analysis should be monitored frequently during the first 6 months when the optimum dose schedule is being determined, and at 6-month intervals thereafter. Abdominal roentogenogram (KUB) is advised on a yearly basis to monitor the size and appearance/disappearance of stone(s).
# Adverse Reactions
## Clinical Trials Experience
- Some patients may develop drug fever, usually during the first month of therapy. THIOLA® treatment should be discontinued until the fever subsides. It may be reinstated at a small dose, with a gradual increase in dosage until the desired level is achieved.
- A generalized rash (erythematous, maculopapular or morbilliform) accompanied by pruritis may develop during the first few months of treatment. It may be controlled by antihistamine therapy, typically recedes when THIOLA® treatment is discontinued, and seldom recurs when THIOLA® treatment is restarted at a lower dosage. Less commonly, rash may appear late in the course of treatment (of more than 6 months). Located usually in the trunk, the late rash is associated with intense pruritis, recedes slowly after discontinuing treatment, and usually recurs upon resumption of treatment.
- A drug reaction simulating lupus erythematous, manifested by fever, arthralgia and lymphadenopathy may develop. It may be associated with a positive antinuclear antibody test, but not necessarily with nephropathy. It may require discontinuance of THIOLA® treatment.
- A reduction in taste perception may develop. It is believed to be the result of chelation of trace metals by THIOLA™. Hypogeusia is often self-limiting.
- Unlike during d-penicillamine therapy, vitamin B6 deficiency is uncommonly associated with THIOLA® treatment.
- Some patients may complain of wrinkling and friability of skin. This complication usually occurs after long-term treatment, and is believed to result from the effect of THIOLA® on collagen.
- A multiclinic trial involving 66 cystinuric patients in the United States indicated that THIOLA® is associated with fewer or less severe adverse reactions than d-penicillamine. Among those who had to stop taking d-penicillamine due to toxicity, 64.7% could take THIOLA® . In those without prior history of d-penicillamine treatment, only 5.9% developed reactions of sufficient severity to require THIOLA® withdrawal. A review of available literature supports the findings from this trial.
- Despite this apparent reduced toxicity to THIOLA® relative to d-penicillamine, THIOLA® treatment may potentially be associated with all the adverse reactions reported with d-penicillamine. They include:
- Nausea, emesis, diarrhea or soft stools, anorexia, abdominal pain, bloating or flatus) in about 1 in 6 patients, Impairment in taste and smell in about 1 in 25 patients,
- Increased bleeding, anemia, leukopenia, thrombocytopenia, eosinophilia) in about 1 in 25 patients;
- Myasthenic syndrome in about 1 in 50 patients.
- Bronchiolitis, hemoptysis, pulmonary infiltrates, dyspnea in about 1 in 50 patients
- Dermatologic complications (pharyngitis, oral ulcers, rash, ecchymosis, prurites, uritcaria, warts, skin wrinkling, pemphigus, elastosis perforans serpiginosa) in about 1 in 6 patients
- Hypersensitivity reactions (laryngeal edema, dyspnea, respiratory distress, fever, chills, arthralgia, weakness, fatigue, myalgia, adenopathy) in about 1 in 25 patients
- Proteinuria, nephrotic syndrome, hematuria) in about 1 in 20 patients.
- These reactions are more likely to develop during THIOLA® therapy among patients who had previously shown toxicity to d-penicillamine.
- In patients who had previously manifested adverse reactions to d-penicillamine, adverse reactions to THIOLA® are more likely to occur than in patients who took THIOLA® for the first time. A close supervision with a careful monitoring of potential side effects is mandatory during THIOLA® treatment. Patients should be told to report promptly any symptoms suggesting toxicity. The treatment with THIOLA® should be stopped if severe toxicity develops.
- Jaundice and abnormal liver function tests have been reported during THIOLA® therapy for non-cystinuric conditions. A direct cause and effect relationship, based upon these foreign reports, has not been established. Although such complications were not encountered in the small multi-center trials in the United States, patients should be carefully monitored and if any abnormalities are noted, the drug should be discontinued and the patient treated by appropriate measures.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tiopronin in the drug label.
# Drug Interactions
There is limited information regarding Drug Interactions of Tiopronin in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- D-penicillamine has been shown to cause skeletal defects and cleft palates in the fetus when given to pregnant rats at 10 times the dose recommended for human use. A similar teratogenicity might be expected for THIOLA® although no such findings could be related to the drug in studies in mice and rats at doses up to 10 times the highest recommended human dose.
- There are no adequate and well-controlled studies in pregnant women. THIOLA® should be used during pregnancy only if the potential benefit justifies potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tiopronin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tiopronin during labor and delivery.
### Nursing Mothers
- Because THIOLA® may be excreted in milk and because of the potential serious adverse reactions of nursing infants from THIOLA®, mothers taking THIOLA® should not nurse their infants.
### Pediatric Use
- Safety and effectiveness below the age of 9 have not been established.
### Geriatic Use
There is no FDA guidance on the use of Tiopronin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Tiopronin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tiopronin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tiopronin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tiopronin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tiopronin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tiopronin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Tiopronin in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Tiopronin in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Tiopronin in the drug label.
# Pharmacology
There is limited information regarding Tiopronin Pharmacology in the drug label.
## Mechanism of Action
- THIOLA® is an active reducing agent which undergoes thiol-disulfide exchange with cystine to form a mixed disulfide of Thiola-cysteine.
- From this reaction, a water-soluble mixed disulfide is formed and the amount of sparingly soluble cystine is reduced. When THIOLA® is given orally, up to 48% of dose appears in urine during the first 4 hours and up to 78% by 72 hours. Thus, in patients with cystinuria, sufficient amount of THIOLA® or its active metabolites could appear in urine to react with cystine, lowering cystine excretion.
## Structure
- THIOLA® (Tiopronin) is a reducing and complexing thiol compound. Tiopronin is N-(2-Mercaptopropionyl) glycine and has the following structure:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tiopronin in the drug label.
## Pharmacokinetics
- The decrement in urinary cystine produced by THIOLA® is generally proportional to the dose. A reduction in urinary cystine of 250-350 mg/day at a THIOLA® dosage of 1 g/day, and a decline of approximately 500 mg/day at a dosage of 2 g/day, might be expected. THIOLA® causes a sustained reduction in cystine excretion without apparent loss of effectiveness. THIOLA® has a rapid onset and offset of action, showing a fall in cystine excretion on the first day of administration and a rise on the first day of drug withdrawal.
## Nonclinical Toxicology
- Long-term carcino-genicity studies in animals have not been performed. High doses of THIOLA® in experimental animals have been shown to interfere with maintenance of pregnancy and viability of the fetus.
# Clinical Studies
There is limited information regarding Clinical Studies of Tiopronin in the drug label.
# How Supplied
THIOLA® (NDC 0178-0900-01), is available for oral administration as 100 mg. round, white, sugar coated tablets in bottles of 100 tablets each. Each tablet is imprinted in red with “M” on one side and blank on the other side.
C05 Rev 010060
MISSION PHARMACAL COMPANY, San Antonio, TX 78230 1355
## Storage
- Store at 25°C (77°F); excursions permitted to 15- 30°C (59-86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
THIOLA® Label
NDC: 0178-0900-01
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Tiopronin in the drug label.
# Precautions with Alcohol
- Alcohol-Tiopronin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- THIOLA®
# Look-Alike Drug Names
There is limited information regarding Tiopronin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Thiola | |
83b8126bc928cdf07b30a636946fe2e71b7a9b60 | wikidoc | Thiolutin | Thiolutin
Thiolutin is a sulfur-containing antibiotic, which is a potent inhibitor of bacterial and yeast RNA polymerases. It was found to inhibit in vitro RNA synthesis directed by all three yeast RNA polymerases (I, II, and III). Thiolutin is also an inhibitor of mannan and glucan formation in Saccharomyces cerevisiae and used for the analysis of mRNA stability. Studies have shown that thiolutin inhibits adhesion of human umbilical vein endothelial cells (HUVECs) to vitronectin and thus suppresses tumor cell-induced angiogenesis in vivo.
Thiolutin is formed in submerged fermentation by several strains of Streptomycetes (source: Fermentek product page)
Synonyms: farcinicin, propiopyvothine, acetopyrrothine
Some sources erroneously specify "aureothricin" as a synonym of thiolutin. Aureothricin is an antibiotic very similar to Thiolutin, and is created as a by-product during the Thiolutin fermentation. | Thiolutin
Thiolutin is a sulfur-containing antibiotic, which is a potent inhibitor of bacterial and yeast RNA polymerases. It was found to inhibit in vitro RNA synthesis directed by all three yeast RNA polymerases (I, II, and III). Thiolutin is also an inhibitor of mannan and glucan formation in Saccharomyces cerevisiae and used for the analysis of mRNA stability. Studies have shown that thiolutin inhibits adhesion of human umbilical vein endothelial cells (HUVECs) to vitronectin and thus suppresses tumor cell-induced angiogenesis in vivo.
Thiolutin is formed in submerged fermentation by several strains of Streptomycetes (source: Fermentek product page)
Synonyms: farcinicin, propiopyvothine, acetopyrrothine
Some sources erroneously specify "aureothricin" as a synonym of thiolutin. Aureothricin is an antibiotic very similar to Thiolutin, and is created as a by-product during the Thiolutin fermentation. | https://www.wikidoc.org/index.php/Thiolutin | |
c20b86dd58783fdcc4425e5e07d2817a7d1142ef | wikidoc | Thylakoid | Thylakoid
Thylakoids are a membrane-bound compartment inside chloroplasts and cyanobacteria. They are the site of the light-dependent reactions of photosynthesis. The word "thylakoid" is derived from the Greek thylakos, meaning "sac". Thylakoids consists of a thylakoid membrane surrounding a thylakoid lumen. Chloroplast thylakoids frequently form stacks of disks referred to as "grana" (singular: granum). "Grana" is Latin for "stacks of coins". Grana are connected by intergrana or stroma thylakoids, which join granum stacks together as a single functional compartment.
# Thylakoid structure
Thylakoids are membrane-bound structures embedded into the chloroplast stroma.
## Membrane
The thylakoid membrane is the site of the light-dependent reactions of photosynthesis with the photosynthetic pigments embedded directly in the membrane. The thylakoid lipid bilayer shares characteristic features with prokaryotic membranes and the inner chloroplast membrane. For example, acidic lipids can be found in thylakoid membranes, cyanobacteria and other photosynthetic bacteria and are involved in the functional integrity of the photosystems. The thylakoid membranes of higher plants are composed primarily of galactolipids that are asymmetrically arranged along and across the membranes. The lipids for the thylakoid membranes are synthesized in a complex pathway involving exchange of lipid precursors between the endoplasmic reticulum and inner membrane of the plastid envelope and transported from the inner membrane to the thylakoids via vesicles.
## Granum
A granum (plural grana) is a stack of thylakoid discs. Chloroplasts can have from 10 to 100 grana. Grana are connected by stroma thylakoids, also called intergrana thylakoids or lamellae. Grana thylakoids and stroma thylakoids can be distinguished by their different protein composition.
# Thylakoid formation
Chloroplasts develop from proplastids when seedlings emerge from the ground. Thylakoid formation requires light. In the plant embryo and in the absence of light, proplastids develop into etioplasts that contain semicrystalline membrane structures called prolamellar bodies. When exposed to light, these prolamellar bodies develop into thylakoids. This does not happen in seedlings grown in the dark, which undergo etiolation. An underexposure to light can cause the thylakoids to fail. This causes the chloroplasts to fail resulting in the death of the plant.
Thylakoid formation requires the action of vesicle-inducing protein in plastids 1 (VIPP1). Plants cannot survive without this protein, and reduced VIPP1 levels lead to slower growth and paler plants with reduced ability to photosynthesize. VIPP1 appears to be required for basic thylakoid membrane formation, but not for the assembly of protein complexes of the thylakoid membrane. It is conserved in all organisms containing thylakoids, including cyanobacteria, green algae, such as Chlamydomonas, and higher plants, such as Arabidopsis.
# Thylakoid isolation and fractionation
Thylakoids can be purified from plant cells using a combination of differential and gradient centrifugation. Disruption of isolated thylakoids, for example by mechanical shearing, releases the lumenal fraction. Peripheral and integral membrane fractions can be extracted from the remaining membrane fraction. Treatment with sodium carbonate (Na2CO3) detaches peripheral membrane proteins, whereas treatment with detergents and organic solvents solubilizes integral membrane proteins.
# Thylakoid proteins
Thylakoids contain many integral and peripheral membrane proteins, as well as lumenal proteins. Recent proteomics studies of thylakoid fractions have provided further details on the protein composition of the thylakoids. These data have been summarized in several plastid protein databases that are available online.
According to these studies, the thylakoid proteome consists of at least 335 different proteins. Out of these, 89 are in the lumen, 116 are integral membrane proteins, 62 are peripheral proteins on the stroma side, and 68 peripheral proteins on the lumenal side. Additional low-abundance lumenal proteins can be predicted through computational methods. Of the thylakoid proteins with known functions, 42% are involved in photosynthesis. The next largest functional groups include proteins involved in protein targeting, processing and folding with 11%, oxidative stress response (9%) and translation (8%).
## Integral membrane proteins
Thylakoid membranes contain integral membrane proteins which play an important role in light harvesting and the light-dependent reactions of photosynthesis. There are four major protein complexes in the thylakoid membrane:
- Photosystems I and II
- Cytochrome b6f complex
- ATP synthase
Photosystem II is located mostly in the grana thylakoids, whereas photosystem I and ATP synthase are mostly located in the stroma thylakoids and the outer layers of grana. The cytochrome b6f complex is distributed evenly throughout thylakoid membranes. Due to the separate location of the two photosystems in the thylakoid membrane system, mobile electron carriers are required to shuttle electrons between them. These carriers are plastoquinone and plastocyanin. Plastoquinone shuttles electrons from photosystem II to the cytochrome b6f complex, whereas plastocyanin carries electrons from the cytochrome b6f complex to photosystem I.
Together, these proteins make use of light energy to drive electron transport chains that generate a chemiosmotic potential across the thylakoid membrane and NADPH, a product of the terminal redox reaction. The ATP synthase uses the chemiosmotic potential to make ATP during photophosphorylation.
### Photosystems
These photosystems are light-driven redox centers, each consisting of an antenna complex that uses chlorophylls and accessory photosynthetic pigments such as carotenoids and phycobiliproteins to harvest light at a variety of wavelengths. Each antenna complex has between 250 and 400 pigment molecules and the energy they absorb is shuttled by resonance energy transfer to a specialized chlorophyll a at the reaction center of each photosystem. When either of the two chlorophyll a molecules at the reaction center absorb energy, an electron is excited and transferred to an electron-acceptor molecule. Photosystem I contains a pair of chlorophyll a molecules, designated P700, at its reaction center that maximally absorbs 700 nm light. Photosystem II contains P680 chlorophyll that absorbs 680 nm light best (note that these wavelengths correspond to deep red - see the visible spectrum). The P is short for pigment and the number is the specific absorption peak in nanometers for the chlorophyll molecules in each reaction center.
### Cytochrome b6f complex
The cytochrome b6f complex is part of the thylakoid electron transport chain and couples electron transfer to the pumping of protons into the thylakoid lumen. Energetically, it is situated between the two photosystems and transfers electrons from photosystem II-plastoquinone to plastocyanin-photosystem I.
### ATP synthase
The thylakoid ATP synthase is a CF1FO-ATP synthase similar to the mitochondrial ATPase. It is integrated into the thylakoid membrane with the CF1-part sticking into stroma. Thus, ATP synthesis occurs on the stromal side of the thylakoids where the ATP is needed for the light-independent reactions of photosynthesis.
## Thylakoid lumen proteins
The electron transport protein plastocyanin is present in the lumen and shuttles electrons from the cytochrome b6f protein complex to photosystem I. While plastoquinones are lipid-soluble and therefore move within the thylakoid membrane, plastocyanin moves through the thylakoid lumen.
The lumen of the thylakoids is also the site of water oxidation by the oxygen evolving complex associated with the lumenal side of photosystem II.
Lumenal proteins can be predicted computationally based on their targeting signals. In Arabidopsis, out of the predicted lumenal proteins possessing the "TAT" signal, the largest groups with known functions are 19% involved in protein processing (proteolysis and folding), 18% in photosynthesis, 11% in metabolism, and 7% redox carriers and defense.
## Thylakoid protein expression
Chloroplasts have their own genome, which encodes a number of thylakoid proteins. However, during the course of plastid evolution from their cyanobacterial endosymbiotic ancestors, extensive gene transfer from the chloroplast genome to the cell nucleus took place. This results in the four major thylakoid protein complexes being encoded in part by the chloroplast genome and in part by the nuclear genome. Plants have developed several mechanisms to co-regulate the expression of the different subunits encoded in the two different organelles to assure the proper stoichiometry and assembly of these protein complexes. For example, transcription of nuclear genes encoding parts of the photosynthetic apparatus is regulated by light. Biogenesis, stability and turnover of thylakoid protein complexes is regulated by phosphorylation via redox-sensitive kinases in the thylakoid membranes. The translation rate of chloroplast-encoded proteins is controlled by the presence or absence of assembly partners (control by epistasy of synthesis). This mechanism involves negative feedback through binding of excess protein to the 5' untranslated region of the chloroplast mRNA. Chloroplasts also need to balance the ratios of photosystem I and II for the electron transfer chain. The redox state of the electron carrier plastoquinone in the thylakoid membrane directly affects the transcription of chloroplast genes encoding proteins of the reaction centers of the photosystems, thus counteracting imbalances in the electron transfer chain.
## Protein targeting to the thylakoids
Thylakoid proteins are targeted to their destination via signal peptides and prokaryotic-type secretory pathways inside the chloroplast. Most thylakoid proteins encoded by a plant's nuclear genome need two targeting signals for proper localization: An N-terminal chloroplast targeting peptide (shown in yellow in the figure), followed by a thylakoid targeting peptide (shown in blue). Proteins are imported through the translocon of outer and inner membrane (Toc and Tic) complexes. After entering the chloroplast, the first targeting peptide is cleaved off by a protease processing imported proteins. This unmasks the second targeting signal and the protein is exported from the stroma into the thylakoid in a second targeting step. This second step requires the action of protein translocation components of the thylakoids and is energy-dependent. Proteins are inserted into the membrane via the SRP-dependent pathway (1), the Tat-dependent pathway (2), or spontaneously via their transmembrane domains (not shown in figure). Lumenal proteins are exported across the thylakoid membrane into the lumen by either the Tat-dependent pathway (2) or the Sec-dependent pathway (3) and released by cleavage from the thylakoid targeting signal. The different pathways utilize different signals and energy sources. The Sec (secretory) pathway requires ATP as energy source and consists of SecA, which binds to the imported protein, and a Sec membrane complex to shuttle the protein across. Proteins with a twin arginine motif in their thylakoid signal peptide are shuttled through the Tat (twin arginine translocation) pathway, which requires a membrane-bound Tat complex and the pH gradient as an energy source. Some other proteins are inserted into the membrane via the SRP (signal recognition particle) pathway. The chloroplast SRP can interact with its target proteins either post-translationally or co-translationally, thus transporting imported proteins as well as those that are translated inside the chloroplast. The SRP pathway requires GTP and the pH gradient as energy sources. Some transmembrane proteins may also spontaneously insert into the membrane from the stromal side without energy requirement.
# Thylakoid function
The thylakoids are the site of the light-dependent reactions of photosynthesis. These include light-driven water oxidation and oxygen evolution, the pumping of protons across the thylakoid membranes coupled with the electron transport chain of the photosystems and cytochrome b6f complex, and ATP synthesis by the ATP synthase utilizing the generated proton gradient.
## Water photolysis
The first step in photosynthesis is the light-driven oxidation (splitting) of water to provide the electrons for the photosynthetic electron transport chains as well as protons for the establishment of a proton gradient. The water-splitting reaction occurs on the lumenal side of the thylakoid membrane and is driven by the light energy captured by the photosystems. It is interesting to note that this oxidation of water conveniently produces the waste product O2 that is vital for cellular respiration. The molecular oxygen formed by the reaction is released into the atmosphere.
## Electron transport chains
Two different variations of electron transport are used during photosynthesis:
- Noncyclic electron transport or Non-cyclic photophosphorylation produces NADPH + H+ and ATP.
- Cyclic electron transport or Cyclic photophosphorylation produces only ATP.
The noncyclic variety involves the participation of both photosystems, while the cyclic electron flow is dependent on only photosystem I.
- Photosystem I uses light energy to reduce NADP+ to NADPH + H+, and is active in both noncyclic and cyclic electron transport. In cyclic mode, the energized electron is passed down a chain that ultimately returns it (in its base state) to the chlorophyll that energized it.
- Photosystem II uses light energy to oxidize water molecules, producing electrons (e-), protons (H+), and molecular oxygen (O2), and is only active in noncyclic transport. Electrons in this system are not conserved, but are rather continually entering from oxidized 2H2O (O2 + 4 H+ + 4 e-) and exiting with NADP+ when it is finally reduced to NADPH.
## Chemiosmosis
A major function of the thylakoid membrane and its integral photosystems is the establishment of chemiosmotic potential. The carriers in the electron transport chain use some of the electron's energy to actively transport protons from the stroma to the lumen. During photosynthesis, the lumen becomes acidic, as low as pH 4, compared to pH 8 in the stroma. This represents a 10,000 fold concentration gradient for protons across the thylakoid membrane.
### Source of proton gradient
The protons in the lumen come from three primary sources.
- Photolysis by photosystem II oxidises water to oxygen, protons and electrons in the lumen.
- The transfer of electrons from photosystem II to plastoquinone during non-cyclic electron transport consumes two protons from the stroma. These are released in the lumen when the reduced plastoquinol is oxidized by the cytochrome b6f protein complex on the lumen side of the thylakoid membrane. From the plastoquinone pool, electrons passs through the cytochrome b6f complex. This integral membrane assembly resembles cytochrome bc1.
- The reduction of plastoquinone by ferredoxin during cyclic electron transport also transfers two protons from the stroma to the lumen.
The proton gradient is also caused by the consumption of protons in the stroma to make NADPH from NADP+ at the NADP reductase.
### ATP generation
The molecular mechanism of ATP generation in chloroplasts is similar to that in mitochondria and takes the required energy from the proton motive force (PMF). However, chloroplasts rely more on the chemical potential of the PMF to generate the potential energy required for ATP synthesis. The PMF is the sum of a proton chemical potential (given by the proton concentration gradient) and a transmembrane electrical potential (given by charge separation across the membrane). Compared to the inner membranes of mitochondria, which have a significantly higher membrane potential due to charge separation, thylakoid membranes lack a charge gradient. To compensate for this, the 10,000 fold proton concentration gradient across the thylakoid membrane is much higher compared to a 10 fold gradient across the inner membrane of mitochondria. The resulting chemiosmotic potential between the lumen and stroma is high enough to drive ATP synthesis using the ATP synthase. As the protons travel back down the gradient through channels in ATP synthase, ADP + Pi is combined into ATP. In this manner, the light-dependent reactions are coupled to the synthesis of ATP via the proton gradient.
# Thylakoid Membranes in Cyanobacteria
Cyanobacteria are photosynthetic prokaryotes with highly differentiated membrane systems. Cyanobacteria have an internal system of thylakoid membranes where the fully functional electron transfer chains of photosynthesis and respiration reside. The presence of different membrane systems lends these cells a unique complexity among bacteria. Cyanobacteria must be able to reorganize the membranes, synthesize new membrane lipids, and properly target proteins to the correct membrane system. The outer membrane, plasma membrane, and thylakoid membranes each have specialized roles in the cyanobacterial cell. Understanding the organization, functionality, protein composition and dynamics of the membrane systems remains a great challenge in cyanobacterial cell biology. | Thylakoid
Thylakoids are a membrane-bound compartment inside chloroplasts and cyanobacteria. They are the site of the light-dependent reactions of photosynthesis. The word "thylakoid" is derived from the Greek thylakos, meaning "sac". Thylakoids consists of a thylakoid membrane surrounding a thylakoid lumen. Chloroplast thylakoids frequently form stacks of disks referred to as "grana" (singular: granum). "Grana" is Latin for "stacks of coins". Grana are connected by intergrana or stroma thylakoids, which join granum stacks together as a single functional compartment.
# Thylakoid structure
Thylakoids are membrane-bound structures embedded into the chloroplast stroma.
## Membrane
The thylakoid membrane is the site of the light-dependent reactions of photosynthesis with the photosynthetic pigments embedded directly in the membrane. The thylakoid lipid bilayer shares characteristic features with prokaryotic membranes and the inner chloroplast membrane. For example, acidic lipids can be found in thylakoid membranes, cyanobacteria and other photosynthetic bacteria and are involved in the functional integrity of the photosystems.[1] The thylakoid membranes of higher plants are composed primarily of galactolipids that are asymmetrically arranged along and across the membranes.[2] The lipids for the thylakoid membranes are synthesized in a complex pathway involving exchange of lipid precursors between the endoplasmic reticulum and inner membrane of the plastid envelope and transported from the inner membrane to the thylakoids via vesicles.[3]
## Granum
A granum (plural grana) is a stack of thylakoid discs. Chloroplasts can have from 10 to 100 grana. Grana are connected by stroma thylakoids, also called intergrana thylakoids or lamellae. Grana thylakoids and stroma thylakoids can be distinguished by their different protein composition.
# Thylakoid formation
Chloroplasts develop from proplastids when seedlings emerge from the ground. Thylakoid formation requires light. In the plant embryo and in the absence of light, proplastids develop into etioplasts that contain semicrystalline membrane structures called prolamellar bodies. When exposed to light, these prolamellar bodies develop into thylakoids. This does not happen in seedlings grown in the dark, which undergo etiolation. An underexposure to light can cause the thylakoids to fail. This causes the chloroplasts to fail resulting in the death of the plant.
Thylakoid formation requires the action of vesicle-inducing protein in plastids 1 (VIPP1). Plants cannot survive without this protein, and reduced VIPP1 levels lead to slower growth and paler plants with reduced ability to photosynthesize. VIPP1 appears to be required for basic thylakoid membrane formation, but not for the assembly of protein complexes of the thylakoid membrane.[4] It is conserved in all organisms containing thylakoids, including cyanobacteria,[5] green algae, such as Chlamydomonas,[6] and higher plants, such as Arabidopsis.[7]
# Thylakoid isolation and fractionation
Thylakoids can be purified from plant cells using a combination of differential and gradient centrifugation.[8] Disruption of isolated thylakoids, for example by mechanical shearing, releases the lumenal fraction. Peripheral and integral membrane fractions can be extracted from the remaining membrane fraction. Treatment with sodium carbonate (Na2CO3) detaches peripheral membrane proteins, whereas treatment with detergents and organic solvents solubilizes integral membrane proteins.
# Thylakoid proteins
Thylakoids contain many integral and peripheral membrane proteins, as well as lumenal proteins. Recent proteomics studies of thylakoid fractions have provided further details on the protein composition of the thylakoids.[9] These data have been summarized in several plastid protein databases that are available online.[10][11]
According to these studies, the thylakoid proteome consists of at least 335 different proteins. Out of these, 89 are in the lumen, 116 are integral membrane proteins, 62 are peripheral proteins on the stroma side, and 68 peripheral proteins on the lumenal side. Additional low-abundance lumenal proteins can be predicted through computational methods.[12][8] Of the thylakoid proteins with known functions, 42% are involved in photosynthesis. The next largest functional groups include proteins involved in protein targeting, processing and folding with 11%, oxidative stress response (9%) and translation (8%).[10]
## Integral membrane proteins
Thylakoid membranes contain integral membrane proteins which play an important role in light harvesting and the light-dependent reactions of photosynthesis. There are four major protein complexes in the thylakoid membrane:
- Photosystems I and II
- Cytochrome b6f complex
- ATP synthase
Photosystem II is located mostly in the grana thylakoids, whereas photosystem I and ATP synthase are mostly located in the stroma thylakoids and the outer layers of grana. The cytochrome b6f complex is distributed evenly throughout thylakoid membranes. Due to the separate location of the two photosystems in the thylakoid membrane system, mobile electron carriers are required to shuttle electrons between them. These carriers are plastoquinone and plastocyanin. Plastoquinone shuttles electrons from photosystem II to the cytochrome b6f complex, whereas plastocyanin carries electrons from the cytochrome b6f complex to photosystem I.
Together, these proteins make use of light energy to drive electron transport chains that generate a chemiosmotic potential across the thylakoid membrane and NADPH, a product of the terminal redox reaction. The ATP synthase uses the chemiosmotic potential to make ATP during photophosphorylation.
### Photosystems
These photosystems are light-driven redox centers, each consisting of an antenna complex that uses chlorophylls and accessory photosynthetic pigments such as carotenoids and phycobiliproteins to harvest light at a variety of wavelengths. Each antenna complex has between 250 and 400 pigment molecules and the energy they absorb is shuttled by resonance energy transfer to a specialized chlorophyll a at the reaction center of each photosystem. When either of the two chlorophyll a molecules at the reaction center absorb energy, an electron is excited and transferred to an electron-acceptor molecule. Photosystem I contains a pair of chlorophyll a molecules, designated P700, at its reaction center that maximally absorbs 700 nm light. Photosystem II contains P680 chlorophyll that absorbs 680 nm light best (note that these wavelengths correspond to deep red - see the visible spectrum). The P is short for pigment and the number is the specific absorption peak in nanometers for the chlorophyll molecules in each reaction center.
### Cytochrome b6f complex
The cytochrome b6f complex is part of the thylakoid electron transport chain and couples electron transfer to the pumping of protons into the thylakoid lumen. Energetically, it is situated between the two photosystems and transfers electrons from photosystem II-plastoquinone to plastocyanin-photosystem I.
### ATP synthase
The thylakoid ATP synthase is a CF1FO-ATP synthase similar to the mitochondrial ATPase. It is integrated into the thylakoid membrane with the CF1-part sticking into stroma. Thus, ATP synthesis occurs on the stromal side of the thylakoids where the ATP is needed for the light-independent reactions of photosynthesis.
## Thylakoid lumen proteins
The electron transport protein plastocyanin is present in the lumen and shuttles electrons from the cytochrome b6f protein complex to photosystem I. While plastoquinones are lipid-soluble and therefore move within the thylakoid membrane, plastocyanin moves through the thylakoid lumen.
The lumen of the thylakoids is also the site of water oxidation by the oxygen evolving complex associated with the lumenal side of photosystem II.
Lumenal proteins can be predicted computationally based on their targeting signals. In Arabidopsis, out of the predicted lumenal proteins possessing the "TAT" signal, the largest groups with known functions are 19% involved in protein processing (proteolysis and folding), 18% in photosynthesis, 11% in metabolism, and 7% redox carriers and defense.[8]
## Thylakoid protein expression
Chloroplasts have their own genome, which encodes a number of thylakoid proteins. However, during the course of plastid evolution from their cyanobacterial endosymbiotic ancestors, extensive gene transfer from the chloroplast genome to the cell nucleus took place. This results in the four major thylakoid protein complexes being encoded in part by the chloroplast genome and in part by the nuclear genome. Plants have developed several mechanisms to co-regulate the expression of the different subunits encoded in the two different organelles to assure the proper stoichiometry and assembly of these protein complexes. For example, transcription of nuclear genes encoding parts of the photosynthetic apparatus is regulated by light. Biogenesis, stability and turnover of thylakoid protein complexes is regulated by phosphorylation via redox-sensitive kinases in the thylakoid membranes.[13] The translation rate of chloroplast-encoded proteins is controlled by the presence or absence of assembly partners (control by epistasy of synthesis).[14] This mechanism involves negative feedback through binding of excess protein to the 5' untranslated region of the chloroplast mRNA.[15] Chloroplasts also need to balance the ratios of photosystem I and II for the electron transfer chain. The redox state of the electron carrier plastoquinone in the thylakoid membrane directly affects the transcription of chloroplast genes encoding proteins of the reaction centers of the photosystems, thus counteracting imbalances in the electron transfer chain.[16]
## Protein targeting to the thylakoids
Thylakoid proteins are targeted to their destination via signal peptides and prokaryotic-type secretory pathways inside the chloroplast. Most thylakoid proteins encoded by a plant's nuclear genome need two targeting signals for proper localization: An N-terminal chloroplast targeting peptide (shown in yellow in the figure), followed by a thylakoid targeting peptide (shown in blue). Proteins are imported through the translocon of outer and inner membrane (Toc and Tic) complexes. After entering the chloroplast, the first targeting peptide is cleaved off by a protease processing imported proteins. This unmasks the second targeting signal and the protein is exported from the stroma into the thylakoid in a second targeting step. This second step requires the action of protein translocation components of the thylakoids and is energy-dependent. Proteins are inserted into the membrane via the SRP-dependent pathway (1), the Tat-dependent pathway (2), or spontaneously via their transmembrane domains (not shown in figure). Lumenal proteins are exported across the thylakoid membrane into the lumen by either the Tat-dependent pathway (2) or the Sec-dependent pathway (3) and released by cleavage from the thylakoid targeting signal. The different pathways utilize different signals and energy sources. The Sec (secretory) pathway requires ATP as energy source and consists of SecA, which binds to the imported protein, and a Sec membrane complex to shuttle the protein across. Proteins with a twin arginine motif in their thylakoid signal peptide are shuttled through the Tat (twin arginine translocation) pathway, which requires a membrane-bound Tat complex and the pH gradient as an energy source. Some other proteins are inserted into the membrane via the SRP (signal recognition particle) pathway. The chloroplast SRP can interact with its target proteins either post-translationally or co-translationally, thus transporting imported proteins as well as those that are translated inside the chloroplast. The SRP pathway requires GTP and the pH gradient as energy sources. Some transmembrane proteins may also spontaneously insert into the membrane from the stromal side without energy requirement.[17]
# Thylakoid function
The thylakoids are the site of the light-dependent reactions of photosynthesis. These include light-driven water oxidation and oxygen evolution, the pumping of protons across the thylakoid membranes coupled with the electron transport chain of the photosystems and cytochrome b6f complex, and ATP synthesis by the ATP synthase utilizing the generated proton gradient.
## Water photolysis
The first step in photosynthesis is the light-driven oxidation (splitting) of water to provide the electrons for the photosynthetic electron transport chains as well as protons for the establishment of a proton gradient. The water-splitting reaction occurs on the lumenal side of the thylakoid membrane and is driven by the light energy captured by the photosystems. It is interesting to note that this oxidation of water conveniently produces the waste product O2 that is vital for cellular respiration. The molecular oxygen formed by the reaction is released into the atmosphere.
## Electron transport chains
Two different variations of electron transport are used during photosynthesis:
- Noncyclic electron transport or Non-cyclic photophosphorylation produces NADPH + H+ and ATP.
- Cyclic electron transport or Cyclic photophosphorylation produces only ATP.
The noncyclic variety involves the participation of both photosystems, while the cyclic electron flow is dependent on only photosystem I.
- Photosystem I uses light energy to reduce NADP+ to NADPH + H+, and is active in both noncyclic and cyclic electron transport. In cyclic mode, the energized electron is passed down a chain that ultimately returns it (in its base state) to the chlorophyll that energized it.
- Photosystem II uses light energy to oxidize water molecules, producing electrons (e-), protons (H+), and molecular oxygen (O2), and is only active in noncyclic transport. Electrons in this system are not conserved, but are rather continually entering from oxidized 2H2O (O2 + 4 H+ + 4 e-) and exiting with NADP+ when it is finally reduced to NADPH.
## Chemiosmosis
A major function of the thylakoid membrane and its integral photosystems is the establishment of chemiosmotic potential. The carriers in the electron transport chain use some of the electron's energy to actively transport protons from the stroma to the lumen. During photosynthesis, the lumen becomes acidic, as low as pH 4, compared to pH 8 in the stroma. This represents a 10,000 fold concentration gradient for protons across the thylakoid membrane.
### Source of proton gradient
The protons in the lumen come from three primary sources.
- Photolysis by photosystem II oxidises water to oxygen, protons and electrons in the lumen.
- The transfer of electrons from photosystem II to plastoquinone during non-cyclic electron transport consumes two protons from the stroma. These are released in the lumen when the reduced plastoquinol is oxidized by the cytochrome b6f protein complex on the lumen side of the thylakoid membrane. From the plastoquinone pool, electrons passs through the cytochrome b6f complex. This integral membrane assembly resembles cytochrome bc1.
- The reduction of plastoquinone by ferredoxin during cyclic electron transport also transfers two protons from the stroma to the lumen.
The proton gradient is also caused by the consumption of protons in the stroma to make NADPH from NADP+ at the NADP reductase.
### ATP generation
The molecular mechanism of ATP generation in chloroplasts is similar to that in mitochondria and takes the required energy from the proton motive force (PMF). However, chloroplasts rely more on the chemical potential of the PMF to generate the potential energy required for ATP synthesis. The PMF is the sum of a proton chemical potential (given by the proton concentration gradient) and a transmembrane electrical potential (given by charge separation across the membrane). Compared to the inner membranes of mitochondria, which have a significantly higher membrane potential due to charge separation, thylakoid membranes lack a charge gradient. To compensate for this, the 10,000 fold proton concentration gradient across the thylakoid membrane is much higher compared to a 10 fold gradient across the inner membrane of mitochondria. The resulting chemiosmotic potential between the lumen and stroma is high enough to drive ATP synthesis using the ATP synthase. As the protons travel back down the gradient through channels in ATP synthase, ADP + Pi is combined into ATP. In this manner, the light-dependent reactions are coupled to the synthesis of ATP via the proton gradient.
# Thylakoid Membranes in Cyanobacteria
Cyanobacteria are photosynthetic prokaryotes with highly differentiated membrane systems. Cyanobacteria have an internal system of thylakoid membranes where the fully functional electron transfer chains of photosynthesis and respiration reside. The presence of different membrane systems lends these cells a unique complexity among bacteria. Cyanobacteria must be able to reorganize the membranes, synthesize new membrane lipids, and properly target proteins to the correct membrane system. The outer membrane, plasma membrane, and thylakoid membranes each have specialized roles in the cyanobacterial cell. Understanding the organization, functionality, protein composition and dynamics of the membrane systems remains a great challenge in cyanobacterial cell biology.[18] | https://www.wikidoc.org/index.php/Thylakoid | |
18ded9c257158a24c1a7dc292f4b8e99844a6430 | wikidoc | Thymocyte | Thymocyte
Thymocytes are T cell precursors which develop in the thymus. The processes of beta-selection, positive selection and negative selection shape thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens and are immunologically tolerant towards self antigens.
# Stages of maturation
Thymocytes are classified into a number of distinct maturational stages based on the expression of cell surface markers. The earliest thymocyte stage is the double negative stage (negative for both CD4 and CD8), which more recently has been better described as Lineage-negative, and which can be divided into four substages. The next major stage is the double positive stage (positive for both CD4 and CD8). The final stage in maturation is the single positive stage (positive for either CD4 or CD8).
# Events during maturation
## Thymus Settling
Thymocytes are ultimately derived from bone marrow hematopoietic progenitors cells which reach the thymus through the circulation. The number of progenitors that enter the thymus each day is thought to be extremely small. Therefore which progenitors colonize the thymus is unknown. Currently Early Lymphoid Progenitors (ELP) are proposed to settle the thymus and are likely the precursors of most thymocytes. ELPs are Lineage-CD44+CD25-CD117+ and thus closely resemble ETPs, the earliest progenitors in the thymus. Precursors enter the thymus at the cortico-medullary junction. Molecules known to be important for thymus entry include CD44, P-selectin (CD62P), and the chemokine receptor CCR9.
Following thymus entry, progenitors proliferate to generate the ETP population. This step is following by the generation of DN2 thymocytes which migrate from the cortico-medullary junction toward the thymus capsule. DN3 thymocytes are generated at the subcapsular zone and undergo beta selection.
## Beta selection
The ability of T cells to recognise foreign antigens is mediated by the T cell receptor, which is a surface protein able to recognise short protein sequences (peptides) that are presented on MHC. During the double negative stage the major maturation step of thymocytes is to express a T cell receptor.
Unlike most genes, which have a stable sequence in each cell which expresses them, the T cell receptor is made up of a series of alternative gene fragments. In order to create a functional T cell receptor, the double negative thymocytes use a series of DNA-interacting enzymes to clip the DNA and bring separate gene fragments together. The outcome of this process is that each T cell receptor has a different sequence, due to different choice of gene fragments and the errors introduced during the cutting and joining process. The evolutionary advantage in having a large number of unique T cell receptors is that each T cell is capable of recognising a different peptide, providing a defence against rapidly evolving pathogens..
The cellular disadvantage in the rearrangement process is that many of the combinations of the T cell receptor gene fragments are non-functional. To eliminate thymocytes which have made a non-functional T cell receptor, the beta-selection point is required before T cells can advance from the double negative to the double positive stage. The beta-selection point requires that the first T cell receptor gene to be arranged (T cell receptor beta) is capable to binding a pre-T cell receptor alpha protein and assembling on the surface with the signalling proteins. Thymocytes which fail this "beta selection" die by apoptosis.
## Positive selection and lineage commitment
Thymocytes which pass "beta selection" express a T cell receptor which is capable of assembling on the surface. However many of these T cell receptors will still be non-functional, due to an inability to bind MHC. The next major stage of thymocyte development is positive selection, to keep only those thymocytes which have a T cell receptor capable of binding MHC. The T cell receptor requires CD8 as a coreceptor to bind to MHC class I, and CD4 as a coreceptor to bind MHC class II. At this stage thymocytes upregulate both CD4 and CD8, becoming double positive cells.
Double positive thymocytes that have a T cell receptor capable of binding MHC class I or class II with even a weak affinity receive signalling through the T cell receptor.. Thymocytes that have a T cell receptor incapable of binding MHC class I or class II undergo apoptosis. Some thymocytes are able to rescue failed positive selection by receptor editing (rearrangement of the other T cell receptor allele to produce a new T cell receptor).
The double positive thymocytes undergo lineage commitment, maturing into a CD8+ T cell (recognising MHC class I) or a CD4+ T cell (recognising MHC class II). Lineage commitment occurs at the late stage of positive selection and works by downregulation of both CD4 and CD8 (reducing the signal from the T cell receptor) and then upregulation of CD4 only. Thymocytes that start receiving signal again are those that recognise MHC class II, and they become CD4+ T cells. Thymocytes that do not start receiving signal again are those that recognise MHC class I, and they downregulation CD4 and upregulate CD8, to become CD8+ T cells. Both of these thymocytes types are known as single positive thymocytes.
## Negative selection
Success in positive selection allows the thymocyte to undergo a number of maturational changes during the transition to a single positive T cell. The single positive T cells upregulate the chemokine receptor CCR7, causing migration from the cortex to the medulla. At this stage the key maturation process involves negative selection, the elimination of autoreactive thymocytes.
The key disadvantage in a gene rearrangement process for T cell receptors is that by random chance, some arrangements of gene fragments will create a T cell receptor capable of binding self-peptides presented on MHC class I or MHC class II. If T cells bearing these T cell receptors were to enter the periphery, they would be capable of activating an immune response against self, resulting in autoimmunity. Negative selection is the process evolved to reduce this risk. During negative selection, all thymocytes with a high affinity for binding self peptides presented on MHC class I or class II are induced to upregulate Bim, a protein which drives apoptosis. Cells which do not have a high affinity for self ('safe' cells) survive negative selection.
Negative selection can occur at the double positive stage in the cortex. However the repertoire of peptides in the cortex is limited to those expressed by epithelial cells, and double positive cells are poor at undergoing negative selection. Therefore the most important site for negative selection is the medulla, once cells are at the single positive stage. In order to remove thymocytes reactive to peripheral organs, the gene AIRE drives the expression of multiple peripheral antigens, such as insulin, creating an "immunological self-shadow". This allows single positive thymocytes to be exposed to a more complex set of self-antigens than is present in the cortex, and therefore more efficiently deletes those T cells which are autoreactive.
Single positive thymocytes remain in the medulla for 1-2 weeks, surveying self-antigens to test for autoreactivity. During this time they undergo final maturational changes, and then exit the thymus using S1P and CCR7. Upon entry to the peripheral bloodstream, the cells are considered mature T cells, and not thymocytes.
# Cancer
Thymocytes that gain oncogenic mutations allowing uncontrolled proliferation can become thymic lymphomas.
# Alternative lineages
As well as classical T cells, a number of alternative cell lineages develop in the thymus, including gamma-delta T cells, Natural Killer T cells and lymphoid dendritic cells. | Thymocyte
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Thymocytes are T cell precursors which develop in the thymus. The processes of beta-selection, positive selection and negative selection shape thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens and are immunologically tolerant towards self antigens.
# Stages of maturation
Thymocytes are classified into a number of distinct maturational stages based on the expression of cell surface markers. The earliest thymocyte stage is the double negative stage (negative for both CD4 and CD8), which more recently has been better described as Lineage-negative, and which can be divided into four substages. The next major stage is the double positive stage (positive for both CD4 and CD8). The final stage in maturation is the single positive stage (positive for either CD4 or CD8).
# Events during maturation
## Thymus Settling
Thymocytes are ultimately derived from bone marrow hematopoietic progenitors cells [see hematopoietic stem cell, hematopoiesis] which reach the thymus through the circulation.[2] The number of progenitors that enter the thymus each day is thought to be extremely small. Therefore which progenitors colonize the thymus is unknown. Currently Early Lymphoid Progenitors (ELP) are proposed to settle the thymus and are likely the precursors of most thymocytes. ELPs are Lineage-CD44+CD25-CD117+ and thus closely resemble ETPs, the earliest progenitors in the thymus. Precursors enter the thymus at the cortico-medullary junction. Molecules known to be important for thymus entry include CD44, P-selectin (CD62P), and the chemokine receptor CCR9.[3]
Following thymus entry, progenitors proliferate to generate the ETP population. This step is following by the generation of DN2 thymocytes which migrate from the cortico-medullary junction toward the thymus capsule. DN3 thymocytes are generated at the subcapsular zone and undergo beta selection.
## Beta selection
The ability of T cells to recognise foreign antigens is mediated by the T cell receptor, which is a surface protein able to recognise short protein sequences (peptides) that are presented on MHC. During the double negative stage the major maturation step of thymocytes is to express a T cell receptor.
Unlike most genes, which have a stable sequence in each cell which expresses them, the T cell receptor is made up of a series of alternative gene fragments. In order to create a functional T cell receptor, the double negative thymocytes use a series of DNA-interacting enzymes to clip the DNA and bring separate gene fragments together. The outcome of this process is that each T cell receptor has a different sequence, due to different choice of gene fragments and the errors introduced during the cutting and joining process. The evolutionary advantage in having a large number of unique T cell receptors is that each T cell is capable of recognising a different peptide, providing a defence against rapidly evolving pathogens.[4].
The cellular disadvantage in the rearrangement process is that many of the combinations of the T cell receptor gene fragments are non-functional. To eliminate thymocytes which have made a non-functional T cell receptor, the beta-selection point is required before T cells can advance from the double negative to the double positive stage. The beta-selection point requires that the first T cell receptor gene to be arranged (T cell receptor beta) is capable to binding a pre-T cell receptor alpha protein and assembling on the surface with the signalling proteins. Thymocytes which fail this "beta selection" die by apoptosis.
## Positive selection and lineage commitment
Thymocytes which pass "beta selection" express a T cell receptor which is capable of assembling on the surface. However many of these T cell receptors will still be non-functional, due to an inability to bind MHC. The next major stage of thymocyte development is positive selection, to keep only those thymocytes which have a T cell receptor capable of binding MHC. The T cell receptor requires CD8 as a coreceptor to bind to MHC class I, and CD4 as a coreceptor to bind MHC class II. At this stage thymocytes upregulate both CD4 and CD8, becoming double positive cells.
Double positive thymocytes that have a T cell receptor capable of binding MHC class I or class II with even a weak affinity receive signalling through the T cell receptor.[5]. Thymocytes that have a T cell receptor incapable of binding MHC class I or class II undergo apoptosis. Some thymocytes are able to rescue failed positive selection by receptor editing (rearrangement of the other T cell receptor allele to produce a new T cell receptor).
The double positive thymocytes undergo lineage commitment, maturing into a CD8+ T cell (recognising MHC class I) or a CD4+ T cell (recognising MHC class II). Lineage commitment occurs at the late stage of positive selection and works by downregulation of both CD4 and CD8 (reducing the signal from the T cell receptor) and then upregulation of CD4 only. Thymocytes that start receiving signal again are those that recognise MHC class II, and they become CD4+ T cells. Thymocytes that do not start receiving signal again are those that recognise MHC class I, and they downregulation CD4 and upregulate CD8, to become CD8+ T cells. Both of these thymocytes types are known as single positive thymocytes.
## Negative selection
Success in positive selection allows the thymocyte to undergo a number of maturational changes during the transition to a single positive T cell. The single positive T cells upregulate the chemokine receptor CCR7, causing migration from the cortex to the medulla. At this stage the key maturation process involves negative selection, the elimination of autoreactive thymocytes.
The key disadvantage in a gene rearrangement process for T cell receptors is that by random chance, some arrangements of gene fragments will create a T cell receptor capable of binding self-peptides presented on MHC class I or MHC class II. If T cells bearing these T cell receptors were to enter the periphery, they would be capable of activating an immune response against self, resulting in autoimmunity. Negative selection is the process evolved to reduce this risk. During negative selection, all thymocytes with a high affinity for binding self peptides presented on MHC class I or class II are induced to upregulate Bim, a protein which drives apoptosis. Cells which do not have a high affinity for self ('safe' cells) survive negative selection.
Negative selection can occur at the double positive stage in the cortex. However the repertoire of peptides in the cortex is limited to those expressed by epithelial cells, and double positive cells are poor at undergoing negative selection. Therefore the most important site for negative selection is the medulla, once cells are at the single positive stage. In order to remove thymocytes reactive to peripheral organs, the gene AIRE drives the expression of multiple peripheral antigens, such as insulin, creating an "immunological self-shadow".[6][7] This allows single positive thymocytes to be exposed to a more complex set of self-antigens than is present in the cortex, and therefore more efficiently deletes those T cells which are autoreactive.
Single positive thymocytes remain in the medulla for 1-2 weeks, surveying self-antigens to test for autoreactivity. During this time they undergo final maturational changes, and then exit the thymus using S1P and CCR7. Upon entry to the peripheral bloodstream, the cells are considered mature T cells, and not thymocytes.
# Cancer
Thymocytes that gain oncogenic mutations allowing uncontrolled proliferation can become thymic lymphomas.
# Alternative lineages
As well as classical T cells, a number of alternative cell lineages develop in the thymus, including gamma-delta T cells, Natural Killer T cells and lymphoid dendritic cells. | https://www.wikidoc.org/index.php/Thymocyte | |
d802e13685812dc39aa7e3af9c695608444506e8 | wikidoc | Tine test | Tine test
# Overview
The Tine test is a multiple puncture tuberculin skin test used to aid in the medical diagnosis of tuberculosis (TB).
This test uses a small "button" that has four to six short needles coated with TB antigens (tuberculin). The needles are pressed into the skin (usually on the inner side of the forearm), forcing the antigens into skin.
The test is read by measuring the size of the largest papule. A negative result is the presence of no papules.
Because it is not possible to control precisely the amount of tuberculin used in the tine test, a positive test should be verified using the Mantoux test. For this reason, the tine test is not as widely used as the Mantoux test and is considered to be less reliable. It is not recommended for use by the American Thoracic Society or Centers for Disease Control and Prevention (CDC).
Mono-vacc Test (O.T.), Aplitest, and the Tine test are names of multiple tine tuberculin skin tests. | Tine test
# Overview
The Tine test is a multiple puncture tuberculin skin test used to aid in the medical diagnosis of tuberculosis (TB).
This test uses a small "button" that has four to six short needles coated with TB antigens (tuberculin). The needles are pressed into the skin (usually on the inner side of the forearm), forcing the antigens into skin.
The test is read by measuring the size of the largest papule. A negative result is the presence of no papules.
Because it is not possible to control precisely the amount of tuberculin used in the tine test, a positive test should be verified using the Mantoux test. For this reason, the tine test is not as widely used as the Mantoux test and is considered to be less reliable. It is not recommended for use by the American Thoracic Society or Centers for Disease Control and Prevention (CDC).
Mono-vacc Test (O.T.), Aplitest, and the Tine test are names of multiple tine tuberculin skin tests. | https://www.wikidoc.org/index.php/Tine_test | |
e38d04c489d840676863e50d5cadd0d49a9842e3 | wikidoc | Tipu Aziz | Tipu Aziz
Tipu Aziz is a professor of neurosurgery at the John Radcliffe Hospital in Oxford, and a lecturer at Magdalen College, Oxford and the Imperial College London medical school. He specialises in the study and treatment of Parkinson's disease, multiple sclerosis, dystonia, spasmodic torticollis, fixed abnormal posture of the neck, tremor, and intractable neuropathic pain.
Aziz came to public prominence in the UK in February 2006 when he spoke out in favour of the use of animals in medical research to several hundred demonstrators during a rally held by Pro-Test, a new British group set up to promote the construction by Oxford University of a new biomedical centre in which research on animals will be conducted. Aziz is one of two Oxford neurosurgeons who sit on the Pro-Test committee.
He came to public attention again in March 2006 when he defended the use of animals in cosmetics testing, which is banned in Britain. His comments were described as "unfortunate" by one colleague.
# Early life and education
Aziz was born in East Pakistan, now known as Bangladesh into what The Guardian called a "medical dynasty." He arrived in Britain at the age of 17 with just three O-levels, but after passing A-levels, he studied neurophysiology at University College, London, where he became interested in deep brain stimulation.
He went on to study for a doctorate at Manchester University, where he began his research involving animals.
# Research interests
His work involves inducing Parkinsonian symptoms in monkeys, either surgically or using drugs, then switching off the symptoms using electrodes he has implanted in their brains. During development of his techniques he admits to having used around 30 monkeys in tests over 20 years, and believes that as many as 40,000 people around the world have benefitted from the techniques. The technique, which Aziz pioneered in the UK, has been shown to alleviate symptoms in human sufferers of Parkinson's disease and dystonia. Patients have electrodes permanently implanted in their brains, wires are attached under the skin to a brain pacemaker, and a battery inserted into the chest.
The Guardian writes that some patients have described the surgery as "miraculous." In a 2006 BBC Two documentary Monkeys, Rats and Me: Animal Testing, animal rights philosopher Peter Singer described Aziz's research as "justifiable" on utilitarian grounds.
Aziz has said that his future research interests will focus on viral, gene, and stem cell therapy to treat Parkinson's and similar movement disorders.
# Animal testing
Aziz has been vocal in support of animal testing and his criticism of the animal liberation movement, calling them "misinformed and sometimes illiterate anti-vivisectionists who adopt terrorist tactics" and who " the process of democracy" through "intimidation." Britain has "probably the most violent and absurd animal rights movement in the world", he told The Guardian. "The problem with British society is it has a humanoid perception of animals that's almost cartoon-like."
On February 25, 2006, he spoke out in favour of animal testing at a rally in Oxford organized by Pro-Test in support of the construction of a new biomedical research center, which will conduct experiments on animals, including primates. Pro-Test was formed to counter SPEAK, an animal rights organisation aiming to end vivisection in the UK.
In an interview published on March 4, 2005, Aziz controversially spoke out in favour of testing cosmetics on animals, a practice banned in the UK since 1998 and due to be banned across the European Union by 2009. He said that to argue cosmetics testing is wrong is "a very strange argument," and that "eople talk about cosmetics being the ultimate evil. But beautifying oneself has been going on since we were cavemen. If it's proven to reduce suffering through animal tests, it's not wrong to use them. To say cosmetics is an absolute evil is absurd."
Other scientists who use animals in research have "distanced themselves" from Aziz's remarks. Clive Page, a researcher at the University of London, said: "I don't think we can justify using animals for cosmetics research. , like myself and a few others who talk out about this have worked very hard to try and explain to the public why we do medical research on animals and why it's still necessary. To muddy the waters by bringing back an issue of using animals for something that's not actually approved in the UK is perhaps unfortunate."
Simon Festing, director of the pro-vivisection lobby group Research Defence Society said of Aziz: "He's not involved in cosmetic testing himself, not involved in cosmetic testing, it's been banned here. There's no movement from the scientific community or the cosmetics industry to have it brought back in. I can't see it being particularly relevant apart from being his personal view."
# Notes
- ↑ "The Pro-Test Committee", Pro-Test website, retrieved May 16, 2006
- ↑ Adam Wishart, "What Felix the monkey taught me about animal research", Evening Standard, November 25, 2006.
- ↑ Gareth Walsh, "Father of animal activism backs monkey testing", The Sunday Times, November 26, 2006. | Tipu Aziz
Tipu Aziz is a professor of neurosurgery at the John Radcliffe Hospital in Oxford, and a lecturer at Magdalen College, Oxford and the Imperial College London medical school. He specialises in the study and treatment of Parkinson's disease, multiple sclerosis, dystonia, spasmodic torticollis, fixed abnormal posture of the neck, tremor, and intractable neuropathic pain. [1] [2]
Aziz came to public prominence in the UK in February 2006 when he spoke out in favour of the use of animals in medical research to several hundred demonstrators during a rally held by Pro-Test, a new British group set up to promote the construction by Oxford University of a new biomedical centre in which research on animals will be conducted. [3] Aziz is one of two Oxford neurosurgeons who sit on the Pro-Test committee. [1]
He came to public attention again in March 2006 when he defended the use of animals in cosmetics testing, which is banned in Britain. His comments were described as "unfortunate" by one colleague. [4]
# Early life and education
Aziz was born in East Pakistan, now known as Bangladesh into what The Guardian called a "medical dynasty." [5] He arrived in Britain at the age of 17 with just three O-levels, but after passing A-levels, he studied neurophysiology at University College, London, where he became interested in deep brain stimulation.
He went on to study for a doctorate at Manchester University, where he began his research involving animals.
# Research interests
His work involves inducing Parkinsonian symptoms in monkeys, either surgically or using drugs, then switching off the symptoms using electrodes he has implanted in their brains. During development of his techniques he admits to having used around 30 monkeys in tests over 20 years, and believes that as many as 40,000 people around the world have benefitted from the techniques. [2] The technique, which Aziz pioneered in the UK, has been shown to alleviate symptoms in human sufferers of Parkinson's disease and dystonia. Patients have electrodes permanently implanted in their brains, wires are attached under the skin to a brain pacemaker, and a battery inserted into the chest.
The Guardian writes that some patients have described the surgery as "miraculous." In a 2006 BBC Two documentary Monkeys, Rats and Me: Animal Testing, animal rights philosopher Peter Singer described Aziz's research as "justifiable" on utilitarian grounds. [3]
Aziz has said that his future research interests will focus on viral, gene, and stem cell therapy to treat Parkinson's and similar movement disorders.
# Animal testing
Template:Animal testing
Aziz has been vocal in support of animal testing and his criticism of the animal liberation movement, calling them "misinformed and sometimes illiterate anti-vivisectionists who adopt terrorist tactics" and who "[undermine] the process of democracy" through "intimidation." Britain has "probably the most violent and absurd animal rights movement in the world", he told The Guardian. "The problem with British society is it has a humanoid perception of animals that's almost cartoon-like." [6]
On February 25, 2006, he spoke out in favour of animal testing at a rally in Oxford organized by Pro-Test in support of the construction of a new biomedical research center, which will conduct experiments on animals, including primates. Pro-Test was formed to counter SPEAK, an animal rights organisation aiming to end vivisection in the UK.
In an interview published on March 4, 2005, Aziz controversially spoke out in favour of testing cosmetics on animals, a practice banned in the UK since 1998 and due to be banned across the European Union by 2009. He said that to argue cosmetics testing is wrong is "a very strange argument," and that "[p]eople talk about cosmetics being the ultimate evil. But beautifying oneself has been going on since we were cavemen. If it's proven to reduce suffering through animal tests, it's not wrong to use them. To say cosmetics is an absolute evil is absurd." [7]
Other scientists who use animals in research have "distanced themselves" from Aziz's remarks. Clive Page, a researcher at the University of London, said: "I don't think we can justify using animals for cosmetics research. [Prof Aziz], like myself and a few others who talk out about this have worked very hard to try and explain to the public why we do medical research on animals and why it's still necessary. To muddy the waters by bringing back an issue of using animals for something that's not actually approved in the UK is perhaps unfortunate." [8]
Simon Festing, director of the pro-vivisection lobby group Research Defence Society said of Aziz: "He's not involved in cosmetic testing himself, [Britain's] not involved in cosmetic testing, it's been banned here. There's no movement from the scientific community or the cosmetics industry to have it brought back in. I can't see it being particularly relevant apart from being his personal view." [9]
# Notes
- ↑ "The Pro-Test Committee", Pro-Test website, retrieved May 16, 2006
- ↑ Adam Wishart, "What Felix the monkey taught me about animal research", Evening Standard, November 25, 2006.
- ↑ Gareth Walsh, "Father of animal activism backs monkey testing", The Sunday Times, November 26, 2006. | https://www.wikidoc.org/index.php/Tipu_Aziz | |
3bbfbbef3a4c5a911713c22e173e4d961648c05c | wikidoc | Tirilazad | Tirilazad
# Overview
Tirilazad is a drug proposed to treat acute ischaemic stroke, however results are mixed as to whether the drug truly treats stroke.
# Mixed results
When tested on animal models, tirilazad protects brain tissue, and reduces any brain damage. On the contrary, the drug fails to treat, and even worsens a stroke when studied on a human being.
# Usage in treatment of stroke
Tirilazad currently has no usage in the clinical treatment of stroke. | Tirilazad
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tirilazad is a drug proposed to treat acute ischaemic stroke, however results are mixed as to whether the drug truly treats stroke.[1]
# Mixed results
When tested on animal models, tirilazad protects brain tissue, and reduces any brain damage. On the contrary, the drug fails to treat, and even worsens a stroke when studied on a human being.
# Usage in treatment of stroke
Tirilazad currently has no usage in the clinical treatment of stroke. | https://www.wikidoc.org/index.php/Tirilazad | |
4c626ed93eca95e7d016287e0607aec35e2d7be3 | wikidoc | Titration | Titration
# Overview
Titration is a common laboratory method of quantitative/chemical analysis that can be used to determine the concentration of a known reactant. Because volume measurements play a key role in titration, it is also known as volumetric analysis.
A reagent, called the titrant, of known concentration (a standard solution) and volume is used to react with a solution of the analyte, whose concentration is not known in advance. Using a calibrated burette to add the titrant, it is possible to determine the exact amount that has been consumed when the endpoint is reached. The endpoint is the point at which the titration is complete, as determined by an indicator (see below). This is ideally the same volume as the equivalence point - the volume of added titrant at which the number of moles of titrant is equal to the number of moles of analyte, or some multiple thereof (as in polyprotic acids). In the classic strong acid-strong base titration, the endpoint of a titration is the point at which the pH of the reactant is just about equal to 7, and often when the solution permanently changes color due to an indicator. There are however many different types of titrations (see below).
Many methods can be used to indicate the endpoint of a reaction; titrations often use visual indicators (the reactant mixture changes colour). In simple acid-base titrations a pH indicator may be used, such as phenolphthalein, which becomes pink when a certain pH (about 8.2) is reached or exceeded. Another example is methyl orange, which is red in acids and yellow in alkali solutions.
Not every titration requires an indicator. In some cases, either the reactants or the products are strongly coloured and can serve as the "indicator". For example, an oxidation-reduction titration using potassium permanganate (pink/purple) as the titrant does not require an indicator. When the titrant is reduced, it turns colourless. After the equivalence point, there is excess titrant present. The equivalence point is identified from the first faint pink colour that persists in the solution being titrated.
Due to the logarithmic nature of the pH curve, the transitions are, in general, extremely sharp; and, thus, a single drop of titrant just before the endpoint can change the pH significantly — leading to an immediate colour change in the indicator. There is a slight difference between the change in indicator color and the actual equivalence point of the titration. This error is referred to as an indicator error, and it is indeterminate.
# History and etymology
The word "titration" comes from the Latin word titalus, meaning inscription or title. The French word titre, also from this origin, means rank. Titration, by definition, is the determination of rank or concentration of a solution with respect to water with a pH of 7 (which is the pH of pure water).
The origins of volumetric analysis are in late-18th-century French chemistry. Francois Antoine Henri Descroizilles developed the first burette (which looked more like a graduated cylinder) in 1791. Joseph Louis Gay-Lussac developed an improved version of the burette that included a side arm, and coined the terms "pipette" and "burette" in an 1824 paper on the standardization of indigo solutions. A major breakthrough in the methodology and popularization of volumetric analysis was due to Karl Friedrich Mohr, who redesigned the burette by placing a clamp and a tip at the bottom, and wrote the first textbook on the topic, Lehrbuch der chemisch-analytischen Titrirmethode (Textbook of analytical-chemical titration methods), published in 1855.
# Preparing a sample for titration
In a titration, both titrant and analyte are required to be aqueous, or in a solution form. If the sample is not a liquid or solution, the samples must be dissolved. If the analyte is very concentrated in the sample, it might be useful to dilute the sample.
Although the vast majority of titrations are carried out in aqueous solution, other solvents such as glacial acetic acid or ethanol (in petrochemistry) are used for special purposes.
A measured amount of the sample can be given in the flask and then be dissolved or diluted. The mathematical result of the titration can be calculated directly with the measured amount. Sometimes the sample is dissolved or diluted beforehand, and a measured amount of the solution is used for titration. In this case the dissolving or diluting must be done accurately with a known coefficient because the mathematical result of the titration must be multiplied with this factor.
Many titrations require buffering to maintain a certain pH for the reaction. Therefore, buffer solutions are added to the reactant solution in the flask.
Some titrations require "masking" of a certain ion. This can be necessary when two reactants in the sample would react with the titrant and only one of them must be analysed, or when the reaction would be disturbed or inhibited by this ion. In this case another solution is added to the sample, which "masks" the unwanted ion (for instance by a weak binding with it or even forming a solid insoluble substance with it).
Some redox reactions may require heating the solution with the sample and titration while the solution is still hot (to increase the reaction rate).
# Procedure
A typical titration begins with a beaker or Erlenmeyer flask containing a precise volume of the reactant and a small amount of indicator, placed underneath a burette containing the reagent. By controlling the amount of reagent added to the reactant, it is possible to detect the point at which the indicator changes colour. As long as the indicator has been chosen correctly, this should also be the point where the reactant and reagent neutralise each other, and, by reading the scale on the burette, the volume of reagent can be measured.
As the concentration of the reagent is known, the number of moles of reagent can be calculated (since concentration = moles / volume). Then, from the chemical equation involving the two substances, the number of moles present in the reactant can be found. Finally, by dividing the number of moles of reactant by its volume, the concentration is calculated.
# Titration curves
Titrations are often recorded on titration curves, whose compositions are generally identical: the independent variable is the volume of the titrant, while the dependent variable is the pH of the solution (which changes depending on the composition of the two solutions). The equivalence point is a significant point on the graph (the point at which all of the starting solution, usually an acid, has been neutralized by the titrant, usually a base). It can be calculated precisely by finding the second derivative of the titration curve and computing the points of inflection (where the graph changes concavity); however, in most cases, simple visual inspection of the curve will suffice (in the curve given to the right, both equivalence points are visible, after roughly 15 and 30 mL of NaOH solution has been titrated into the oxalic acid solution.) To calculate the pKa values, one must find the volume at the half-equivalence point, that is where half the amount of titrant has been added to form the next compound (here, sodium hydrogen oxalate, then disodium oxalate). Halfway between each equivalence point, at 7.5 mL and 22.5 mL, the pH observed was about 1.5 and 4, giving the pKa values.
In monoprotic acids, the point halfway between the beginning of the curve (before any titrant has been added) and the equivalence point is significant: at that point, the concentrations of the two species (the acid and conjugate base) are equal. Therefore, the Henderson-Hasselbalch equation can be solved in this manner:
Therefore, one can easily find the acid dissociation constant of the monoprotic acid by finding the pH of the point halfway between the beginning of the curve and the equivalence point, and solving the simplified equation. In the case of the sample curve, the Ka would be approximately 1.78×10-5 from visual inspection (the actual Ka2 is 1.7×10-5)
For polyprotic acids, calculating the acid dissociation constants is only marginally more difficult: the first acid dissociation constant can be calculated the same way as it would be calculated in a monoprotic acid. The second acid dissociation constant, however, is the point halfway between the first equivalence point and the second equivalence point (and so on for acids that release more than two protons, such as phosphoric acid).
# Types of titrations
Titrations can be classified by the type of reaction. Different types of titration reaction include:
- Acid-base titrations are based on the neutralization reaction between the analyte and an acidic or basic titrant. These most commonly use a pH indicator, a pH meter, or a conductance meter to determine the endpoint.
- Redox titrations are based on an oxidation-reduction reaction between the analyte and titrant. These most commonly use a potentiometer or a redox indicator to determine the endpoint. Frequently either the reactants or the titrant have a colour intense enough that an additional indicator is not needed.
- Complexometric titrations are based on the formation of a complex between the analyte and the titrant. The chelating agent EDTA is very commonly used to titrate metal ions in solution. These titrations generally require specialized indicators that form weaker complexes with the analyte. A common example is Eriochrome Black T for the titration of calcium and magnesium ions.
- A form of titration can also be used to determine the concentration of a virus or bacterium. The original sample is diluted (in some fixed ratio, such as 1:1, 1:2, 1:4, 1:8, etc.) until the last dilution does not give a positive test for the presence of the virus. This value, the titre, may be based on TCID50, EID50, ELD50, LD50 or pfu. This procedure is more commonly known as an assay.
# Measuring the endpoint of a titration
Different methods to determine the endpoint include:
- pH indicator: This is a substance that changes colour in response to a chemical change. An acid-base indicator (e.g., phenolphthalein) changes colour depending on the pH. Redox indicators are also frequently used. A drop of indicator solution is added to the titration at the start; when the colour changes the endpoint has been reached.
- A potentiometer can also be used. This is an instrument that measures the electrode potential of the solution. These are used for titrations based on a redox reaction; the potential of the working electrode will suddenly change as the endpoint is reached.
- pH meter: This is a potentiometer that uses an electrode whose potential depends on the amount of H+ ion present in the solution. (This is an example of an ion-selective electrode. This allows the pH of the solution to be measured throughout the titration. At the endpoint, there will be a sudden change in the measured pH. It can be more accurate than the indicator method, and is very easily automated.
- Conductance: The conductivity of a solution depends on the ions that are present in it. During many titrations, the conductivity changes significantly. (For instance, during an acid-base titration, the H+ and OH- ions react to form neutral H2O. This changes the conductivity of the solution.) The total conductance of the solution depends also on the other ions present in the solution (such as counter ions). Not all ions contribute equally to the conductivity; this also depends on the mobility of each ion and on the total concentration of ions (ionic strength). Thus, predicting the change in conductivity is harder than measuring it.
- Colour change: In some reactions, the solution changes colour without any added indicator. This is often seen in redox titrations, for instance, when the different oxidation states of the product and reactant produce different colours.
- Precipitation: If the reaction forms a solid, then a precipitate will form during the titration. A classic example is the reaction between Ag+ and Cl- to form the very insoluble salt AgCl. This usually makes it difficult to determine the endpoint precisely. As a result, precipitation titrations often have to be done as "back" titrations (see below).
- An isothermal titration calorimeter uses the heat produced or consumed by the reaction to determine the endpoint. This is important in biochemical titrations, such as the determination of how substrates bind to enzymes.
- Thermometric titrimetry is an extraordinarily versatile technique. This is differentiated from calorimetric titrimetry by the fact that the heat of the reaction (as indicated by temperature rise or fall) is not used to determine the amount of analyte in the sample solution. Instead, the endpoint is determined by the rate of temperature change.
- Spectroscopy can be used to measure the absorption of light by the solution during the titration, if the spectrum of the reactant, titrant or product is known. The relative amounts of the product and reactant can be used to determine the endpoint.
- Amperometry can be used as a detection technique (amperometric titration). The current due to the oxidation or reduction of either the reactants or products at a working electrode will depend on the concentration of that species in solution. The endpoint can then be detected as a change in the current. This method is most useful when the excess titrant can be reduced, as in the titration of halides with Ag+. (This is handy also in that it ignores precipitates.)
## Other terms
The term back titration is used when a titration is done "backwards":
instead of titrating the original analyte, one adds a known excess of a
standard reagent to the solution, then titrates the excess. A back titration
is useful if the endpoint of the reverse titration is easier to identify
than the endpoint of the normal titration. They are also useful if
the reaction between the analyte and the titrant is very slow.
# Particular uses
- As applied to biodiesel, titration is the act of determining the acidity of a sample of by the dropwise addition of a known base to the sample while testing with pH paper for the desired neutral pH=7 reading. By knowing how much base neutralizes an amount of WVO, we discern how much base to add to the entire.
- Titrations in the petrochemical or food industry to define oils, fats or biodiesel and similar substances. An example procedure for all three can be found here: .
Acid number: an acid-base titration with colour indicator is used to determine the free fatty acid content. See also: pH of fatty acids.
Iodine number: a redox titration with colour indication, which indicates the amount of unsaturated fatty acids.
Saponification value: an acid-base back titration with colour indicator or potentiometric to get a hint about the average chain length of fatty acids in a fat.
- Acid number: an acid-base titration with colour indicator is used to determine the free fatty acid content. See also: pH of fatty acids.
- Iodine number: a redox titration with colour indication, which indicates the amount of unsaturated fatty acids.
- Saponification value: an acid-base back titration with colour indicator or potentiometric to get a hint about the average chain length of fatty acids in a fat. | Titration
# Overview
Titration is a common laboratory method of quantitative/chemical analysis that can be used to determine the concentration of a known reactant. Because volume measurements play a key role in titration, it is also known as volumetric analysis.
A reagent, called the titrant, of known concentration (a standard solution) and volume is used to react with a solution of the analyte, whose concentration is not known in advance. Using a calibrated burette to add the titrant, it is possible to determine the exact amount that has been consumed when the endpoint is reached. The endpoint is the point at which the titration is complete, as determined by an indicator (see below). This is ideally the same volume as the equivalence point - the volume of added titrant at which the number of moles of titrant is equal to the number of moles of analyte, or some multiple thereof (as in polyprotic acids). In the classic strong acid-strong base titration, the endpoint of a titration is the point at which the pH of the reactant is just about equal to 7, and often when the solution permanently changes color due to an indicator. There are however many different types of titrations (see below).
Many methods can be used to indicate the endpoint of a reaction; titrations often use visual indicators (the reactant mixture changes colour). In simple acid-base titrations a pH indicator may be used, such as phenolphthalein, which becomes pink when a certain pH (about 8.2) is reached or exceeded. Another example is methyl orange, which is red in acids and yellow in alkali solutions.
Not every titration requires an indicator. In some cases, either the reactants or the products are strongly coloured and can serve as the "indicator". For example, an oxidation-reduction titration using potassium permanganate (pink/purple) as the titrant does not require an indicator. When the titrant is reduced, it turns colourless. After the equivalence point, there is excess titrant present. The equivalence point is identified from the first faint pink colour that persists in the solution being titrated.
Due to the logarithmic nature of the pH curve, the transitions are, in general, extremely sharp; and, thus, a single drop of titrant just before the endpoint can change the pH significantly — leading to an immediate colour change in the indicator. There is a slight difference between the change in indicator color and the actual equivalence point of the titration. This error is referred to as an indicator error, and it is indeterminate.
# History and etymology
The word "titration" comes from the Latin word titalus, meaning inscription or title. The French word titre, also from this origin, means rank. Titration, by definition, is the determination of rank or concentration of a solution with respect to water with a pH of 7 (which is the pH of pure water).
The origins of volumetric analysis are in late-18th-century French chemistry. Francois Antoine Henri Descroizilles developed the first burette (which looked more like a graduated cylinder) in 1791. Joseph Louis Gay-Lussac developed an improved version of the burette that included a side arm, and coined the terms "pipette" and "burette" in an 1824 paper on the standardization of indigo solutions. A major breakthrough in the methodology and popularization of volumetric analysis was due to Karl Friedrich Mohr, who redesigned the burette by placing a clamp and a tip at the bottom, and wrote the first textbook on the topic, Lehrbuch der chemisch-analytischen Titrirmethode (Textbook of analytical-chemical titration methods), published in 1855.[1]
# Preparing a sample for titration
In a titration, both titrant and analyte are required to be aqueous, or in a solution form. If the sample is not a liquid or solution, the samples must be dissolved. If the analyte is very concentrated in the sample, it might be useful to dilute the sample.
Although the vast majority of titrations are carried out in aqueous solution, other solvents such as glacial acetic acid or ethanol (in petrochemistry) are used for special purposes.
A measured amount of the sample can be given in the flask and then be dissolved or diluted. The mathematical result of the titration can be calculated directly with the measured amount. Sometimes the sample is dissolved or diluted beforehand, and a measured amount of the solution is used for titration. In this case the dissolving or diluting must be done accurately with a known coefficient because the mathematical result of the titration must be multiplied with this factor.
Many titrations require buffering to maintain a certain pH for the reaction. Therefore, buffer solutions are added to the reactant solution in the flask.
Some titrations require "masking" of a certain ion. This can be necessary when two reactants in the sample would react with the titrant and only one of them must be analysed, or when the reaction would be disturbed or inhibited by this ion. In this case another solution is added to the sample, which "masks" the unwanted ion (for instance by a weak binding with it or even forming a solid insoluble substance with it).
Some redox reactions may require heating the solution with the sample and titration while the solution is still hot (to increase the reaction rate).
# Procedure
A typical titration begins with a beaker or Erlenmeyer flask containing a precise volume of the reactant and a small amount of indicator, placed underneath a burette containing the reagent. By controlling the amount of reagent added to the reactant, it is possible to detect the point at which the indicator changes colour. As long as the indicator has been chosen correctly, this should also be the point where the reactant and reagent neutralise each other, and, by reading the scale on the burette, the volume of reagent can be measured.
As the concentration of the reagent is known, the number of moles of reagent can be calculated (since <math>concentration = moles / volume</math>). Then, from the chemical equation involving the two substances, the number of moles present in the reactant can be found. Finally, by dividing the number of moles of reactant by its volume, the concentration is calculated.
# Titration curves
Titrations are often recorded on titration curves, whose compositions are generally identical: the independent variable is the volume of the titrant, while the dependent variable is the pH of the solution (which changes depending on the composition of the two solutions). The equivalence point is a significant point on the graph (the point at which all of the starting solution, usually an acid, has been neutralized by the titrant, usually a base). It can be calculated precisely by finding the second derivative of the titration curve and computing the points of inflection (where the graph changes concavity); however, in most cases, simple visual inspection of the curve will suffice (in the curve given to the right, both equivalence points are visible, after roughly 15 and 30 mL of NaOH solution has been titrated into the oxalic acid solution.) To calculate the pKa values, one must find the volume at the half-equivalence point, that is where half the amount of titrant has been added to form the next compound (here, sodium hydrogen oxalate, then disodium oxalate). Halfway between each equivalence point, at 7.5 mL and 22.5 mL, the pH observed was about 1.5 and 4, giving the pKa values.
In monoprotic acids, the point halfway between the beginning of the curve (before any titrant has been added) and the equivalence point is significant: at that point, the concentrations of the two species (the acid and conjugate base) are equal. Therefore, the Henderson-Hasselbalch equation can be solved in this manner:
Therefore, one can easily find the acid dissociation constant of the monoprotic acid by finding the pH of the point halfway between the beginning of the curve and the equivalence point, and solving the simplified equation. In the case of the sample curve, the Ka would be approximately 1.78×10-5 from visual inspection (the actual Ka2 is 1.7×10-5)
For polyprotic acids, calculating the acid dissociation constants is only marginally more difficult: the first acid dissociation constant can be calculated the same way as it would be calculated in a monoprotic acid. The second acid dissociation constant, however, is the point halfway between the first equivalence point and the second equivalence point (and so on for acids that release more than two protons, such as phosphoric acid).
# Types of titrations
Titrations can be classified by the type of reaction. Different types of titration reaction include:
- Acid-base titrations are based on the neutralization reaction between the analyte and an acidic or basic titrant. These most commonly use a pH indicator, a pH meter, or a conductance meter to determine the endpoint.
- Redox titrations are based on an oxidation-reduction reaction between the analyte and titrant. These most commonly use a potentiometer or a redox indicator to determine the endpoint. Frequently either the reactants or the titrant have a colour intense enough that an additional indicator is not needed.
- Complexometric titrations are based on the formation of a complex between the analyte and the titrant. The chelating agent EDTA is very commonly used to titrate metal ions in solution. These titrations generally require specialized indicators that form weaker complexes with the analyte. A common example is Eriochrome Black T for the titration of calcium and magnesium ions.
- A form of titration can also be used to determine the concentration of a virus or bacterium. The original sample is diluted (in some fixed ratio, such as 1:1, 1:2, 1:4, 1:8, etc.) until the last dilution does not give a positive test for the presence of the virus. This value, the titre, may be based on TCID50, EID50, ELD50, LD50 or pfu. This procedure is more commonly known as an assay.
# Measuring the endpoint of a titration
Different methods to determine the endpoint include:
- pH indicator: This is a substance that changes colour in response to a chemical change. An acid-base indicator (e.g., phenolphthalein) changes colour depending on the pH. Redox indicators are also frequently used. A drop of indicator solution is added to the titration at the start; when the colour changes the endpoint has been reached.
- A potentiometer can also be used. This is an instrument that measures the electrode potential of the solution. These are used for titrations based on a redox reaction; the potential of the working electrode will suddenly change as the endpoint is reached.
- pH meter: This is a potentiometer that uses an electrode whose potential depends on the amount of H+ ion present in the solution. (This is an example of an ion-selective electrode. This allows the pH of the solution to be measured throughout the titration. At the endpoint, there will be a sudden change in the measured pH. It can be more accurate than the indicator method, and is very easily automated.
- Conductance: The conductivity of a solution depends on the ions that are present in it. During many titrations, the conductivity changes significantly. (For instance, during an acid-base titration, the H+ and OH- ions react to form neutral H2O. This changes the conductivity of the solution.) The total conductance of the solution depends also on the other ions present in the solution (such as counter ions). Not all ions contribute equally to the conductivity; this also depends on the mobility of each ion and on the total concentration of ions (ionic strength). Thus, predicting the change in conductivity is harder than measuring it.
- Colour change: In some reactions, the solution changes colour without any added indicator. This is often seen in redox titrations, for instance, when the different oxidation states of the product and reactant produce different colours.
- Precipitation: If the reaction forms a solid, then a precipitate will form during the titration. A classic example is the reaction between Ag+ and Cl- to form the very insoluble salt AgCl. This usually makes it difficult to determine the endpoint precisely. As a result, precipitation titrations often have to be done as "back" titrations (see below).
- An isothermal titration calorimeter uses the heat produced or consumed by the reaction to determine the endpoint. This is important in biochemical titrations, such as the determination of how substrates bind to enzymes.
- Thermometric titrimetry is an extraordinarily versatile technique. This is differentiated from calorimetric titrimetry by the fact that the heat of the reaction (as indicated by temperature rise or fall) is not used to determine the amount of analyte in the sample solution. Instead, the endpoint is determined by the rate of temperature change.
- Spectroscopy can be used to measure the absorption of light by the solution during the titration, if the spectrum of the reactant, titrant or product is known. The relative amounts of the product and reactant can be used to determine the endpoint.
- Amperometry can be used as a detection technique (amperometric titration). The current due to the oxidation or reduction of either the reactants or products at a working electrode will depend on the concentration of that species in solution. The endpoint can then be detected as a change in the current. This method is most useful when the excess titrant can be reduced, as in the titration of halides with Ag+. (This is handy also in that it ignores precipitates.)
## Other terms
The term back titration is used when a titration is done "backwards":
instead of titrating the original analyte, one adds a known excess of a
standard reagent to the solution, then titrates the excess. A back titration
is useful if the endpoint of the reverse titration is easier to identify
than the endpoint of the normal titration. They are also useful if
the reaction between the analyte and the titrant is very slow.
# Particular uses
- As applied to biodiesel, titration is the act of determining the acidity of a sample of by the dropwise addition of a known base to the sample while testing with pH paper for the desired neutral pH=7 reading. By knowing how much base neutralizes an amount of WVO, we discern how much base to add to the entire.
- Titrations in the petrochemical or food industry to define oils, fats or biodiesel and similar substances. An example procedure for all three can be found here: [1].
Acid number: an acid-base titration with colour indicator is used to determine the free fatty acid content. See also: pH of fatty acids.
Iodine number: a redox titration with colour indication, which indicates the amount of unsaturated fatty acids.
Saponification value: an acid-base back titration with colour indicator or potentiometric to get a hint about the average chain length of fatty acids in a fat.
- Acid number: an acid-base titration with colour indicator is used to determine the free fatty acid content. See also: pH of fatty acids.
- Iodine number: a redox titration with colour indication, which indicates the amount of unsaturated fatty acids.
- Saponification value: an acid-base back titration with colour indicator or potentiometric to get a hint about the average chain length of fatty acids in a fat. | https://www.wikidoc.org/index.php/Titrate | |
44c6423c983f05f5366bad9de8f5d3d8dc0e2a30 | wikidoc | Tocolytic | Tocolytic
Tocolytics are medications used to suppress premature labor (from the Greek tokos, childbirth, and lytic, capable of dissolving). They are given when delivery would result in premature birth. The therapy also buys time for the administration of betamethasone, a glucocorticoid drug which greatly accelerate fetal lung maturity, but takes one to two days to work.
The suppression of contractions is often only partial and tocolytics can only be relied on to delay birth for several days. Depending on the tocolytic used the mother or fetus may require monitoring, as for instance blood pressure monitoring when nifedipine is used as it reduces blood pressure. In any case the risk of preterm labor alone justifies hospitalization.
# Types of agents
Various types of agents are used, with varying success rates and side effects. Some medications are not specifically FDA approved for use in stopping uterine contractions in preterm labor, instead being used off label. Nifedipine is one of the most commonly used tocolytic agents.
Examples:
- MgSO4
- ritodrine (Yutopar)
- fenoterol
- nifedipine (Procardia, Adalat)
- atosiban
- salbutamol
- indomethacin
- terbutaline (Brethine)
Ethyl alcohol was frequently prescribed as a tocolytic in the mid-20th century, but later double-blind studies found it was not effective.
# Contraindications to Tocolysis
Several factors may contraindicate delaying birth with the use of tocolytic medications.
- Fetus is older than 37 weeks gestation
- Fetus weighs more than 2500g or has IUGR
- Fetus is in acute distress or has passed (or has a fatal anomaly)
- Dilation is greater than 4 cm
- Chorioamnionitis or intrauterine infection is present
- Mother has severe Pregnancy-induced hypertension, eclampsia, active vaginal bleeding, a cardiac disease, or another condition which indicates that the pregnancy should not continue. | Tocolytic
Tocolytics are medications used to suppress premature labor (from the Greek tokos, childbirth, and lytic, capable of dissolving). They are given when delivery would result in premature birth. The therapy also buys time for the administration of betamethasone, a glucocorticoid drug which greatly accelerate fetal lung maturity, but takes one to two days to work.
The suppression of contractions is often only partial and tocolytics can only be relied on to delay birth for several days. Depending on the tocolytic used the mother or fetus may require monitoring, as for instance blood pressure monitoring when nifedipine is used as it reduces blood pressure. In any case the risk of preterm labor alone justifies hospitalization.
# Types of agents
Various types of agents are used, with varying success rates and side effects. Some medications are not specifically FDA approved for use in stopping uterine contractions in preterm labor, instead being used off label. Nifedipine is one of the most commonly used tocolytic agents[1].
Examples:
- MgSO4
- ritodrine (Yutopar)
- fenoterol
- nifedipine (Procardia, Adalat)
- atosiban
- salbutamol
- indomethacin
- terbutaline (Brethine)
Ethyl alcohol was frequently prescribed as a tocolytic in the mid-20th century, but later double-blind studies[2] found it was not effective.
# Contraindications to Tocolysis
Several factors may contraindicate delaying birth with the use of tocolytic medications. [3]
- Fetus is older than 37 weeks gestation
- Fetus weighs more than 2500g or has IUGR
- Fetus is in acute distress or has passed (or has a fatal anomaly)
- Dilation is greater than 4 cm
- Chorioamnionitis or intrauterine infection is present
- Mother has severe Pregnancy-induced hypertension, eclampsia, active vaginal bleeding, a cardiac disease, or another condition which indicates that the pregnancy should not continue. | https://www.wikidoc.org/index.php/Tocolysis | |
63bd62a23b109ea374eabe3eacbe627ee45256dc | wikidoc | Tolvaptan | Tolvaptan
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Tolvaptan is a {{{drugClass}}} that is FDA approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia, (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hyperglycemia, constipation, increased thirst, nausea, xerostomia, asthenia, dizziness, polyuria, dehydration.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Hyponatremia
- Dosing information
- Patients should be in a hospital for initiation and re-initiation of therapy to evaluate the therapeutic response and because too rapid correction of hyponatremia can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death.
- Usual strting dosage: 15 mg PO qd without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium.
- Do not administer Tolvaptan for more than 30 days to minimize the risk of liver injury .
- During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Avoid fluid restriction during the first 24 hours of therapy. Patients receiving Tolvaptan should be advised that they can continue ingestion of fluid in response to thirst .
- Drug Withdrawal
- Following discontinuation from Tolvaptan, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium and volume status.
### Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors
- CYP 3A Inhibitors
- Tolvaptan is metabolized by CYP 3A, and use with strong CYP 3A inhibitors causes a marked (5‑fold) increase in exposure . The effect of moderate CYP 3A inhibitors on tolvaptan exposure has not been assessed. Avoid co-administration of Tolvaptan and moderate CYP 3A inhibitors .
- CYP 3A Inducers
- Co-administration of Tolvaptan with potent CYP 3A inducers (e.g., rifampin) reduces tolvaptan plasma concentrations by 85%. Therefore, the expected clinical effects of Tolvaptan may not be observed at the recommended dose. Patient response should be monitored and the dose adjusted accordingly .
- P-gp Inhibitors
- Tolvaptan is a substrate of P-gp. Co-administration of Tolvaptan with inhibitors of P-gp (e.g., cyclosporine) may necessitate a decrease in Tolvaptan dose .
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tolvaptan in adult patients.
### Non–Guideline-Supported Use
### Autosomal dominant polycystic kidney disease
- Dosing information
- Not applicable
### Heart Failure
- Dosing information
- 30 mg/day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of Tolvaptan in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tolvaptan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolvaptan in pediatric patients.
# Contraindications
Tolvaptan is contraindicated in the following conditions:
- Urgent need to raise serum sodium acutely
- Tolvaptan has not been studied in a setting of urgent need to raise serum sodium acutely.
- Inability of the patient to sense or appropriately respond to thirst
- Patients who are unable to auto-regulate fluid balance are at substantially increased risk of incurring an overly rapid correction of serum sodium, hypernatremia and hypovolemia.
- Hypovolemic hyponatremia
- Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits.
- Concomitant use of strong CYP 3A inhibitors
- Ketoconazole 200 mg administered with tolvaptan increased tolvaptan exposure by 5‑fold. Larger doses would be expected to produce larger increases in tolvaptan exposure. There is not adequate experience to define the dose adjustment that would be needed to allow safe use of tolvaptan with strong CYP 3A inhibitors such as clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir], nefazodone, and telithromycin.
- Anuric patients
- In patients unable to make urine, no clinical benefit can be expected.
- Hypersensitivity
- Tolvaptan is contraindicated in patients with hypersensitivity (e.g. anaphylactic shock, rash generalized) to tolvaptan or any component of the product .
# Warnings
- Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae
- Osmotic demyelination syndrome is a risk associated with too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. In controlled clinical trials in which tolvaptan was administered in titrated doses starting at 15 mg once daily, 7% of tolvaptan-treated subjects with a serum sodium <130 mEq/L had an increase in serum sodium greater than 8 mEq/L at approximately 8 hours and 2% had an increase greater than 12 mEq/L at 24 hours. Approximately 1% of placebo-treated subjects with a serum sodium less than 130 mEq/L had a rise greater than 8 mEq/L at 8 hours and no patient had a rise greater than 12 mEq/L/24 hours. Osmotic demyelination syndrome has been reported in association with Tolvaptan therapy . Patients treated with Tolvaptan should be monitored to assess serum sodium concentrations and neurologic status, especially during initiation and after titration. Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving Tolvaptan who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with Tolvaptan and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours of therapy with Tolvaptan may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided.
- Liver Injury
- Tolvaptan can cause serious and potentially fatal liver injury. In a placebo-controlled and open label extension study of chronically administered tolvaptan in patients with autosomal dominant polycystic kidney disease, cases of serious liver injury attributed to tolvaptan were observed. An increased incidence of ALT greater than three times the upper limit of normal was associated with tolvaptan (42/958 or 4.4%) compared to placebo (5/484 or 1.0%). Cases of serious liver injury were generally observed starting 3 months after initiation of tolvaptan although elevations of ALT occurred prior to 3 months.
- Patients with symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice should discontinue treatment with Tolvaptan.
- Limit duration of therapy with Tolvaptan to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover from liver injury may be impaired .
- Dehydration and Hypovolemia
- Tolvaptan therapy induces copious aquaresis, which is normally partially offset by fluid intake. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In multiple-dose, placebo-controlled trials in which 607 hyponatremic patients were treated with tolvaptan, the incidence of dehydration was 3.3% for tolvaptan and 1.5% for placebo-treated patients. In patients receiving Tolvaptan who develop medically significant signs or symptoms of hypovolemia, interrupt or discontinue Tolvaptan therapy and provide supportive care with careful management of vital signs, fluid balance and electrolytes. Fluid restriction during therapy with Tolvaptan may increase the risk of dehydration and hypovolemia. Patients receiving Tolvaptan should continue ingestion of fluid in response to thirst.
- Co-administration with Hypertonic Saline
- Concomitant use with hypertonic saline is not recommended.
- Drug Interactions
- Other Drugs Affecting Exposure to Tolvaptan
- CYP 3A Inhibitors
- Tolvaptan is a substrate of CYP 3A. CYP 3A inhibitors can lead to a marked increase in tolvaptan concentrations . Do not use Tolvaptan with strong inhibitors of CYP 3A and avoid concomitant use with moderate CYP 3A inhibitors.
- CYP 3A Inducers
- Avoid co-administration of CYP 3A inducers (e.g., rifampin, rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine, St. John's Wort) with Tolvaptan, as this can lead to a reduction in the plasma concentration of tolvaptan and decreased effectiveness of Tolvaptan treatment. If co-administered with CYP 3A inducers, the dose of Tolvaptan may need to be increased .
- P-gp Inhibitors
- The dose of Tolvaptan may have to be reduced when Tolvaptan is co-administered with P-gp inhibitors, e.g., cyclosporine .
- Hyperkalemia or Drugs that Increase Serum Potassium
- Treatment with tolvaptan is associated with an acute reduction of the extracellular fluid volume which could result in increased serum potassium. Serum potassium levels should be monitored after initiation of tolvaptan treatment in patients with a serum potassium >5 mEq/L as well as those who are receiving drugs known to increased serum potassium.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
In multiple-dose, placebo-controlled trials, 607 hyponatremic patients (serum sodium <135 mEq/L) were treated with Tolvaptan. The mean age of these patients was 62 years; 70% of patients were male and 82% were Caucasian. One hundred eighty nine (189) tolvaptan-treated patients had a serum sodium <130 mEq/L, and 52 patients had a serum sodium less than 125 mEq/L. Hyponatremia was attributed to cirrhosis in 17% of patients, heart failure in 68% and SIADH/other in 16%. Of these patients, 223 were treated with the recommended dose titration (15 mg titrated to 60 mg as needed to raise serum sodium).
Overall, over 4,000 patients have been treated with oral doses of tolvaptan in open-label or placebo-controlled clinical trials. Approximately 650 of these patients had hyponatremia; approximately 219 of these hyponatremic patients were treated with tolvaptan for 6 months or more.
The most common adverse reactions (incidence ≥5% more than placebo) seen in two 30‑day, double-blind, placebo-controlled hyponatremia trials in which tolvaptan was administered in titrated doses (15 mg to 60 mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia. In these trials, 10% (23/223) of tolvaptan-treated patients discontinued treatment because of an adverse event, compared to 12% (26/220) of placebo-treated patients; no adverse reaction resulting in discontinuation of trial medication occurred at an incidence of greater than 1% in tolvaptan-treated patients.
Table 1 lists the adverse reactions reported in tolvaptan-treated patients with hyponatremia (serum sodium <135 mEq/L) and at a rate at least 2% greater than placebo-treated patients in two 30‑day, double-blind, placebo-controlled trials. In these studies, 223 patients were exposed to tolvaptan (starting dose 15 mg, titrated to 30 and 60 mg as needed to raise serum sodium). Adverse events resulting in death in these trials were 6% in tolvaptan-treated-patients and 6% in placebo-treated patients.
In a subgroup of patients with hyponatremia (N = 475, serum sodium <135 mEq/L) enrolled in a double-blind, placebo-controlled trial (mean duration of treatment was 9 months) of patients with worsening heart failure, the following adverse reactions occurred in tolvaptan-treated patients at a rate at least 2% greater than placebo: mortality (42% tolvaptan, 38% placebo), nausea (21% tolvaptan, 16% placebo), thirst (12% tolvaptan, 2% placebo), dry mouth (7% tolvaptan, 2% placebo) and polyuria or pollakiuria (4% tolvaptan, 1% placebo).
Gastrointestinal bleeding in patients with cirrhosis
In patients with cirrhosis treated with tolvaptan in the hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) tolvaptan-treated patients and 1 out of 57 (2%) placebo treated patients.
The following adverse reactions occurred in <2% of hyponatremic patients treated with Tolvaptan and at a rate greater than placebo in double-blind placebo-controlled trials (N = 607 tolvaptan; N = 518 placebo) or in <2% of patients in an uncontrolled trial of patients with hyponatremia (N = 111) and are not mentioned elsewhere in the label.
Blood and Lymphatic System Disorders: Disseminated intravascular coagulation
Cardiac Disorders: Intracardiac thrombus, ventricular fibrillation
Investigations: Prothrombin time prolonged
Gastrointestinal Disorders: Ischemic colitis
Metabolism and Nutrition Disorders: Diabetic ketoacidosis
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis
Nervous System: Cerebrovascular accident
Renal and Urinary Disorders: Urethral hemorrhage
Reproductive System and Breast Disorders (female): Vaginal hemorrhage
Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure
Vascular disorder: Deep vein thrombosis
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Tolvaptan. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Neurologic: Osmotic demyelination syndrome
Investigations: Hypernatremia
Removal of excess free body water increases serum osmolality and serum sodium concentrations. All patients treated with tolvaptan, especially those whose serum sodium levels become normal, should continue to be monitored to ensure serum sodium remains within normal limits. If hypernatremia is observed, management may include dose decreases or interruption of tolvaptan treatment, combined with modification of free-water intake or infusion. During clinical trials of hyponatremic patients, hypernatremia was reported as an adverse event in 0.7% of patients receiving tolvaptan vs. 0.6% of patients receiving placebo; analysis of laboratory values demonstrated an incidence of hypernatremia of 1.7% in patients receiving tolvaptan vs. 0.8% in patients receiving placebo.
Immune System Disorders: Hypersensitivity reactions including anaphylactic shock and rash generalized .
# Drug Interactions
- Effects of Drugs on Tolvaptan
- Ketoconazole and Other Strong CYP 3A Inhibitors
- Tolvaptan is metabolized primarily by CYP 3A. Ketoconazole is a strong inhibitor of CYP 3A and also an inhibitor of P-gp. Co-administration of Tolvaptan and ketoconazole 200 mg daily results in a 5‑fold increase in exposure to tolvaptan. Co-administration of Tolvaptan with 400 mg ketoconazole daily or with other strong CYP 3A inhibitors (e.g., clarithromycin, itraconazole, telithromycin, saquinavir, nelfinavir, ritonavir and nefazodone) at the highest labeled dose would be expected to cause an even greater increase in tolvaptan exposure. Thus, Tolvaptan and strong CYP 3A inhibitors should not be co-administered .
- Moderate CYP 3A Inhibitors
- The impact of moderate CYP 3A inhibitors (e.g., erythromycin, fluconazole, aprepitant, diltiazem and verapamil) on the exposure to co-administered tolvaptan has not been assessed. A substantial increase in the exposure to tolvaptan would be expected when Tolvaptan is co-administered with moderate CYP 3A inhibitors. Co-administration of Tolvaptan with moderate CYP3A inhibitors should therefore generally be avoided .
- Grapefruit Juice
- Co-administration of grapefruit juice and Tolvaptan results in a 1.8‑fold increase in exposure to tolvaptan .
- P-gp Inhibitors
- Reduction in the dose of Tolvaptan may be required in patients concomitantly treated with P-gp inhibitors, such as e.g., cyclosporine, based on clinical response
- Rifampin and Other CYP 3A Inducers
- Rifampin is an inducer of CYP 3A and P-gp. Co-administration of rifampin and Tolvaptan reduces exposure to tolvaptan by 85%. Therefore, the expected clinical effects of Tolvaptan in the presence of rifampin and other inducers (e.g., rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine and St. John's Wort) may not be observed at the usual dose levels of Tolvaptan. The dose of Tolvaptan may have to be increased .
- Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide
- Co-administration of lovastatin, digoxin, furosemide, and hydrochlorothiazide with Tolvaptan has no clinically relevant impact on the exposure to tolvaptan.
- Effects of Tolvaptan on Other Drugs
- Digoxin
- Digoxin is a P-gp substrate. Co-administration of Tolvaptan with digoxin increased digoxin AUC by 20% and Cmax by 30%.
- Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide
- Co-administration of tolvaptan does not appear to alter the pharmacokinetics of warfarin, furosemide, hydrochlorothiazide, or amiodarone (or its active metabolite, desethylamiodarone) to a clinically significant degree.
- Lovastatin
- Tolvaptan is a weak inhibitor of CYP 3A. Co-administration of lovastatin and Tolvaptan increases the exposure to lovastatin and its active metabolite lovastatin-β hydroxyacid by factors of 1.4 and 1.3, respectively. This is not a clinically relevant change.
Pharmacodynamic Interactions
Tolvaptan produces a greater 24 hour urine volume/excretion rate than does furosemide or hydrochlorothiazide. Concomitant administration of tolvaptan with furosemide or hydrochlorothiazide results in a 24 hour urine volume/excretion rate that is similar to the rate after tolvaptan administration alone.
Although specific interaction studies were not performed, in clinical studies tolvaptan was used concomitantly with beta-blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics. Adverse reactions of hyperkalemia were approximately 1-2% higher when tolvaptan was administered with angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics compared to administration of these medications with placebo. Serum potassium levels should be monitored during concomitant drug therapy.
As a V2-receptor antagonist, tolvaptan may interfere with the V2-agonist activity of desmopressin (dDAVP). In a male subject with mild Von Willebrand (vW) disease, intravenous infusion of dDAVP 2 hours after administration of oral tolvaptan did not produce the expected increases in vW Factor Antigen or Factor VIII activity. It is not recommended to administer Tolvaptan with a V2-agonist.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well controlled studies of Tolvaptan use in pregnant women. In animal studies, cleft palate, brachymelia, microphthalmia, skeletal malformations, decreased fetal weight, delayed fetal ossification, and embryo-fetal death occurred. Tolvaptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In embryo-fetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis. Rats received 2 to 162 times the maximum recommended human dose (MRHD) of tolvaptan (on a body surface area basis). Reduced fetal weights and delayed fetal ossification occurred at 162 times the MRHD. Signs of maternal toxicity (reduction in body weight gain and food consumption) occurred at 16 and 162 times the MRHD. When pregnant rabbits received oral tolvaptan at 32 to 324 times the MRHD (on a body surface area basis), there were reductions in maternal body weight gain and food consumption at all doses, and increased abortions at the mid and high doses (about 97 and 324 times the MRHD). At 324 times the MRHD, there were increased rates of embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations .
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolvaptan in women who are pregnant.
### Labor and Delivery
The effect of Tolvaptan on labor and delivery in humans is unknown.
### Nursing Mothers
It is not known whether Tolvaptan is excreted into human milk. Tolvaptan is excreted into the milk of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Tolvaptan, a decision should be made to discontinue nursing or Tolvaptan, taking into consideration the importance of Tolvaptan to the mother.
### Pediatric Use
Safety and effectiveness of Tolvaptan in pediatric patients have not been established.
### Geriatic Use
Of the total number of hyponatremic subjects treated with Tolvaptan in clinical studies, 42% were 65 and over, while 19% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Increasing age has no effect on tolvaptan plasma concentrations.
### Gender
There is no FDA guidance on the use of Tolvaptan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tolvaptan with respect to specific racial populations.
### Renal Impairment
No dose adjustment is necessary based on renal function. There are no clinical trial data in patients with CrCl <10 mL/min, and, because drug effects on serum sodium levels are likely lost at very low levels of renal function, use in patients with a CrCl <10 mL/min is not recommended. No benefit can be expected in patients who are anuric .
### Hepatic Impairment
Moderate and severe hepatic impairment do not affect exposure to tolvaptan to a clinically relevant extent. Avoid use of tolvaptan in patients with underlying liver disease.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tolvaptan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tolvaptan in patients who are immunocompromised.
### Use in Patients with Congestive Heart Failure
The exposure to tolvaptan in patients with congestive heart failure is not clinically relevantly increased. No dose adjustment is necessary.
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA Package Insert for Tolvaptan contains no information regarding drug monitoring.
# IV Compatibility
FDA Package Insert for Tolvaptan contains no information regarding IV compatibility.
# Overdosage
Single oral doses up to 480 mg and multiple doses up to 300 mg once daily for 5 days have been well tolerated in studies in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia.
The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. No mortality was observed in rats or dogs following single oral doses of 2000 mg/kg (maximum feasible dose). A single oral dose of 2000 mg/kg was lethal in mice, and symptoms of toxicity in affected mice included decreased locomotor activity, staggering gait, tremor and hypothermia.
If overdose occurs, estimation of the severity of poisoning is an important first step. A thorough history and details of overdose should be obtained, and a physical examination should be performed. The possibility of multiple drug involvement should be considered.
Treatment should involve symptomatic and supportive care, with respiratory, ECG and blood pressure monitoring and water/electrolyte supplements as needed. A profuse and prolonged aquaresis should be anticipated, which, if not matched by oral fluid ingestion, should be replaced with intravenous hypotonic fluids, while closely monitoring electrolytes and fluid balance.
ECG monitoring should begin immediately and continue until ECG parameters are within normal ranges. Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (>99%). Close medical supervision and monitoring should continue until the patient recovers.
# Pharmacology
## Mechanism of Action
Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V2-receptor is 29 times greater than for the V1a-receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V2-receptors compared with tolvaptan.
Plasma concentrations of native AVP may increase (avg. 2-9 pg/mL) with tolvaptan administration.
## Structure
Tolvaptan is (±)-4'--o-tolu-m-toluidide. The empirical formula is C26H25ClN2O3. Molecular weight is 448.94. The chemical structure is:
Tolvaptan tablets for oral use contain 15 mg or 30 mg of tolvaptan. Inactive ingredients include corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C Blue No. 2 Aluminum Lake as colorant.
## Pharmacodynamics
In healthy subjects receiving a single dose of Tolvaptan 60 mg, the onset of the aquaretic and sodium increasing effects occurs within 2 to 4 hours post-dose. A peak effect of about a 6 mEq increase in serum sodium and about 9 mL/min increase in urine excretion rate is observed between 4 and 8 hours post-dose; thus, the pharmacological activity lags behind the plasma concentrations of tolvaptan. About 60% of the peak effect on serum sodium is sustained at 24 hours post-dose, but the urinary excretion rate is no longer elevated by this time. Doses above 60 mg tolvaptan do not increase aquaresis or serum sodium further. The effects of tolvaptan in the recommended dose range of 15 to 60 mg once daily appear to be limited to aquaresis and the resulting increase in sodium concentration.
In a parallel-arm, double-blind (for tolvaptan and placebo), placebo- and positive-controlled, multiple dose study of the effect of tolvaptan on the QTc interval, 172 healthy subjects were randomized to tolvaptan 30 mg, tolvaptan 300 mg, placebo, or moxifloxacin 400 mg once daily. At both the 30 mg and 300 mg doses, no significant effect of administering tolvaptan on the QTc interval was detected on Day 1 and Day 5. At the 300 mg dose, peak tolvaptan plasma concentrations were approximately 4‑fold higher than the peak concentrations following a 30 mg dose. Moxifloxacin increased the QT interval by 12 ms at 2 hours after dosing on Day 1 and 17 ms at 1 hour after dosing on Day 5, indicating that the study was adequately designed and conducted to detect tolvaptan's effect on the QT interval, had an effect been present.
## Pharmacokinetics
In healthy subjects the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been examined. Area under the curve (AUC) increases proportionally with dose. After administration of doses ≥60 mg, however, Cmax increases less than proportionally with dose. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Food does not impact the bioavailability of tolvaptan. In vitro data indicate that tolvaptan is a substrate and inhibitor of P-gp. Tolvaptan is highly plasma protein bound (99%) and distributed into an apparent volume of distribution of about 3 L/kg. Tolvaptan is eliminated entirely by non-renal routes and mainly, if not exclusively, metabolized by CYP 3A. After oral dosing, clearance is about 4 mL/min/kg and the terminal phase half-life is about 12 hours. The accumulation factor of tolvaptan with the once-daily regimen is 1.3 and the trough concentrations amount to ≤16% of the peak concentrations, suggesting a dominant half-life somewhat shorter than 12 hours. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.
In patients with hyponatremia of any origin the clearance of tolvaptan is reduced to about 2 mL/min/kg. Moderate or severe hepatic impairment or congestive heart failure decrease the clearance and increase the volume of distribution of tolvaptan, but the respective changes are not clinically relevant. Exposure and response to tolvaptan in subjects with creatinine clearance ranging between 79 and 10 mL/min and patients with normal renal function are not different.
In a study in patients with creatinine clearances ranging from 10-124 mL/min administered a single dose of 60 mg tolvaptan, AUC and Cmax of plasma tolvaptan were less than doubled in patients with severe renal impairment relative to the controls. The peak increase in serum sodium was 5-6 mEq/L, regardless of renal function, but the onset and offset of tolvaptan's effect on serum sodium were slower in patients with severe renal impairment .
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
Up to two years of oral administration of tolvaptan to male and female rats at doses up to 1000 mg/kg/day (162 times the maximum recommended human dose on a body surface area basis), to male mice at doses up to 60 mg/kg/day (5 times the MRHD) and to female mice at doses up to 100 mg/kg/day (8 times the MRHD) did not increase the incidence of tumors.
Tolvaptan tested negative for genotoxicity in in vitro (bacterial reverse mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells) and in vivo (rat micronucleus assay) test systems.
In a fertility study in which male and female rats were orally administered tolvaptan at 100, 300 or 1000 mg/kg/day, the highest dose level was associated with significantly fewer corpora lutea and implants than control.
## Reproductive and Developmental Toxicology
In pregnant rats, oral administration of tolvaptan at 10, 100 and 1000 mg/kg/day during organogenesis was associated with a reduction in maternal body weight gain and food consumption at 100 and 1000 mg/kg/day, and reduced fetal weight and delayed ossification of fetuses at 1000 mg/kg/day (162 times the MRHD on a body surface area basis). Oral administration of tolvaptan at 100, 300 and 1000 mg/kg/day to pregnant rabbits during organogenesis was associated with reductions in maternal body weight gain and food consumption at all doses, and abortions at mid- and high-doses. At 1000 mg/kg/day (324 times the MRHD), increased incidences of embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations were observed. There are no adequate and well-controlled studies of Tolvaptan in pregnant women. Tolvaptan should be used in pregnancy only if the potential benefit justifies the risk to the fetus.
# Clinical Studies
## Hyponatremia
In two double-blind, placebo-controlled, multi-center studies (SALT-1 and SALT-2), a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) resulting from a variety of underlying causes (heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone and others) were treated for 30 days with tolvaptan or placebo, then followed for an additional 7 days after withdrawal. Symptomatic patients, patients likely to require saline therapy during the course of therapy, patients with acute and transient hyponatremia associated with head trauma or postoperative state and patients with hyponatremia due to primary polydipsia, uncontrolled adrenal insufficiency or uncontrolled hypothyroidism were excluded. Patients were randomized to receive either placebo (N = 220) or tolvaptan (N = 223) at an initial oral dose of 15 mg once daily. The mean serum sodium concentration at study entry was 129 mEq/L. Fluid restriction was to be avoided if possible during the first 24 hours of therapy to avoid overly rapid correction of serum sodium, and during the first 24 hours of therapy 87% of patients had no fluid restriction. Thereafter, patients could resume or initiate fluid restriction (defined as daily fluid intake of ≤1.0 liter/day) as clinically indicated.
The dose of tolvaptan could be increased at 24 hour intervals to 30 mg once daily, then to 60 mg once daily, until either the maximum dose of 60 mg or normonatremia (serum sodium >135 mEq/L) was reached. Serum sodium concentrations were determined at 8 hours after study drug initiation and daily up to 72 hours, within which time titration was typically completed. Treatment was maintained for 30 days with additional serum sodium assessments on Days 11, 18, 25 and 30. On the day of study discontinuation, all patients resumed previous therapies for hyponatremia and were reevaluated 7 days later. The primary endpoint for these studies was the average daily AUC for change in serum sodium from baseline to Day 4 and baseline to Day 30 in patients with a serum sodium less than 135 mEq/L. Compared to placebo, tolvaptan caused a statistically greater increase in serum sodium (p <0.0001) during both periods in both studies (see Table 2). For patients with a serum sodium of <130 mEq/L or <125 mEq/L, the effects at Day 4 and Day 30 remained significant (see Table 2). This effect was also seen across all disease etiology subsets (e.g., CHF, cirrhosis, SIADH/other).
In patients with hyponatremia (defined as <135 mEq/L), serum sodium concentration increased to a significantly greater degree in tolvaptan-treated patients compared to placebo-treated patients as early as 8 hours after the first dose, and the change was maintained for 30 days. The percentage of patients requiring fluid restriction (defined as ≤1 L/day at any time during the treatment period) was also significantly less (p =0.0017) in the tolvaptan-treated group (30/215, 14%) as compared with the placebo-treated group (51/206, 25%).
Figure 1 shows the change from baseline in serum sodium by visit in patients with serum sodium <135 mEq/L. Within 7 days of tolvaptan discontinuation, serum sodium concentrations in tolvaptan-treated patients declined to levels similar to those of placebo-treated patients.
In the open-label study SALTWATER, 111 patients, 94 of them hyponatremic (serum sodium <135 mEq/L), previously on tolvaptan or placebo therapy were given tolvaptan as a titrated regimen (15 to 60 mg once daily) after having returned to standard care for at least 7 days. By this time, their baseline mean serum sodium concentration had fallen to between their original baseline and post-placebo therapy level. Upon initiation of therapy, average serum sodium concentrations increased to approximately the same levels as observed for those previously treated with tolvaptan, and were sustained for at least a year. Figure 3 shows results from 111 patients enrolled in the SALTWATER Study.
## Heart Failure
In a phase 3 double-blind, placebo-controlled study (EVEREST), 4133 patients with worsening heart failure were randomized to tolvaptan or placebo as an adjunct to standard of care. Long-term tolvaptan treatment (mean duration of treatment of 0.75 years) had no demonstrated effect, either favorable or unfavorable, on all-cause mortality or the combined endpoint of CV mortality or subsequent hospitalization for worsening HF .
# How Supplied
How Supplied
Tolvaptan® (tolvaptan) tablets are available in the following strengths and packages.
Tolvaptan 15 mg tablets are non-scored, blue, triangular, shallow-convex, debossed with "OTSUKA" and "15" on one side.
Blister of 10 NDC 59148-020-50
Tolvaptan 30 mg tablets are non-scored, blue, round, shallow-convex, debossed with "OTSUKA" and "30" on one side.
Blister of 10 NDC 59148-021-50
## Storage
Store at 25 °C (77 °F), excursions permitted between 15 °C and 30 °C (59 °F to 86 °F) .
Keep out of reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
As a part of patient counseling, healthcare providers must review the Tolvaptan Medication Guide with every patient .
## Concomitant Medication
Advise patients to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs since there is a potential for interactions.
Strong and Moderate CYP 3A inhibitors and P-gp inhibitors
Advise patients to inform their physician if they use strong (e.g., ketoconazole, itraconazole, clarithromycin, telithromycin, nelfinavir, saquinavir, indinavir, ritonavir) or moderate CYP 3A inhibitors (e.g., aprepitant, erythromycin, diltiazem, verapamil, fluconazole) or P-gp inhibitors (e.g., cyclosporine) .
## Nursing
Advise patients not to breastfeed an infant if they are taking Tolvaptan .
Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850
Tolvaptan is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
© 2014 Otsuka Pharmaceutical Co., Ltd.
## FDA-Approved Medication Guide
MEDICATION GUIDE
Tolvaptan® (sam-sca)
tolvaptan
Tablets
Read the Medication Guide that comes with Tolvaptan before you take it and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. Share this important information with members of your household.
# Precautions with Alcohol
Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.
# Brand Names
Tolvaptan
# Look-Alike Drug Names
There is limited information about the look-alike names.
# Drug Shortage Status
# Price | Tolvaptan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2];Aparna Vuppala, M.B.B.S. [3]
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# Black Box Warning
# Overview
Tolvaptan is a {{{drugClass}}} that is FDA approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia, (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hyperglycemia, constipation, increased thirst, nausea, xerostomia, asthenia, dizziness, polyuria, dehydration.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Hyponatremia
- Dosing information
- Patients should be in a hospital for initiation and re-initiation of therapy to evaluate the therapeutic response and because too rapid correction of hyponatremia can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death.
- Usual strting dosage: 15 mg PO qd without regard to meals. Increase the dose to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium.
- Do not administer Tolvaptan for more than 30 days to minimize the risk of liver injury .
- During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Avoid fluid restriction during the first 24 hours of therapy. Patients receiving Tolvaptan should be advised that they can continue ingestion of fluid in response to thirst .
- Drug Withdrawal
- Following discontinuation from Tolvaptan, patients should be advised to resume fluid restriction and should be monitored for changes in serum sodium and volume status.
### Co-Administration with CYP 3A Inhibitors, CYP 3A Inducers and P-gp Inhibitors
- CYP 3A Inhibitors
- Tolvaptan is metabolized by CYP 3A, and use with strong CYP 3A inhibitors causes a marked (5‑fold) increase in exposure . The effect of moderate CYP 3A inhibitors on tolvaptan exposure has not been assessed. Avoid co-administration of Tolvaptan and moderate CYP 3A inhibitors .
- CYP 3A Inducers
- Co-administration of Tolvaptan with potent CYP 3A inducers (e.g., rifampin) reduces tolvaptan plasma concentrations by 85%. Therefore, the expected clinical effects of Tolvaptan may not be observed at the recommended dose. Patient response should be monitored and the dose adjusted accordingly .
- P-gp Inhibitors
- Tolvaptan is a substrate of P-gp. Co-administration of Tolvaptan with inhibitors of P-gp (e.g., cyclosporine) may necessitate a decrease in Tolvaptan dose .
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tolvaptan in adult patients.
### Non–Guideline-Supported Use
### Autosomal dominant polycystic kidney disease
- Dosing information
- Not applicable [1]
### Heart Failure
- Dosing information
- 30 mg/day[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of Tolvaptan in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tolvaptan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolvaptan in pediatric patients.
# Contraindications
Tolvaptan is contraindicated in the following conditions:
- Urgent need to raise serum sodium acutely
- Tolvaptan has not been studied in a setting of urgent need to raise serum sodium acutely.
- Inability of the patient to sense or appropriately respond to thirst
- Patients who are unable to auto-regulate fluid balance are at substantially increased risk of incurring an overly rapid correction of serum sodium, hypernatremia and hypovolemia.
- Hypovolemic hyponatremia
- Risks associated with worsening hypovolemia, including complications such as hypotension and renal failure, outweigh possible benefits.
- Concomitant use of strong CYP 3A inhibitors
- Ketoconazole 200 mg administered with tolvaptan increased tolvaptan exposure by 5‑fold. Larger doses would be expected to produce larger increases in tolvaptan exposure. There is not adequate experience to define the dose adjustment that would be needed to allow safe use of tolvaptan with strong CYP 3A inhibitors such as clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir], nefazodone, and telithromycin.
- Anuric patients
- In patients unable to make urine, no clinical benefit can be expected.
- Hypersensitivity
- Tolvaptan is contraindicated in patients with hypersensitivity (e.g. anaphylactic shock, rash generalized) to tolvaptan or any component of the product .
# Warnings
- Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae
- Osmotic demyelination syndrome is a risk associated with too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. In controlled clinical trials in which tolvaptan was administered in titrated doses starting at 15 mg once daily, 7% of tolvaptan-treated subjects with a serum sodium <130 mEq/L had an increase in serum sodium greater than 8 mEq/L at approximately 8 hours and 2% had an increase greater than 12 mEq/L at 24 hours. Approximately 1% of placebo-treated subjects with a serum sodium less than 130 mEq/L had a rise greater than 8 mEq/L at 8 hours and no patient had a rise greater than 12 mEq/L/24 hours. Osmotic demyelination syndrome has been reported in association with Tolvaptan therapy . Patients treated with Tolvaptan should be monitored to assess serum sodium concentrations and neurologic status, especially during initiation and after titration. Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving Tolvaptan who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with Tolvaptan and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours of therapy with Tolvaptan may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided.
- Liver Injury
- Tolvaptan can cause serious and potentially fatal liver injury. In a placebo-controlled and open label extension study of chronically administered tolvaptan in patients with autosomal dominant polycystic kidney disease, cases of serious liver injury attributed to tolvaptan were observed. An increased incidence of ALT greater than three times the upper limit of normal was associated with tolvaptan (42/958 or 4.4%) compared to placebo (5/484 or 1.0%). Cases of serious liver injury were generally observed starting 3 months after initiation of tolvaptan although elevations of ALT occurred prior to 3 months.
- Patients with symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice should discontinue treatment with Tolvaptan.
- Limit duration of therapy with Tolvaptan to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover from liver injury may be impaired .
- Dehydration and Hypovolemia
- Tolvaptan therapy induces copious aquaresis, which is normally partially offset by fluid intake. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In multiple-dose, placebo-controlled trials in which 607 hyponatremic patients were treated with tolvaptan, the incidence of dehydration was 3.3% for tolvaptan and 1.5% for placebo-treated patients. In patients receiving Tolvaptan who develop medically significant signs or symptoms of hypovolemia, interrupt or discontinue Tolvaptan therapy and provide supportive care with careful management of vital signs, fluid balance and electrolytes. Fluid restriction during therapy with Tolvaptan may increase the risk of dehydration and hypovolemia. Patients receiving Tolvaptan should continue ingestion of fluid in response to thirst.
- Co-administration with Hypertonic Saline
- Concomitant use with hypertonic saline is not recommended.
- Drug Interactions
- Other Drugs Affecting Exposure to Tolvaptan
- CYP 3A Inhibitors
- Tolvaptan is a substrate of CYP 3A. CYP 3A inhibitors can lead to a marked increase in tolvaptan concentrations . Do not use Tolvaptan with strong inhibitors of CYP 3A and avoid concomitant use with moderate CYP 3A inhibitors.
- CYP 3A Inducers
- Avoid co-administration of CYP 3A inducers (e.g., rifampin, rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine, St. John's Wort) with Tolvaptan, as this can lead to a reduction in the plasma concentration of tolvaptan and decreased effectiveness of Tolvaptan treatment. If co-administered with CYP 3A inducers, the dose of Tolvaptan may need to be increased .
- P-gp Inhibitors
- The dose of Tolvaptan may have to be reduced when Tolvaptan is co-administered with P-gp inhibitors, e.g., cyclosporine .
- Hyperkalemia or Drugs that Increase Serum Potassium
- Treatment with tolvaptan is associated with an acute reduction of the extracellular fluid volume which could result in increased serum potassium. Serum potassium levels should be monitored after initiation of tolvaptan treatment in patients with a serum potassium >5 mEq/L as well as those who are receiving drugs known to increased serum potassium.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
In multiple-dose, placebo-controlled trials, 607 hyponatremic patients (serum sodium <135 mEq/L) were treated with Tolvaptan. The mean age of these patients was 62 years; 70% of patients were male and 82% were Caucasian. One hundred eighty nine (189) tolvaptan-treated patients had a serum sodium <130 mEq/L, and 52 patients had a serum sodium less than 125 mEq/L. Hyponatremia was attributed to cirrhosis in 17% of patients, heart failure in 68% and SIADH/other in 16%. Of these patients, 223 were treated with the recommended dose titration (15 mg titrated to 60 mg as needed to raise serum sodium).
Overall, over 4,000 patients have been treated with oral doses of tolvaptan in open-label or placebo-controlled clinical trials. Approximately 650 of these patients had hyponatremia; approximately 219 of these hyponatremic patients were treated with tolvaptan for 6 months or more.
The most common adverse reactions (incidence ≥5% more than placebo) seen in two 30‑day, double-blind, placebo-controlled hyponatremia trials in which tolvaptan was administered in titrated doses (15 mg to 60 mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia. In these trials, 10% (23/223) of tolvaptan-treated patients discontinued treatment because of an adverse event, compared to 12% (26/220) of placebo-treated patients; no adverse reaction resulting in discontinuation of trial medication occurred at an incidence of greater than 1% in tolvaptan-treated patients.
Table 1 lists the adverse reactions reported in tolvaptan-treated patients with hyponatremia (serum sodium <135 mEq/L) and at a rate at least 2% greater than placebo-treated patients in two 30‑day, double-blind, placebo-controlled trials. In these studies, 223 patients were exposed to tolvaptan (starting dose 15 mg, titrated to 30 and 60 mg as needed to raise serum sodium). Adverse events resulting in death in these trials were 6% in tolvaptan-treated-patients and 6% in placebo-treated patients.
In a subgroup of patients with hyponatremia (N = 475, serum sodium <135 mEq/L) enrolled in a double-blind, placebo-controlled trial (mean duration of treatment was 9 months) of patients with worsening heart failure, the following adverse reactions occurred in tolvaptan-treated patients at a rate at least 2% greater than placebo: mortality (42% tolvaptan, 38% placebo), nausea (21% tolvaptan, 16% placebo), thirst (12% tolvaptan, 2% placebo), dry mouth (7% tolvaptan, 2% placebo) and polyuria or pollakiuria (4% tolvaptan, 1% placebo).
Gastrointestinal bleeding in patients with cirrhosis
In patients with cirrhosis treated with tolvaptan in the hyponatremia trials, gastrointestinal bleeding was reported in 6 out of 63 (10%) tolvaptan-treated patients and 1 out of 57 (2%) placebo treated patients.
The following adverse reactions occurred in <2% of hyponatremic patients treated with Tolvaptan and at a rate greater than placebo in double-blind placebo-controlled trials (N = 607 tolvaptan; N = 518 placebo) or in <2% of patients in an uncontrolled trial of patients with hyponatremia (N = 111) and are not mentioned elsewhere in the label.
Blood and Lymphatic System Disorders: Disseminated intravascular coagulation
Cardiac Disorders: Intracardiac thrombus, ventricular fibrillation
Investigations: Prothrombin time prolonged
Gastrointestinal Disorders: Ischemic colitis
Metabolism and Nutrition Disorders: Diabetic ketoacidosis
Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis
Nervous System: Cerebrovascular accident
Renal and Urinary Disorders: Urethral hemorrhage
Reproductive System and Breast Disorders (female): Vaginal hemorrhage
Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure
Vascular disorder: Deep vein thrombosis
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Tolvaptan. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Neurologic: Osmotic demyelination syndrome
Investigations: Hypernatremia
Removal of excess free body water increases serum osmolality and serum sodium concentrations. All patients treated with tolvaptan, especially those whose serum sodium levels become normal, should continue to be monitored to ensure serum sodium remains within normal limits. If hypernatremia is observed, management may include dose decreases or interruption of tolvaptan treatment, combined with modification of free-water intake or infusion. During clinical trials of hyponatremic patients, hypernatremia was reported as an adverse event in 0.7% of patients receiving tolvaptan vs. 0.6% of patients receiving placebo; analysis of laboratory values demonstrated an incidence of hypernatremia of 1.7% in patients receiving tolvaptan vs. 0.8% in patients receiving placebo.
Immune System Disorders: Hypersensitivity reactions including anaphylactic shock and rash generalized .
# Drug Interactions
- Effects of Drugs on Tolvaptan
- Ketoconazole and Other Strong CYP 3A Inhibitors
- Tolvaptan is metabolized primarily by CYP 3A. Ketoconazole is a strong inhibitor of CYP 3A and also an inhibitor of P-gp. Co-administration of Tolvaptan and ketoconazole 200 mg daily results in a 5‑fold increase in exposure to tolvaptan. Co-administration of Tolvaptan with 400 mg ketoconazole daily or with other strong CYP 3A inhibitors (e.g., clarithromycin, itraconazole, telithromycin, saquinavir, nelfinavir, ritonavir and nefazodone) at the highest labeled dose would be expected to cause an even greater increase in tolvaptan exposure. Thus, Tolvaptan and strong CYP 3A inhibitors should not be co-administered .
- Moderate CYP 3A Inhibitors
- The impact of moderate CYP 3A inhibitors (e.g., erythromycin, fluconazole, aprepitant, diltiazem and verapamil) on the exposure to co-administered tolvaptan has not been assessed. A substantial increase in the exposure to tolvaptan would be expected when Tolvaptan is co-administered with moderate CYP 3A inhibitors. Co-administration of Tolvaptan with moderate CYP3A inhibitors should therefore generally be avoided .
- Grapefruit Juice
- Co-administration of grapefruit juice and Tolvaptan results in a 1.8‑fold increase in exposure to tolvaptan .
- P-gp Inhibitors
- Reduction in the dose of Tolvaptan may be required in patients concomitantly treated with P-gp inhibitors, such as e.g., cyclosporine, based on clinical response
- Rifampin and Other CYP 3A Inducers
- Rifampin is an inducer of CYP 3A and P-gp. Co-administration of rifampin and Tolvaptan reduces exposure to tolvaptan by 85%. Therefore, the expected clinical effects of Tolvaptan in the presence of rifampin and other inducers (e.g., rifabutin, rifapentin, barbiturates, phenytoin, carbamazepine and St. John's Wort) may not be observed at the usual dose levels of Tolvaptan. The dose of Tolvaptan may have to be increased .
- Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide
- Co-administration of lovastatin, digoxin, furosemide, and hydrochlorothiazide with Tolvaptan has no clinically relevant impact on the exposure to tolvaptan.
- Effects of Tolvaptan on Other Drugs
- Digoxin
- Digoxin is a P-gp substrate. Co-administration of Tolvaptan with digoxin increased digoxin AUC by 20% and Cmax by 30%.
- Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide
- Co-administration of tolvaptan does not appear to alter the pharmacokinetics of warfarin, furosemide, hydrochlorothiazide, or amiodarone (or its active metabolite, desethylamiodarone) to a clinically significant degree.
- Lovastatin
- Tolvaptan is a weak inhibitor of CYP 3A. Co-administration of lovastatin and Tolvaptan increases the exposure to lovastatin and its active metabolite lovastatin-β hydroxyacid by factors of 1.4 and 1.3, respectively. This is not a clinically relevant change.
Pharmacodynamic Interactions
Tolvaptan produces a greater 24 hour urine volume/excretion rate than does furosemide or hydrochlorothiazide. Concomitant administration of tolvaptan with furosemide or hydrochlorothiazide results in a 24 hour urine volume/excretion rate that is similar to the rate after tolvaptan administration alone.
Although specific interaction studies were not performed, in clinical studies tolvaptan was used concomitantly with beta-blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics. Adverse reactions of hyperkalemia were approximately 1-2% higher when tolvaptan was administered with angiotensin receptor blockers, angiotensin converting enzyme inhibitors and potassium sparing diuretics compared to administration of these medications with placebo. Serum potassium levels should be monitored during concomitant drug therapy.
As a V2-receptor antagonist, tolvaptan may interfere with the V2-agonist activity of desmopressin (dDAVP). In a male subject with mild Von Willebrand (vW) disease, intravenous infusion of dDAVP 2 hours after administration of oral tolvaptan did not produce the expected increases in vW Factor Antigen or Factor VIII activity. It is not recommended to administer Tolvaptan with a V2-agonist.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well controlled studies of Tolvaptan use in pregnant women. In animal studies, cleft palate, brachymelia, microphthalmia, skeletal malformations, decreased fetal weight, delayed fetal ossification, and embryo-fetal death occurred. Tolvaptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In embryo-fetal development studies, pregnant rats and rabbits received oral tolvaptan during organogenesis. Rats received 2 to 162 times the maximum recommended human dose (MRHD) of tolvaptan (on a body surface area basis). Reduced fetal weights and delayed fetal ossification occurred at 162 times the MRHD. Signs of maternal toxicity (reduction in body weight gain and food consumption) occurred at 16 and 162 times the MRHD. When pregnant rabbits received oral tolvaptan at 32 to 324 times the MRHD (on a body surface area basis), there were reductions in maternal body weight gain and food consumption at all doses, and increased abortions at the mid and high doses (about 97 and 324 times the MRHD). At 324 times the MRHD, there were increased rates of embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations .
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolvaptan in women who are pregnant.
### Labor and Delivery
The effect of Tolvaptan on labor and delivery in humans is unknown.
### Nursing Mothers
It is not known whether Tolvaptan is excreted into human milk. Tolvaptan is excreted into the milk of lactating rats. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Tolvaptan, a decision should be made to discontinue nursing or Tolvaptan, taking into consideration the importance of Tolvaptan to the mother.
### Pediatric Use
Safety and effectiveness of Tolvaptan in pediatric patients have not been established.
### Geriatic Use
Of the total number of hyponatremic subjects treated with Tolvaptan in clinical studies, 42% were 65 and over, while 19% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Increasing age has no effect on tolvaptan plasma concentrations.
### Gender
There is no FDA guidance on the use of Tolvaptan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tolvaptan with respect to specific racial populations.
### Renal Impairment
No dose adjustment is necessary based on renal function. There are no clinical trial data in patients with CrCl <10 mL/min, and, because drug effects on serum sodium levels are likely lost at very low levels of renal function, use in patients with a CrCl <10 mL/min is not recommended. No benefit can be expected in patients who are anuric .
### Hepatic Impairment
Moderate and severe hepatic impairment do not affect exposure to tolvaptan to a clinically relevant extent. Avoid use of tolvaptan in patients with underlying liver disease.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tolvaptan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tolvaptan in patients who are immunocompromised.
### Use in Patients with Congestive Heart Failure
The exposure to tolvaptan in patients with congestive heart failure is not clinically relevantly increased. No dose adjustment is necessary.
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA Package Insert for Tolvaptan contains no information regarding drug monitoring.
# IV Compatibility
FDA Package Insert for Tolvaptan contains no information regarding IV compatibility.
# Overdosage
Single oral doses up to 480 mg and multiple doses up to 300 mg once daily for 5 days have been well tolerated in studies in healthy subjects. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia.
The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. No mortality was observed in rats or dogs following single oral doses of 2000 mg/kg (maximum feasible dose). A single oral dose of 2000 mg/kg was lethal in mice, and symptoms of toxicity in affected mice included decreased locomotor activity, staggering gait, tremor and hypothermia.
If overdose occurs, estimation of the severity of poisoning is an important first step. A thorough history and details of overdose should be obtained, and a physical examination should be performed. The possibility of multiple drug involvement should be considered.
Treatment should involve symptomatic and supportive care, with respiratory, ECG and blood pressure monitoring and water/electrolyte supplements as needed. A profuse and prolonged aquaresis should be anticipated, which, if not matched by oral fluid ingestion, should be replaced with intravenous hypotonic fluids, while closely monitoring electrolytes and fluid balance.
ECG monitoring should begin immediately and continue until ECG parameters are within normal ranges. Dialysis may not be effective in removing tolvaptan because of its high binding affinity for human plasma protein (>99%). Close medical supervision and monitoring should continue until the patient recovers.
# Pharmacology
## Mechanism of Action
Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan affinity for the V2-receptor is 29 times greater than for the V1a-receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. Urinary excretion of sodium and potassium and plasma potassium concentrations are not significantly changed. Tolvaptan metabolites have no or weak antagonist activity for human V2-receptors compared with tolvaptan.
Plasma concentrations of native AVP may increase (avg. 2-9 pg/mL) with tolvaptan administration.
## Structure
Tolvaptan is (±)-4'-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-o-tolu-m-toluidide. The empirical formula is C26H25ClN2O3. Molecular weight is 448.94. The chemical structure is:
Tolvaptan tablets for oral use contain 15 mg or 30 mg of tolvaptan. Inactive ingredients include corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C Blue No. 2 Aluminum Lake as colorant.
## Pharmacodynamics
In healthy subjects receiving a single dose of Tolvaptan 60 mg, the onset of the aquaretic and sodium increasing effects occurs within 2 to 4 hours post-dose. A peak effect of about a 6 mEq increase in serum sodium and about 9 mL/min increase in urine excretion rate is observed between 4 and 8 hours post-dose; thus, the pharmacological activity lags behind the plasma concentrations of tolvaptan. About 60% of the peak effect on serum sodium is sustained at 24 hours post-dose, but the urinary excretion rate is no longer elevated by this time. Doses above 60 mg tolvaptan do not increase aquaresis or serum sodium further. The effects of tolvaptan in the recommended dose range of 15 to 60 mg once daily appear to be limited to aquaresis and the resulting increase in sodium concentration.
In a parallel-arm, double-blind (for tolvaptan and placebo), placebo- and positive-controlled, multiple dose study of the effect of tolvaptan on the QTc interval, 172 healthy subjects were randomized to tolvaptan 30 mg, tolvaptan 300 mg, placebo, or moxifloxacin 400 mg once daily. At both the 30 mg and 300 mg doses, no significant effect of administering tolvaptan on the QTc interval was detected on Day 1 and Day 5. At the 300 mg dose, peak tolvaptan plasma concentrations were approximately 4‑fold higher than the peak concentrations following a 30 mg dose. Moxifloxacin increased the QT interval by 12 ms at 2 hours after dosing on Day 1 and 17 ms at 1 hour after dosing on Day 5, indicating that the study was adequately designed and conducted to detect tolvaptan's effect on the QT interval, had an effect been present.
## Pharmacokinetics
In healthy subjects the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been examined. Area under the curve (AUC) increases proportionally with dose. After administration of doses ≥60 mg, however, Cmax increases less than proportionally with dose. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Food does not impact the bioavailability of tolvaptan. In vitro data indicate that tolvaptan is a substrate and inhibitor of P-gp. Tolvaptan is highly plasma protein bound (99%) and distributed into an apparent volume of distribution of about 3 L/kg. Tolvaptan is eliminated entirely by non-renal routes and mainly, if not exclusively, metabolized by CYP 3A. After oral dosing, clearance is about 4 mL/min/kg and the terminal phase half-life is about 12 hours. The accumulation factor of tolvaptan with the once-daily regimen is 1.3 and the trough concentrations amount to ≤16% of the peak concentrations, suggesting a dominant half-life somewhat shorter than 12 hours. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.
In patients with hyponatremia of any origin the clearance of tolvaptan is reduced to about 2 mL/min/kg. Moderate or severe hepatic impairment or congestive heart failure decrease the clearance and increase the volume of distribution of tolvaptan, but the respective changes are not clinically relevant. Exposure and response to tolvaptan in subjects with creatinine clearance ranging between 79 and 10 mL/min and patients with normal renal function are not different.
In a study in patients with creatinine clearances ranging from 10-124 mL/min administered a single dose of 60 mg tolvaptan, AUC and Cmax of plasma tolvaptan were less than doubled in patients with severe renal impairment relative to the controls. The peak increase in serum sodium was 5-6 mEq/L, regardless of renal function, but the onset and offset of tolvaptan's effect on serum sodium were slower in patients with severe renal impairment .
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
Up to two years of oral administration of tolvaptan to male and female rats at doses up to 1000 mg/kg/day (162 times the maximum recommended human dose [MRHD] on a body surface area basis), to male mice at doses up to 60 mg/kg/day (5 times the MRHD) and to female mice at doses up to 100 mg/kg/day (8 times the MRHD) did not increase the incidence of tumors.
Tolvaptan tested negative for genotoxicity in in vitro (bacterial reverse mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells) and in vivo (rat micronucleus assay) test systems.
In a fertility study in which male and female rats were orally administered tolvaptan at 100, 300 or 1000 mg/kg/day, the highest dose level was associated with significantly fewer corpora lutea and implants than control.
## Reproductive and Developmental Toxicology
In pregnant rats, oral administration of tolvaptan at 10, 100 and 1000 mg/kg/day during organogenesis was associated with a reduction in maternal body weight gain and food consumption at 100 and 1000 mg/kg/day, and reduced fetal weight and delayed ossification of fetuses at 1000 mg/kg/day (162 times the MRHD on a body surface area basis). Oral administration of tolvaptan at 100, 300 and 1000 mg/kg/day to pregnant rabbits during organogenesis was associated with reductions in maternal body weight gain and food consumption at all doses, and abortions at mid- and high-doses. At 1000 mg/kg/day (324 times the MRHD), increased incidences of embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia and skeletal malformations were observed. There are no adequate and well-controlled studies of Tolvaptan in pregnant women. Tolvaptan should be used in pregnancy only if the potential benefit justifies the risk to the fetus.
# Clinical Studies
## Hyponatremia
In two double-blind, placebo-controlled, multi-center studies (SALT-1 and SALT-2), a total of 424 patients with euvolemic or hypervolemic hyponatremia (serum sodium <135 mEq/L) resulting from a variety of underlying causes (heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone [SIADH] and others) were treated for 30 days with tolvaptan or placebo, then followed for an additional 7 days after withdrawal. Symptomatic patients, patients likely to require saline therapy during the course of therapy, patients with acute and transient hyponatremia associated with head trauma or postoperative state and patients with hyponatremia due to primary polydipsia, uncontrolled adrenal insufficiency or uncontrolled hypothyroidism were excluded. Patients were randomized to receive either placebo (N = 220) or tolvaptan (N = 223) at an initial oral dose of 15 mg once daily. The mean serum sodium concentration at study entry was 129 mEq/L. Fluid restriction was to be avoided if possible during the first 24 hours of therapy to avoid overly rapid correction of serum sodium, and during the first 24 hours of therapy 87% of patients had no fluid restriction. Thereafter, patients could resume or initiate fluid restriction (defined as daily fluid intake of ≤1.0 liter/day) as clinically indicated.
The dose of tolvaptan could be increased at 24 hour intervals to 30 mg once daily, then to 60 mg once daily, until either the maximum dose of 60 mg or normonatremia (serum sodium >135 mEq/L) was reached. Serum sodium concentrations were determined at 8 hours after study drug initiation and daily up to 72 hours, within which time titration was typically completed. Treatment was maintained for 30 days with additional serum sodium assessments on Days 11, 18, 25 and 30. On the day of study discontinuation, all patients resumed previous therapies for hyponatremia and were reevaluated 7 days later. The primary endpoint for these studies was the average daily AUC for change in serum sodium from baseline to Day 4 and baseline to Day 30 in patients with a serum sodium less than 135 mEq/L. Compared to placebo, tolvaptan caused a statistically greater increase in serum sodium (p <0.0001) during both periods in both studies (see Table 2). For patients with a serum sodium of <130 mEq/L or <125 mEq/L, the effects at Day 4 and Day 30 remained significant (see Table 2). This effect was also seen across all disease etiology subsets (e.g., CHF, cirrhosis, SIADH/other).
In patients with hyponatremia (defined as <135 mEq/L), serum sodium concentration increased to a significantly greater degree in tolvaptan-treated patients compared to placebo-treated patients as early as 8 hours after the first dose, and the change was maintained for 30 days. The percentage of patients requiring fluid restriction (defined as ≤1 L/day at any time during the treatment period) was also significantly less (p =0.0017) in the tolvaptan-treated group (30/215, 14%) as compared with the placebo-treated group (51/206, 25%).
Figure 1 shows the change from baseline in serum sodium by visit in patients with serum sodium <135 mEq/L. Within 7 days of tolvaptan discontinuation, serum sodium concentrations in tolvaptan-treated patients declined to levels similar to those of placebo-treated patients.
In the open-label study SALTWATER, 111 patients, 94 of them hyponatremic (serum sodium <135 mEq/L), previously on tolvaptan or placebo therapy were given tolvaptan as a titrated regimen (15 to 60 mg once daily) after having returned to standard care for at least 7 days. By this time, their baseline mean serum sodium concentration had fallen to between their original baseline and post-placebo therapy level. Upon initiation of therapy, average serum sodium concentrations increased to approximately the same levels as observed for those previously treated with tolvaptan, and were sustained for at least a year. Figure 3 shows results from 111 patients enrolled in the SALTWATER Study.
## Heart Failure
In a phase 3 double-blind, placebo-controlled study (EVEREST), 4133 patients with worsening heart failure were randomized to tolvaptan or placebo as an adjunct to standard of care. Long-term tolvaptan treatment (mean duration of treatment of 0.75 years) had no demonstrated effect, either favorable or unfavorable, on all-cause mortality [HR (95% CI): 0.98 (0.9, 1.1)] or the combined endpoint of CV mortality or subsequent hospitalization for worsening HF [HR (95% CI): 1.0 (0.9, 1.1)].
# How Supplied
How Supplied
Tolvaptan® (tolvaptan) tablets are available in the following strengths and packages.
Tolvaptan 15 mg tablets are non-scored, blue, triangular, shallow-convex, debossed with "OTSUKA" and "15" on one side.
Blister of 10 NDC 59148-020-50
Tolvaptan 30 mg tablets are non-scored, blue, round, shallow-convex, debossed with "OTSUKA" and "30" on one side.
Blister of 10 NDC 59148-021-50
## Storage
Store at 25 °C (77 °F), excursions permitted between 15 °C and 30 °C (59 °F to 86 °F) [see USP controlled Room Temperature].
Keep out of reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
As a part of patient counseling, healthcare providers must review the Tolvaptan Medication Guide with every patient .
## Concomitant Medication
Advise patients to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs since there is a potential for interactions.
Strong and Moderate CYP 3A inhibitors and P-gp inhibitors
Advise patients to inform their physician if they use strong (e.g., ketoconazole, itraconazole, clarithromycin, telithromycin, nelfinavir, saquinavir, indinavir, ritonavir) or moderate CYP 3A inhibitors (e.g., aprepitant, erythromycin, diltiazem, verapamil, fluconazole) or P-gp inhibitors (e.g., cyclosporine) .
## Nursing
Advise patients not to breastfeed an infant if they are taking Tolvaptan .
Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850
Tolvaptan is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan
© 2014 Otsuka Pharmaceutical Co., Ltd.
## FDA-Approved Medication Guide
MEDICATION GUIDE
Tolvaptan® (sam-sca)
tolvaptan
Tablets
Read the Medication Guide that comes with Tolvaptan before you take it and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. Share this important information with members of your household.
# Precautions with Alcohol
Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable.
# Brand Names
Tolvaptan
# Look-Alike Drug Names
There is limited information about the look-alike names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tolvaptan | |
ab07872297c044708bf86f56df2ef89cbb647ca7 | wikidoc | Tom Mason | Tom Mason
Dr. Thomas Robert "Tom" Mason (April 29, 1920 – December 1, 1980) was a chiropractor who lived in Los Angeles in the 1950s. He is best known as the stand-in for the then recently deceased Bela Lugosi in Edward D. Wood, Jr.'s infamous movie Plan 9 From Outer Space. Dr. Mason, who was taller than and bore a questionable physical resemblance to Lugosi, hunched over with a cape held over his face in all of his scenes.
Dr. Mason appeared in and helped to produce a couple of Wood's other movies, Night of the Ghouls (in which he was allowed to show his face) and Final Curtain, after which his career in showbiz ended. He died in 1980.
# In popular culture
Dr. Mason was portrayed by actor Ned Bellamy in the 1994 in film Ed Wood. | Tom Mason
Template:Infobox Actor
Dr. Thomas Robert "Tom" Mason (April 29, 1920 – December 1, 1980) was a chiropractor who lived in Los Angeles in the 1950s. He is best known as the stand-in for the then recently deceased Bela Lugosi in Edward D. Wood, Jr.'s infamous movie Plan 9 From Outer Space. Dr. Mason, who was taller than and bore a questionable physical resemblance to Lugosi, hunched over with a cape held over his face in all of his scenes.[1][2]
Dr. Mason appeared in and helped to produce a couple of Wood's other movies, Night of the Ghouls (in which he was allowed to show his face) and Final Curtain, after which his career in showbiz ended. He died in 1980.
# In popular culture
Dr. Mason was portrayed by actor Ned Bellamy in the 1994 in film Ed Wood.[3] | https://www.wikidoc.org/index.php/Tom_Mason | |
6a1e4e92ba18252f64984d0ab2995bb7b74ea7b4 | wikidoc | Tormentil | Tormentil
Tormentil (Potentilla erecta) is a herbaceous perennial belonging to the rose family (Rosaceae), also known as "septifoil".
It is a low, clumb-forming plant with slender, procumbent to arcuately upright stalks, growing 10-30 cm. tall and with non-rooting runners It grows wild all over Asia and northern Europe, mostly in a wide variety of habitats, such as clearings, meadows, sandy soils and dunes.
This plant is flowering from May to August/September. There is one yellow, 7-11 mm wide flower, growing at the tip of a long stalk. There are almost always four notched petals, each with a length between 3 and 6 mm. Four petals are rather uncommon in the rose family. The petals are somewhat longer than the sepals. There are 20-25 stamens.
The glossy leaves are pinnately compound. The radical leaves have a long petiole, while the leaves on the stalks are usually sessile and have sometimes shorter petioles. Each leaf consists of three obovate leaflets with serrate leaf margins. The stipules are leaflike and palmately lobed.
The rhizomatous root is thick. A lotion prepared from the dried root has been used both as medicine to treat a number of ailments (to stop bleedings or against diarrhea), for food in times of need and to dye leather red.
There are 2-8 dry, inedible fruits.
# Gallery
- File:Potentilla erecta.JPG
- Common Tormentil (on Faroese stamp
Common Tormentil (on Faroese stamp | Tormentil
Tormentil (Potentilla erecta) is a herbaceous perennial belonging to the rose family (Rosaceae), also known as "septifoil"[1].
It is a low, clumb-forming plant with slender, procumbent to arcuately upright stalks, growing 10-30 cm. tall and with non-rooting runners It grows wild all over Asia and northern Europe, mostly in a wide variety of habitats, such as clearings, meadows, sandy soils and dunes.
This plant is flowering from May to August/September. There is one yellow, 7-11 mm wide flower, growing at the tip of a long stalk. There are almost always four notched petals, each with a length between 3 and 6 mm. Four petals are rather uncommon in the rose family. The petals are somewhat longer than the sepals. There are 20-25 stamens.
The glossy leaves are pinnately compound. The radical leaves have a long petiole, while the leaves on the stalks are usually sessile and have sometimes shorter petioles. Each leaf consists of three obovate leaflets with serrate leaf margins. The stipules are leaflike and palmately lobed.
The rhizomatous root is thick. A lotion prepared from the dried root has been used both as medicine to treat a number of ailments (to stop bleedings or against diarrhea), for food in times of need and to dye leather red.
There are 2-8 dry, inedible fruits.
# Gallery
- File:Potentilla erecta.JPG
- Common Tormentil (on Faroese stamp
Common Tormentil (on Faroese stamp | https://www.wikidoc.org/index.php/Tormentil | |
41f12452bab428153aa9d543127addb2e952a508 | wikidoc | Toxidrome | Toxidrome
# Overview
A toxidrome (portmanteau of toxic and syndrome) is a syndrome caused by a dangerous level of toxins in the body. Common symptoms include dizziness, disorientation, nausea, vomiting, and oscillopsia. A toxidrome may indicate a medical emergency requiring treatment at a poison control center. Aside from poisoning, a systemic infection may also lead to a toxidrome.
# Classification
The most common toxidromes are classified as:
- Anticholinergic
- Cholinergic
- Hallucinogenic
- Opiate
- Sedative/hypnotic
- Sympathomimetic
## Anticholinergic Toxidrome
The symptoms of an anticholinergic toxidrome include blurred vision, choreoathetosis, coma, decreased bowel sounds, delirium, dry skin, fever, flushing, hallucinations, ileus, memory loss, mydriasis (dilated pupils), myoclonus, psychosis, seizures, and urinary retention. Complications include hypertension, hyperthermia, and tachycardia. Substances that may cause this toxidrome include antihistamines, atropine, benztropine, datura, tricyclic antidepressants, and scopolamine.
Due to the characteristic appearance and behavior of patients with this toxidrome, they are colloquially described as "Hot as a Hare, Dry as a Bone, Red as a Beet, Mad as a Hatter, Blind as a Bat".
## Cholinergic Toxidrome
The symptoms of a cholinergic toxidrome include bronchorrhea, confusion, defecation, diaphoresis, diarrhea, emesis, lacrimation, miosis, muscle fasciculations, salivation, seizures, urination, and weakness. Complications include bradycardia, hypothermia, and tachypnea. Substances that may cause this toxidrome include carbamates, mushrooms, and organophosphates.
A mnemonic device to remember the signs/symptoms of organophosphate toxicity is SLUDGE- Salivation, Lacrimation, Urination, Defecation, Gastrointestinal distress, and Emesis.
## Hallucinogenic Toxidrome
The symptoms of a hallucinogenic toxidrome include disorientation, hallucinations, hyperactive bowel sounds, panic, and seizures. Complications include hypertension, tachycardia, and tachypnea. Substances that may cause this toxidrome include amphetamines, cocaine, and phencyclidine.
## Opiate Toxidrome
The symptoms of an opiate toxidrome include altered mental states, miosis, shock, and unresponsiveness. Complications include bradycardia, hypotension, hypothermia, shallow respirations, and a slow respiratory rate. Substances that may cause this toxidrome include dextromethorphan, opiates, and propoxyphene.
## Sedative/hypnotic Toxidrome
The symptoms of a sedative/hypnotic toxidrome include ataxia, blurred vision, coma, confusion, delirium, deterioration of central nervous system functions, diplopia, dysesthesias, hallucinations, nystagmus, paresthesias, sedation, slurred speech, and stupor. Apnea is a potential complication. Substances that may cause this toxidrome include anticonvulsants, barbiturates, benzodiazepines, and ethanol.
## Sympathomimetic Toxidrome
The symptoms of a sympathomimetic toxidrome include anxiety, delusions, diaphoresis, hyperreflexia, mydriasis, paranoia, piloerection, and seizures. Complications include bradycardia, hypertension, and tachycardia. Substances that may cause this toxidrome include albuterol, amphetamines, cocaine, ephedrine (Ma Huang), methamphetamine, phenylpropanolamine (PPA's), and pseudoephedrine. | Toxidrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A toxidrome (portmanteau of toxic and syndrome) is a syndrome caused by a dangerous level of toxins in the body. Common symptoms include dizziness, disorientation, nausea, vomiting, and oscillopsia. A toxidrome may indicate a medical emergency requiring treatment at a poison control center. Aside from poisoning, a systemic infection may also lead to a toxidrome.
# Classification
The most common toxidromes are classified as:
- Anticholinergic
- Cholinergic
- Hallucinogenic
- Opiate
- Sedative/hypnotic
- Sympathomimetic
## Anticholinergic Toxidrome
The symptoms of an anticholinergic toxidrome include blurred vision, choreoathetosis, coma, decreased bowel sounds, delirium, dry skin, fever, flushing, hallucinations, ileus, memory loss, mydriasis (dilated pupils), myoclonus, psychosis, seizures, and urinary retention. Complications include hypertension, hyperthermia, and tachycardia. Substances that may cause this toxidrome include antihistamines, atropine, benztropine, datura, tricyclic antidepressants, and scopolamine.
Due to the characteristic appearance and behavior of patients with this toxidrome, they are colloquially described as "Hot as a Hare, Dry as a Bone, Red as a Beet, Mad as a Hatter, Blind as a Bat".
## Cholinergic Toxidrome
The symptoms of a cholinergic toxidrome include bronchorrhea, confusion, defecation, diaphoresis, diarrhea, emesis, lacrimation, miosis, muscle fasciculations, salivation, seizures, urination, and weakness. Complications include bradycardia, hypothermia, and tachypnea. Substances that may cause this toxidrome include carbamates, mushrooms, and organophosphates.
A mnemonic device to remember the signs/symptoms of organophosphate toxicity is SLUDGE- Salivation, Lacrimation, Urination, Defecation, Gastrointestinal distress, and Emesis.
## Hallucinogenic Toxidrome
The symptoms of a hallucinogenic toxidrome include disorientation, hallucinations, hyperactive bowel sounds, panic, and seizures. Complications include hypertension, tachycardia, and tachypnea. Substances that may cause this toxidrome include amphetamines, cocaine, and phencyclidine.
## Opiate Toxidrome
The symptoms of an opiate toxidrome include altered mental states, miosis, shock, and unresponsiveness. Complications include bradycardia, hypotension, hypothermia, shallow respirations, and a slow respiratory rate. Substances that may cause this toxidrome include dextromethorphan, opiates, and propoxyphene.
## Sedative/hypnotic Toxidrome
The symptoms of a sedative/hypnotic toxidrome include ataxia, blurred vision, coma, confusion, delirium, deterioration of central nervous system functions, diplopia, dysesthesias, hallucinations, nystagmus, paresthesias, sedation, slurred speech, and stupor. Apnea is a potential complication. Substances that may cause this toxidrome include anticonvulsants, barbiturates, benzodiazepines, and ethanol.
## Sympathomimetic Toxidrome
The symptoms of a sympathomimetic toxidrome include anxiety, delusions, diaphoresis, hyperreflexia, mydriasis, paranoia, piloerection, and seizures. Complications include bradycardia, hypertension, and tachycardia. Substances that may cause this toxidrome include albuterol, amphetamines, cocaine, ephedrine (Ma Huang), methamphetamine, phenylpropanolamine (PPA's), and pseudoephedrine. | https://www.wikidoc.org/index.php/Toxidrome | |
6a48204cb467174e123ce9547be865f20fd88da4 | wikidoc | Trabecula | Trabecula
A trabecula (plural trabeculae. From Latin for small beam.) is a small, often microscopic, tissue element in the form of a small beam, strut or rod, generally having a mechanical function, and usually but not necessarily composed of dense collagenous tissue.
On histological section, a trabecula can look like a septum, but in three dimensions they are topologically distinct, with trabeculae being roughly rod or pillar-shaped and septa being sheet-like.
Trabeculae are usually composed of dense fibrous tissue, i.e. mainly of collagen, and in most cases provide mechanical strengthening or stiffening to a soft solid organ, such as the spleen.
They can be composed of other materials, such as bone or muscle.
When crossing fluid-filled spaces, trabeculae may have the function of resisting tension (as in the penis) or providing a cell filter (as in the eye.)
Multiple perforations in a septum may reduce it to a collection of trabeculae, as happens to the walls of some of the pulmonary alveoli in emphysema.
# Examples of trabeculae
- trabeculae of bone
- trabeculae of corpora cavernosa of penis
- trabeculae of corpus spongiosum of penis
- trabecular meshwork of the eye
- trabeculae of spleen
- trabeculae carneae
- septomarginal trabecula
# Etymology
Diminutive form of Latin trabs, which means a beam or bar. In the 19th century, the neologism trabeculum (with an assumed plural of trabecula) became popular, but is less etymologically correct. Trabeculum persists in some countries as a synonym for the trabecular meshwork of the eye, but this can be considered poor usage on the grounds of both etymology and descriptive accuracy. | Trabecula
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A trabecula (plural trabeculae. From Latin for small beam.) is a small, often microscopic, tissue element in the form of a small beam, strut or rod, generally having a mechanical function, and usually but not necessarily composed of dense collagenous tissue.
On histological section, a trabecula can look like a septum, but in three dimensions they are topologically distinct, with trabeculae being roughly rod or pillar-shaped and septa being sheet-like.
Trabeculae are usually composed of dense fibrous tissue, i.e. mainly of collagen, and in most cases provide mechanical strengthening or stiffening to a soft solid organ, such as the spleen.
They can be composed of other materials, such as bone or muscle.
When crossing fluid-filled spaces, trabeculae may have the function of resisting tension (as in the penis) or providing a cell filter (as in the eye.)
Multiple perforations in a septum may reduce it to a collection of trabeculae, as happens to the walls of some of the pulmonary alveoli in emphysema.
# Examples of trabeculae
- trabeculae of bone
- trabeculae of corpora cavernosa of penis
- trabeculae of corpus spongiosum of penis
- trabecular meshwork of the eye
- trabeculae of spleen
- trabeculae carneae
- septomarginal trabecula
# Etymology
Diminutive form of Latin trabs, which means a beam or bar. In the 19th century, the neologism trabeculum (with an assumed plural of trabecula) became popular, but is less etymologically correct. Trabeculum persists in some countries as a synonym for the trabecular meshwork of the eye, but this can be considered poor usage on the grounds of both etymology and descriptive accuracy.
# External links
- Template:EMedicineDictionary
de:Trabekel
Template:WH
Template:WikiDoc Sources
Template:Jb1 | https://www.wikidoc.org/index.php/Trabecula | |
8d5a37b98568a5634afcb5687ed87fccac806b59 | wikidoc | Trans fat | Trans fat
Trans fat is the common name for a type of unsaturated fat with trans isomer fatty acid(s). Trans fats may be monounsaturated or polyunsaturated.
Most trans fats consumed today are industrially created by partially hydrogenating plant oils — a process developed in the early 1900s and first commercialized as Crisco in 1911. The goal of partial hydrogenation is to add hydrogen atoms to unsaturated fats, making them more saturated. These more saturated fats have a higher melting point making them attractive for baking, and extending their shelf-life. Another particular class of trans fats, vaccenic acid occurs in trace amounts in meat and dairy products from ruminants.
Unlike other dietary fats, trans fats are neither required nor beneficial for health. Eating trans fats increases the risk of coronary heart disease.
Trans fat raises your ("bad") LDL cholesterol and lowers your ("good") HDL cholesterol.
Health authorities worldwide recommend that consumption of trans fat be reduced to trace amounts. Trans fats from partially hydrogenated oils are generally considered to be more of a health risk than naturally occurring oils.
Chemically, trans fats are made of the same building blocks as non-trans fats, but have a different arrangement. In trans fatty acid molecules, the hydrogen atoms bonded to pair(s) of doubly bonded carbon atoms (characteristic of all unsaturated fats) are in the trans rather than the cis arrangement. This results in a straight, rather than kinked, shape for the carbon chain, more like the straight chain of a fully saturated fat.
# History
Nobel laureate Paul Sabatier worked in the 1890s to develop the chemistry of hydrogenation which enabled the margarine, oil hydrogenation, and synthetic methanol industries. While Sabatier only considered hydrogenation of vapours, the German chemist Wilhelm Normann showed in 1901 that liquid oils could be hydrogenated, and patented the process in 1902.
During the years 1905 - 1910 Normann built a fat hardening facility in the Herford company. At the same time the invention was extended to a large scale plant in Warrington, England at Joseph Crosfield & Sons, Limited. It took only two years until the hardened fat could be successfully produced in the plant in Warrington, commencing production in the autumn of 1909. The initial year's production was nearly 3000 tonnes.
In 1909, Procter & Gamble acquired the US rights to the Normann patent;
in 1911, they began marketing the first hydrogenated shortening, Crisco (composed largely of partially hydrogenated cottonseed oil). Further success came from the marketing technique of giving away free cookbooks in which every recipe called for Crisco.
Normann's hydrogenation process made it possible to stabilize inexpensive whale oil or fish oil for human consumption, a practice kept secret to avoid consumer distaste.
Production of hydrogenated fats increased steadily until the 1960s as processed vegetable fats replaced animal fats in the US and other western countries. At first, the argument was a financial one due to lower costs; however, advocates also said that the unsaturated trans fats of margarine were healthier than the saturated fats of butter. The Center for Science in the Public Interest (CSPI) campaigned against the use of saturated fats for fast food cooking starting in 1984. When fast food companies replaced the saturated fat with partially hydrogenated unsaturated fats, CSPI's campaign against them ended. While CSPI defended trans fats in their 1987 Nutrition Action newsletter, by 1992 CSPI began to speak against trans fats and is currently strongly against their use.
There were suggestions in the scientific literature as early as 1988 that trans fats could be a cause of the large increase in coronary artery disease. In 1994, it was estimated that trans fats caused 30,000 deaths annually in the US from heart disease.
In January 2007, faced with the prospect of an outright ban on the sale of their product, Crisco was reformulated to meet the US FDA definition of "zero grams trans fats per serving" (that is less than one gram per tablespoon) by boosting the saturation and then cutting the resulting solid with oils. Meanwhile, at the University of Guelph,
Alejandro Marangoni's research group found a way to mix oil, water, monoglycerides and fatty acids to form a "cooking fat" that acts the same way as trans and saturated fats — the stuff that makes baked goods taste so good. The big difference here is Marangoni's process works with "healthier" oils like olive, soybean and canola. He's hoping to get food manufacturers interested in the process this year, as the pressure mounts on the makers of commercial foods to dump trans fats.
# Chemistry
Chemically, fats are large molecules consisting of three fatty acid groups connected to a single glycerol derivative. The term trans fat generally refers to a fat that contains one or more trans fatty acid groups. Fatty acid molecules are essentially long-chain hydrocarbons with a terminal carboxyl group. Fatty acids are characterized as saturated or unsaturated based on the number of hydrogen atoms in the acid. If the molecule contains the maximum possible number of hydrogen atoms, it is said to be saturated; otherwise, it is unsaturated to some degree.
Carbon atoms are tetravalent, forming four covalent bonds with other atoms, while hydrogen atoms bond with only one other atom. In saturated fatty acids, each carbon atom is connected to its two neighbour carbon atoms as well as two hydrogen atoms (see structure diagram, below). In unsaturated fatty acids the carbon atoms that are missing a hydrogen atom are joined by double bonds rather than single bonds (see structure graphic below) so that each carbon atom participates in four bonds.
Hydrogenation of an unsaturated fatty acid refers to the addition of hydrogen atoms to the acid, causing double bonds to become single ones as carbon atoms acquire new hydrogen partners (to maintain four bonds per carbon atom). Full hydrogenation results in a molecule containing the maximum amount of hydrogen (in other words the conversion of an unsaturated fatty acid into a saturated one). Partial hydrogenation results in the addition of hydrogen atoms at some of the empty positions, with a corresponding reduction in the number of double bonds. Commercial hydrogenation is typically partial in order to obtain a malleable fat that is solid at room temperature, but melts upon baking (or consumption).
In most naturally occurring unsaturated fatty acids, the hydrogen atoms are on the same side of the double bonds of the carbon chain (cis' configuration — meaning "on the same side" in Latin). However, partial hydrogenation reconfigures most of the double bonds that do not become chemically saturated, twisting them so that the hydrogen atoms end up on different sides of the chain. This type of configuration is called trans, which means "across" in Latin. The trans conformation is the lower energy form, and is favored in the hydrogenation process.
The same molecule, containing the same number of atoms, with a double bond in the same location, can be either a 'trans or a cis fatty acid depending on the conformation of the double bond. For example, oleic acid and elaidic acid are both unsaturated fatty acids with the chemical formula C9H17C9H17O2. They both have a double bond located midway along the carbon chain. It is the conformation of this bond that sets them apart. The conformation has implications for the physical-chemical properties of the molecule. The trans configuration is straighter, while the cis configuration is noticeably kinked as can be seen from the following three-dimensional representation.
The trans fatty acid elaidic acid has different chemical and physical properties owing to the slightly different bond configuration. Notably, it has a much higher melting point, 45 °C rather than oleic acid's 13.4 °C, due to the ability of the trans molecules to pack more tightly, forming a solid that is more difficult to break apart. It is notably a solid at human body temperatures.
In food production, the goal is not to simply change the configuration of double bonds while maintaining the same ratios of hydrogen to carbon. Instead, the goal is to decrease the number of double bonds and increase the amount of hydrogen in the fatty acid. This changes the consistency of the fatty acid and makes it less prone to rancidity (in which free radicals attack double bonds). Production of trans fatty acids is therefore a side-effect of partial hydrogenation.
Researchers at the United States Department of Agriculture have investigated whether hydrogenation can be achieved without the side effect of trans fat production. They varied the pressure under which the chemical reaction was conducted — applying 1400 kPa (200 psi) of pressure to soybean oil in a 2 litre vessel while heating it to between 140 °C and 170 °C. The standard 140 kPa (20 psi) process of hydrogenation produces a product of about 40% trans fatty acid by weight, compared to about 17% using the high pressure method. Blended with unhydrogenated liquid soybean oil, the high pressure processed oil produced margarine containing 5 to 6% trans fat. Based on current U.S. labelling requirements (see below) the manufacturer could claim the product was free of trans fat. The level of trans fat may also be altered by modification of the temperature and the length of time during hydrogenation.
Trans fat levels may be measured. Measurement techniques include chromatography (by silver ion chromatography on thin layer chromatography plates, or small high performance liquid chromatography columns of silica gel with bonded phenylsulfonic acid groups whose hydrogen atoms have been exchanged for silver ions). The role of silver lies in its ability to form complexes with unsaturated compounds. Gas chromatography and mid-infrared spectroscopy are other methods in use.
# Presence in food
A type of trans fat occurs naturally in the milk and body fat of ruminants (such as cows and sheep) at a level of 2–5% of total fat. Natural trans fats, which include conjugated linoleic acid and vaccenic acid, originate in the rumen of these animals.
Animal-based fats were once the only trans fats consumed, but by far the largest amount of trans fat consumed today is created by the processed food industry as a side-effect of partially hydrogenating unsaturated plant fats (generally vegetable oils). These partially hydrogenated fats have displaced natural solid fats and liquid oils in many areas, notably in the fast food, snack food, fried food and baked good industries.
Partially hydrogenated oils have been used in food for many reasons. Partial hydrogenation increases product shelf life and decreases refrigeration requirements. Because baking requires semi-solid fats to suspend solids at room temperature, partially hydrogenated oils can replace the animal fats traditionally used by bakers (such as butter and lard). They are also an inexpensive alternative to other semi-solid oils such as palm oil. Because partially hydrogenated plant oils can replace animal fats, the resulting products can be consumed (barring other ingredient and preparation violations) by adherents to Kashrut (kosher) and Halal, as well as by adherents to vegetarianism in Buddhism, ahimsa in Jainism and Hinduism, veganism, and other forms of vegetarianism.
Foods containing artificial trans fats formed by partially hydrogenating plant fats may contain up to 45% trans fat compared to their total fat. Baking shortenings generally contain 30% trans fats compared to their total fats, while animal fats from ruminants such as butter contain up to 4%. Those margarines not reformulated to reduce trans fats may contain up to 15% trans fat by weight.
It has been established that trans fats in human milk fluctuate with maternal consumption of trans fat, and that the amount of trans fats in the bloodstream of breastfed infants fluctuates with the amounts found in their milk. Reported percentages of trans fats (compared to total fats) in human milk range from 1% in Spain, 2% in France, 4% in Germany, and 7% in Canada.
Trans fats are also found in shortenings commonly used for deep frying in restaurants. In the past, the decreased rancidity of partially hydrogenated oils meant that they could be reused for a longer time than conventional oils. Recently, however, non-hydrogenated vegetable oils have become available that have lifespans exceeding that of the frying shortenings. As fast food chains routinely use different fats in different locations, trans fat levels in products can have large variation. For example, an analysis of samples of McDonald's french fries collected in 2004 and 2005 found that fries served in New York City contained twice as much trans fat as in Hungary, and 28 times as much trans fat as in Denmark (where trans fats are restricted). At KFC, the pattern was reversed with Hungary's product containing twice the trans fat of the New York product. Even within the US there was variation, with fries in New York containing 30% more trans fat than those from Atlanta.
# Nutritional guidelines
The National Academy of Sciences (NAS) advises the United States and Canadian governments on nutritional science for use in Public policy and product labeling programs. Their 2002 Dietary reference intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids contains their findings and recommendations regarding consumption of trans fat (summary).
Their recommendations are based on two key facts. First, "trans fatty acids are not essential and provide no known benefit to human health", whether of animal or plant origin. Second, while both saturated and trans fats increase levels of LDL cholesterol (so-called bad cholesterol), trans fats also lower levels of HDL cholesterol (good cholesterol); this increases the risk of coronary heart disease (CHD). The NAS is concerned "that dietary trans fatty acids are more deleterious with respect to CHD than saturated fatty acids". This analysis is supported by a 2006 New England Journal of Medicine (NEJM) scientific review that states "from a nutritional standpoint, the consumption of trans fatty acids results in considerable potential harm but no apparent benefit."
Because of these facts and concerns, the NAS has concluded there is no safe level of trans fat consumption. There is no adequate level, recommended daily amount or tolerable upper limit for trans fats. This is because any incremental increase in trans fat intake increases the risk of coronary heart disease.
Despite this concern, the NAS dietary recommendations have not recommended the elimination of trans fat from the diet. This is because trans fat is naturally present in many animal foods in trace quantities, and therefore its removal from ordinary diets might introduce undesirable side effects and nutritional imbalances if proper nutritional planning is not undertaken. The NAS has therefore "recommended that trans fatty acid consumption be as low as possible while consuming a nutritionally adequate diet". Like the NAS, the World Health Organization has tried to balance public health goals with a practical level of trans fat consumption, recommending in 2003 that trans fats be limited to less than 1% of overall energy intake.
The US National Dairy Council has asserted that the trans fats present in animal foods are of a different type than those in partially hydrogenated oils, and do not appear to exhibit the same negative effects. While a recent scientific review agrees with the conclusion (stating that "the sum of the current evidence suggests that the Public health implications of consuming trans fats from ruminant products are relatively limited") it cautions that this may be due to the relatively low consumption of trans fats from animal sources compared to artificial ones.
# Health risks
Partially hydrogenated vegetable oils have been an increasingly significant part of the human diet for about 100 years (particularly so in the latter half of the 20th century), and some deleterious effects of trans fat consumption are scientifically accepted, forming the basis of the health guidelines discussed above.
The exact biochemical methods by which trans fats produce specific health problems are a topic of continuing research. The most prevalent theory is that the human lipase enzyme is specific to the cis configuration. This enzyme can hydrolize the cis double bond, resulting in two lower molecular weight fatty acids that can be further metabolized. The human lipase enzyme is ineffective with the trans configuration, so trans fat remains in the blood stream for a much longer period of time and is more prone to arterial deposition and subsequent plaque formation. While the mechanisms through which trans fats contribute to coronary heart disease are fairly well understood, the mechanism for trans fat's effect on diabetes is still under investigation.
## Coronary heart disease
The primary health risk identified for trans fat consumption is an elevated risk of coronary heart disease (CHD). A comprehensive review of studies of trans fats was published in 2006 in the New England Journal of Medicine that concludes that there is a strong and reliable connection between trans fat consumption and CHD.
The major evidence for the effect of trans fat on CHD comes from the Nurses' Health Study (NHS) — a cohort study that has been following 120,000 female nurses since its inception in 1976. In this study, Hu and colleagues analyzed data from 900 coronary events from the NHS population during 14 years of followup. He determined that a nurse's CHD risk roughly doubled (relative risk of 1.94, CI: 1.43 to 2.61) for each 2% increase in trans fat calories consumed (instead of carbohydrate calories). By contrast, it takes more than a 15% increase in saturated fat calories (instead of carbohydrate calories) to produce a similar increase in risk. Eating non-trans unsaturated fats instead of carbohydrates reduces the risk of CHD rather than increasing it. Hu also reports on the benefits of reducing trans fat consumption. Replacing 2% of food energy from trans fat with non-trans unsaturated fats more than halves the risk of CHD (53%). By comparison, replacing a larger 5% of food energy from saturated fat with non-trans unsaturated fats reduces the risk of CHD by 43%.
Another study considered deaths due to CHD, with consumption of trans fats being linked to an increase in mortality, and consumption of polyunsaturated fats being linked to a decrease in mortality.
There are two accepted tests that measure an individual's risk for coronary heart disease, both blood tests. The first considers ratios of two types of cholesterol, the other the amount of a cell-signalling cytokine called C-reactive protein. The ratio test is more accepted, while the cytokine test may be more powerful but is still being studied. The effect of trans fat consumption has been documented on each as follows:
- Cholesterol ratio: This ratio compares the levels of LDL (so-called "bad" cholesterol) to HDL (so-called "good" cholesterol). Trans fat behaves like saturated fat by raising the level of LDL, but unlike saturated fat it has the additional effect of decreasing levels of HDL. The net increase in LDL/HDL ratio with trans fat is approximately double that due to saturated fat. (Higher ratios are worse.) One randomized crossover study published in 2003 comparing the postprandial effect on blood lipids of (relatively) cis and trans fat rich meals showed that cholesteryl ester transfer (CET) was 28% higher after the trans meal than after the cis meal and that lipoprotein concentrations were enriched in apolipoprotein(a) after the trans meals.
- C-reactive protein (CRP): A study of over 700 nurses showed that those in the highest quartile of trans fat consumption had blood levels of CRP that were 73% higher than those in the lowest quartile.
## Other effects
There are suggestions that the negative consequences of trans fat consumption go beyond the cardiovascular risk. In general, there is much less scientific consensus that eating trans fat specifically increases the risk of other chronic health problems:
- Cancer: There is no scientific consensus that consumption of trans fats significantly increases cancer risks across the board. The American Cancer Society states that a relationship between trans fats and cancer "has not been determined." However, one recent study has found connections between trans fat and prostate cancer.
- Diabetes: There is a growing concern that the risk of type 2 diabetes increases with trans fat consumption. However, consensus has not been reached. For example, one study found that risk is higher for those in the highest quartile of trans fat consumption. Another study has found no diabetes risk once other factors such as total fat intake and BMI were accounted for.
- Obesity: Research indicates that trans fat may increase weight gain and abdominal fat, despite a similar caloric intake. A 6-year experiment revealed that monkeys fed a trans-fat diet gained 7.2% of their body weight, as compared to 1.8% for monkeys on a mono-unsaturated fat diet. Although obesity is frequently linked to trans fat in the popular media, this is generally in the context of eating too many calories; there is no scientific consensus connecting trans fat and obesity.
- Liver Dysfunction: Trans fats are metabolized differently by the liver than other fats and interfere with delta 6 desaturase. Delta 6 desaturase is an enzyme involved in converting essential fatty acids to arachidonic acid and prostaglandins, both of which are important to the functioning of cells.
- Infertility: One 2007 study found, "Each 2% increase in the intake of energy from trans unsaturated fats, as opposed to that from carbohydrates, was associated with a 73% greater risk of ovulatory infertility…".
# Public response and regulation
## International
The international trade in food is standardized in the Codex Alimentarius. Hydrogenated oils and fats come under the scope of Codex Stan 19. Non-dairy fat spreads are covered by Codex Stan 256-2007..
## Australia
The Australian federal government has indicated that it wants to actively pursue a policy of reducing trans fats from fast foods. The former federal assistant health minister, Christopher Pyne, asked fast food outlets to reduce their trans fat usage. A draft plan was proposed, with a September 2007 timetable, in order to reduce reliance on trans fats and saturated fats.
Currently, Australia's food labeling laws do not require trans fats to be shown separately from the total fat content.
## Canada
Canada is one of the largest consumers of trans fats in the world. In November 2004, an opposition day motion seeking a ban similar to Denmark's was introduced by Jack Layton of the New Democratic Party, and passed through the House of Commons by an overwhelming 193-73 vote.
Since December 2005, Health Canada has required that food labels list the amount of trans fat in the nutrition facts section for most foods. Products with less than 0.2 grams of trans fat per serving may be labeled as free of trans fats. These labelling allowances are not widely known, but as an awareness of them develops, controversy over truthful labelling is growing. In Canada, trans fat quantities on labels include naturally occurring trans fats from animal sources.
In June 2006, a task force co-chaired by Health Canada and the Heart and Stroke Foundation of Canada recommended a limit of 5% trans fat (of total fat) in all products sold to consumers in Canada (2% for tub margarines and spreads). The amount was selected such that "most of the industrially produced trans fats would be removed from the Canadian diet, and about half of the remaining trans fat intake would be of naturally occurring trans fats". This recommendation has been endorsed by the Canadian Restaurant and Foodservices Association and Food & Consumer Products of Canada has congratulated the task force on the report, although it did not recommend delaying implementation to 2010 as they had previously advocated.
Ten months after submitting their report the Heart and Stroke Foundation of Canada and Toronto Public Health issued a plea to the government of Canada: "to act immediately on the task force's recommendations and to eliminate harmful trans fat from Canada's food supply."
On June 20, 2007, the federal government announced its intention to regulate trans fats to the June 2006 standard unless the food industry voluntarily complied with these limits within two years.
## Denmark
Denmark became the first country to introduce laws strictly regulating the sale of many foods containing trans fats in March 2003, a move which effectively bans partially hydrogenated oils. The limit is 2% of fats and oils destined for human consumption. It should be noted that this restriction is on the ingredients rather than the final products. This regulatory approach has made Denmark the only country in which it is possible to eat "far less" than 1 g of industrially produced trans fats on a daily basis, even with a diet including prepared foods.
## European Union
The European Food Safety Authority was asked to produce a scientific opinion on trans fats.
## United Kingdom
In October 2005, the Food Standards Agency (FSA) asked for better labelling in the UK. In the July 29, 2006 edition of the British Medical Journal, an editorial also called for better labelling. In January 2007, the British Retail Consortium announced that major UK retailers, including ASDA, Boots, Co-op, Iceland, Marks and Spencer, Sainsbury's, Tesco and Waitrose intend to cease adding trans fatty acids to their own products by the end of 2007.
Sainsbury's became the first UK major retailer to ban all trans fat from all their own brand foods.
On 13 December 2007, the Food Standards Agency issued news releases stating that voluntary measures to reduce trans fats in food had already resulted in safe levels of consumer intake.
## United States
Before 2006, consumers in the United States could not directly determine the presence (or quantity) of trans fats in food products. This information could only be inferred from the ingredient list, notably from the partially hydrogenated ingredients.
On July 11, 2003, the Food and Drug Administration (FDA) issued a regulation requiring manufacturers to list trans fat on the Nutrition Facts panel of foods and some dietary supplements. The new labeling rule allowed for immediate voluntary compliance with mandatory compliance by January 1, 2006 (although companies may petition for an extension to January 1, 2008). The regulation allows trans fat levels of less than 0.5 grams per serving to be labeled as 0 grams per serving. The FDA did not approve nutrient content claims such as "trans fat free" or "low trans fat", as they could not determine a "recommended daily value", however the agency is planning a consumer study to evaluate the consumer understanding of such claims and perhaps consider a regulation allowing their use on packaged foods. The FDA defines trans fats as containing one or more trans linkage that are not in a conjugated system. This is an important distinction, as it distinguishes non-conjugated synthetic trans fats from naturally occurring fatty acids with conjugated trans double bonds, such as conjugated linoleic acid.
Critics of the plan, including FDA advisor Dr. Carlos Camargo, have expressed concern that the 0.5 gram per serving threshold is too high to refer to a food as free of trans fat. This is because a person eating many servings of a product, or eating multiple products over the course of the day may still consume a significant amount of trans fat. Despite this, the FDA estimates that by 2009, trans fat labeling will have prevented from 600 to 1,200 cases of coronary heart disease and 250 to 500 deaths each year. This benefit is expected to result from consumers choosing alternative foods lower in trans fats as well as manufacturers reducing the amount of trans fats in their products.
Some US cities are acting to reduce consumption of trans fats. In May 2005, Tiburon, California, became the first American city where all restaurants voluntarily cook with trans fat-free oils. Montgomery County, MD approved a ban on partially hydrogenated oils, becoming the first county in the nation to restrict trans fats.
New York City has embarked on a campaign to reduce consumption of trans fats, noting that heart disease is the primary cause of resident deaths. This has included a Public education campaign (see trans fat pamphlet) and a request to restaurant owners to voluntarily eliminate trans fat from their offerings. Finding that the voluntary program was not successful, New York City's Board of Health has solicited public comments on a proposal to ban artificial trans fats in restaurants. The board voted to ban trans fat in restaurant food on December 5, 2006. New York is the first large US city to strictly limit trans fats in restaurants. Restaurants were barred from using most frying and spreading fats containing artificial trans fats above 0.5 g per serving on July 1, 2007, and will have to meet the same target in all of their foods by July 1, 2008.
Philadelphia also recently passed a ban on trans fats. Philadelphia's City Council voted unanimously to pass a ban on February 8, 2007, which was signed into law on February 15, 2007, by Mayor John F. Street. By September 1, 2007, eateries must cease frying food in trans fats. A year later, trans fat must not be used as an ingredient in commercial kitchens. The law does not apply to prepackaged foods sold in the city. On October 10, 2007, the Philadelphia City Council approved the use of trans-fats by small bakeries throughout the city.
Albany County of New York passed a ban on trans fats. The ban was adopted after a unanimous vote by the county legislature on May 14, 2007. The decision was made after New York City's decision, but no plan has been put into place. Legislators received a letter from Rick J. Sampson, president and CEO of the New York State Restaurant Association, calling on them to "delay any action on this issue until the full impact of the New York City ban is known."
Chicago is also considering a ban on oils containing trans fats for large chain restaurants.
On December 19, 2006, Massachusetts state representative Peter Koutoujian filed the first state level legislation that would ban restaurants from preparing foods with trans fats. Similarly, Maryland, California, and Vermont are also considering statewide bans of trans fats.
King County of Washington passed a ban on artificial trans fats effective February 1, 2009.
The 2007 Indiana State Fair went to a complete ban on Trans Fats in cooking oils used.
# Food industry response
## Manufacturer response
The J.M. Smucker Company, American manufacturer of Crisco (the original partially hydrogenated vegetable shortening), in 2004 released a new formulation made from solid saturated palm oil cut with soybean oil and sunflower oil. This blend yielded an equivalent shortening much like the previous partially hydrogenated Crisco, and was labelled zero grams of trans fat per 1 tablespoon serving (as compared with 1.5 grams per tablespoon of original Crisco). As of January 24, 2007, Smucker claims that all Crisco shortening products in the US have been reformulated to contain less than one gram of trans fat per serving while keeping saturated fat content less than butter. The separately marketed trans-fat free version introduced in 2004 was discontinued.
On May 22, 2004, Unilever, the corporate descendant of Joseph Crosfield & Sons (the original producer of Wilhelm Normann's hydrogenation hardened oils) announced that they have eliminated transfats from all their margarine products in Canada, including their flagship Becel brand.
Agribusiness giant Bunge Limited, through their Bunge Oils division are now producing and marketing an NH product line of non-hydrogenated oils, margarines and shortenings, made from corn, canola, and soya oils.
## Major users' response
Some major food chains have chosen to remove or reduce trans fats in their products. In some cases these changes have been voluntary. In other cases, however, food vendors have been targeted by legal action that has generated a lot of media attention. In May 2003, BanTransFats.com Inc., a U.S. non-profit corporation, filed a lawsuit against the food manufacturer Kraft Foods in an attempt to force Kraft to remove trans fats from the Oreo cookie. The lawsuit was withdrawn when Kraft agreed to work on ways to find a substitute for the trans fat in the Oreo. In November 2006, Arby's announced that by May 2007, it would be eliminating trans fat from its french fries and reducing it in other products.
Similarly, in 2006, the Center for Science in the Public Interest sued KFC over its use of trans fats in fried foods. concerning their class action complaint. KFC reviewed alternative oil options, saying "there are a number of factors to consider including maintaining KFC's unique taste and flavor of Colonel Sanders' Original Recipe". On October 30, 2006, KFC announced that it will replace the partially hydrogenated soybean oil it currently uses with a zero-trans-fat low linolenic soybean oil in all restaurants in the US by April 2007, although its biscuits will still contain trans-fats. Despite the US-specific nature of the lawsuit, KFC is making changes outside of the US as well; in Canada, KFC's brand owner is switching to trans-fat free Canadian canola oil by early 2007. Wendy's announced in June 2006 plans to eliminate trans-fats from 6,300 restaurants in the United States and Canada, starting in August 2006. In November 2006, Taco Bell made a similar announcement, pledging to remove Trans Fat from many of their menu items by switching to canola oil. By April 2007, 15 Taco Bell menu items were completely free of Trans Fat. In January 2007, McDonald's announced they will start phasing out the trans fat in their fries after years of testing and several delays. This can be partially attributed to New York's recent ban, with the company stating they would not be selling a unique oil just for New York customers but would implement a nationwide change.
In response to a May 2007 law suit from the Center for Science in the Public Interest, Burger King announced that its 7,100 US restaurants will begin the switch to zero trans-fat oil by the end of 2007.
The Walt Disney Company announced that they will begin getting rid of trans fats in meals at US theme parks by the end of 2007, and will stop the inclusion of trans fats in licensed or promotional products by 2008.
Health Canada's monitoring program, which tracks the changing amounts of TFA and SFA in fast and prepared foods shows considerable progress in TFA reduction by some industrial users while others lag behind. In many cases, SFAs are being substituted for the TFAs. | Trans fat
Template:Fats
Trans fat is the common name for a type of unsaturated fat with trans isomer fatty acid(s). Trans fats may be monounsaturated or polyunsaturated.
Most trans fats consumed today are industrially created by partially hydrogenating plant oils — a process developed in the early 1900s and first commercialized as Crisco in 1911. The goal of partial hydrogenation is to add hydrogen atoms to unsaturated fats, making them more saturated. These more saturated fats have a higher melting point making them attractive for baking, and extending their shelf-life. Another particular class of trans fats, vaccenic acid occurs in trace amounts in meat and dairy products from ruminants.
Unlike other dietary fats, trans fats are neither required nor beneficial for health.[1] Eating trans fats increases the risk of coronary heart disease.[2]
Trans fat raises your ("bad") LDL cholesterol and lowers your ("good") HDL cholesterol. [3]
Health authorities worldwide recommend that consumption of trans fat be reduced to trace amounts. Trans fats from partially hydrogenated oils are generally considered to be more of a health risk than naturally occurring oils.[4]
Chemically, trans fats are made of the same building blocks as non-trans fats, but have a different arrangement. In trans fatty acid molecules, the hydrogen atoms bonded to pair(s) of doubly bonded carbon atoms (characteristic of all unsaturated fats) are in the trans rather than the cis arrangement. This results in a straight, rather than kinked, shape for the carbon chain, more like the straight chain of a fully saturated fat.
# History
Nobel laureate Paul Sabatier worked in the 1890s to develop the chemistry of hydrogenation which enabled the margarine, oil hydrogenation, and synthetic methanol industries.[5] While Sabatier only considered hydrogenation of vapours, the German chemist Wilhelm Normann showed in 1901 that liquid oils could be hydrogenated, and patented the process in 1902.[6][7]
During the years 1905 - 1910 Normann built a fat hardening facility in the Herford company. At the same time the invention was extended to a large scale plant in Warrington, England at Joseph Crosfield & Sons, Limited. It took only two years until the hardened fat could be successfully produced in the plant in Warrington, commencing production in the autumn of 1909. The initial year's production was nearly 3000 tonnes.[8]
In 1909, Procter & Gamble acquired the US rights to the Normann patent;[9]
in 1911, they began marketing the first hydrogenated shortening, Crisco (composed largely of partially hydrogenated cottonseed oil). Further success came from the marketing technique of giving away free cookbooks in which every recipe called for Crisco.
Normann's hydrogenation process made it possible to stabilize inexpensive whale oil or fish oil for human consumption, a practice kept secret to avoid consumer distaste.[10]
Production of hydrogenated fats increased steadily until the 1960s as processed vegetable fats replaced animal fats in the US and other western countries. At first, the argument was a financial one due to lower costs; however, advocates also said that the unsaturated trans fats of margarine were healthier than the saturated fats of butter.[11] The Center for Science in the Public Interest (CSPI) campaigned against the use of saturated fats for fast food cooking starting in 1984. When fast food companies replaced the saturated fat with partially hydrogenated unsaturated fats, CSPI's campaign against them ended. While CSPI defended trans fats in their 1987 Nutrition Action newsletter, by 1992 CSPI began to speak against trans fats and is currently strongly against their use.[12]
There were suggestions in the scientific literature as early as 1988 that trans fats could be a cause of the large increase in coronary artery disease.[11][13] In 1994, it was estimated that trans fats caused 30,000 deaths annually in the US from heart disease.[14]
In January 2007, faced with the prospect of an outright ban on the sale of their product, Crisco was reformulated to meet the US FDA definition of "zero grams trans fats per serving" (that is less than one gram per tablespoon) by boosting the saturation and then cutting the resulting solid with oils. Meanwhile, at the University of Guelph,
Alejandro Marangoni's research group found a way to mix oil, water, monoglycerides and fatty acids to form a "cooking fat" that acts the same way as trans and saturated fats — the stuff that makes baked goods taste so good. The big difference here is Marangoni's process works with "healthier" oils like olive, soybean and canola. He's hoping to get food manufacturers interested in the process this year, as the pressure mounts on the makers of commercial foods to dump trans fats.[15][16]
# Chemistry
Chemically, fats are large molecules consisting of three fatty acid groups connected to a single glycerol derivative. The term trans fat generally refers to a fat that contains one or more trans fatty acid groups. Fatty acid molecules are essentially long-chain hydrocarbons with a terminal carboxyl group. Fatty acids are characterized as saturated or unsaturated based on the number of hydrogen atoms in the acid. If the molecule contains the maximum possible number of hydrogen atoms, it is said to be saturated; otherwise, it is unsaturated to some degree.
Carbon atoms are tetravalent, forming four covalent bonds with other atoms, while hydrogen atoms bond with only one other atom. In saturated fatty acids, each carbon atom is connected to its two neighbour carbon atoms as well as two hydrogen atoms (see structure diagram, below). In unsaturated fatty acids the carbon atoms that are missing a hydrogen atom are joined by double bonds rather than single bonds (see structure graphic below) so that each carbon atom participates in four bonds.
Hydrogenation of an unsaturated fatty acid refers to the addition of hydrogen atoms to the acid, causing double bonds to become single ones as carbon atoms acquire new hydrogen partners (to maintain four bonds per carbon atom). Full hydrogenation results in a molecule containing the maximum amount of hydrogen (in other words the conversion of an unsaturated fatty acid into a saturated one). Partial hydrogenation results in the addition of hydrogen atoms at some of the empty positions, with a corresponding reduction in the number of double bonds. Commercial hydrogenation is typically partial in order to obtain a malleable fat that is solid at room temperature, but melts upon baking (or consumption).
In most naturally occurring unsaturated fatty acids, the hydrogen atoms are on the same side of the double bonds of the carbon chain (cis' configuration — meaning "on the same side" in Latin). However, partial hydrogenation reconfigures most of the double bonds that do not become chemically saturated, twisting them so that the hydrogen atoms end up on different sides of the chain. This type of configuration is called trans, which means "across" in Latin. The trans conformation is the lower energy form, and is favored in the hydrogenation process.
The same molecule, containing the same number of atoms, with a double bond in the same location, can be either a 'trans or a cis fatty acid depending on the conformation of the double bond. For example, oleic acid and elaidic acid are both unsaturated fatty acids with the chemical formula C9H17C9H17O2.[17] They both have a double bond located midway along the carbon chain. It is the conformation of this bond that sets them apart. The conformation has implications for the physical-chemical properties of the molecule. The trans configuration is straighter, while the cis configuration is noticeably kinked as can be seen from the following three-dimensional representation.
The trans fatty acid elaidic acid has different chemical and physical properties owing to the slightly different bond configuration. Notably, it has a much higher melting point, 45 °C rather than oleic acid's 13.4 °C, due to the ability of the trans molecules to pack more tightly, forming a solid that is more difficult to break apart.[17] It is notably a solid at human body temperatures.
In food production, the goal is not to simply change the configuration of double bonds while maintaining the same ratios of hydrogen to carbon. Instead, the goal is to decrease the number of double bonds and increase the amount of hydrogen in the fatty acid. This changes the consistency of the fatty acid and makes it less prone to rancidity (in which free radicals attack double bonds). Production of trans fatty acids is therefore a side-effect of partial hydrogenation.
Researchers at the United States Department of Agriculture have investigated whether hydrogenation can be achieved without the side effect of trans fat production. They varied the pressure under which the chemical reaction was conducted — applying 1400 kPa (200 psi) of pressure to soybean oil in a 2 litre vessel while heating it to between 140 °C and 170 °C. The standard 140 kPa (20 psi) process of hydrogenation produces a product of about 40% trans fatty acid by weight, compared to about 17% using the high pressure method. Blended with unhydrogenated liquid soybean oil, the high pressure processed oil produced margarine containing 5 to 6% trans fat. Based on current U.S. labelling requirements (see below) the manufacturer could claim the product was free of trans fat.[18] The level of trans fat may also be altered by modification of the temperature and the length of time during hydrogenation.
Trans fat levels may be measured. Measurement techniques include chromatography (by silver ion chromatography on thin layer chromatography plates, or small high performance liquid chromatography columns of silica gel with bonded phenylsulfonic acid groups whose hydrogen atoms have been exchanged for silver ions). The role of silver lies in its ability to form complexes with unsaturated compounds. Gas chromatography and mid-infrared spectroscopy are other methods in use.
# Presence in food
A type of trans fat occurs naturally in the milk and body fat of ruminants (such as cows and sheep) at a level of 2–5% of total fat.[19] Natural trans fats, which include conjugated linoleic acid and vaccenic acid, originate in the rumen of these animals.
Animal-based fats were once the only trans fats consumed, but by far the largest amount of trans fat consumed today is created by the processed food industry as a side-effect of partially hydrogenating unsaturated plant fats (generally vegetable oils). These partially hydrogenated fats have displaced natural solid fats and liquid oils in many areas, notably in the fast food, snack food, fried food and baked good industries.
Partially hydrogenated oils have been used in food for many reasons. Partial hydrogenation increases product shelf life and decreases refrigeration requirements. Because baking requires semi-solid fats to suspend solids at room temperature, partially hydrogenated oils can replace the animal fats traditionally used by bakers (such as butter and lard). They are also an inexpensive alternative to other semi-solid oils such as palm oil. Because partially hydrogenated plant oils can replace animal fats, the resulting products can be consumed (barring other ingredient and preparation violations) by adherents to Kashrut (kosher) and Halal, as well as by adherents to vegetarianism in Buddhism, ahimsa in Jainism and Hinduism, veganism, and other forms of vegetarianism.
Foods containing artificial trans fats formed by partially hydrogenating plant fats may contain up to 45% trans fat compared to their total fat.[19] Baking shortenings generally contain 30% trans fats compared to their total fats, while animal fats from ruminants such as butter contain up to 4%. Those margarines not reformulated to reduce trans fats may contain up to 15% trans fat by weight.[20]
It has been established that trans fats in human milk fluctuate with maternal consumption of trans fat, and that the amount of trans fats in the bloodstream of breastfed infants fluctuates with the amounts found in their milk. Reported percentages of trans fats (compared to total fats) in human milk range from 1% in Spain, 2% in France, 4% in Germany, and 7% in Canada.[21]
Trans fats are also found in shortenings commonly used for deep frying in restaurants. In the past, the decreased rancidity of partially hydrogenated oils meant that they could be reused for a longer time than conventional oils. Recently, however, non-hydrogenated vegetable oils have become available that have lifespans exceeding that of the frying shortenings.[22] As fast food chains routinely use different fats in different locations, trans fat levels in products can have large variation. For example, an analysis of samples of McDonald's french fries collected in 2004 and 2005 found that fries served in New York City contained twice as much trans fat as in Hungary, and 28 times as much trans fat as in Denmark (where trans fats are restricted). At KFC, the pattern was reversed with Hungary's product containing twice the trans fat of the New York product. Even within the US there was variation, with fries in New York containing 30% more trans fat than those from Atlanta.[23]
# Nutritional guidelines
The National Academy of Sciences (NAS) advises the United States and Canadian governments on nutritional science for use in Public policy and product labeling programs. Their 2002 Dietary reference intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids[24] contains their findings and recommendations regarding consumption of trans fat (summary).
Their recommendations are based on two key facts. First, "trans fatty acids are not essential and provide no known benefit to human health",[1] whether of animal or plant origin.[25] Second, while both saturated and trans fats increase levels of LDL cholesterol (so-called bad cholesterol), trans fats also lower levels of HDL cholesterol (good cholesterol);[2] this increases the risk of coronary heart disease (CHD). The NAS is concerned "that dietary trans fatty acids are more deleterious with respect to CHD than saturated fatty acids".[2] This analysis is supported by a 2006 New England Journal of Medicine (NEJM) scientific review that states "from a nutritional standpoint, the consumption of trans fatty acids results in considerable potential harm but no apparent benefit."[4]
Because of these facts and concerns, the NAS has concluded there is no safe level of trans fat consumption. There is no adequate level, recommended daily amount or tolerable upper limit for trans fats. This is because any incremental increase in trans fat intake increases the risk of coronary heart disease.[2]
Despite this concern, the NAS dietary recommendations have not recommended the elimination of trans fat from the diet. This is because trans fat is naturally present in many animal foods in trace quantities, and therefore its removal from ordinary diets might introduce undesirable side effects and nutritional imbalances if proper nutritional planning is not undertaken. The NAS has therefore "recommended that trans fatty acid consumption be as low as possible while consuming a nutritionally adequate diet".[26] Like the NAS, the World Health Organization has tried to balance public health goals with a practical level of trans fat consumption, recommending in 2003 that trans fats be limited to less than 1% of overall energy intake.[19]
The US National Dairy Council has asserted that the trans fats present in animal foods are of a different type than those in partially hydrogenated oils, and do not appear to exhibit the same negative effects.[27] While a recent scientific review agrees with the conclusion (stating that "the sum of the current evidence suggests that the Public health implications of consuming trans fats from ruminant products are relatively limited") it cautions that this may be due to the relatively low consumption of trans fats from animal sources compared to artificial ones. [4]
# Health risks
Partially hydrogenated vegetable oils have been an increasingly significant part of the human diet for about 100 years (particularly so in the latter half of the 20th century), and some deleterious effects of trans fat consumption are scientifically accepted, forming the basis of the health guidelines discussed above.
The exact biochemical methods by which trans fats produce specific health problems are a topic of continuing research. The most prevalent theory is that the human lipase enzyme is specific to the cis configuration. This enzyme can hydrolize the cis double bond, resulting in two lower molecular weight fatty acids that can be further metabolized. The human lipase enzyme is ineffective with the trans configuration, so trans fat remains in the blood stream for a much longer period of time and is more prone to arterial deposition and subsequent plaque formation. While the mechanisms through which trans fats contribute to coronary heart disease are fairly well understood, the mechanism for trans fat's effect on diabetes is still under investigation.
## Coronary heart disease
The primary health risk identified for trans fat consumption is an elevated risk of coronary heart disease (CHD).[28] A comprehensive review of studies of trans fats was published in 2006 in the New England Journal of Medicine that concludes that there is a strong and reliable connection between trans fat consumption and CHD.[4]
The major evidence for the effect of trans fat on CHD comes from the Nurses' Health Study (NHS) — a cohort study that has been following 120,000 female nurses since its inception in 1976. In this study, Hu and colleagues analyzed data from 900 coronary events from the NHS population during 14 years of followup. He determined that a nurse's CHD risk roughly doubled (relative risk of 1.94, CI: 1.43 to 2.61) for each 2% increase in trans fat calories consumed (instead of carbohydrate calories). By contrast, it takes more than a 15% increase in saturated fat calories (instead of carbohydrate calories) to produce a similar increase in risk. Eating non-trans unsaturated fats instead of carbohydrates reduces the risk of CHD rather than increasing it.[29] Hu also reports on the benefits of reducing trans fat consumption. Replacing 2% of food energy from trans fat with non-trans unsaturated fats more than halves the risk of CHD (53%). By comparison, replacing a larger 5% of food energy from saturated fat with non-trans unsaturated fats reduces the risk of CHD by 43%.[29]
Another study considered deaths due to CHD, with consumption of trans fats being linked to an increase in mortality, and consumption of polyunsaturated fats being linked to a decrease in mortality.[28][30]
There are two accepted tests that measure an individual's risk for coronary heart disease, both blood tests. The first considers ratios of two types of cholesterol, the other the amount of a cell-signalling cytokine called C-reactive protein. The ratio test is more accepted, while the cytokine test may be more powerful but is still being studied.[28] The effect of trans fat consumption has been documented on each as follows:
- Cholesterol ratio: This ratio compares the levels of LDL (so-called "bad" cholesterol) to HDL (so-called "good" cholesterol). Trans fat behaves like saturated fat by raising the level of LDL, but unlike saturated fat it has the additional effect of decreasing levels of HDL. The net increase in LDL/HDL ratio with trans fat is approximately double that due to saturated fat.[31] (Higher ratios are worse.) One randomized crossover study published in 2003 comparing the postprandial effect on blood lipids of (relatively) cis and trans fat rich meals showed that cholesteryl ester transfer (CET) was 28% higher after the trans meal than after the cis meal and that lipoprotein concentrations were enriched in apolipoprotein(a) after the trans meals.[32]
- C-reactive protein (CRP): A study of over 700 nurses showed that those in the highest quartile of trans fat consumption had blood levels of CRP that were 73% higher than those in the lowest quartile.[33]
## Other effects
There are suggestions that the negative consequences of trans fat consumption go beyond the cardiovascular risk. In general, there is much less scientific consensus that eating trans fat specifically increases the risk of other chronic health problems:
- Cancer: There is no scientific consensus that consumption of trans fats significantly increases cancer risks across the board.[28] The American Cancer Society states that a relationship between trans fats and cancer "has not been determined."[34] However, one recent study has found connections between trans fat and prostate cancer.[35]
- Diabetes: There is a growing concern that the risk of type 2 diabetes increases with trans fat consumption.[28] However, consensus has not been reached.[4] For example, one study found that risk is higher for those in the highest quartile of trans fat consumption.[36] Another study has found no diabetes risk once other factors such as total fat intake and BMI were accounted for.[37]
- Obesity: Research indicates that trans fat may increase weight gain and abdominal fat, despite a similar caloric intake.[38] A 6-year experiment revealed that monkeys fed a trans-fat diet gained 7.2% of their body weight, as compared to 1.8% for monkeys on a mono-unsaturated fat diet.[39] Although obesity is frequently linked to trans fat in the popular media,[40] this is generally in the context of eating too many calories; there is no scientific consensus connecting trans fat and obesity.
- Liver Dysfunction: Trans fats are metabolized differently by the liver than other fats and interfere with delta 6 desaturase. Delta 6 desaturase is an enzyme involved in converting essential fatty acids to arachidonic acid and prostaglandins, both of which are important to the functioning of cells.[41]
- Infertility: One 2007 study found, "Each 2% increase in the intake of energy from trans unsaturated fats, as opposed to that from carbohydrates, was associated with a 73% greater risk of ovulatory infertility…".[42]
# Public response and regulation
## International
The international trade in food is standardized in the Codex Alimentarius. Hydrogenated oils and fats come under the scope of Codex Stan 19.[43] Non-dairy fat spreads are covered by Codex Stan 256-2007.[44].
## Australia
The Australian federal government has indicated that it wants to actively pursue a policy of reducing trans fats from fast foods. The former federal assistant health minister, Christopher Pyne, asked fast food outlets to reduce their trans fat usage. A draft plan was proposed, with a September 2007 timetable, in order to reduce reliance on trans fats and saturated fats.[45]
Currently, Australia's food labeling laws do not require trans fats to be shown separately from the total fat content.
## Canada
Canada is one of the largest consumers of trans fats in the world.[46] In November 2004, an opposition day motion seeking a ban similar to Denmark's was introduced by Jack Layton of the New Democratic Party, and passed through the House of Commons by an overwhelming 193-73 vote.[47]
Since December 2005, Health Canada has required that food labels list the amount of trans fat in the nutrition facts section for most foods. Products with less than 0.2 grams of trans fat per serving may be labeled as free of trans fats.[48] These labelling allowances are not widely known, but as an awareness of them develops, controversy over truthful labelling is growing. In Canada, trans fat quantities on labels include naturally occurring trans fats from animal sources.[49]
In June 2006, a task force co-chaired by Health Canada and the Heart and Stroke Foundation of Canada recommended a limit of 5% trans fat (of total fat) in all products sold to consumers in Canada (2% for tub margarines and spreads).[19] The amount was selected such that "most of the industrially produced trans fats would be removed from the Canadian diet, and about half of the remaining trans fat intake would be of naturally occurring trans fats". This recommendation has been endorsed by the Canadian Restaurant and Foodservices Association[50] and Food & Consumer Products of Canada has congratulated the task force on the report,[51] although it did not recommend delaying implementation to 2010 as they had previously advocated.[52]
Ten months after submitting their report the Heart and Stroke Foundation of Canada and Toronto Public Health issued a plea to the government of Canada: "to act immediately on the task force's recommendations and to eliminate harmful trans fat from Canada's food supply."[53]
On June 20, 2007, the federal government announced its intention to regulate trans fats to the June 2006 standard unless the food industry voluntarily complied with these limits within two years.[54][55]
## Denmark
Denmark became the first country to introduce laws strictly regulating the sale of many foods containing trans fats in March 2003, a move which effectively bans partially hydrogenated oils. The limit is 2% of fats and oils destined for human consumption. It should be noted that this restriction is on the ingredients rather than the final products. This regulatory approach has made Denmark the only country in which it is possible to eat "far less" than 1 g of industrially produced trans fats on a daily basis, even with a diet including prepared foods.[56]
## European Union
The European Food Safety Authority was asked to produce a scientific opinion on trans fats.[57]
## United Kingdom
In October 2005, the Food Standards Agency (FSA) asked for better labelling in the UK.[58] In the July 29, 2006 edition of the British Medical Journal, an editorial also called for better labelling.[59] In January 2007, the British Retail Consortium announced that major UK retailers, including ASDA, Boots, Co-op, Iceland, Marks and Spencer, Sainsbury's, Tesco and Waitrose intend to cease adding trans fatty acids to their own products by the end of 2007.[60]
Sainsbury's became the first UK major retailer to ban all trans fat from all their own brand foods.
On 13 December 2007, the Food Standards Agency issued news releases stating that voluntary measures to reduce trans fats in food had already resulted in safe levels of consumer intake.[61][62]
## United States
Before 2006, consumers in the United States could not directly determine the presence (or quantity) of trans fats in food products. This information could only be inferred from the ingredient list, notably from the partially hydrogenated ingredients.
On July 11, 2003, the Food and Drug Administration (FDA) issued a regulation requiring manufacturers to list trans fat on the Nutrition Facts panel of foods and some dietary supplements.[63][64] The new labeling rule allowed for immediate voluntary compliance with mandatory compliance by January 1, 2006 (although companies may petition for an extension to January 1, 2008). The regulation allows trans fat levels of less than 0.5 grams per serving to be labeled as 0 grams per serving. The FDA did not approve nutrient content claims such as "trans fat free" or "low trans fat", as they could not determine a "recommended daily value", however the agency is planning a consumer study to evaluate the consumer understanding of such claims and perhaps consider a regulation allowing their use on packaged foods.[65] The FDA defines trans fats as containing one or more trans linkage that are not in a conjugated system. This is an important distinction, as it distinguishes non-conjugated synthetic trans fats from naturally occurring fatty acids with conjugated trans double bonds, such as conjugated linoleic acid.
Critics of the plan, including FDA advisor Dr. Carlos Camargo, have expressed concern that the 0.5 gram per serving threshold is too high to refer to a food as free of trans fat. This is because a person eating many servings of a product, or eating multiple products over the course of the day may still consume a significant amount of trans fat.[66] Despite this, the FDA estimates that by 2009, trans fat labeling will have prevented from 600 to 1,200 cases of coronary heart disease and 250 to 500 deaths each year. This benefit is expected to result from consumers choosing alternative foods lower in trans fats as well as manufacturers reducing the amount of trans fats in their products.
Some US cities are acting to reduce consumption of trans fats. In May 2005, Tiburon, California, became the first American city where all restaurants voluntarily cook with trans fat-free oils.[67] Montgomery County, MD approved a ban on partially hydrogenated oils, becoming the first county in the nation to restrict trans fats.[68]
New York City has embarked on a campaign to reduce consumption of trans fats, noting that heart disease is the primary cause of resident deaths. This has included a Public education campaign (see trans fat pamphlet) and a request to restaurant owners to voluntarily eliminate trans fat from their offerings.[69] Finding that the voluntary program was not successful, New York City's Board of Health has solicited public comments on a proposal to ban artificial trans fats in restaurants.[70] The board voted to ban trans fat in restaurant food on December 5, 2006. New York is the first large US city to strictly limit trans fats in restaurants. Restaurants were barred from using most frying and spreading fats containing artificial trans fats above 0.5 g per serving on July 1, 2007, and will have to meet the same target in all of their foods by July 1, 2008.[71]
Philadelphia also recently passed a ban on trans fats. Philadelphia's City Council voted unanimously to pass a ban on February 8, 2007, which was signed into law on February 15, 2007, by Mayor John F. Street.[72][73] By September 1, 2007, eateries must cease frying food in trans fats. A year later, trans fat must not be used as an ingredient in commercial kitchens. The law does not apply to prepackaged foods sold in the city. On October 10, 2007, the Philadelphia City Council approved the use of trans-fats by small bakeries throughout the city. [74]
Albany County of New York passed a ban on trans fats. The ban was adopted after a unanimous vote by the county legislature on May 14, 2007. The decision was made after New York City's decision, but no plan has been put into place. Legislators received a letter from Rick J. Sampson, president and CEO of the New York State Restaurant Association, calling on them to "delay any action on this issue until the full impact of the New York City ban is known."
Chicago is also considering a ban on oils containing trans fats for large chain restaurants.[75]
On December 19, 2006, Massachusetts state representative Peter Koutoujian filed the first state level legislation that would ban restaurants from preparing foods with trans fats.[76] Similarly, Maryland, California, and Vermont are also considering statewide bans of trans fats.[77][78]
King County of Washington passed a ban on artificial trans fats effective February 1, 2009.[79]
The 2007 Indiana State Fair went to a complete ban on Trans Fats in cooking oils used.
# Food industry response
## Manufacturer response
The J.M. Smucker Company, American manufacturer of Crisco (the original partially hydrogenated vegetable shortening), in 2004 released a new formulation made from solid saturated palm oil cut with soybean oil and sunflower oil. This blend yielded an equivalent shortening much like the previous partially hydrogenated Crisco, and was labelled zero grams of trans fat per 1 tablespoon serving (as compared with 1.5 grams per tablespoon of original Crisco).[80] As of January 24, 2007, Smucker claims that all Crisco shortening products in the US have been reformulated to contain less than one gram of trans fat per serving while keeping saturated fat content less than butter.[81] The separately marketed trans-fat free version introduced in 2004 was discontinued.
On May 22, 2004, Unilever, the corporate descendant of Joseph Crosfield & Sons (the original producer of Wilhelm Normann's hydrogenation hardened oils) announced that they have eliminated transfats from all their margarine products in Canada, including their flagship Becel brand.[82]
Agribusiness giant Bunge Limited, through their Bunge Oils division are now producing and marketing an NH product line of non-hydrogenated oils, margarines and shortenings, made from corn, canola, and soya oils.[83]
## Major users' response
Some major food chains have chosen to remove or reduce trans fats in their products. In some cases these changes have been voluntary. In other cases, however, food vendors have been targeted by legal action that has generated a lot of media attention. In May 2003, BanTransFats.com Inc., a U.S. non-profit corporation, filed a lawsuit against the food manufacturer Kraft Foods in an attempt to force Kraft to remove trans fats from the Oreo cookie. The lawsuit was withdrawn when Kraft agreed to work on ways to find a substitute for the trans fat in the Oreo. In November 2006, Arby's announced[84] that by May 2007, it would be eliminating trans fat from its french fries and reducing it in other products.
Similarly, in 2006, the Center for Science in the Public Interest sued KFC over its use of trans fats in fried foods.[85] concerning their class action complaint.[86] KFC reviewed alternative oil options, saying "there are a number of factors to consider including maintaining KFC's unique taste and flavor of Colonel Sanders' Original Recipe".[87] On October 30, 2006, KFC announced that it will replace the partially hydrogenated soybean oil it currently uses with a zero-trans-fat low linolenic soybean oil in all restaurants in the US by April 2007, although its biscuits will still contain trans-fats.[88] Despite the US-specific nature of the lawsuit, KFC is making changes outside of the US as well; in Canada, KFC's brand owner is switching to trans-fat free Canadian canola oil by early 2007.[89] Wendy's announced in June 2006 plans to eliminate trans-fats from 6,300 restaurants in the United States and Canada, starting in August 2006.[90] In November 2006, Taco Bell made a similar announcement, pledging to remove Trans Fat from many of their menu items by switching to canola oil. By April 2007, 15 Taco Bell menu items were completely free of Trans Fat. In January 2007, McDonald's announced they will start phasing out the trans fat in their fries after years of testing and several delays.[91] This can be partially attributed to New York's recent ban, with the company stating they would not be selling a unique oil just for New York customers but would implement a nationwide change.
In response to a May 2007 law suit from the Center for Science in the Public Interest, Burger King announced that its 7,100 US restaurants will begin the switch to zero trans-fat oil by the end of 2007.[92]
The Walt Disney Company announced that they will begin getting rid of trans fats in meals at US theme parks by the end of 2007, and will stop the inclusion of trans fats in licensed or promotional products by 2008.[93]
Health Canada's monitoring program, which tracks the changing amounts of TFA and SFA in fast and prepared foods shows considerable progress in TFA reduction by some industrial users while others lag behind. In many cases, SFAs are being substituted for the TFAs.[94][95] | https://www.wikidoc.org/index.php/Trans-fats | |
f06fb11703446e277fc124c7ed53889b6a361980 | wikidoc | Treatment | Treatment
# Overview
Compliance with avoidance is important. The key to avoidance is proper evaluation and detection of causative allergen. Wear appropriate clothing to protect against irritants at home and in a work environment.
# Treatment
High-potency topical corticosteroids, e.g. clobetasol propionate 0.05% cream, may be used to reduce the inflammation. As a general rule, high-potency corticosteroids should not be used on thin skin, e.g. face, genitals, intertriginous areas, to avoid the risk of skin atrophy. Antihistamines such as hydroxyzine and cetirizine are recommended to control pruritus. Systemic steroids are advised in severe cases but should be tapered gradually to prevent recurrences. Friction should be avoided as well as the use of soaps, perfumes, and dyes. Emollients are used for hydrating the skin. Tacrolimus ointment and pimecrolimus cream are immunomodulating drugs that inhibit calcineurin and are helpful in allergic contact dermatitis.
# Reference
- ↑ Soltanipoor M, Kezic S, Sluiter JK, de Wit F, Bosma AL, van Asperen R; et al. (2019). "Effectiveness of a skin care programme for the prevention of contact dermatitis in healthcare workers (the Healthy Hands Project): A single-centre, cluster randomized controlled trial". Contact Dermatitis. 80 (6): 365–373. doi:10.1111/cod.13214. PMC 6593800 Check |pmc= value (help). PMID 30652317.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Nedorost S (2018). "A diagnostic checklist for generalized dermatitis". Clin Cosmet Investig Dermatol. 11: 545–549. doi:10.2147/CCID.S185357. PMC 6217130. PMID 30464569.
- ↑ Vernon HJ, Olsen EA (1990). "A controlled trial of clobetasol propionate ointment 0.05% in the treatment of experimentally induced Rhus dermatitis". J Am Acad Dermatol. 23 (5 Pt 1): 829–32. doi:10.1016/0190-9622(90)70297-u. PMID 2147698. | Treatment
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2], Ogechukwu Hannah Nnabude, MD
# Overview
Compliance with avoidance is important. The key to avoidance is proper evaluation and detection of causative allergen. Wear appropriate clothing to protect against irritants at home and in a work environment. [1] [2]
# Treatment
High-potency topical corticosteroids, e.g. clobetasol propionate 0.05% cream, may be used to reduce the inflammation. [3] As a general rule, high-potency corticosteroids should not be used on thin skin, e.g. face, genitals, intertriginous areas, to avoid the risk of skin atrophy. Antihistamines such as hydroxyzine and cetirizine are recommended to control pruritus. Systemic steroids are advised in severe cases but should be tapered gradually to prevent recurrences. Friction should be avoided as well as the use of soaps, perfumes, and dyes. Emollients are used for hydrating the skin. Tacrolimus ointment and pimecrolimus cream are immunomodulating drugs that inhibit calcineurin and are helpful in allergic contact dermatitis.
# Reference
- ↑ Soltanipoor M, Kezic S, Sluiter JK, de Wit F, Bosma AL, van Asperen R; et al. (2019). "Effectiveness of a skin care programme for the prevention of contact dermatitis in healthcare workers (the Healthy Hands Project): A single-centre, cluster randomized controlled trial". Contact Dermatitis. 80 (6): 365–373. doi:10.1111/cod.13214. PMC 6593800 Check |pmc= value (help). PMID 30652317.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Nedorost S (2018). "A diagnostic checklist for generalized dermatitis". Clin Cosmet Investig Dermatol. 11: 545–549. doi:10.2147/CCID.S185357. PMC 6217130. PMID 30464569.
- ↑ Vernon HJ, Olsen EA (1990). "A controlled trial of clobetasol propionate ointment 0.05% in the treatment of experimentally induced Rhus dermatitis". J Am Acad Dermatol. 23 (5 Pt 1): 829–32. doi:10.1016/0190-9622(90)70297-u. PMID 2147698. | https://www.wikidoc.org/index.php/Treatment | |
e1c25ac8419884c8ff8c2be38d099c39b94758ec | wikidoc | Trehalase | Trehalase
The enzyme Trehalase is a glycoside hydrolase, produced by cells in the brush border of the small intestine, which catalyzes the conversion of trehalose to glucose. It is found in most animals.
The non-reducing disaccharide trehalose (α-D-glucopyranosyl-1,1-α-D-glucopyranoside) is one of the most important storage carbohydrates, and is produced by almost all forms of life except mammals. The disaccharide is hydrolyzed into two molecules of glucose by the enzyme trehalase. There are two types of trehalases found in Saccharomyces cerevisiae, viz. neutral trehalase (NT) and acid trehalase (AT) classified according to their pH optima . NT has an optimum pH of 7.0, while that of AT is 4.5.
Recently it has been reported that more than 90% of total AT activity in S. cerevisiae is extracellular and cleaves extracellular trehalose into glucose in the periplasmic space.
# Trehalose hydrolysis
One molecule of trehalose is hydrolyzed to two molecules of glucose by the enzyme trehalase. Enzymatic hydrolysis of trehalose was first observed in Aspergillus niger by Bourquelot in 1893. Fischer reported this reaction in S. cerevisiae in 1895. Since then the trehalose hydrolyzing enzyme, trehalase (α, α-trehalose-1-C-glucohydrolase, EC 3.2.1.28) has been reported from many other organisms including plants and animals. Though trehalose is not known to be present in mammals, trehalase enzyme is found to be present in the kidney brush border membrane and the intestinal villi membranes. In the intestine the function of this enzyme is to hydrolyze ingested trehalose. Individuals with a defect in their intestinal trehalase have diarrhea when they eat foods with high trehalose content, such as mushrooms. Trehalose hydrolysis by trehalase enzyme is an important physiological process for various organisms, such as fungal spore germination, insect flight, and the resumption of growth in resting cells.
# Bacterial trehalase
Trehalose has been reported to be present as a storage carbohydrate in Pseudomonas, Bacillus, Rhizobium and in several actinomycetes and may be partially responsible for their resistance properties. Most of the trehalase enzymes isolated from bacteria have as optimum pH of 6.5–7.5. The trehalase enzyme of Mycobacterium smegmatis is a membrane bound protein. Periplasmic trehalase of Escherichia coli K12 is induced by growth at high osmolarity. The hydrolysis of trehalose into glucose takes place in the periplasm, and the glucose is then transported into the bacterial cell. Another cytoplasmic trehalase has also been reported from E. coli. The gene, which encodes this cytoplasmic trehalase, exhibits high homology to the periplasmic trehalase.
# Trehalase in plants
In plant kingdom, though trehalose has been reported from several pteridophytes including Selaginella lepidophylla and Botrychium lunaria; the sugar is rare in vascular plants and reported only in ripening fruits of several members of Apiaceae and in the leaves of the desiccation-tolerant angiosperm Myrothamnus flabellifolius. But, the enzyme trehalase is ubiquitous in plants. This is puzzling that trehalase is present in higher plants, though its substrate is absent. No clear role has been demonstrated for trehalase activity in plants. However, trehalose inhibits the synthesis of its precursor, trehalose 6-phosphate, a plant metabolism regulator; hence, its removal may be required. It has been suggested that trehalases could play a role in defense mechanisms or the enzyme could play a role in the degradation of trehalose derived from plant-associated microorganisms.
# Fungal trehalase
Two distinct trehalases have been reported from S. cerevisiae. One is regulated by cAMP-dependent phosphorylation and localized to the cytosol. The second trehalase activity is found in the vacuoles. The pH optimum of cytosolic trehalse was determined to be approximately 7.0 and is thus referred to as 'neutral trehalase' (NT); whereas the vacuolar trehalase is most active at pH 4.5 and consequently termed 'acid trehalase' (AT). These enzymes are encoded by two different genes – NTH1 and ATH1 respectively.
# Neutral trehalase
The cytosolic trehalase enzyme, NT, has been purified and characterized extensively from S. cerevisiae. In non-denaturing gels this enzyme protein exhibited a molecular mass of 160 kDa, while in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) it showed a mass of 80 kDa. This hydrolase enzyme is specific for trehalose. The Km of NT has been reported to be 5.7mM. The gene responsible for trehalase activity in S. cerevisiae is NTH1. This gene is with an open reading frame of 2079 base pairs (bp), encoding a protein of 693 amino acids, corresponding to a molecular mass of 79569 Da.
NT activity is regulated by protein phosphorylation-dephosphorylation. Phosphorylation with cAMP-dependent protein kinase activates NT. Dephosphorylation of the purified phosphorylated enzyme by alkaline phosphatase caused an almost complete inactivation of the enzyme activity; but a recovery of the enzyme activity could be observed by rephosphorylation while incubating with ATP and protein kinase. The activity of NT in crude extracts is enhanced by polycations, while the activity of purified phosphorylated NT is inhibited by them. The activation of crude extracts was found to be due to the removal of polyphosphates, both of which inhibit NT activity.
# Acid Trehalase
The molecular weight of AT was found to be 218 kDa by gel filtration chromatography. AT is a glycoprotein. It has 86% carbohydrate content. It has been reported that the maturation of AT is a stepwise process beginning with a carbohydrate-free 41 kDa protein; this form is then core-glycosylated in the endoplasmic reticulum to form a 76 kDa glycol-protein. In Golgi bodies, the protein is further glycosylated yielding a 180 kDa form, which ultimately attains a maturity in vacuoles, where its molecular weight becomes around 220 kDa. The 41 kDa carbohydrate free protein moiety of the enzyme was obtained by Endoglycosidase H treatment of purified AT, resulted after sodium dodecyl sulfate gel electrophoresis27. AT exhibited an apparent Km for trehalose of about 4.7 mM at pH 4.5. The gene responsible for AT activity in S. cerevisiae is ATH1.
Ath1p, i.e. AT, has been reported to be necessary for S. cerevisiae to utilize extracellular trehalose as carbon source16. ATH1 deletion mutant of the yeast could not grow in the medium with trehalose as the carbon source.
Researchers have suggested that AT moves from its site of synthesis to the periplasmic space, where it binds exogenous trehalose to internalize it and hydrolyze it in the vacuoles. Recently it has been shown that more than 90% of AT activity in S. cerevisiae is extracellular and the hydrolysis of trehalose into glucose takes place at the periplasmic space. Previously, a highly glycosylated protein, gp37, which is the product of YGP1 gene, was reported to be co-purified with AT activity. Invertase activity was also reported to be co-purified with AT activity. The physical association of AT with these two proteins was thought to suffice for the AT to be secreted by invertase and gp37 secretion pathways in absence of any known secretion signal for Ath1p.
In a Candida utils strain, one regulatory a one non-regulatory trehalase were also reported. These two enzymes were reported to be distinguishable by their molecular weight, behavior in ion-exchange chromatography and kinetic properties. The regulatory trehalase appeared to be a cytoplasmic enzyme and the nonregulatory enzyme was mostly detected in vacuoles. But, in a more recent report, a C. utils strain was demonstrated to lack any detectable AT activity but contain only NT activity. AT activity was not detectable in this strain, though the strain was shown to utilize extracellular trehalose as carbon source. | Trehalase
The enzyme Trehalase is a glycoside hydrolase, produced by cells in the brush border of the small intestine, which catalyzes the conversion of trehalose to glucose.[2][3][4][5] It is found in most animals.
The non-reducing disaccharide trehalose (α-D-glucopyranosyl-1,1-α-D-glucopyranoside) is one of the most important storage carbohydrates, and is produced by almost all forms of life except mammals. The disaccharide is hydrolyzed into two molecules of glucose by the enzyme trehalase. There are two types of trehalases found in Saccharomyces cerevisiae, viz. neutral trehalase (NT) and acid trehalase (AT) classified according to their pH optima [4]. NT has an optimum pH of 7.0, while that of AT is 4.5.
Recently it has been reported that more than 90% of total AT activity in S. cerevisiae is extracellular and cleaves extracellular trehalose into glucose in the periplasmic space.
# Trehalose hydrolysis
One molecule of trehalose is hydrolyzed to two molecules of glucose by the enzyme trehalase. Enzymatic hydrolysis of trehalose was first observed in Aspergillus niger by Bourquelot in 1893. Fischer reported this reaction in S. cerevisiae in 1895. Since then the trehalose hydrolyzing enzyme, trehalase (α, α-trehalose-1-C-glucohydrolase, EC 3.2.1.28) has been reported from many other organisms including plants and animals. Though trehalose is not known to be present in mammals, trehalase enzyme is found to be present in the kidney brush border membrane and the intestinal villi membranes. In the intestine the function of this enzyme is to hydrolyze ingested trehalose. Individuals with a defect in their intestinal trehalase have diarrhea when they eat foods with high trehalose content, such as mushrooms. Trehalose hydrolysis by trehalase enzyme is an important physiological process for various organisms, such as fungal spore germination, insect flight, and the resumption of growth in resting cells.
# Bacterial trehalase
Trehalose has been reported to be present as a storage carbohydrate in Pseudomonas, Bacillus, Rhizobium and in several actinomycetes and may be partially responsible for their resistance properties. Most of the trehalase enzymes isolated from bacteria have as optimum pH of 6.5–7.5. The trehalase enzyme of Mycobacterium smegmatis is a membrane bound protein. Periplasmic trehalase of Escherichia coli K12 is induced by growth at high osmolarity. The hydrolysis of trehalose into glucose takes place in the periplasm, and the glucose is then transported into the bacterial cell. Another cytoplasmic trehalase has also been reported from E. coli. The gene, which encodes this cytoplasmic trehalase, exhibits high homology to the periplasmic trehalase.
# Trehalase in plants
In plant kingdom, though trehalose has been reported from several pteridophytes including Selaginella lepidophylla and Botrychium lunaria; the sugar is rare in vascular plants and reported only in ripening fruits of several members of Apiaceae and in the leaves of the desiccation-tolerant angiosperm Myrothamnus flabellifolius. But, the enzyme trehalase is ubiquitous in plants. This is puzzling that trehalase is present in higher plants, though its substrate is absent. No clear role has been demonstrated for trehalase activity in plants. However, trehalose inhibits the synthesis of its precursor, trehalose 6-phosphate, a plant metabolism regulator[6]; hence, its removal may be required[7]. It has been suggested that trehalases could play a role in defense mechanisms or the enzyme could play a role in the degradation of trehalose derived from plant-associated microorganisms.
# Fungal trehalase
Two distinct trehalases have been reported from S. cerevisiae. One is regulated by cAMP-dependent phosphorylation and localized to the cytosol. The second trehalase activity is found in the vacuoles. The pH optimum of cytosolic trehalse was determined to be approximately 7.0 and is thus referred to as 'neutral trehalase' (NT); whereas the vacuolar trehalase is most active at pH 4.5 and consequently termed 'acid trehalase' (AT). These enzymes are encoded by two different genes – NTH1 and ATH1 respectively.
# Neutral trehalase
The cytosolic trehalase enzyme, NT, has been purified and characterized extensively from S. cerevisiae. In non-denaturing gels this enzyme protein exhibited a molecular mass of 160 kDa, while in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) it showed a mass of 80 kDa. This hydrolase enzyme is specific for trehalose. The Km of NT has been reported to be 5.7mM. The gene responsible for trehalase activity in S. cerevisiae is NTH1. This gene is with an open reading frame of 2079 base pairs (bp), encoding a protein of 693 amino acids, corresponding to a molecular mass of 79569 Da.
NT activity is regulated by protein phosphorylation-dephosphorylation. Phosphorylation with cAMP-dependent protein kinase activates NT. Dephosphorylation of the purified phosphorylated enzyme by alkaline phosphatase caused an almost complete inactivation of the enzyme activity; but a recovery of the enzyme activity could be observed by rephosphorylation while incubating with ATP and protein kinase. The activity of NT in crude extracts is enhanced by polycations, while the activity of purified phosphorylated NT is inhibited by them. The activation of crude extracts was found to be due to the removal of polyphosphates, both of which inhibit NT activity.
# Acid Trehalase
The molecular weight of AT was found to be 218 kDa by gel filtration chromatography. AT is a glycoprotein. It has 86% carbohydrate content. It has been reported that the maturation of AT is a stepwise process beginning with a carbohydrate-free 41 kDa protein; this form is then core-glycosylated in the endoplasmic reticulum to form a 76 kDa glycol-protein. In Golgi bodies, the protein is further glycosylated yielding a 180 kDa form, which ultimately attains a maturity in vacuoles, where its molecular weight becomes around 220 kDa. The 41 kDa carbohydrate free protein moiety of the enzyme was obtained by Endoglycosidase H treatment of purified AT, resulted after sodium dodecyl sulfate gel electrophoresis27. AT exhibited an apparent Km for trehalose of about 4.7 mM at pH 4.5. The gene responsible for AT activity in S. cerevisiae is ATH1.
Ath1p, i.e. AT, has been reported to be necessary for S. cerevisiae to utilize extracellular trehalose as carbon source16. ATH1 deletion mutant of the yeast could not grow in the medium with trehalose as the carbon source.
Researchers have suggested that AT moves from its site of synthesis to the periplasmic space, where it binds exogenous trehalose to internalize it and hydrolyze it in the vacuoles. Recently it has been shown that more than 90% of AT activity in S. cerevisiae is extracellular and the hydrolysis of trehalose into glucose takes place at the periplasmic space. Previously, a highly glycosylated protein, gp37, which is the product of YGP1 gene, was reported to be co-purified with AT activity. Invertase activity was also reported to be co-purified with AT activity. The physical association of AT with these two proteins was thought to suffice for the AT to be secreted by invertase and gp37 secretion pathways in absence of any known secretion signal for Ath1p.
In a Candida utils strain, one regulatory a one non-regulatory trehalase were also reported. These two enzymes were reported to be distinguishable by their molecular weight, behavior in ion-exchange chromatography and kinetic properties. The regulatory trehalase appeared to be a cytoplasmic enzyme and the nonregulatory enzyme was mostly detected in vacuoles. But, in a more recent report, a C. utils strain was demonstrated to lack any detectable AT activity but contain only NT activity. AT activity was not detectable in this strain, though the strain was shown to utilize extracellular trehalose as carbon source. | https://www.wikidoc.org/index.php/Trehalase | |
133ca2e29dbb1e816f8567f68a9542ff2a76af81 | wikidoc | Trehalose | Trehalose
# Overview
Trehalose, also known as mycose, is a type of alpha-linked disaccharide formed by an α, α-1, 1-glucoside bond between α-glucose units found extensively but not abundantly in nature. Molecular Formula C12H22O11, Molecular Mass 342.29. CAS number 99-20-7. In 1832 Wiggers discovered trehalose in rye and in 1859 Berthelot isolated it from trehalamanna (manna) made by weevils, and named it trehalose. It can be synthesised by fungi, plants and invertebrate animals. It is implicated in anhydrobiosis—the ability of plants and animals to withstand prolonged periods of desiccation.It has high water retention capabilities and is used in food and cosmetics. The sugar is thought to form a gel phase as cells dehydrate, which prevents disruption of internal cell organelles by effectively splinting them in position. Rehydration then allows normal cellular activity to be resumed without the major, generally lethal damage, that would normally follow a dehydration/reyhdration cycle. Trehalose has the added advantage of being an antioxidant. Extracting trehalose used to be a difficult and costly process, but recently, the Hayashibara company (Okayama, Japan) confirmed an inexpensive extraction technology from starch for mass production. Trehalose is now being used for a broad spectrum of applications, as mentioned above.
# Structure
Trehalose is a disaccharide formed by a 1, 1-glucoside bond between two α-glucose units. Because trehalose is formed by the bonding of two reducing groups, it has no reducibility.
# Physical Properties
- Powder like white crystals at ordinary temperature and pressures.
- Dissolve 68.9g in 100g of water at 20 ºC
- 45% as sweet as sucrose.
# Chemical properties
Reducibility Non-reductive
Solubility Broken down by trehalase into glucose.
Trehalose was first isolated from ergot of rye. Emil Fischer first described the trehalose-hydrolyzing enzyme in yeast. Trehalose is a non-reducing sugar formed from two glucose units joined by a 1-1 alpha bond giving it the name of α-D-glucopyranosyl-(1→1)-α-D-glucopyranoside. The bonding makes trehalose very resistant to acid hydrolysis, and therefore stable in solution at high temperatures even under acidic conditions. The bonding also keeps non-reducing sugars in closed-ring form, such that the aldehyde or ketone end-groups do not bind to the lysine or arginine residues of proteins (a process called glycation).
Trehalose has about 45% the sweetness of sucrose. Trehalose is less soluble than sucrose, except at high temperatures (>80°C).
Trehalose forms a rhomboid crystal as the dihydrate, and has 90% of the calorific content of sucrose in that form. Anhydrous forms of trehalose readily regain moisture to form the dihydrate.
Anhydrous forms of trehalose can show interesting physical properties when heat treated.
# Biological properties
Present in: Trehalose can be found in nature; in animals, plants and microorganisms.
In animals, trehalose is present in shrimp and it is present in insects, including grasshoppers, locusts, butterflies and bees in which their blood-sugar is trehalose. The trehalose is then broken down into glucose by the catabolic enzyme trehalase for use. Trehalose is also present in the nutrition exchange liquid of hornets and their larvae.
In plants its presence is seen in sunflower seeds, selaginella mosses, and sea algae. Again, within the fungus family, some mushrooms such as shitake, maitake (grifola fondosa), nameko (pholiota nameko), and Judas's ear (A. auricularia-judae) contain 1 to 17% percent of trehalose in dry weight form, and is also referred to as mushroom sugar. Trehalose can also be found in such microorganisms as baker's yeast and wine yeast.
===Cryptobiosis===
When Tardigrades (water bears) dry out, the glucose in their bodies changes to trehalose when they enter a state called cryptobiosis -- a state where they look as though they are dead. However, when they receive water, they revive and return to their metabolic state. Besides these, it is also thought that the reason the larva of sleeping chironomid (polypedihum vanderplanki) and artemia (sea monkeys) are able to withstand dehydration is because they store trehalose within their cells.
Even within the plant kingdom, selaginella mosses that grow in desert and mountainous areas, although they may be cracked and dried out, will turn green again and revive after a rain. It is because they contain trehalose, it is called the resurrection plant. It is also said that the reason dried shitake mushrooms spring back into shape so well in water is because they contain trehalose.
The theories as to how trehalose works within the organism in the state of cryptobiosis are that of either the vitrification theory, a state that maintains limited molecular activity, or the water displacement theory, whereby water is replaced by trehalose, or a combination of the two theories are at work.
Trehalose is metabolized by a number of bacteria, including Streptococcus mutans, the common oral bacteria responsible for oral plaque.
The enzyme trehalase, a glycoside hydrolase, present but not abundant in most people, breaks trehalose into two glucose molecules, which can then be readily absorbed in the gut.
Trehalose is the major carbohydrate energy storage molecule used by insects for flight. One possible reason for this is that the double glycosidic linkage of trehalose, when acted upon by an insect trehalase, releases two molecules of glucose, which is required for the rapid energy requirements of flight. This is double the efficiency of glucose release from the storage polymer starch, for which cleavage of one glycosidic linkage releases only one glucose molecule.
# Natural sources
- Trehala manna
- Locust
- Resurrection plant
- Fungi
# Use
Trehalose has been accepted as a novel food ingredient under the GRAS terms in the U.S. and the EU. Trehalose has also found commercial application as a food ingredient. The uses for trehalose span a broad spectrum that cannot be found in other sugars, the primary one being its use in the processing of foods. Trehalose is used in a variety of processed foods such as dinners, western and Japanese confectionery, bread, vegetables side dishes, animal derived deli foods, pouch-packed foods, frozen foods, and beverages, as well as used in foods for lunches, eating out, or prepared at home. This use in such a wide range of products is due to the multi-faceted effects of trehalose's properties, such as: its inherently mild sweet flavor, its preservative properties which maintain the quality of one of the three main nutrients, one being carbohydrates (such as starch), as well as proteins and fats; its powerful water-retention properties that preserve the texture of foods by protecting them from drying out or freezing, its properties to suppress smells and tastes such as bitterness, stringency, harsh flavors, and the stench of raw foods, meats, and packaged foods; which when combined can potentially bring about promising results. However, less-soluble and less-sweet than sucrose, trehalose is seldom used as a direct replacement for conventional sweeteners, such as sucrose, regarded as the "gold standard." Technology for the production of trehalose was developed in Japan, where enzyme-based processes converts wheat and corn syrups to trehalose. It is also used as a protein stabilizing agent in research . It is particularly effective when combined with phosphate ions. Trehalose has also been used in at least one biopharmaceutical formulation, the monoclonal antibody trastuzumab, marketed as Herceptin.
===Cosmetics===
Capitalizing on trehalose's moisture retaining capacity, it is used as a moisturizer in many basic toiletries as bath oils and hair growth tonics.
===Pharmaceuticals===
Using trehalose's properties to preserve tissue and protein to full advantage, it is used in organ protection solutions for organ transplants.
===Other===
Other fields of use for trehalose span a broad spectrum including fabrics that have deodorization qualities and are compatible to Japan's official 'Cool Biz' attire; plant activation, antibacterial sheets and nutrients for larvae.
# Solubility
68.9 g/100 g H2O at 20 °C | Trehalose
Template:Chembox new
# Overview
Trehalose, also known as mycose, is a type of alpha-linked disaccharide formed by an α, α-1, 1-glucoside bond between α-glucose units found extensively but not abundantly in nature. Molecular Formula C12H22O11, Molecular Mass 342.29. CAS number 99-20-7. In 1832 Wiggers discovered trehalose in rye and in 1859 Berthelot isolated it from trehalamanna (manna) made by weevils, and named it trehalose. It can be synthesised by fungi, plants and invertebrate animals. It is implicated in anhydrobiosis—the ability of plants and animals to withstand prolonged periods of desiccation.It has high water retention capabilities and is used in food and cosmetics. The sugar is thought to form a gel phase as cells dehydrate, which prevents disruption of internal cell organelles by effectively splinting them in position. Rehydration then allows normal cellular activity to be resumed without the major, generally lethal damage, that would normally follow a dehydration/reyhdration cycle. Trehalose has the added advantage of being an antioxidant. Extracting trehalose used to be a difficult and costly process, but recently, the Hayashibara company (Okayama, Japan) confirmed an inexpensive extraction technology from starch for mass production. Trehalose is now being used for a broad spectrum of applications, as mentioned above.
# Structure
Trehalose is a disaccharide formed by a 1, 1-glucoside bond between two α-glucose units. Because trehalose is formed by the bonding of two reducing groups, it has no reducibility.
# Physical Properties
- Powder like white crystals at ordinary temperature and pressures.
- Dissolve 68.9g in 100g of water at 20 ºC
- 45% as sweet as sucrose.
# Chemical properties
Reducibility Non-reductive
Solubility Broken down by trehalase into glucose.
Trehalose was first isolated from ergot of rye. Emil Fischer first described the trehalose-hydrolyzing enzyme in yeast. Trehalose is a non-reducing sugar formed from two glucose units joined by a 1-1 alpha bond giving it the name of α-D-glucopyranosyl-(1→1)-α-D-glucopyranoside. The bonding makes trehalose very resistant to acid hydrolysis, and therefore stable in solution at high temperatures even under acidic conditions. The bonding also keeps non-reducing sugars in closed-ring form, such that the aldehyde or ketone end-groups do not bind to the lysine or arginine residues of proteins (a process called glycation).
Trehalose has about 45% the sweetness of sucrose. Trehalose is less soluble than sucrose, except at high temperatures (>80°C).
Trehalose forms a rhomboid crystal as the dihydrate, and has 90% of the calorific content of sucrose in that form. Anhydrous forms of trehalose readily regain moisture to form the dihydrate.
Anhydrous forms of trehalose can show interesting physical properties when heat treated.
# Biological properties
Present in: Trehalose can be found in nature; in animals, plants and microorganisms.
In animals, trehalose is present in shrimp and it is present in insects, including grasshoppers, locusts, butterflies and bees in which their blood-sugar is trehalose. The trehalose is then broken down into glucose by the catabolic enzyme trehalase for use. Trehalose is also present in the nutrition exchange liquid of hornets and their larvae.
In plants its presence is seen in sunflower seeds, selaginella mosses, and sea algae. Again, within the fungus family, some mushrooms such as shitake, maitake (grifola fondosa), nameko (pholiota nameko), and Judas's ear (A. auricularia-judae) contain 1 to 17% percent of trehalose in dry weight form, and is also referred to as mushroom sugar. Trehalose can also be found in such microorganisms as baker's yeast and wine yeast.
===Cryptobiosis===
When Tardigrades (water bears) dry out, the glucose in their bodies changes to trehalose when they enter a state called cryptobiosis -- a state where they look as though they are dead. However, when they receive water, they revive and return to their metabolic state. Besides these, it is also thought that the reason the larva of sleeping chironomid (polypedihum vanderplanki) and artemia (sea monkeys) are able to withstand dehydration is because they store trehalose within their cells.
Even within the plant kingdom, selaginella mosses that grow in desert and mountainous areas, although they may be cracked and dried out, will turn green again and revive after a rain. It is because they contain trehalose, it is called the resurrection plant. It is also said that the reason dried shitake mushrooms spring back into shape so well in water is because they contain trehalose.
The theories as to how trehalose works within the organism in the state of cryptobiosis are that of either the vitrification theory, a state that maintains limited molecular activity, or the water displacement theory, whereby water is replaced by trehalose, or a combination of the two theories are at work.
Trehalose is metabolized by a number of bacteria, including Streptococcus mutans, the common oral bacteria responsible for oral plaque.
The enzyme trehalase, a glycoside hydrolase, present but not abundant in most people, breaks trehalose into two glucose molecules, which can then be readily absorbed in the gut.
Trehalose is the major carbohydrate energy storage molecule used by insects for flight. One possible reason for this is that the double glycosidic linkage of trehalose, when acted upon by an insect trehalase, releases two molecules of glucose, which is required for the rapid energy requirements of flight. This is double the efficiency of glucose release from the storage polymer starch, for which cleavage of one glycosidic linkage releases only one glucose molecule.
# Natural sources
- Trehala manna
- Locust
- Resurrection plant
- Fungi
# Use
Trehalose has been accepted as a novel food ingredient under the GRAS terms in the U.S. and the EU. Trehalose has also found commercial application as a food ingredient. The uses for trehalose span a broad spectrum that cannot be found in other sugars, the primary one being its use in the processing of foods. Trehalose is used in a variety of processed foods such as dinners, western and Japanese confectionery, bread, vegetables side dishes, animal derived deli foods, pouch-packed foods, frozen foods, and beverages, as well as used in foods for lunches, eating out, or prepared at home. This use in such a wide range of products is due to the multi-faceted effects of trehalose's properties, such as: its inherently mild sweet flavor, its preservative properties which maintain the quality of one of the three main nutrients, one being carbohydrates (such as starch), as well as proteins and fats; its powerful water-retention properties that preserve the texture of foods by protecting them from drying out or freezing, its properties to suppress smells and tastes such as bitterness, stringency, harsh flavors, and the stench of raw foods, meats, and packaged foods; which when combined can potentially bring about promising results. However, less-soluble and less-sweet than sucrose, trehalose is seldom used as a direct replacement for conventional sweeteners, such as sucrose, regarded as the "gold standard." Technology for the production of trehalose was developed in Japan, where enzyme-based processes converts wheat and corn syrups to trehalose. It is also used as a protein stabilizing agent in research [1]. It is particularly effective when combined with phosphate ions[2]. Trehalose has also been used in at least one biopharmaceutical formulation, the monoclonal antibody trastuzumab, marketed as Herceptin.
===Cosmetics===
Capitalizing on trehalose's moisture retaining capacity, it is used as a moisturizer in many basic toiletries as bath oils and hair growth tonics.
===Pharmaceuticals===
Using trehalose's properties to preserve tissue and protein to full advantage, it is used in organ protection solutions for organ transplants.
===Other===
Other fields of use for trehalose span a broad spectrum including fabrics that have deodorization qualities and are compatible to Japan's official 'Cool Biz' attire; plant activation, antibacterial sheets and nutrients for larvae.
# Solubility
68.9 g/100 g H2O at 20 °C
[3]
# External links
- Cryopreservation with Sugars
- Novel functions and applications of trehalose | https://www.wikidoc.org/index.php/Trehalose | |
cce26c6ef43d7380cec08b83c65f05e22a298d1a | wikidoc | Triclofos | Triclofos
# Overview
Triclofos is a sedative drug used rarely for treating insomnia, usually as a second-line treatment after other drugs have failed. Triclofos may cause dependence and should not be withdrawn suddenly. This drug should only be used for the short term relief of severe insomnia and should not be mixed with alcohol or other depressant drugs. Patients should not drive or use machinery after taking triclofos.
Triclofos is a prodrug which is metabolised in the liver into the active drug trichloroethanol. This delayed action means that the half-life of triclofos is fairly long and it may cause drowsiness the next day. Trichloroethanol may cause liver damage and triclofos should not be used for extended periods.
# Side effects
Side effects may include: headache, rash, dizziness, flatulence, confusion, nightmares, dependence, diarrhoea, constipation, nausea, vomiting, abdominal pain, and ataxia. | Triclofos
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Triclofos is a sedative drug used rarely for treating insomnia, usually as a second-line treatment after other drugs have failed. Triclofos may cause dependence and should not be withdrawn suddenly. This drug should only be used for the short term relief of severe insomnia and should not be mixed with alcohol or other depressant drugs. Patients should not drive or use machinery after taking triclofos.
Triclofos is a prodrug which is metabolised in the liver into the active drug trichloroethanol. This delayed action means that the half-life of triclofos is fairly long and it may cause drowsiness the next day. Trichloroethanol may cause liver damage and triclofos should not be used for extended periods.
# Side effects
Side effects may include: headache, rash, dizziness, flatulence, confusion, nightmares, dependence, diarrhoea, constipation, nausea, vomiting, abdominal pain, and ataxia. | https://www.wikidoc.org/index.php/Triclofos | |
e4d223120f9e3a449d3fc11405112b75e22c3408 | wikidoc | Triclosan | Triclosan
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Triclosan is an antiseptic that is FDA approved for the treatment of for hand washing to decrease bacteria on skin. Common adverse reactions include hypersensitivity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For hand washing to decrease bacteria on skin
- Recommended for repeated use
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triclosan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Triclosan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- For hand washing to decrease bacteria on skin
- Recommended for repeated use
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triclosan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Triclosan in pediatric patients.
# Contraindications
There is limited information regarding Triclosan Contraindications in the drug label.
# Warnings
- For external use only.
- When using this product avoid contact with eyes. In case of eye contact, flush eyes with water.
- Stop use and ask a doctor if irritation or redness develops, or if condition persists for more than 72 hours.
- Keep out of reach of children.
- If swallowed, get medical help or contact a Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Triclosan in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Triclosan in the drug label.
# Drug Interactions
There is limited information regarding Triclosan Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Triclosan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Triclosan during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Triclosan with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Triclosan with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Triclosan with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Triclosan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Triclosan with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Triclosan in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Triclosan in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Triclosan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Triclosan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Triclosan in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Triclosan in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Triclosan in the drug label.
# Pharmacology
## Mechanism of Action
- At high concentrations, triclosan acts as a biocide with multiple cytoplasmic and membrane targets. However, at the lower concentrations seen in commercial products, triclosan appears bacteriostatic, and it targets bacteria primarily by inhibiting fatty acid synthesis.
- Triclosan binds to bacterial enoyl-acyl carrier protein reductase (ENR) enzyme, which is encoded by the gene FabI. This binding increases the enzyme's affinity for nicotinamide adenine dinucleotide (NAD+). This results in the formation of a stable, ternary complex of ENR-NAD+-triclosan, which is unable to participate in fatty acid synthesis. Fatty acids are necessary for building and reproducing cell membranes. Humans do not have an ENR enzyme and thus are not affected.
## Structure
There is limited information regarding Triclosan Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Triclosan in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Triclosan in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Triclosan in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Triclosan in the drug label.
# How Supplied
There is limited information regarding Triclosan How Supplied in the drug label.
## Storage
There is limited information regarding Triclosan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Triclosan in the drug label.
# Precautions with Alcohol
- Alcohol-Triclosan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ANTIBACTERIAL SPRAY®
# Look-Alike Drug Names
There is limited information regarding Triclosan Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Triclosan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Triclosan is an antiseptic that is FDA approved for the treatment of for hand washing to decrease bacteria on skin. Common adverse reactions include hypersensitivity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For hand washing to decrease bacteria on skin
- Recommended for repeated use
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triclosan in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Triclosan in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- For hand washing to decrease bacteria on skin
- Recommended for repeated use
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Triclosan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Triclosan in pediatric patients.
# Contraindications
There is limited information regarding Triclosan Contraindications in the drug label.
# Warnings
- For external use only.
- When using this product avoid contact with eyes. In case of eye contact, flush eyes with water.
- Stop use and ask a doctor if irritation or redness develops, or if condition persists for more than 72 hours.
- Keep out of reach of children.
- If swallowed, get medical help or contact a Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Triclosan in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Triclosan in the drug label.
# Drug Interactions
There is limited information regarding Triclosan Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Triclosan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Triclosan during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Triclosan with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Triclosan with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Triclosan with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Triclosan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Triclosan with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Triclosan in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Triclosan in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Triclosan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Triclosan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Triclosan in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Triclosan in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Triclosan in the drug label.
# Pharmacology
## Mechanism of Action
- At high concentrations, triclosan acts as a biocide with multiple cytoplasmic and membrane targets.[1] However, at the lower concentrations seen in commercial products, triclosan appears bacteriostatic, and it targets bacteria primarily by inhibiting fatty acid synthesis.
- Triclosan binds to bacterial enoyl-acyl carrier protein reductase (ENR) enzyme, which is encoded by the gene FabI. This binding increases the enzyme's affinity for nicotinamide adenine dinucleotide (NAD+). This results in the formation of a stable, ternary complex of ENR-NAD+-triclosan, which is unable to participate in fatty acid synthesis. Fatty acids are necessary for building and reproducing cell membranes. Humans do not have an ENR enzyme and thus are not affected.
## Structure
There is limited information regarding Triclosan Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Triclosan in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Triclosan in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Triclosan in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Triclosan in the drug label.
# How Supplied
There is limited information regarding Triclosan How Supplied in the drug label.
## Storage
There is limited information regarding Triclosan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Triclosan in the drug label.
# Precautions with Alcohol
- Alcohol-Triclosan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ANTIBACTERIAL SPRAY®[2]
# Look-Alike Drug Names
There is limited information regarding Triclosan Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Triclosan | |
e7a775c2d5d73423cce6fde5d2e14bdd77383a61 | wikidoc | Trientine | Trientine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Trientine is a heavy metal chelator that is FDA approved for the treatment of Wilson's disease. Common adverse reactions include iron deficiency, systemic lupus erythematosus,dystonia, muscular spasm, myasthenia gravis..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- SYPRINE is indicated in the treatment of patients with Wilson's disease who are intolerant of penicillamine. Clinical experience with SYPRINE is limited and alternate dosing regimens have not been well-characterized; all endpoints in determining an individual patient's dose have not been well defined. SYPRINE and penicillamine cannot be considered interchangeable. SYPRINE should be used when continued treatment with penicillamine is no longer possible because of intolerable or life endangering side effects.
- Unlike penicillamine, SYPRINE is not recommended in cystinuria or rheumatoid arthritis. The absence of a sulfhydryl moiety renders it incapable of binding cystine and, therefore, it is of no use in cystinuria. In 15 patients with rheumatoid arthritis, SYPRINE was reported not to be effective in improving any clinical or biochemical parameter after 12 weeks of treatment.
- SYPRINE is not indicated for treatment of biliary cirrhosis.
# Dosage
- Systemic evaluation of dose and/or interval between dose has not been done. However, on limited clinical experience, the recommended initial dose of SYPRINE is 500-750 mg/day for pediatric patients and 750-1250 mg/day for adults given in divided doses two, three or four times daily. This may be increased to a maximum of 2000 mg/day for adults or 1500 mg/day for pediatric patients age 12 or under.
- The daily dose of SYPRINE should be increased only when the clinical response is not adequate or the concentration of free serum copper is persistently above 20 mcg/dL. Optimal long-term maintenance dosage should be determined at 6-12 month intervals.
- It is important that SYPRINE be given on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. The capsules should be swallowed whole with water and should not be opened or chewed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trientine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Trientine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
- SYPRINE is indicated in the treatment of patients with Wilson's disease who are intolerant of penicillamine. Clinical experience with SYPRINE is limited and alternate dosing regimens have not been well-characterized; all endpoints in determining an individual patient's dose have not been well defined. SYPRINE and penicillamine cannot be considered interchangeable. SYPRINE should be used when continued treatment with penicillamine is no longer possible because of intolerable or life endangering side effects.
- Unlike penicillamine, SYPRINE is not recommended in cystinuria or rheumatoid arthritis. The absence of a sulfhydryl moiety renders it incapable of binding cystine and, therefore, it is of no use in cystinuria. In 15 patients with rheumatoid arthritis, SYPRINE was reported not to be effective in improving any clinical or biochemical parameter after 12 weeks of treatment.
- SYPRINE is not indicated for treatment of biliary cirrhosis.
# Dosage
- Systemic evaluation of dose and/or interval between dose has not been done. However, on limited clinical experience, the recommended initial dose of SYPRINE is 500-750 mg/day for pediatric patients and 750-1250 mg/day for adults given in divided doses two, three or four times daily. This may be increased to a maximum of 2000 mg/day for adults or 1500 mg/day for pediatric patients age 12 or under.
- The daily dose of SYPRINE should be increased only when the clinical response is not adequate or the concentration of free serum copper is persistently above 20 mcg/dL. Optimal long-term maintenance dosage should be determined at 6-12 month intervals.
- It is important that SYPRINE be given on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. The capsules should be swallowed whole with water and should not be opened or chewed.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Trientine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Trientine in pediatric patients.
# Contraindications
- Hypersensitivity to this product.
# Warnings
- Patient experience with trientine hydrochloride is limited. Patients receiving SYPRINE should remain under regular medical supervision throughout the period of drug administration. Patients (especially women) should be closely monitored for evidence of iron deficiency anemia.
# Adverse Reactions
## Clinical Trials Experience
- Clinical experience with SYPRINE has been limited. The following adverse reactions have been reported in a clinical study in patients with Wilson's disease who were on therapy with trientine hydrochloride: iron deficiency, systemic lupus erythematosus. In addition, the following adverse reactions have been reported in marketed use: dystonia, muscular spasm, myasthenia gravis.
- SYPRINE is not indicated for treatment of biliary cirrhosis, but in one study of 4 patients treated with trientine hydrochloride for primary biliary cirrhosis, the following adverse reactions were reported: heartburn; epigastric pain and tenderness; thickening, fissuring and flaking of the skin; hypochromic microcytic anemia; acute gastritis; aphthoid ulcers; abdominal pain; melena; anorexia; malaise; cramps; muscle pain; weakness; rhabdomyolysis. A causal relationship of these reactions to drug therapy could not be rejected or established.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Trientine in the drug label.
# Drug Interactions
- In general, mineral supplements should not be given since they may block the absorption of SYPRINE. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and SYPRINE each inhibit absorption of the other, two hours should elapse between administration of SYPRINE and iron.
- It is important that SYPRINE be taken on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. This permits maximum absorption and reduces the likelihood of inactivation of the drug by metal binding in the gastrointestinal tract.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- Trientine hydrochloride was teratogenic in rats at doses similar to the human dose. The frequencies of both resorptions and fetal abnormalities, including hemorrhage and edema, increased while fetal copper levels decreased when trientine hydrochloride was given in the maternal diets of rats. There are no adequate and well-controlled studies in pregnant women. SYPRINE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trientine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Trientine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SYPRINE is administered to a nursing mother.
### Pediatric Use
- Controlled studies of the safety and effectiveness of SYPRINE in pediatric patients have not been conducted. It has been used clinically in pediatric patients as young as 6 years with no reported adverse experiences.
### Geriatic Use
- Clinical studies of SYPRINE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience is insufficient to determine differences in responses between the elderly and younger patients. In general, dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
### Gender
- There is no FDA guidance on the use of Trientine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Trientine with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Trientine in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Trientine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Trientine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Trientine in patients who are immunocompromised.
### Others
# Administration and Monitoring
### Administration
- Oral
- Patients should be directed to take SYPRINE on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. The capsules should be swallowed whole with water and should not be opened or chewed. Because of the potential for contact dermatitis, any site of exposure to the capsule contents should be washed with water promptly. For the first month of treatment, the patient should have his temperature taken nightly, and he should be asked to report any symptom such as fever or skin eruption.
### Monitoring
- There is limited information regarding Monitoring of Trientine in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Trientine in the drug label.
# Overdosage
## Acute Overdose
- There is a report of an adult woman who ingested 30 grams of trientine hydrochloride without apparent ill effects. No other data on overdosage are available.
# Pharmacology
## Mechanism of Action
- There is limited information regarding Mechanism Of Action of Trientine in the drug label.
## Structure
- Trientine hydrochloride is N,N'-bis (2-aminoethyl)-1,2-ethanediamine dihydrochloride. It is a white to pale yellow crystalline hygroscopic powder. It is freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform and ether.
The empirical formula is C6H18N42HCl with a molecular weight of 219.2. The structural formula is:
Trientine hydrochloride is a chelating compound for removal of excess copper from the body. SYPRINE1 (Trientine Hydrochloride) is available as 250 mg capsules for oral administration. Capsules SYPRINE contain gelatin, iron oxides, stearic acid, and titanium dioxide as inactive ingredients.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Trientine in the drug label.
## Pharmacokinetics
- Data on the pharmacokinetics of trientine hydrochloride are not available. Dosage adjustment recommendations are based upon clinical use of the drug.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Data on carcinogenesis, mutagenesis, and impairment of fertility are not available.
# Clinical Studies
- There is limited information regarding Clinical Studies of Trientine in the drug label.
# How Supplied
- Capsules SYPRINE, 250 mg, are light brown opaque capsules coded SYPRINE on one side and ATON 710 on the other. They are supplied as follows:
- NDC 0187-2120-10 in bottles of 100.
## Storage
- Keep container tightly closed.
- Store at 2-8°C (36-46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- There is limited information regarding Patient Counseling Information of Trientine in the drug label.
# Precautions with Alcohol
- Alcohol-Trientine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SYPRINE ®
# Look-Alike Drug Names
There is limited information regarding Trientine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Trientine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Trientine is a heavy metal chelator that is FDA approved for the treatment of Wilson's disease. Common adverse reactions include iron deficiency, systemic lupus erythematosus,dystonia, muscular spasm, myasthenia gravis..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- SYPRINE is indicated in the treatment of patients with Wilson's disease who are intolerant of penicillamine. Clinical experience with SYPRINE is limited and alternate dosing regimens have not been well-characterized; all endpoints in determining an individual patient's dose have not been well defined. SYPRINE and penicillamine cannot be considered interchangeable. SYPRINE should be used when continued treatment with penicillamine is no longer possible because of intolerable or life endangering side effects.
- Unlike penicillamine, SYPRINE is not recommended in cystinuria or rheumatoid arthritis. The absence of a sulfhydryl moiety renders it incapable of binding cystine and, therefore, it is of no use in cystinuria. In 15 patients with rheumatoid arthritis, SYPRINE was reported not to be effective in improving any clinical or biochemical parameter after 12 weeks of treatment.
- SYPRINE is not indicated for treatment of biliary cirrhosis.
# Dosage
- Systemic evaluation of dose and/or interval between dose has not been done. However, on limited clinical experience, the recommended initial dose of SYPRINE is 500-750 mg/day for pediatric patients and 750-1250 mg/day for adults given in divided doses two, three or four times daily. This may be increased to a maximum of 2000 mg/day for adults or 1500 mg/day for pediatric patients age 12 or under.
- The daily dose of SYPRINE should be increased only when the clinical response is not adequate or the concentration of free serum copper is persistently above 20 mcg/dL. Optimal long-term maintenance dosage should be determined at 6-12 month intervals.
- It is important that SYPRINE be given on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. The capsules should be swallowed whole with water and should not be opened or chewed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trientine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Trientine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
- SYPRINE is indicated in the treatment of patients with Wilson's disease who are intolerant of penicillamine. Clinical experience with SYPRINE is limited and alternate dosing regimens have not been well-characterized; all endpoints in determining an individual patient's dose have not been well defined. SYPRINE and penicillamine cannot be considered interchangeable. SYPRINE should be used when continued treatment with penicillamine is no longer possible because of intolerable or life endangering side effects.
- Unlike penicillamine, SYPRINE is not recommended in cystinuria or rheumatoid arthritis. The absence of a sulfhydryl moiety renders it incapable of binding cystine and, therefore, it is of no use in cystinuria. In 15 patients with rheumatoid arthritis, SYPRINE was reported not to be effective in improving any clinical or biochemical parameter after 12 weeks of treatment.
- SYPRINE is not indicated for treatment of biliary cirrhosis.
# Dosage
- Systemic evaluation of dose and/or interval between dose has not been done. However, on limited clinical experience, the recommended initial dose of SYPRINE is 500-750 mg/day for pediatric patients and 750-1250 mg/day for adults given in divided doses two, three or four times daily. This may be increased to a maximum of 2000 mg/day for adults or 1500 mg/day for pediatric patients age 12 or under.
- The daily dose of SYPRINE should be increased only when the clinical response is not adequate or the concentration of free serum copper is persistently above 20 mcg/dL. Optimal long-term maintenance dosage should be determined at 6-12 month intervals.
- It is important that SYPRINE be given on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. The capsules should be swallowed whole with water and should not be opened or chewed.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Trientine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Trientine in pediatric patients.
# Contraindications
- Hypersensitivity to this product.
# Warnings
- Patient experience with trientine hydrochloride is limited. Patients receiving SYPRINE should remain under regular medical supervision throughout the period of drug administration. Patients (especially women) should be closely monitored for evidence of iron deficiency anemia.
# Adverse Reactions
## Clinical Trials Experience
- Clinical experience with SYPRINE has been limited. The following adverse reactions have been reported in a clinical study in patients with Wilson's disease who were on therapy with trientine hydrochloride: iron deficiency, systemic lupus erythematosus. In addition, the following adverse reactions have been reported in marketed use: dystonia, muscular spasm, myasthenia gravis.
- SYPRINE is not indicated for treatment of biliary cirrhosis, but in one study of 4 patients treated with trientine hydrochloride for primary biliary cirrhosis, the following adverse reactions were reported: heartburn; epigastric pain and tenderness; thickening, fissuring and flaking of the skin; hypochromic microcytic anemia; acute gastritis; aphthoid ulcers; abdominal pain; melena; anorexia; malaise; cramps; muscle pain; weakness; rhabdomyolysis. A causal relationship of these reactions to drug therapy could not be rejected or established.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Trientine in the drug label.
# Drug Interactions
- In general, mineral supplements should not be given since they may block the absorption of SYPRINE. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and SYPRINE each inhibit absorption of the other, two hours should elapse between administration of SYPRINE and iron.
- It is important that SYPRINE be taken on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. This permits maximum absorption and reduces the likelihood of inactivation of the drug by metal binding in the gastrointestinal tract.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- Trientine hydrochloride was teratogenic in rats at doses similar to the human dose. The frequencies of both resorptions and fetal abnormalities, including hemorrhage and edema, increased while fetal copper levels decreased when trientine hydrochloride was given in the maternal diets of rats. There are no adequate and well-controlled studies in pregnant women. SYPRINE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trientine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Trientine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SYPRINE is administered to a nursing mother.
### Pediatric Use
- Controlled studies of the safety and effectiveness of SYPRINE in pediatric patients have not been conducted. It has been used clinically in pediatric patients as young as 6 years with no reported adverse experiences.
### Geriatic Use
- Clinical studies of SYPRINE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience is insufficient to determine differences in responses between the elderly and younger patients. In general, dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
### Gender
- There is no FDA guidance on the use of Trientine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Trientine with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Trientine in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Trientine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Trientine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Trientine in patients who are immunocompromised.
### Others
# Administration and Monitoring
### Administration
- Oral
- Patients should be directed to take SYPRINE on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. The capsules should be swallowed whole with water and should not be opened or chewed. Because of the potential for contact dermatitis, any site of exposure to the capsule contents should be washed with water promptly. For the first month of treatment, the patient should have his temperature taken nightly, and he should be asked to report any symptom such as fever or skin eruption.
### Monitoring
- There is limited information regarding Monitoring of Trientine in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Trientine in the drug label.
# Overdosage
## Acute Overdose
- There is a report of an adult woman who ingested 30 grams of trientine hydrochloride without apparent ill effects. No other data on overdosage are available.
# Pharmacology
## Mechanism of Action
- There is limited information regarding Mechanism Of Action of Trientine in the drug label.
## Structure
- Trientine hydrochloride is N,N'-bis (2-aminoethyl)-1,2-ethanediamine dihydrochloride. It is a white to pale yellow crystalline hygroscopic powder. It is freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform and ether.
The empirical formula is C6H18N4•2HCl with a molecular weight of 219.2. The structural formula is:
Trientine hydrochloride is a chelating compound for removal of excess copper from the body. SYPRINE1 (Trientine Hydrochloride) is available as 250 mg capsules for oral administration. Capsules SYPRINE contain gelatin, iron oxides, stearic acid, and titanium dioxide as inactive ingredients.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Trientine in the drug label.
## Pharmacokinetics
- Data on the pharmacokinetics of trientine hydrochloride are not available. Dosage adjustment recommendations are based upon clinical use of the drug.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Data on carcinogenesis, mutagenesis, and impairment of fertility are not available.
# Clinical Studies
- There is limited information regarding Clinical Studies of Trientine in the drug label.
# How Supplied
- Capsules SYPRINE, 250 mg, are light brown opaque capsules coded SYPRINE on one side and ATON 710 on the other. They are supplied as follows:
- NDC 0187-2120-10 in bottles of 100.
## Storage
- Keep container tightly closed.
- Store at 2-8°C (36-46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- There is limited information regarding Patient Counseling Information of Trientine in the drug label.
# Precautions with Alcohol
- Alcohol-Trientine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SYPRINE ®[1]
# Look-Alike Drug Names
There is limited information regarding Trientine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Trientine | |
652e3ae8987ebd89d2baacecc09de118ee98736d | wikidoc | Triflusal | Triflusal
# Overview
Triflusal is a platelet aggregation inhibitor that was discovered and developed in the Uriach Laboratories, and commercialised in Spain since 1981. Currently, it is available in 25 countries in Europe, Asia, Africa and America. It is a drug of the salicylate family but it is not a derivative of acetylsalicylic acid (ASA). Trade names include Disgren, Grendis, Aflen and Triflux
# Mechanism of action
Triflusal is a selective platelet antiaggregant through;
- blocks cyclooxygenase inhibiting thromboxane A2, preventing aggregation
- preserves vascular prostacyclin, thus promoting anti-aggregant effect
- blocks phosphodiesterase thereby increasing cAMP concentration, thereby promoting anti-aggregant effect due to inhibition of calcium mobilization
# Indication
Triflusal is indicated for;
- Prevention of cardiovascular events such as stroke
- Acute treatment of cerebral infarction, myocardial infarction
- Thromboprophylaxis due to atrial fibrillation
# Prevention of Stroke
In the 2008 guidelines for stroke management from the European Stroke Organization, triflusal was for the first time recommended as lone therapy, as an alternative to acetylsalicylic acid plus dipyridamole, or clopidogrel alone for secondary prevention of atherothrombotic stroke. This recommendation was based on the double-blind, randomised TACIP and TAPIRSS trials, which found triflusal to be equally as effective as Aspirin in preventing post-stroke vascular events, while having a more favourable safety profile.
# Pharmacokinetics
It is absorbed in the small intestine and its bio-availability ranges from 83% to 100%. | Triflusal
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Triflusal is a platelet aggregation inhibitor that was discovered and developed in the Uriach Laboratories, and commercialised in Spain since 1981. Currently, it is available in 25 countries in Europe, Asia, Africa and America. It is a drug of the salicylate family but it is not a derivative of acetylsalicylic acid (ASA). Trade names include Disgren, Grendis, Aflen and Triflux [1]
# Mechanism of action
Triflusal is a selective platelet antiaggregant through;
- blocks cyclooxygenase inhibiting thromboxane A2, preventing aggregation
- preserves vascular prostacyclin, thus promoting anti-aggregant effect
- blocks phosphodiesterase thereby increasing cAMP concentration, thereby promoting anti-aggregant effect due to inhibition of calcium mobilization
# Indication
Triflusal is indicated for;
- Prevention of cardiovascular events such as stroke
- Acute treatment of cerebral infarction, myocardial infarction
- Thromboprophylaxis due to atrial fibrillation
# Prevention of Stroke
In the 2008 guidelines for stroke management from the European Stroke Organization, triflusal was for the first time recommended as lone therapy, as an alternative to acetylsalicylic acid plus dipyridamole, or clopidogrel alone for secondary prevention of atherothrombotic stroke. This recommendation was based on the double-blind, randomised TACIP and TAPIRSS trials, which found triflusal to be equally as effective as Aspirin in preventing post-stroke vascular events, while having a more favourable safety profile.[2][3][4]
# Pharmacokinetics
It is absorbed in the small intestine and its bio-availability ranges from 83% to 100%.[5][6] | https://www.wikidoc.org/index.php/Triflusal | |
7bc87c10814fb3cacb3b5fa5917ebe1b12522cc8 | wikidoc | Triiodide | Triiodide
In chemistry, triiodide (sometimes written tri-iodide) can have several meanings. Triiodide primarily refers to the triiodide ion, I3−, a polyatomic anion composed of three iodine atoms. For some chemical compounds, triiodide indicates a salt of the named cation with the triiodide anion. Examples include sodium triiodide, thallium triiodide, and ammonium triiodide (NH4I3). Each of these compounds has a iodide counterpart. For other chemical compounds, triiodide indicates that each molecule contains three iodine atoms that are not bonded to each other, not forming the triiodide ion. Examples include nitrogen triiodide (NI3), phosphorus triiodide, antimony triiodide, and gallium triiodide (Ga2I6). Some anions have the theoretical possibility to form either kind of triiodide. Thallium triiodide is described as thallium(I) triiodide; thallium(III) iodide is unknown.
# Trioidide ion
The triiodide ion, is the simplest polyiodide; several higher polyiodides exist. In solution, it appears yellow in low concentration, and brown at higher concentration. The triiodide ion is responsible for the well-known blue-black color which arises when iodine solutions react with starch. Iodide does not react with starch; nor do solutions of iodine in nonpolar solvents. Lugol's iodine contains potassium iodide as well, so that significant amounts of triiodide ion can exist in solution. Tincture of iodine contains significant amounts of triiodide.
# Formation and structure
The following endergonic equilibrium gives rise to the triiodide ion:
In this reaction, iodide is viewed as a Lewis base, and the iodine is a Lewis acid. The process is analogous to the reaction of S8 with sodium sulfide, except that the higher polyiodides have branched structures.
The ion is linear, as predicted by VSEPR theory. A common explanation for the hypervalent bonding on the central atom involves a three-center four-electron bond. The bond lengths and angles of triiodide vary, depending on the compound. The dimensions of the tri-iodide Ia−Ib−Ic bonds in a few sample compounds are shown below: | Triiodide
In chemistry, triiodide (sometimes written tri-iodide) can have several meanings. Triiodide primarily refers to the triiodide ion, I3−, a polyatomic anion composed of three iodine atoms. For some chemical compounds, triiodide indicates a salt of the named cation with the triiodide anion. Examples include sodium triiodide, thallium triiodide, and ammonium triiodide (NH4I3). Each of these compounds has a [mono]iodide counterpart. For other chemical compounds, triiodide indicates that each molecule contains three iodine atoms that are not bonded to each other, not forming the triiodide ion. Examples include nitrogen triiodide (NI3), phosphorus triiodide, antimony triiodide, and gallium triiodide (Ga2I6). Some anions have the theoretical possibility to form either kind of triiodide. Thallium triiodide is described as thallium(I) triiodide; thallium(III) iodide is unknown.
# Trioidide ion
The triiodide ion, is the simplest polyiodide; several higher polyiodides exist. In solution, it appears yellow in low concentration, and brown at higher concentration. The triiodide ion is responsible for the well-known blue-black color which arises when iodine solutions react with starch. Iodide does not react with starch; nor do solutions of iodine in nonpolar solvents. Lugol's iodine contains potassium iodide as well, so that significant amounts of triiodide ion can exist in solution. Tincture of iodine contains significant amounts of triiodide.
# Formation and structure
The following endergonic equilibrium gives rise to the triiodide ion:
In this reaction, iodide is viewed as a Lewis base, and the iodine is a Lewis acid. The process is analogous to the reaction of S8 with sodium sulfide, except that the higher polyiodides have branched structures.[1]
The ion is linear, as predicted by VSEPR theory. A common explanation for the hypervalent bonding on the central atom involves a three-center four-electron bond. The bond lengths and angles of triiodide vary, depending on the compound. The dimensions of the tri-iodide Ia−Ib−Ic bonds in a few sample compounds are shown below: | https://www.wikidoc.org/index.php/Triiodide | |
176836c84823dcdeebb3c6fc8a4ccdef227b5754 | wikidoc | Triplegia | Triplegia
Triplegia is a medical condition is which the patient has paralysis of three limbs. It is frequently associated with cerebral palsy, although other medical conditions, such as a stroke, can also lead to it. Triplegia has also been found to be due to an increase in intracranial pressure associated with hydrocephalus resulting from traumatic brain injury. A person with triplegia can be referred to as a triplegic.
In cases of cerebral palsy, triplegia is often thought of as hemiplegia overlapping with diplegia. It may also be due to quadriplegia with much less involvement of one limb. In most cases, both of the legs and one arm are affected, but both arms and one leg can be affected also. Resources for children with quadriplegia are generally the most beneficial for children with triplegia.
A similar condition is triparesis, in which the patient suffers from paresis in three limbs, meaning that the limbs are very weak, but not completely paralyzed. | Triplegia
Triplegia is a medical condition is which the patient has paralysis of three limbs. It is frequently associated with cerebral palsy, although other medical conditions, such as a stroke, can also lead to it. Triplegia has also been found to be due to an increase in intracranial pressure associated with hydrocephalus resulting from traumatic brain injury.[1] A person with triplegia can be referred to as a triplegic.
In cases of cerebral palsy, triplegia is often thought of as hemiplegia overlapping with diplegia. It may also be due to quadriplegia with much less involvement of one limb. In most cases, both of the legs and one arm are affected, but both arms and one leg can be affected also. Resources for children with quadriplegia are generally the most beneficial for children with triplegia.
A similar condition is triparesis, in which the patient suffers from paresis in three limbs, meaning that the limbs are very weak, but not completely paralyzed. | https://www.wikidoc.org/index.php/Triplegia | |
b1462808327758dde2fc53bade0448a093fd499b | wikidoc | Troxipide | Troxipide
# Overview
Troxipide is a drug used in the treatment of gastroesophageal reflux disease. Troxipide is a novel systemic non-antisecretory gastric cytoprotective agent with anti-ulcer, anti-inflammatory and mucus secreting properties irrespective of pH of stomach or duodenum. Troxipide is currently marketed in Japan (Aplace), China (Shuqi), South Korea (Defensa), and India (Troxip). It is used for the management of gastric ulcers, and amelioration of gastric mucosal lesions in acute gastritis and acute exacerbation of chronic gastritis.
# Mechanism of action
The unique gastric pH and content independent properties of troxipide include the following:
## Gastric mucosal protection
Gastric mucosa typically is composed of salts and other dialyzable components, free proteins, carbohydrate rich glycoprotein and water. Troxipide fortifies this gastric mucosal barrier by increasing the content of glucosamine, mucopolysaccharides and collagen. Glucosamine is an amino-sugar that is known to stimulate glycoprotein synthesis and protective mechanisms of the gastric mucosa, thereby aiding in ulcer healing. Mucopolysaccharides impart structural integrity to the gastric mucosa and collagen imparts properties like ionic capability to attract blood components essential to tissue regeneration, mechanical protection, high tensile strength and slow digestibility to the gastric mucosa.
## Stimulation of cytoprotective prostaglandins
Almost all of the gastric mucosal defense mechanisms are stimulated and/or facilitated by prostaglandins (PGs), especially PGE2. These cytoprotective PGs stimulate mucus, bicarbonate, and phospholipid secretion; increase mucosal blood flow; and accelerate epithelial restitution and mucosal healing. They also inhibit mast cell activation, and leukocyte and platelet adherence to the vascular endothelium. Thus, continuous generation of PGE2 by gastric mucosa is crucial for the maintenance of mucosal integrity and protection against ulcerogenic and necrotizing agents. Troxipide is known to stimulate the release of PGE2 and PGD2 in experimental as well as clinical studies. Troxipide has been observed to enhance PG-stimulated increase in gastric mucosal output, accelerated epithelial restitution and mucosal healing.
## Suppression of gastric inflammation
Gastric inflammation is a highly complex biochemical protective response to cellular injury. In the multitude of mechanisms involved in the development of gastric mucosal inflammation, derangement of the microcirculatory system is a common initial pathway.
Troxipide inhibits various proinflammatory mediators present at different stages of the microcirculatory system, thereby restoring the normal gastric mucosa. Troxipide caused the inhibition of recombinant interleukin-8 (IL-8) induced migration of the inflammatory cells. Two other pro-inflammatory mediators causing oxidative stress that are inhibited by Troxipide include the formyl-methionyl-leucyl-phenylalanine (fMLP) and the Platelet Activating Factor (PAF).
In addition to inhibition of pro-inflammatory mediators, troxipide directly acts on the enzymes such as xanthine oxidase and myeloperoxidase that generate free oxygen radicals in gastric mucosa. Experimental studies have demonstrated that troxipide restrains NSAID-induced generation of porphyrins, tissue peroxidation and gastric lesion formation.
## Enhancement of mucosal metabolism
Gastric parietal cells are rich in mitochondria which provide energy in the form of ATP for cells by oxidative phosphorylation, critical to maintain the proper morphology and function of gastric mucosa. The mitochondrion is the major target of intracellular oxidative stress associated with aggressive factors like H. pylori, alcohol and NSAIDs, which disturb the energy metabolism of mitochondria. Troxipide accelerates oxygen intake of marginal gastric mucosa and glycogen consumptive stimulation of the gastric mucosa of the corpus, thereby elevating the tissue respiration and energy metabolism.
## Stimulation of mucosal microcirculation
Troxipide enhances mucosal blood flow, which is the secondary defense barrier of gastric mucosa that supplies nutrients and oxygen to the epithelium, and removes, dilutes and neutralizes toxic substances that have diffused into the mucosa from the lumen. The increment in mucosal blood flow with troxipide is more pronounced in the gastric antrum than in the gastric corpus.
## Anti-Helicobacter pylori action
Troxipide inhibits H. pylori-derived urease, a multimeric nickel-containing enzyme that catalyses the hydrolysis of urea to yield ammonia and carbonic acid, which damage host tissues and trigger inflammatory response, including recruitment of leukocytes and triggering of the oxidative burst in neutrophils.
# Pharmacokinetics
Troxipide is well absorbed throughout the gastrointestinal tract with a relative bioavailability of 99.6%. At any time, a mean concentration of 5.3- 8.9 µg of troxipide is present per gram of tissue, which is capable of inhibiting the chemotactic migration and superoxide generation in the gastric mucosa. Thus, even 3 hrs after attaining peak serum levels, troxipide is found in therapeutically active concentrations in the small intestine, liver and stomach. The elimination half-life of troxipide is 7.5 hours, and is mainly excreted in urine (96% as metabolites).
# Clinical experience
Troxipide has been well established in the treatment of gastric ulcers showing an overall amelioration rate of 79.4%. An overall endoscopic healing rate of 66.7% after 8 weeks and 80% after 12 weeks of drug administration was achieved with troxipide (100 mg t.i.d. (three times a day)). In patients with duodenal ulcers, troxipide showed endoscopic healing rate of 53.3% and 73% at 8 weeks and 12 weeks respectively. At the end of the treatment, an overall improvement of 86.6% and 93.3% was achieved in patients with gastric ulcer and duodenal ulcer respectively.
In patients with acute gastritis and acute gastric mucosal lesions, an overall amelioration rate of 82.9% has been observed with troxipide. In a comparative study evaluating the efficacy of troxipide (100 mg t.i.d.) with Ranitidine (150 mg b.i.d. (two times a day)), administered over 28 days in patients with gastritis, troxipide was statistically superior to Ranitidine, both with respect to resolution of gastritis clinical signs (abdominal pain, bloating, belching and heartburn) as well as the endoscopic evidences (erosion, oozing, redness and edema). A study comparing the efficacy of troxipide (100 mg t.i.d for 28 days) with Rabeprazole (20 mg o.d. for 28 days) in patients suffering from gastritis showed that improvement in abdominal pain and nausea was significantly superior with troxipide at the end of 14 days. Troxipide administration caused a marked reduction in clinical (abdominal pain, bloating, belching, nausea, vomiting, loss of appetite and heartburn) and endoscopic signs of gastritis by the end of the treatment, though it did not significantly differ from that of Rabeprazole.
In patients with APDs like dyspepsia, gastritis, GERD and/or gastric ulcer, uncontrolled with acid inhibitors viz. proton pump inhibitors (PPIs), histamine receptor antagonists (H2RAs) etc., troxipide (100 mg t.i.d. for 28 days) showed significant improvement in all major symptoms such as nausea, vomiting, belching, heartburn, epigastric pain, acid regurgitation, abdominal bloating & loss of appetite.
# Safety and tolerability
A post-marketing study, conducted by the innovator, in over 12,000 patients showed that only 0.75% of them developed adverse events attributable to the drug. The adverse reactions were mild to moderate, which resolved when the drug was discontinued. Commonly observed adverse events included constipation (0.19%) and increase in levels of liver enzymes, AST (0.17%) and ALT (0.25%). In a post-marketing study conducted in 1500 Indian patients, only 9 adverse events were reported in 9 patients (0.63%) that were of mild to moderate intensity. Adverse events observed included constipation, acidity, nausea, fatigue and headache, and were of mild to moderate intensity.
In all clinical studies, troxipide was well tolerated. In a comparative study with ranitidine, troxipide was assessed as a more tolerable medication than ranitidine. A favorable tolerability profile for troxipide was reported by 95.45% of the investigators as compared to 65.45% for ranitidine while favorable tolerability profile was reported by 93.67% of the patients for troxipide and 64.55% for ranitidine. | Troxipide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Troxipide is a drug used in the treatment of gastroesophageal reflux disease. Troxipide is a novel systemic non-antisecretory gastric cytoprotective agent with anti-ulcer, anti-inflammatory and mucus secreting properties irrespective of pH of stomach or duodenum. Troxipide is currently marketed in Japan (Aplace),[1] China (Shuqi),[2] South Korea (Defensa),[3] and India (Troxip).[4] It is used for the management of gastric ulcers, and amelioration of gastric mucosal lesions in acute gastritis and acute exacerbation of chronic gastritis.
# Mechanism of action
The unique gastric pH and content independent properties of troxipide include the following:
## Gastric mucosal protection
Gastric mucosa typically is composed of salts and other dialyzable components, free proteins, carbohydrate rich glycoprotein and water. Troxipide fortifies this gastric mucosal barrier by increasing the content of glucosamine, mucopolysaccharides and collagen.[5][6] Glucosamine is an amino-sugar that is known to stimulate glycoprotein synthesis and protective mechanisms of the gastric mucosa, thereby aiding in ulcer healing.[7] Mucopolysaccharides impart structural integrity to the gastric mucosa and collagen imparts properties like ionic capability to attract blood components essential to tissue regeneration, mechanical protection, high tensile strength and slow digestibility to the gastric mucosa.[8][9]
## Stimulation of cytoprotective prostaglandins
Almost all of the gastric mucosal defense mechanisms are stimulated and/or facilitated by prostaglandins (PGs), especially PGE2.[10] These cytoprotective PGs stimulate mucus, bicarbonate, and phospholipid secretion; increase mucosal blood flow; and accelerate epithelial restitution and mucosal healing. They also inhibit mast cell activation, and leukocyte and platelet adherence to the vascular endothelium. Thus, continuous generation of PGE2 by gastric mucosa is crucial for the maintenance of mucosal integrity and protection against ulcerogenic and necrotizing agents.[10] Troxipide is known to stimulate the release of PGE2 and PGD2 in experimental as well as clinical studies. Troxipide has been observed to enhance PG-stimulated increase in gastric mucosal output, accelerated epithelial restitution and mucosal healing.[11]
## Suppression of gastric inflammation
Gastric inflammation is a highly complex biochemical protective response to cellular injury.[12] In the multitude of mechanisms involved in the development of gastric mucosal inflammation, derangement of the microcirculatory system is a common initial pathway.[13]
Troxipide inhibits various proinflammatory mediators present at different stages of the microcirculatory system, thereby restoring the normal gastric mucosa. Troxipide caused the inhibition of recombinant interleukin-8 (IL-8) induced migration of the inflammatory cells.[14] Two other pro-inflammatory mediators causing oxidative stress that are inhibited by Troxipide include the formyl-methionyl-leucyl-phenylalanine (fMLP) and the Platelet Activating Factor (PAF).[14]
In addition to inhibition of pro-inflammatory mediators, troxipide directly acts on the enzymes such as xanthine oxidase and myeloperoxidase that generate free oxygen radicals in gastric mucosa.[15] Experimental studies have demonstrated that troxipide restrains NSAID-induced generation of porphyrins, tissue peroxidation and gastric lesion formation.[16]
## Enhancement of mucosal metabolism
Gastric parietal cells are rich in mitochondria which provide energy in the form of ATP for cells by oxidative phosphorylation, critical to maintain the proper morphology and function of gastric mucosa. The mitochondrion is the major target of intracellular oxidative stress associated with aggressive factors like H. pylori, alcohol and NSAIDs,[17] which disturb the energy metabolism of mitochondria. Troxipide accelerates oxygen intake of marginal gastric mucosa and glycogen consumptive stimulation of the gastric mucosa of the corpus,[18] thereby elevating the tissue respiration and energy metabolism.
## Stimulation of mucosal microcirculation
Troxipide enhances mucosal blood flow, which is the secondary defense barrier of gastric mucosa that supplies nutrients and oxygen to the epithelium, and removes, dilutes and neutralizes toxic substances that have diffused into the mucosa from the lumen.[19][20] The increment in mucosal blood flow with troxipide is more pronounced in the gastric antrum than in the gastric corpus.[20]
## Anti-Helicobacter pylori action
Troxipide inhibits H. pylori-derived urease, a multimeric nickel-containing enzyme that catalyses the hydrolysis of urea to yield ammonia and carbonic acid, which damage host tissues and trigger inflammatory response, including recruitment of leukocytes and triggering of the oxidative burst in neutrophils.[14][21]
# Pharmacokinetics
Troxipide is well absorbed throughout the gastrointestinal tract with a relative bioavailability of 99.6%.[22] At any time, a mean concentration of 5.3- 8.9 µg of troxipide is present per gram of tissue, which is capable of inhibiting the chemotactic migration and superoxide generation in the gastric mucosa. Thus, even 3 hrs after attaining peak serum levels, troxipide is found in therapeutically active concentrations in the small intestine, liver and stomach.[14] The elimination half-life of troxipide is 7.5 hours, and is mainly excreted in urine (96% as metabolites).[6][23]
# Clinical experience
Troxipide has been well established in the treatment of gastric ulcers showing an overall amelioration rate of 79.4%.[6] An overall endoscopic healing rate of 66.7% after 8 weeks and 80% after 12 weeks of drug administration was achieved with troxipide (100 mg t.i.d. (three times a day)). In patients with duodenal ulcers, troxipide showed endoscopic healing rate of 53.3% and 73% at 8 weeks and 12 weeks respectively. At the end of the treatment, an overall improvement of 86.6% and 93.3% was achieved in patients with gastric ulcer and duodenal ulcer respectively.[24]
In patients with acute gastritis and acute gastric mucosal lesions, an overall amelioration rate of 82.9% has been observed with troxipide.[6] In a comparative study evaluating the efficacy of troxipide (100 mg t.i.d.) with Ranitidine (150 mg b.i.d. (two times a day)), administered over 28 days in patients with gastritis, troxipide was statistically superior to Ranitidine, both with respect to resolution of gastritis clinical signs (abdominal pain, bloating, belching and heartburn) as well as the endoscopic evidences (erosion, oozing, redness and edema).[25] A study comparing the efficacy of troxipide (100 mg t.i.d for 28 days) with Rabeprazole (20 mg o.d. for 28 days) in patients suffering from gastritis showed that improvement in abdominal pain and nausea was significantly superior with troxipide at the end of 14 days. Troxipide administration caused a marked reduction in clinical (abdominal pain, bloating, belching, nausea, vomiting, loss of appetite and heartburn) and endoscopic signs of gastritis by the end of the treatment, though it did not significantly differ from that of Rabeprazole.[26]
In patients with APDs like dyspepsia, gastritis, GERD and/or gastric ulcer, uncontrolled with acid inhibitors viz. proton pump inhibitors (PPIs), histamine receptor antagonists (H2RAs) etc., troxipide (100 mg t.i.d. for 28 days) showed significant improvement in all major symptoms such as nausea, vomiting, belching, heartburn, epigastric pain, acid regurgitation, abdominal bloating & loss of appetite.[27]
# Safety and tolerability
A post-marketing study, conducted by the innovator, in over 12,000 patients showed that only 0.75% of them developed adverse events attributable to the drug.[6] The adverse reactions were mild to moderate, which resolved when the drug was discontinued. Commonly observed adverse events included constipation (0.19%) and increase in levels of liver enzymes, AST (0.17%) and ALT (0.25%). In a post-marketing study conducted in 1500 Indian patients, only 9 adverse events were reported in 9 patients (0.63%) that were of mild to moderate intensity.[27] Adverse events observed included constipation, acidity, nausea, fatigue and headache, and were of mild to moderate intensity.[27]
In all clinical studies, troxipide was well tolerated. In a comparative study with ranitidine, troxipide was assessed as a more tolerable medication than ranitidine. A favorable tolerability profile for troxipide was reported by 95.45% of the investigators as compared to 65.45% for ranitidine while favorable tolerability profile was reported by 93.67% of the patients for troxipide and 64.55% for ranitidine.[25] | https://www.wikidoc.org/index.php/Troxipide | |
dd4a9985791dc031b3fc3c5ebcc54f8672f45b00 | wikidoc | Tubulinea | Tubulinea
The Tubulinea are a major class of Amoebozoa, including most of the larger and more familiar amoebae like
Amoeba, Arcella, and Difflugia. During locomotion most Tubulinea have a roughly cylindrical
form or produce numerous cylindrical pseudopods. Each cylinder advances by a single central stream of cytoplasm,
granular in appearance, and has no subpseudopodia. This distinguishes them from other amoeboid groups, although in
some members this is not the normal type of locomotion.
This class was anticipated by some biologists like Jahn, who grouped all amoebae with granular pseudopodia together, but most split the lobose amoebae into testate Testacealobosia and naked Gymnamoebia. The latter are polyphyletic, but molecular trees by Bolivar et al. identified a core monophyletic subgroup. Subsequent studies showed the testate lobose amoebae belong to the same group, which was thus renamed Lobosea sensu stricto or Tubulinea. | Tubulinea
The Tubulinea are a major class of Amoebozoa, including most of the larger and more familiar amoebae like
Amoeba, Arcella, and Difflugia. During locomotion most Tubulinea have a roughly cylindrical
form or produce numerous cylindrical pseudopods. Each cylinder advances by a single central stream of cytoplasm,
granular in appearance, and has no subpseudopodia. This distinguishes them from other amoeboid groups, although in
some members this is not the normal type of locomotion.
This class was anticipated by some biologists like Jahn, who grouped all amoebae with granular pseudopodia together[1], but most split the lobose amoebae into testate Testacealobosia and naked Gymnamoebia. The latter are polyphyletic, but molecular trees by Bolivar et al.[2] identified a core monophyletic subgroup. Subsequent studies showed the testate lobose amoebae belong to the same group, which was thus renamed Lobosea sensu stricto[3] or Tubulinea.[4] | https://www.wikidoc.org/index.php/Tubulinea | |
c4dc2a70dc5318fe737dc3dde0b7d8782c7c5179 | wikidoc | Tungiasis | Tungiasis
# Overview
Tungiasis is a skin infestation of the Tunga penetrans flea (also known as chigoe flea, jigger, nigua or sand flea), found in the tropical parts of Africa, Caribbean, Central and South America, and India. This disease is endemic in Nigeria and Trinidad and Tobago where in the 1980s the prevalence of tungiasis among children approached 40%. It is rarely found outside these areas.
# History
The first reported case of tungiasis was noted in the 1500s by Gonzalez Fernandez De Oviedo y Valdes, when sailors from the Santa Maria who sailed with Christopher Columbus were shipwrecked on Haiti and became infected. Tungiasis also infected many of the soldiers of the Spanish conquistadores, who also reported that an entire village in Colombia was abandoned because of this disease. The first clinical account of tungiasis was provided by the Portuguese doctor Aleixo de Abreu.
# Symptoms
The symptoms of this disease include:
- Severe pruritus
- Pain
- Inflammation and swelling
- Lesions and ulcerations, with black dots in the center
Left untreated, secondary infections such as bacteremia, tetanus, and gangrene can occur.
# Prevention
Because of their limited jumping ability, the most common sites of infection are the soles of the feet, the toe web and toenails. Preventing infection by chigoe flea is easily achieved by wearing shoes when traveling in endemic regions and spraying insecticides on infested soil. Walking barefoot, especially in children, remains the most common reason why tungiasis remains prevalent in poor, rural populations.
# Diagnosis
## Physical Examination
### Skin
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
- Tungiasis. Adapted from Dermatology Atlas.
# Treatment
Treatment for tungiasis include physical removal of the flea by use of forceps or needles, application of topical anti-parasitic medicine, and surgery to completely remove the nodules. If the flea is discovered in the early stages in can be easily removed, though it is slightly harder without breaking the egg sack. It appears similar to a pustule on the thick skin of the feet or hands.
Other successful reported treatment include applying a thick wax, nail polish, or petroleum solution to suffocate the flea and locally freezing the lesion by using liquid nitrogen. Local application of formaldehyde, chloroform and DDT have also been reported although their use is discouraged due to potential side effects.
Even without treatment, the burrowed fleas will die within two weeks and are naturally sloughed off as the skin sheds. | Tungiasis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Tungiasis is a skin infestation of the Tunga penetrans flea (also known as chigoe flea, jigger, nigua or sand flea), found in the tropical parts of Africa, Caribbean, Central and South America, and India. This disease is endemic in Nigeria and Trinidad and Tobago where in the 1980s the prevalence of tungiasis among children approached 40%. It is rarely found outside these areas.
# History
The first reported case of tungiasis was noted in the 1500s by Gonzalez Fernandez De Oviedo y Valdes, when sailors from the Santa Maria who sailed with Christopher Columbus were shipwrecked on Haiti and became infected. Tungiasis also infected many of the soldiers of the Spanish conquistadores, who also reported that an entire village in Colombia was abandoned because of this disease. The first clinical account of tungiasis was provided by the Portuguese doctor Aleixo de Abreu.
# Symptoms
The symptoms of this disease include:
- Severe pruritus
- Pain
- Inflammation and swelling
- Lesions and ulcerations, with black dots in the center
Left untreated, secondary infections such as bacteremia, tetanus, and gangrene can occur.
# Prevention
Because of their limited jumping ability, the most common sites of infection are the soles of the feet, the toe web and toenails. Preventing infection by chigoe flea is easily achieved by wearing shoes when traveling in endemic regions and spraying insecticides on infested soil. Walking barefoot, especially in children, remains the most common reason why tungiasis remains prevalent in poor, rural populations.
# Diagnosis
## Physical Examination
### Skin
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
- Tungiasis. Adapted from Dermatology Atlas.[1]
# Treatment
Treatment for tungiasis include physical removal of the flea by use of forceps or needles, application of topical anti-parasitic medicine, and surgery to completely remove the nodules. If the flea is discovered in the early stages in can be easily removed, though it is slightly harder without breaking the egg sack. It appears similar to a pustule on the thick skin of the feet or hands.
Other successful reported treatment include applying a thick wax, nail polish, or petroleum solution to suffocate the flea and locally freezing the lesion by using liquid nitrogen. Local application of formaldehyde, chloroform and DDT have also been reported although their use is discouraged due to potential side effects.
Even without treatment, the burrowed fleas will die within two weeks and are naturally sloughed off as the skin sheds.
# External links
- eMedicine - Tungiasis
- Health in Plain English - Tungiasis with pictures
- Afro-Nets - Tungiasis
- Seasonal variation of Tungiasis in an endemic community. The American Journal of Tropical Medicine and Hygiene. Also contains background about the parasite. | https://www.wikidoc.org/index.php/Tungiasis | |
276dd5da89a8346df7d57ca77b26107d473f028a | wikidoc | Tyloxapol | Tyloxapol
# Overview
Tyloxapol is a nonionic liquid polymer of the alkyl aryl polyether alcohol type. It is used as a surfactant to aid liquefaction and removal of mucopurulent(containing mucus and pus) bronchopulmonary secretions, or with a stream of oxygen.
With intraperitoneal injection, tyloxapol also blocks plasma lipolytic activity, and thus the breakdown of triglyceride-rich lipoproteins. This mechanism is used to induce experimental hyperlipidemia in animals.
Tyloxapol is the main active ingredient of the medical device Tacholiquin. Tacholiquin is an Expectorant designated for inhalation and instillation reaching the upper and lower airways.
Other brand names of pharmaceutical products containing Tyloxpol are: Exosurf, Alevaire | Tyloxapol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tyloxapol is a nonionic liquid polymer of the alkyl aryl polyether alcohol type. It is used as a surfactant to aid liquefaction and removal of mucopurulent(containing mucus and pus) bronchopulmonary secretions, or with a stream of oxygen.
With intraperitoneal injection, tyloxapol also blocks plasma lipolytic activity, and thus the breakdown of triglyceride-rich lipoproteins. This mechanism is used to induce experimental hyperlipidemia in animals.
Tyloxapol is the main active ingredient of the medical device Tacholiquin. Tacholiquin is an Expectorant designated for inhalation and instillation reaching the upper and lower airways.
Other brand names of pharmaceutical products containing Tyloxpol are: Exosurf, Alevaire | https://www.wikidoc.org/index.php/Tyloxapol | |
e78717457783fa1e2e566d8ca0ed4a0537c972cb | wikidoc | Tyrocidin | Tyrocidin
Tyrocidine is a mixture of cyclic decapeptides produced by the bacteria Bacillus brevis found in soil. It can be composed of 4 different amino acid sequences, giving tyrocidine A-D. (See figure 1). Tyrocidine is the major constituent of tyrothricin, which also contains gramicidin. Tyrocidine was the first commercially available antibiotic, but has been found to be toxic toward human blood and reproductive cells. The function of tyrocidine within its host ‘’B. brevis’’ is thought to be regulation of sporulation .
Tyrocidines A, B, and C are cyclic decapeptides. The biosynthesis of tyrocidine involves three enzymes. Parts of its sequence are identical to gramicidin S.
# History
In 1939 the American microbiologist René Dubos discovered the soil microbe Bacillus brevis. He observed the ability of the microbe to decompose the capsule of pneumococcus bacterium, rendering it harmless. From the soil microbe B. brevis he isolated tyrothricin which had a high toxicity to a large range of bacteria. Tyrothricin was later found to be a mixture of the peptides gramicidin and tyrocidine. These were observed to have toxic effects in red blood cells and reproductive cells in humans, however if applied externally as an ointment tyrocidine could be used as a potent antimicrobial agent
Dubos's discovery helped revive interest in research on penicillin.
# Mechanism of Action
Tyrocidine has a unique mode of action in which it disrupts the cell membrane function, making it a favorable target for engineering derivatives . Tyrocidine appears to perturb the lipid bilayer of a microbe’s inner membrane through permeating the lipid phase of the membrane. Further studies need to be performed in order to determine the affinity and location of tyrocidine within the phospholipid bilayer .
# Biosynthesis
The biosynthesis of Tyrocidine is similar to Gramicidin S, and is achieved through the use of nonribosomal protein synthetases (NRPSs) . Its biosynthesis is accomplished through enzymatic assembly consisting of 3 peptide synthetase proteins, TycA, TycB, and TycC, which contain 10 modules. It is important to note that the tyrocidine analogues (A-D) are not produced by different enzymes, but rather by an enzyme system which is capable of incorporating different amino acids of structural similarity at specified sites. The amino acid sequence is determined by the organization of the enzyme and not by any RNA template .
The tyrocine synthetases TycA, TycB, and TycC are encoded on the tyrocine operon. This consists of the three genes encoding for the three synthetases as well as three additional open reading frames (ORFs). These ORFs, labeled as TycD, TycE, and TycF are downstream of the three synthetase genes (see figure 2). TycD &TycE have the highest similarity to members of the ATP-binding cassette (ABC) transporter family which aid in the transport of substrates across a membrane. It has been suggested that the tandem transporters play a role in conferring resistance in the producer cell through tyrocidine secretion. TycF has been identified as a thioesterase (TE) and is similar to other TEs in bacterial operons used for encoding peptide synthetases. However, the precise function of these TEs remains unknown . The size of the peptide synthetases corresponds to the amount of activation they carry out. TycA is the smallest and activates a single amino acid from one module, TycB is intermediate in size and activates 3 amino acids with 3 modules, and TycC is the largest and activates 6 amino acids with 6 modules (See figure 3) .
Each module performs all the catalytic reactions necessary to incorporate a single amino acid onto the peptide chain. This is accomplished through the subdomains for adenylation (A), peptityl carrier protein (PCP), condensation (C), and depending on the amino acid position, an epimerization (E). The adenylation subdomain is used in activating the specific amino acid. Each module uses one molecule of the selected substrate amino acid with one molecule of ATP to give an aminoacyl adenylate enzyme complex and pyrophosphate. The activated amino acid can then be transferred to the enzyme bound 4'-phosphopantetheine of the carrier protein with the expulsion of AMP from the system. The carrier protein uses the 4’-phosphopantetheine prosthetic group for loading of the growing peptide and their monomer precursors . Elongation of the peptide chain is achieved through condensation of the upstream PCP onto an adjacent downstream PCP-bound monomer. In certain domains you will find modification subdomains, such as the E subdomain seen in domains 1 and 4 in tyrocidine, which will generate the D-configured amino acid. On the final module is the TE domain used as a catalyst for cyclization or product release. The release of the product from the carrier protein is achieved through acylation of the active site serine of TE in which the decapeptide is transferred from the thiol ether to the serine residue. Deacylation can then occur through intramolecular cyclization or through hydrolysis to give the cyclic or linear product respectively (See figure 4).
In the case of tyrocidine, ring closure has been shown to be highly favorable due to 4 H-bonds helping the decapeptide backbone to adopt a stable conformation (See figure 5) . This intramolecular cyclization occurs in a head-to-tail fashion involving the N-terminus of the D-Phe1 and the C-terminus of the L-Leu10 (See figure 4) .
# Chemoenzymatic Strategies
There is no chemical solution for macrocyclization of a peptide chain. Isolated tyrocidine (Tyc) TE domains can be used to cyclize chemically derived peptidyl-thioester substrates, providing a powerful route to new cyclic compounds. In order for this macrocyclization to occur the peptides must be C-terminally activated with an N-acethylcysteamine (SNAC) leaving group . An “alanine-scan” through the 10 positions of tyrocidine shows that only the D-Phe and L-Orn are required for sufficient cyclization.
Tyc TE can also be used biomimetically in which it mimics the environment created by the TE domain with the substrate’s PCP through use of a synthetic tether linked to a polyethylene glycol (PEG) amide resin . Use of this resin bound to a desired substrate with isolated TE can allow for catalytic release of the resin as well as macrocyclization of the substrate (See figure 6 ). Use of solid phase peptide synthesis (SPPS) can be utilized in the incorporation of a diverse array of monomers into the peptide chain. Later studies used the high tolerance of Tyc TE in order to modify the peptide backbone post-synthetically. This also allowed for glycosylation of the tyrosine or serine residues to be incorporated . Use of these methods has led to many promising new therapeutic agents. | Tyrocidin
Template:Chembox new
Tyrocidine is a mixture of cyclic decapeptides produced by the bacteria Bacillus brevis found in soil. It can be composed of 4 different amino acid sequences, giving tyrocidine A-D. (See figure 1). Tyrocidine is the major constituent of tyrothricin, which also contains gramicidin[1]. Tyrocidine was the first commercially available antibiotic, but has been found to be toxic toward human blood and reproductive cells. The function of tyrocidine within its host ‘’B. brevis’’ is thought to be regulation of sporulation [2].
Tyrocidines A, B, and C are cyclic decapeptides. The biosynthesis of tyrocidine involves three enzymes. Parts of its sequence are identical to gramicidin S.
# History
In 1939 the American microbiologist René Dubos discovered the soil microbe Bacillus brevis. He observed the ability of the microbe to decompose the capsule of pneumococcus bacterium, rendering it harmless. From the soil microbe B. brevis he isolated tyrothricin which had a high toxicity to a large range of bacteria. Tyrothricin was later found to be a mixture of the peptides gramicidin and tyrocidine. These were observed to have toxic effects in red blood cells and reproductive cells in humans, however if applied externally as an ointment tyrocidine could be used as a potent antimicrobial agent [3]
Dubos's discovery helped revive interest in research on penicillin.
# Mechanism of Action
Tyrocidine has a unique mode of action in which it disrupts the cell membrane function, making it a favorable target for engineering derivatives [4]. Tyrocidine appears to perturb the lipid bilayer of a microbe’s inner membrane through permeating the lipid phase of the membrane. Further studies need to be performed in order to determine the affinity and location of tyrocidine within the phospholipid bilayer [5].
# Biosynthesis
The biosynthesis of Tyrocidine is similar to Gramicidin S, and is achieved through the use of nonribosomal protein synthetases (NRPSs) [6]. Its biosynthesis is accomplished through enzymatic assembly consisting of 3 peptide synthetase proteins, TycA, TycB, and TycC, which contain 10 modules. It is important to note that the tyrocidine analogues (A-D) are not produced by different enzymes, but rather by an enzyme system which is capable of incorporating different amino acids of structural similarity at specified sites. The amino acid sequence is determined by the organization of the enzyme and not by any RNA template [7].
The tyrocine synthetases TycA, TycB, and TycC are encoded on the tyrocine operon. This consists of the three genes encoding for the three synthetases as well as three additional open reading frames (ORFs). These ORFs, labeled as TycD, TycE, and TycF are downstream of the three synthetase genes (see figure 2). TycD &TycE have the highest similarity to members of the ATP-binding cassette (ABC) transporter family which aid in the transport of substrates across a membrane. It has been suggested that the tandem transporters play a role in conferring resistance in the producer cell through tyrocidine secretion. TycF has been identified as a thioesterase (TE) and is similar to other TEs in bacterial operons used for encoding peptide synthetases. However, the precise function of these TEs remains unknown [2]. The size of the peptide synthetases corresponds to the amount of activation they carry out. TycA is the smallest and activates a single amino acid from one module, TycB is intermediate in size and activates 3 amino acids with 3 modules, and TycC is the largest and activates 6 amino acids with 6 modules (See figure 3) [2].
Each module performs all the catalytic reactions necessary to incorporate a single amino acid onto the peptide chain. This is accomplished through the subdomains for adenylation (A), peptityl carrier protein (PCP), condensation (C), and depending on the amino acid position, an epimerization (E). The adenylation subdomain is used in activating the specific amino acid. Each module uses one molecule of the selected substrate amino acid with one molecule of ATP to give an aminoacyl adenylate enzyme complex and pyrophosphate. The activated amino acid can then be transferred to the enzyme bound 4'-phosphopantetheine of the carrier protein with the expulsion of AMP from the system. The carrier protein uses the 4’-phosphopantetheine prosthetic group for loading of the growing peptide and their monomer precursors [8]. Elongation of the peptide chain is achieved through condensation of the upstream PCP onto an adjacent downstream PCP-bound monomer. In certain domains you will find modification subdomains, such as the E subdomain seen in domains 1 and 4 in tyrocidine, which will generate the D-configured amino acid. On the final module is the TE domain used as a catalyst for cyclization or product release. The release of the product from the carrier protein is achieved through acylation of the active site serine of TE in which the decapeptide is transferred from the thiol ether to the serine residue. Deacylation can then occur through intramolecular cyclization or through hydrolysis to give the cyclic or linear product respectively (See figure 4).
In the case of tyrocidine, ring closure has been shown to be highly favorable due to 4 H-bonds helping the decapeptide backbone to adopt a stable conformation (See figure 5) [4] [8]. This intramolecular cyclization occurs in a head-to-tail fashion involving the N-terminus of the D-Phe1 and the C-terminus of the L-Leu10 (See figure 4) [6] [9].
# Chemoenzymatic Strategies
There is no chemical solution for macrocyclization of a peptide chain. Isolated tyrocidine (Tyc) TE domains can be used to cyclize chemically derived peptidyl-thioester substrates, providing a powerful route to new cyclic compounds. In order for this macrocyclization to occur the peptides must be C-terminally activated with an N-acethylcysteamine (SNAC) leaving group [6]. An “alanine-scan” through the 10 positions of tyrocidine shows that only the D-Phe and L-Orn are required for sufficient cyclization.
Tyc TE can also be used biomimetically in which it mimics the environment created by the TE domain with the substrate’s PCP through use of a synthetic tether linked to a polyethylene glycol (PEG) amide resin [8]. Use of this resin bound to a desired substrate with isolated TE can allow for catalytic release of the resin as well as macrocyclization of the substrate (See figure 6 [8]). Use of solid phase peptide synthesis (SPPS) can be utilized in the incorporation of a diverse array of monomers into the peptide chain. Later studies used the high tolerance of Tyc TE in order to modify the peptide backbone post-synthetically. This also allowed for glycosylation of the tyrosine or serine residues to be incorporated [6]. Use of these methods has led to many promising new therapeutic agents. | https://www.wikidoc.org/index.php/Tyrocidin | |
e30a4944ea860b579f3dd325a6b11026dc8905c1 | wikidoc | UN number | UN number
UN numbers or UN IDs are four-digit numbers that identify hazardous substances, and articles (such as explosives, flammable liquids, toxic substances, etc.) in the framework of international transport.
Some hazardous substances have their own UN numbers (e.g. acrylamide has UN2074), while sometimes groups of chemicals or products with similar properties receive a common UN number (e.g. flammable liquid, not otherwise specified, have UN1993). A chemical in its solid state may receive a different UN number than the liquid phase if their hazardous properties differ significantly; substances with different levels of purity (or concentration in solution) may also receive different UN numbers.
UN numbers range from UN0001 to about UN3500 and are assigned by the United Nations Committee of Experts on the Transport of Dangerous Goods. They are published as part of their Recommendations on the Transport of Dangerous Goods, also known as the Orange Book. These recommendations are adopted by the regulatory organization responsible for the different modes of transport.
For more details, see List of UN Numbers.
NA numbers (North America), also known as DOT numbers are issued by the United States Department of Transportation and are identical to UN numbers, except that some substances without a UN number may have an NA number. These additional NA numbers use the range NA8000 - NA9999.
Associated with each UN number is a hazard identifier, which encodes the general hazard class and subdivision (and, in the case of explosives, their compatibility group). For instance, the hazard identifier of acrylamide is 6.1 and the one of cigarette lighters is 2.1. If a substance poses several dangers, then subsidiary risk identifiers may be specified. It is not possible to deduce the hazard class(es) of a substance from its UN number: they have to be looked up in a table. | UN number
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
UN numbers or UN IDs are four-digit numbers that identify hazardous substances, and articles (such as explosives, flammable liquids, toxic substances, etc.) in the framework of international transport.
Some hazardous substances have their own UN numbers (e.g. acrylamide has UN2074), while sometimes groups of chemicals or products with similar properties receive a common UN number (e.g. flammable liquid, not otherwise specified, have UN1993). A chemical in its solid state may receive a different UN number than the liquid phase if their hazardous properties differ significantly; substances with different levels of purity (or concentration in solution) may also receive different UN numbers.
UN numbers range from UN0001 to about UN3500 and are assigned by the United Nations Committee of Experts on the Transport of Dangerous Goods. They are published as part of their Recommendations on the Transport of Dangerous Goods, also known as the Orange Book. These recommendations are adopted by the regulatory organization responsible for the different modes of transport.
For more details, see List of UN Numbers.
NA numbers (North America), also known as DOT numbers are issued by the United States Department of Transportation and are identical to UN numbers, except that some substances without a UN number may have an NA number. These additional NA numbers use the range NA8000 - NA9999.
Associated with each UN number is a hazard identifier, which encodes the general hazard class and subdivision (and, in the case of explosives, their compatibility group). For instance, the hazard identifier of acrylamide is 6.1 and the one of cigarette lighters is 2.1. If a substance poses several dangers, then subsidiary risk identifiers may be specified. It is not possible to deduce the hazard class(es) of a substance from its UN number: they have to be looked up in a table. | https://www.wikidoc.org/index.php/UN_number | |
27b1bba08d7d2dd12f2d1d62e68c06b35c8ec868 | wikidoc | Ube3a-ATS | Ube3a-ATS
UBE3A-ATS/Ube3a-ATS (human/mouse), otherwise known as ubiquitin ligase E3A-ATS, is the name for the antisense DNA strand that is transcribed as part of a larger transcript called LNCAT (large non-coding antisense transcript) at the Ube3a locus. The Ube3a locus is imprinted and in the central nervous system expressed only from the maternal allele. Silencing of Ube3a on the paternal allele is thought to occur through the Ube3a-ATS part of LNCAT, since non-coding antisense transcripts are often found at imprinted loci. The deletion and/or mutation of Ube3a on the maternal chromosome causes Angelman Syndrome (AS) and Ube3a-ATS may prove to be an important aspect in finding a therapy for this disease. While in patients with AS the maternal Ube3a allele is inactive, the paternal allele is intact but epigenetically silenced. If unsilenced, the paternal allele could be a source of active Ube3a protein in AS patients. Therefore, understanding the mechanisms of how Ube3a-ATS might be involved in silencing the paternal Ube3a may lead to new therapies for AS. This possibility has been demonstrated by a recent study where the drug topotecan, administered to mice suffering from AS, activated expression of the paternal Ube3a gene by lowering the transcription of Ube3a-ATS.
# LNCAT organization
The human UBE3A-ATS is expressed as a part of LNCAT mainly from the paternal allele in the central nervous system (CNS). The transcript is about 450 kbs long, starts at the U-exons and extends as far as UBE3A on the opposite strand, possibly beyond. The promoter for Snurf/Snrpn and the imprinting center are found in the U-exon region. The promoter region is imperative, as deletion of this area abolishes Ube3a-ATS transcription. Near the promoter is the PWS-IC and about 35 kbs upstream of the PWS-IC is the AS-IC. These two regions are thought to control the expression of the entire LNCAT strand. Starting at the promoter, the entire transcript can be transcribed and after transcription is further processed and spliced. Reviewed in Trends in Neurosci.
Located next to the U-exon promoter region is Snrpn/Snurf which can be alternatively spliced into either Snrpn or Snurf in humans (in mice this remains as one bicistronic transcript). Snrpn codes for a protein of unknown function which localizes to the cell nucleus. Snurf codes for a small nuclear ribonucleoprotein. While most of these proteins are involved in splicing, the role of this particular protein is not yet known. Downstream from Snrpn/Snurf and within its introns are sequences for several C/D box snoRNAs. Most C/D box snoRNAs function in non-mRNA methylation. However, recently, one snoRNA on Ube3a-ATS, SNORD 115, has been found to change the alternative splicing of the serotonin receptor 2C pre-mRNA. In addition, this snoRNA has the ability to change the splicing of five different mRNAs. Among the sequences for the snoRNAs is nested IPW (imprinted Prader-Willi), a non-coding region whose deletion is thought to cause Prader-Willi syndrome.
# Model systems
The mouse and human Ube3a-ATS/Ube3a are orthologous and the general organizations of the regions are similar. For example, the mouse locus also contains Snurf/Snrpn, snoRNAs and IPW. The main differences are the locations and the lengths of the Ube3a-ATS transcripts. The human Ube3a/Ube3a-ATS is located on chromosome 15, while the mouse Ube3a is located on chromosome 7. The mouse LNCAT, including Ube3a-ATS, is about 1000 kb long, much longer than the human 450 kb LNCAT. Due to the similar organization of the mouse and human LNCAT/Ube3a-ATS and the fact that the mouse Ube3a locus is also imprinted, the mouse is an excellent model system to study imprinting and the interactions between Ube3a/Ube3a-ATs. In addition, mouse neurons continue to retain their imprinting pattern in culture.
# Splice variants and locations
While the entire LNCAT transcript, including the Ube3a-ATS transcript may be transcribed, it is often spliced to include and exclude a variety of exons. Different splice variants are expressed in different tissue types and situations. For the most part, it is thought that at least some type of Ube3a-ATS is expressed in CNS cells that are imprinted, such as Purkinje cells and hippocampal neurons. However, there is spatiotemporal regulation of both the downstream and the upstream part of this transcript. and Journal of Neuroscience.
In mouse embryos, Snurf/Snrpn exons were detected in blastocysts about 7 days post coitem and continued to be expressed throughout development. The Snurf/Snrpn exons are restricted to CNS tissue during development, and only later during adulthood are expressed in other tissue. Ube3a-ATS exons were not detected until 10 days post coitem and their expression was also limited to the CNS during development. In general, Ube3a-ATS is detected during the initial stages of neurogenesis while Snurf/Snrpn is expressed in undifferentiated precursor cells and throughout the course of differentiation. There are at least 10 different splice isoforms according to the UCSC genome browser.
According to one study, the splice variant that directly overlaps the Ube3a is found in the cytoplasm.
# Preventing expression on both alleles
A specific imprinting center cluster was thought to control the differential expression of Ube3a-ATS on the maternal and paternal alleles. There are two regions in the imprinting centers (ICs) that exist associated with AS and PWS- the AS-IC and the PWS-IC. These imprinting centers are control regions that dictate whether surrounding genes and regions can be expressed and are found on both the maternal and paternal alleles. While differential methylation patterns on the maternal and paternal genes are often associated with imprinting, the AS-IC remains unmethylated at both alleles. However, the neighboring PWS-IC is methylated on the maternal allele, but remains unmethylated on the paternal allele.
The PWS-IC is suspected of controlling the expression of LNCAT and Ube3a-ATS. In mice where the PWS-IC has been deleted, expression of the Ube3a-ATS is decreased. In the central neural system, Ube3a-ATS is preferentially expressed from the paternal allele where the PWS-IC is not methylated. On the other hand, on the maternal allele, where the PWS-IC is methylated, Ube3a-ATS is not expressed, suggesting that the methylation of the PWS-IC somehow prevents Ube3a-ATS expression. This is supported by several studies where preventing methylation of the PWS-IC by knocking out methyl transferases in embryonic stem cells results in bialellic expression of Ube3a-ATS and silencing of Ube3a on the maternal allele.
However, methylation is not the only process involved in preventing the expression of the maternal Ube3a-ATS. It is expected that the imprinting domains interact with other proteins, which contribute to the silencing of LNCAT and Ube3a-ATS on the maternal allele. For example, when MECP2 is knocked out, such as in Rett Syndrome patients, Ube3a-ATS is biallelically expressed, decreasing expression of Ube3a from the maternal allele.
# Collision model
There are currently three models that explain how the Ube3a-ATS of LNCAT silences the paternal Ube3a- the collision model, the RNA-DNA interaction model, and the double stranded RNA interference model. While these models have not been demonstrated directly for Ube3a/Ube3a-ATS, they are considered plausible based on evidence for the silencing of other natural antisense transcripts by these methods. However, the collision model, due to most recent supporting studies, appears most likely.
The collision model can be thought of as a road wide enough for only one car. A smart car is traveling from one direction, and a plough from the other direction, eventually colliding. After the collision, the plough pushes the smart car backwards, as it continues to travel forward. In the collision model for Ube3a/Ube3a-ATS, RNA polymerases (RNAPs) travel towards each other along the sense and antisense templates during transcription. The sense and antisense templates overlap for Ube3a and Ube3a-ATS. The two transcription bubbles will collide head-on, and the RNAP transcribing the Ube3a-ATS, being the plough, will push the RNAP transcribing the Ube3a (smart car), backwards and eventually off of the template. This prevents complete transcription of Ube3a.
The support for this model comes from two recent studies. The first study looked at transcription of genes on sense strands that were overlapped by genes being expressed on the antisense strand. The longer the region of overlap, the less efficient the transcription of the sense strand was, indicating that transcription on one strand interferes with the transcription on the other strand. Another study directly monitored collisions between RNAPs transcribing a template using atomic force microscopy. RNAPs were stalled on DNA fragments and collided with other elongating RNAPs. The images showed stalling of the two RNAPs immediately after the collision, in addition to backtracking of one of the RNAPs.
While these studies have not been performed for Ube3a/Ube3a-ATS, the use of atomic force microscopy to monitor transcription at this locus might provide insight as to how Ube3a is actually silenced via Ube3a-ATS. Further studies are still very much necessary to confirm these models for Ube3a.
# Contradictory studies
While several studies support the idea that Ube3a-ATS might be involved in paternal Ube3a silencing, other studies contradict this. One study in particular argues against the in cis silencing of Ube3a by Ube3a-ATS. In this study, when the maternal Ube3a allele was deleted, an increase in paternal Ube3a-ATS expression was seen. This suggests that rather than the paternal Ube3a-ATS controlling paternal Ube3a, the maternal Ube3a somehow suppresses expression of the paternal Ube3a-ATs, possibly in trans rather than in cis. An interaction between the maternal and paternal homolgous regions of these genes was in fact observed in human and mouse cells during interphase.
One mechanism to explain in trans silencing includes an interaction between the paternal Ube3a-ATS RNA and the maternal Ube3a mRNA. It is possible that the maternal Ube3a mRNA interacts with the paternal Ube3a-ATS RNA and decreases the stability of both of these transcripts. When only Ube3a-ATS is made without Ube3a, the Ube3a-ATS becomes more stable.
Another study has suggested that Ube3a-ATS expression does not occur in imprinted regions. In situ hybridizations did not reveal Ube3a-ATS in Purkinje cells or hippocampal neurons. However, other upstream exons that correspond to Snurf/Snrpn were expressed, indicating that the collision model could still be occurring. Thus further research is still required.
# The future
Several studies have attempted to utilize the possibility of controlling Ube3a expression through Ube3a-ATS. In AS, the paternal PWS-IC is not methylated, supposedly allowing Ube3a-ATS expression. Therefore, if methylation of the PWS-IC were possible, Ube3a-ATS transcription could be prohibited, allowing Ube3a expression from the paternal allele to make up for the lack of expression from the maternal allele. A one year study was performed with several AS patients. These patients were put on methylation promoting diets that consisted of betaine, metafolin, creatine, and vitamin B12 supplements. However, after one year, methylation patterns in these patients did not change.
Another study tested a large library of different drugs, and identified several topoisomerase I and II inhibitors which increased expression of paternal Ube3a in mouse neurons and mice. Topoisomerase inhibitors are widely used as chemotherapeutics and cause replicating cells to undergo apoptosis by inducing double strand breaks that stall the replication fork. However, their mechanism of action in activating the paternal Ube3a is not yet known, but may involve transcriptional interference with Ube3a-ATS, as Ube3a-ATS transcripts decreased after drug treatment. The group specifically chose to study topotecan, which was the most effective at a low nanomolar range and is already Food and Drug Administration approved for treating several types of cancers. | Ube3a-ATS
UBE3A-ATS/Ube3a-ATS (human/mouse), otherwise known as ubiquitin ligase E3A-ATS, is the name for the antisense DNA strand that is transcribed as part of a larger transcript called LNCAT (large non-coding antisense transcript) at the Ube3a locus. The Ube3a locus is imprinted and in the central nervous system expressed only from the maternal allele. Silencing of Ube3a on the paternal allele is thought to occur through the Ube3a-ATS part of LNCAT,[1] since non-coding antisense transcripts are often found at imprinted loci.[2] The deletion and/or mutation of Ube3a on the maternal chromosome causes Angelman Syndrome (AS) and Ube3a-ATS may prove to be an important aspect in finding a therapy for this disease. While in patients with AS the maternal Ube3a allele is inactive, the paternal allele is intact but epigenetically silenced. If unsilenced, the paternal allele could be a source of active Ube3a protein in AS patients. Therefore, understanding the mechanisms of how Ube3a-ATS might be involved in silencing the paternal Ube3a may lead to new therapies for AS. This possibility has been demonstrated by a recent study where the drug topotecan, administered to mice suffering from AS, activated expression of the paternal Ube3a gene by lowering the transcription of Ube3a-ATS.[3]
# LNCAT organization
The human UBE3A-ATS is expressed as a part of LNCAT mainly from the paternal allele in the central nervous system (CNS).[1][6] The transcript is about 450 kbs long, starts at the U-exons and extends as far as UBE3A on the opposite strand, possibly beyond. The promoter for Snurf/Snrpn and the imprinting center are found in the U-exon region. The promoter region is imperative, as deletion of this area abolishes Ube3a-ATS transcription. Near the promoter is the PWS-IC and about 35 kbs upstream of the PWS-IC is the AS-IC. These two regions are thought to control the expression of the entire LNCAT strand. Starting at the promoter, the entire transcript can be transcribed and after transcription is further processed and spliced. Reviewed in Trends in Neurosci.[5]
Located next to the U-exon promoter region is Snrpn/Snurf which can be alternatively spliced into either Snrpn or Snurf in humans (in mice this remains as one bicistronic transcript).[7] Snrpn codes for a protein of unknown function which localizes to the cell nucleus. Snurf codes for a small nuclear ribonucleoprotein. While most of these proteins are involved in splicing, the role of this particular protein is not yet known.[7] Downstream from Snrpn/Snurf and within its introns are sequences for several C/D box snoRNAs. Most C/D box snoRNAs function in non-mRNA methylation.[7][8] However, recently, one snoRNA on Ube3a-ATS, SNORD 115, has been found to change the alternative splicing of the serotonin receptor 2C pre-mRNA. In addition, this snoRNA has the ability to change the splicing of five different mRNAs.[9] Among the sequences for the snoRNAs is nested IPW (imprinted Prader-Willi), a non-coding region whose deletion is thought to cause Prader-Willi syndrome.[10]
# Model systems
The mouse and human Ube3a-ATS/Ube3a are orthologous and the general organizations of the regions are similar. For example, the mouse locus also contains Snurf/Snrpn, snoRNAs and IPW. The main differences are the locations and the lengths of the Ube3a-ATS transcripts. The human Ube3a/Ube3a-ATS is located on chromosome 15, while the mouse Ube3a is located on chromosome 7. The mouse LNCAT, including Ube3a-ATS, is about 1000 kb long, much longer than the human 450 kb LNCAT.[1][5][6] Due to the similar organization of the mouse and human LNCAT/Ube3a-ATS and the fact that the mouse Ube3a locus is also imprinted, the mouse is an excellent model system to study imprinting and the interactions between Ube3a/Ube3a-ATs. In addition, mouse neurons continue to retain their imprinting pattern in culture.[11]
# Splice variants and locations
While the entire LNCAT transcript, including the Ube3a-ATS transcript may be transcribed, it is often spliced to include and exclude a variety of exons. Different splice variants are expressed in different tissue types and situations. For the most part, it is thought that at least some type of Ube3a-ATS is expressed in CNS cells that are imprinted, such as Purkinje cells and hippocampal neurons. However, there is spatiotemporal regulation of both the downstream and the upstream part of this transcript.[12] and Journal of Neuroscience.[13]
In mouse embryos, Snurf/Snrpn exons were detected in blastocysts about 7 days post coitem and continued to be expressed throughout development. The Snurf/Snrpn exons are restricted to CNS tissue during development, and only later during adulthood are expressed in other tissue. Ube3a-ATS exons were not detected until 10 days post coitem and their expression was also limited to the CNS during development. In general, Ube3a-ATS is detected during the initial stages of neurogenesis while Snurf/Snrpn is expressed in undifferentiated precursor cells and throughout the course of differentiation.[12] There are at least 10 different splice isoforms according to the UCSC genome browser.
According to one study, the splice variant that directly overlaps the Ube3a is found in the cytoplasm.[14]
# Preventing expression on both alleles
A specific imprinting center cluster was thought to control the differential expression of Ube3a-ATS on the maternal and paternal alleles. There are two regions in the imprinting centers (ICs) that exist associated with AS and PWS- the AS-IC and the PWS-IC. These imprinting centers are control regions that dictate whether surrounding genes and regions can be expressed and are found on both the maternal and paternal alleles. While differential methylation patterns on the maternal and paternal genes are often associated with imprinting, the AS-IC remains unmethylated at both alleles. However, the neighboring PWS-IC is methylated on the maternal allele, but remains unmethylated on the paternal allele.[15]
The PWS-IC is suspected of controlling the expression of LNCAT and Ube3a-ATS. In mice where the PWS-IC has been deleted, expression of the Ube3a-ATS is decreased.[4] In the central neural system, Ube3a-ATS is preferentially expressed from the paternal allele where the PWS-IC is not methylated.[12] On the other hand, on the maternal allele, where the PWS-IC is methylated, Ube3a-ATS is not expressed, suggesting that the methylation of the PWS-IC somehow prevents Ube3a-ATS expression. This is supported by several studies where preventing methylation of the PWS-IC by knocking out methyl transferases in embryonic stem cells results in bialellic expression of Ube3a-ATS and silencing of Ube3a on the maternal allele.[9]
However, methylation is not the only process involved in preventing the expression of the maternal Ube3a-ATS. It is expected that the imprinting domains interact with other proteins, which contribute to the silencing of LNCAT and Ube3a-ATS on the maternal allele. For example, when MECP2 is knocked out, such as in Rett Syndrome patients, Ube3a-ATS is biallelically expressed, decreasing expression of Ube3a from the maternal allele.[9]
# Collision model
There are currently three models that explain how the Ube3a-ATS of LNCAT silences the paternal Ube3a- the collision model, the RNA-DNA interaction model, and the double stranded RNA interference model.[5][14] While these models have not been demonstrated directly for Ube3a/Ube3a-ATS, they are considered plausible based on evidence for the silencing of other natural antisense transcripts by these methods. However, the collision model, due to most recent supporting studies, appears most likely.[16][17][18]
The collision model can be thought of as a road wide enough for only one car. A smart car is traveling from one direction, and a plough from the other direction, eventually colliding. After the collision, the plough pushes the smart car backwards, as it continues to travel forward. In the collision model for Ube3a/Ube3a-ATS, RNA polymerases (RNAPs) travel towards each other along the sense and antisense templates during transcription. The sense and antisense templates overlap for Ube3a and Ube3a-ATS. The two transcription bubbles will collide head-on, and the RNAP transcribing the Ube3a-ATS, being the plough, will push the RNAP transcribing the Ube3a (smart car), backwards and eventually off of the template. This prevents complete transcription of Ube3a.[5]
The support for this model comes from two recent studies. The first study looked at transcription of genes on sense strands that were overlapped by genes being expressed on the antisense strand. The longer the region of overlap, the less efficient the transcription of the sense strand was, indicating that transcription on one strand interferes with the transcription on the other strand.[18] Another study directly monitored collisions between RNAPs transcribing a template using atomic force microscopy. RNAPs were stalled on DNA fragments and collided with other elongating RNAPs. The images showed stalling of the two RNAPs immediately after the collision, in addition to backtracking of one of the RNAPs.[16]
While these studies have not been performed for Ube3a/Ube3a-ATS, the use of atomic force microscopy to monitor transcription at this locus might provide insight as to how Ube3a is actually silenced via Ube3a-ATS. Further studies are still very much necessary to confirm these models for Ube3a.[citation needed]
# Contradictory studies
While several studies support the idea that Ube3a-ATS might be involved in paternal Ube3a silencing, other studies contradict this. One study in particular argues against the in cis silencing of Ube3a by Ube3a-ATS. In this study, when the maternal Ube3a allele was deleted, an increase in paternal Ube3a-ATS expression was seen. This suggests that rather than the paternal Ube3a-ATS controlling paternal Ube3a, the maternal Ube3a somehow suppresses expression of the paternal Ube3a-ATs, possibly in trans rather than in cis. An interaction between the maternal and paternal homolgous regions of these genes was in fact observed in human and mouse cells during interphase.[14]
One mechanism to explain in trans silencing includes an interaction between the paternal Ube3a-ATS RNA and the maternal Ube3a mRNA. It is possible that the maternal Ube3a mRNA interacts with the paternal Ube3a-ATS RNA and decreases the stability of both of these transcripts. When only Ube3a-ATS is made without Ube3a, the Ube3a-ATS becomes more stable.[14]
Another study has suggested that Ube3a-ATS expression does not occur in imprinted regions. In situ hybridizations did not reveal Ube3a-ATS in Purkinje cells or hippocampal neurons. However, other upstream exons that correspond to Snurf/Snrpn were expressed,[12] indicating that the collision model could still be occurring. Thus further research is still required.
# The future
Several studies have attempted to utilize the possibility of controlling Ube3a expression through Ube3a-ATS. In AS, the paternal PWS-IC is not methylated, supposedly allowing Ube3a-ATS expression. Therefore, if methylation of the PWS-IC were possible, Ube3a-ATS transcription could be prohibited, allowing Ube3a expression from the paternal allele to make up for the lack of expression from the maternal allele. A one year study was performed with several AS patients. These patients were put on methylation promoting diets that consisted of betaine, metafolin, creatine, and vitamin B12 supplements. However, after one year, methylation patterns in these patients did not change.[19]
Another study tested a large library of different drugs, and identified several topoisomerase I and II inhibitors which increased expression of paternal Ube3a in mouse neurons and mice. Topoisomerase inhibitors are widely used as chemotherapeutics and cause replicating cells to undergo apoptosis by inducing double strand breaks that stall the replication fork. However, their mechanism of action in activating the paternal Ube3a is not yet known, but may involve transcriptional interference with Ube3a-ATS, as Ube3a-ATS transcripts decreased after drug treatment. The group specifically chose to study topotecan, which was the most effective at a low nanomolar range and is already Food and Drug Administration approved for treating several types of cancers.[3] | https://www.wikidoc.org/index.php/Ube3a-ATS | |
a8fb5e6eba6abc5b65ad2d2bc9eea4a1d9bce788 | wikidoc | Uric acid | Uric acid
# Overview
Uric acid (or urate) is an organic compound of carbon, nitrogen, oxygen and hydrogen with the formula C5H4N4O3.
# Metabolic processes
Xanthine oxidase oxidizes oxypurines such as xanthine and hypoxanthine to uric acid. In humans and higher primates, uric acid is the final oxidation product of purine catabolism. In most other mammals, the enzyme uricase further oxidizes uric acid to allantoin. The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid. This may be because in higher primates uric acid (urate) partially replaces ascorbic acid. Both urate and ascorbate are strong reducing agents (electron donors) and potent antioxidants. In humans, about half the antioxidant capacity of plasma comes from uric acid.
Uric acid is also the end product of nitrogen catabolism in birds and reptiles. In such species, it is excreted in feces as a dry mass. While this compound is produced through a complex and energetically costly metabolic pathway (in comparison to other nitrogenated wastes such as urea or ammonia), its elimination minimizes water loss. It is therefore commonly found in the excretions of animals—such as the kangaroo rat—that live in very dry environments.
The Dalmatian dog has a defect in uric acid uptake by liver, resulting in decreased conversion to allantoin, so this breed excretes uric acid, and not allantoin, in the urine.
# Medical issues
Humans produce large quantities of uric acid. In human blood, uric acid concentrations between 3.6 mg/dL (~214µmol/L) and 8.3 mg/dL (~494µmol/L) (1mg/dL=59.48 µmol/L) are considered normal by the American Medical Association, although significantly lower levels are common in vegetarians due to a decreased intake of purine-rich meat.
## High uric acid
### Gout
Excess serum accumulation of uric acid can lead to a type of arthritis known as gout.
Elevated (serum uric acid) level (hyperuricemia) can result from high intake of purine-rich foods, high fructose intake (regardless of fructose's low Glycemic Index (GI) value) and/or impaired excretion by the kidneys. Saturation levels of uric acid in blood may result in one form of kidney stones when the urate crystallizes in the kidney. These uric acid stones are radiolucent and so do not appear on an abdominal x-ray. Their presence must be diagnosed by ultrasound for this reason. Some patients with gout eventually get uric kidney stones.
Gout can occur where serum uric acid levels are as low as 6 mg/dL (~357µmol/L), but an individual can have serum values as high as 9.5 mg/dL (~565µmol/L) and not have gout (no abstract available; levels reported at).
### Lesch-Nyhan syndrome
Lesch-Nyhan syndrome is also associated with very high serum uric acid levels.
Spasticity, involuntary movement and cognitive retardation as well as manifestations of gout are seen in cases of this syndrome.
### Cardiovascular disease
Although uric acid can act as an antioxidant, excess serum accumulation is often associated with cardiovascular disease. It is not known whether this is causative (e.g., by acting as a prooxidant ) or a protective reaction taking advantage of urate's antioxidant properties.
High uric acid can cause kidney stones, gouts in joints, and disable the body to produce purines, which build up the genetic "blueprint".
Cohort studies have proposed a relationship between hyperuricemia and cardiovascular disease, including the Kuopio Ischaemic Heart Disease Risk Factor Study of Finnish males and the U.S. National Health and Nutrition Examination Survey (NHANES).
On the other hand, the Framingham cohort study finds that the association between hyperuricemia nd cardiovascular disease is due to confounding.
A randomized controlled trial found that although febuxostat lowers uric acid levels more than does allopurinol, febuxostat increased cardiac mortality.
The above CARES trial by White has been included in a systematic review.
A more recent trial is the FAST trial.
A more recent systematic review finds no association.
### Diabetes
The association of high serum uric acid with insulin resistance has been known since the early part of the 20th century, nevertheless, recognition of high serum uric acid as a risk factor for diabetes has been a matter of debate. In fact, hyperuricemia has always been presumed to be a consequence of insulin resistance rather than its precursor . However, it was shown in a prospective follow-up study that high serum uric acid is associated with higher risk of type 2 diabetes independent of obesity, dyslipidemia, and hypertension .
### Metabolic syndrome
Hyperuricemia is associated with components of metabolic syndrome and it has been debated for a while to be a component of it. It has been shown in a recent study that fructose-induced hyperuricemia may play a pathogenic role in the metabolic syndrome. This agrees with the increased consumption of fructose-base drinks in recent decades and the epidemic of diabetes and obesity .
## Low uric acid
### Multiple sclerosis
Lower serum values of uric acid have been associated with Multiple Sclerosis.
Multiple sclerosis (MS) patients have been found to have serum levels ~194µmol/L, with patients in relapse averaging ~160µmol/L and patients in remission averaging ~230µmol/L. Serum uric acid in healthy controls was ~290µmol/L. (1mg/dL=59.48 µmol/L)
A 1998 study completed a statistical analysis of 20 million patient records, comparing serum uric acid values in patients with gout and patients with multiple sclerosis. Almost no overlap between the groups was found.
Uric acid has been successfully used in the treatment and prevention of the animal (murine) model of MS. A 2006 study found that elevation of serum uric acid values in multiple sclerosis patients, by oral supplementation with inosine, resulted in lower relapse rates, and no adverse effects.
## Oxidative stress
Uric acid may be a marker of oxidative stress, and may have a potential therapeutic role as an antioxidant (PMID 16375736). On the other hand, like other strong reducing substances such as ascorbate, uric acid can also act as a prooxidant, particularly at elevated levels. Thus, it is unclear whether elevated levels of uric acid in diseases associated with oxidative stress such as stroke and atherosclerosis are a protective response or a primary cause.
For example, some researchers propose that hyperuricemia-induced oxidative stress is a cause of Metabolic syndrome. On the other hand, plasma uric acid levels correlate with longevity in primates and other mammals. This is presumably a function of urate's antioxidant properties.
# Sources of uric acid
In many instances, people have elevated uric acid levels for hereditary reasons.
Diet may also be a factor.
Purines are found in high amounts in animal food products, especially internal organs.
Examples of high purine sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g Oxo, Bovril), herring, mackerel, scallops, game meats, and gravy.
A moderate amount of purine is also contained in beef, pork, poultry, fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran and wheat germ.
Moderate intake of purine-containing food is not associated with an increased risk of gout.
Serum uric acid can be elevated due to high fructose intake , reduced excretion by the kidneys, and or high intake of dietary purine.
Fructose can be found in processed foods and soda beverages - in some countries, in the form of high fructose corn syrup.
# Causes of low uric acid
Aside from avoidance of purine foods, both accumulated copper and low vitamin B2 can exacerbate low uric acid levels, which in turn is hypothesized to lead to myelin degeneration seen in multiple sclerosis.
# Other uric acid facts
The high nitrogen content of uric acid makes guano a useful agricultural fertilizer.
The crystalline form of uric acid is used as a reflector in certain species of fireflies. | Uric acid
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [21]
# Overview
Uric acid (or urate) is an organic compound of carbon, nitrogen, oxygen and hydrogen with the formula C5H4N4O3.
# Metabolic processes
Xanthine oxidase oxidizes oxypurines such as xanthine and hypoxanthine to uric acid. In humans and higher primates, uric acid is the final oxidation product of purine catabolism. In most other mammals, the enzyme uricase further oxidizes uric acid to allantoin.[1] The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid.[2] This may be because in higher primates uric acid (urate) partially replaces ascorbic acid.[3] Both urate and ascorbate are strong reducing agents (electron donors) and potent antioxidants. In humans, about half the antioxidant capacity of plasma comes from uric acid.
Uric acid is also the end product of nitrogen catabolism in birds and reptiles. In such species, it is excreted in feces as a dry mass. While this compound is produced through a complex and energetically costly metabolic pathway (in comparison to other nitrogenated wastes such as urea or ammonia), its elimination minimizes water loss. It is therefore commonly found in the excretions of animals—such as the kangaroo rat—that live in very dry environments.
The Dalmatian dog has a defect in uric acid uptake by liver, resulting in decreased conversion to allantoin, so this breed excretes uric acid, and not allantoin, in the urine.
# Medical issues
Humans produce large quantities of uric acid. In human blood, uric acid concentrations between 3.6 mg/dL (~214µmol/L) and 8.3 mg/dL (~494µmol/L) (1mg/dL=59.48 µmol/L)[4] are considered normal by the American Medical Association, although significantly lower levels are common in vegetarians due to a decreased intake of purine-rich meat.[5]
## High uric acid
### Gout
Excess serum accumulation of uric acid can lead to a type of arthritis known as gout.[6]
Elevated (serum uric acid) level (hyperuricemia) can result from high intake of purine-rich foods, high fructose intake (regardless of fructose's low Glycemic Index (GI) value) and/or impaired excretion by the kidneys. Saturation levels of uric acid in blood may result in one form of kidney stones when the urate crystallizes in the kidney. These uric acid stones are radiolucent and so do not appear on an abdominal x-ray. Their presence must be diagnosed by ultrasound for this reason. Some patients with gout eventually get uric kidney stones.
Gout can occur where serum uric acid levels are as low as 6 mg/dL (~357µmol/L), but an individual can have serum values as high as 9.5 mg/dL (~565µmol/L) and not have gout[7] (no abstract available; levels reported at[8]).
### Lesch-Nyhan syndrome
Lesch-Nyhan syndrome is also associated with very high serum uric acid levels.[9]
Spasticity, involuntary movement and cognitive retardation as well as manifestations of gout are seen in cases of this syndrome.[10]
### Cardiovascular disease
Although uric acid can act as an antioxidant, excess serum accumulation is often associated with cardiovascular disease. It is not known whether this is causative (e.g., by acting as a prooxidant ) or a protective reaction taking advantage of urate's antioxidant properties.
High uric acid can cause kidney stones, gouts in joints, and disable the body to produce purines, which build up the genetic "blueprint".
[11]
Cohort studies have proposed a relationship between hyperuricemia and cardiovascular disease, including the Kuopio Ischaemic Heart Disease Risk Factor Study of Finnish males[12] and the U.S. National Health and Nutrition Examination Survey (NHANES)[12].
On the other hand, the Framingham cohort study finds that the association between hyperuricemia nd cardiovascular disease is due to confounding[13].
A randomized controlled trial found that although febuxostat lowers uric acid levels more than does allopurinol, febuxostat increased cardiac mortality[14].
The above CARES trial by White has been included in a systematic review[15].
A more recent trial is the FAST trial[16].
A more recent systematic review finds no association[17].
### Diabetes
The association of high serum uric acid with insulin resistance has been known since the early part of the 20th century, nevertheless, recognition of high serum uric acid as a risk factor for diabetes has been a matter of debate. In fact, hyperuricemia has always been presumed to be a consequence of insulin resistance rather than its precursor [18]. However, it was shown in a prospective follow-up study that high serum uric acid is associated with higher risk of type 2 diabetes independent of obesity, dyslipidemia, and hypertension [19].
### Metabolic syndrome
Hyperuricemia is associated with components of metabolic syndrome and it has been debated for a while to be a component of it. It has been shown in a recent study that fructose-induced hyperuricemia may play a pathogenic role in the metabolic syndrome. This agrees with the increased consumption of fructose-base drinks in recent decades and the epidemic of diabetes and obesity [20].
## Low uric acid
### Multiple sclerosis
Lower serum values of uric acid have been associated with Multiple Sclerosis.[21]
Multiple sclerosis (MS) patients have been found to have serum levels ~194µmol/L, with patients in relapse averaging ~160µmol/L and patients in remission averaging ~230µmol/L. Serum uric acid in healthy controls was ~290µmol/L.[22] (1mg/dL=59.48 µmol/L)[23]
A 1998 study completed a statistical analysis of 20 million patient records, comparing serum uric acid values in patients with gout and patients with multiple sclerosis. Almost no overlap between the groups was found.[24]
Uric acid has been successfully used in the treatment and prevention of the animal (murine) model of MS. A 2006 study found that elevation of serum uric acid values in multiple sclerosis patients, by oral supplementation with inosine, resulted in lower relapse rates, and no adverse effects.[25]
## Oxidative stress
Uric acid may be a marker of oxidative stress,[26] and may have a potential therapeutic role as an antioxidant (PMID 16375736). On the other hand, like other strong reducing substances such as ascorbate, uric acid can also act as a prooxidant,[27] particularly at elevated levels. Thus, it is unclear whether elevated levels of uric acid in diseases associated with oxidative stress such as stroke and atherosclerosis are a protective response or a primary cause.[28]
For example, some researchers propose that hyperuricemia-induced oxidative stress is a cause of Metabolic syndrome.[29][30] On the other hand, plasma uric acid levels correlate with longevity in primates and other mammals.[31] This is presumably a function of urate's antioxidant properties.
# Sources of uric acid
In many instances, people have elevated uric acid levels for hereditary reasons.
Diet may also be a factor.
Purines are found in high amounts in animal food products, especially internal organs.[32]
Examples of high purine sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g Oxo, Bovril), herring, mackerel, scallops, game meats, and gravy.
A moderate amount of purine is also contained in beef, pork, poultry, fish and seafood, asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran and wheat germ.[33]
Moderate intake of purine-containing food is not associated with an increased risk of gout.[34]
Serum uric acid can be elevated due to high fructose intake [35], reduced excretion by the kidneys, and or high intake of dietary purine.
Fructose can be found in processed foods and soda beverages - in some countries, in the form of high fructose corn syrup.
# Causes of low uric acid
Aside from avoidance of purine foods, both accumulated copper and low vitamin B2 can exacerbate low uric acid levels, which in turn is hypothesized to lead to myelin degeneration seen in multiple sclerosis.[36]
# Other uric acid facts
The high nitrogen content of uric acid makes guano a useful agricultural fertilizer.
The crystalline form of uric acid is used as a reflector in certain species of fireflies. | https://www.wikidoc.org/index.php/Urate | |
e2e1be6094923721b74edb4ce748de9e1fa30aff | wikidoc | Urocortin | Urocortin
Urocortin is a protein that in humans is encoded by the UCN gene. Urocortin belongs to the corticotropin-releasing factor (CRF) family of proteins which includes CRF, urotensin I, sauvagine, urocortin II and urocortin III. Urocortin is involved in the mammalian stress response, and regulates aspects of appetite and stress response.
# Structure, localization, and interactions
Urocortin is a peptide composed of 40 amino acids. Urocortin is composed of a single alpha helix structure. The human UCN gene contains two exons, and the entirety of the coding region is contained within the second exon. Urocortin is expressed widely in the central and peripheral nervous systems, with a pattern similar to that of CRF. Areas of similarity between urocortin and CRF expression include the supraoptic nucleus and the hippocampus. Urocortin is also expressed in areas distinct from CRF expression; these areas notably include the median eminence, the Edinger-Westphal nucleus, and the sphenoid nucleus. Additionally, Urocortin is expressed in peripheral tissues such as the heart.
Urocortin is known to interact both with the CRF type 1 and CRF type 2 receptors. Furthermore, Urocortin is thought to be the primary ligand for the CRF type 2 receptor, as it has higher binding affinity for the CRF type 2 receptor than CRF. Additionally, urocortin interacts with CRF Binding Protein in the mammalian brain.
# Stress response and social behavior
Urocortin is closely related to CRF, which mediates the mammalian stress response. Urocortin is consequently implicated in a number of stress responses, primarily relating to appetite and food intake. Administration of urocortin to the central nervous system of mice and rats has been shown to decrease appetite. Additionally, central urocortin treatment increases anxiety-linked behaviors and increases motor activity in mice and rats. These general anxiety-linked behaviors are likely induced through the CRF type 1 receptor, and the appetite behaviors are likely induced through the CRF type 2 receptor. The reduction in appetite from urocortin treatment could be a result of suppression of gastric emptying and/or hypoglycemia, which have been shown to result from urocortin treatment. Urocortin expression is stimulated in response to osmotic stress; water deprivation in rats has been shown to induce urocortin expression in the supraoptic nucleus.
Montane Voles and Meadow Voles are closely related species of voles which are regularly studied as a model for social and mating behavior. The distribution of urocortin-expressing neurons differs in meadow voles compared to montane voles, suggesting urocortin may also play a role in modulating social behavior in some species.
# Cardiovascular effects
Urocortin has been shown to induce increases in heart rate and coronary blood flow when applied peripherally. These effects are likely mediated through the CRF type 2 receptor, as this receptor is found in the cardiac atria and ventricles. Urocortin also functions to protect cardiovascular tissue from ischemic injury. Urocortin's cardiovascular effects separate it from other members of the CRF family, and likely represent its primary biological function.
# In non-mammals
Urocortin is not present in all non-mammals; the closet analogue in teleost fish is urotensin I. However, in amphibian species such as Xenopus laevis, urocortin is expressed in tissues such as brain, pituitary, kidney, heart, and skin. Urocortin in Xenopus has been shown to increase cAMP accumulation and inhibit appetite | Urocortin
Urocortin is a protein that in humans is encoded by the UCN gene. Urocortin belongs to the corticotropin-releasing factor (CRF) family of proteins which includes CRF, urotensin I, sauvagine, urocortin II and urocortin III. Urocortin is involved in the mammalian stress response, and regulates aspects of appetite and stress response.[1][2][3]
# Structure, localization, and interactions
Urocortin is a peptide composed of 40 amino acids. Urocortin is composed of a single alpha helix structure. The human UCN gene contains two exons, and the entirety of the coding region is contained within the second exon.[4] Urocortin is expressed widely in the central and peripheral nervous systems, with a pattern similar to that of CRF.[5] Areas of similarity between urocortin and CRF expression include the supraoptic nucleus and the hippocampus.[6][7] Urocortin is also expressed in areas distinct from CRF expression; these areas notably include the median eminence, the Edinger-Westphal nucleus, and the sphenoid nucleus.[7] Additionally, Urocortin is expressed in peripheral tissues such as the heart.[8]
Urocortin is known to interact both with the CRF type 1 and CRF type 2 receptors.[9][10][11] Furthermore, Urocortin is thought to be the primary ligand for the CRF type 2 receptor, as it has higher binding affinity for the CRF type 2 receptor than CRF.[9] Additionally, urocortin interacts with CRF Binding Protein in the mammalian brain.[12]
# Stress response and social behavior
Urocortin is closely related to CRF, which mediates the mammalian stress response. Urocortin is consequently implicated in a number of stress responses, primarily relating to appetite and food intake. Administration of urocortin to the central nervous system of mice and rats has been shown to decrease appetite.[13] Additionally, central urocortin treatment increases anxiety-linked behaviors and increases motor activity in mice and rats.[13] These general anxiety-linked behaviors are likely induced through the CRF type 1 receptor, and the appetite behaviors are likely induced through the CRF type 2 receptor. The reduction in appetite from urocortin treatment could be a result of suppression of gastric emptying and/or hypoglycemia, which have been shown to result from urocortin treatment.[14] Urocortin expression is stimulated in response to osmotic stress; water deprivation in rats has been shown to induce urocortin expression in the supraoptic nucleus.[15]
Montane Voles and Meadow Voles are closely related species of voles which are regularly studied as a model for social and mating behavior. The distribution of urocortin-expressing neurons differs in meadow voles compared to montane voles, suggesting urocortin may also play a role in modulating social behavior in some species.[16]
# Cardiovascular effects
Urocortin has been shown to induce increases in heart rate and coronary blood flow when applied peripherally.[8] These effects are likely mediated through the CRF type 2 receptor, as this receptor is found in the cardiac atria and ventricles.[17] Urocortin also functions to protect cardiovascular tissue from ischemic injury.[18] Urocortin's cardiovascular effects separate it from other members of the CRF family, and likely represent its primary biological function.
# In non-mammals
Urocortin is not present in all non-mammals; the closet analogue in teleost fish is urotensin I.[19] However, in amphibian species such as Xenopus laevis, urocortin is expressed in tissues such as brain, pituitary, kidney, heart, and skin. Urocortin in Xenopus has been shown to increase cAMP accumulation and inhibit appetite[19] | https://www.wikidoc.org/index.php/Urocortin | |
acb01736a42588d9bc114ce080b576d31ad326c3 | wikidoc | Urophagia | Urophagia
# Overview
Urophagia is the consumption of urine.
# Health issues
Urophagia is generally considered harmless, as the urine of healthy individuals is sterile. However, a small risk exists if there is a disease present, or bacterial infection of the urethra. There may also be secondary effects, such as skin rashes in individuals sensitive to urine.
The main dangers are the high salt and mineral content. The high salt content usually does not pose a problem if the urine is sufficiently diluted and not consumed in mass quantities. The effect of the high salt may be mitigated by drinking some water after consuming urine. The urine may be diluted if the person whose urine will be consumed drinks some water (or diet soda, see below) an hour or so before the act. Many people into BDSM drink beer before the act because it dilutes any unpleasant chemicals in the urine, and alcohol acts as a diuretic, stimulating the body to excrete more urine than it normally would.
Since artificial sweeteners are excreted in urine, consuming artificial sweetener before urine play can lend a sweet taste to the urine. Drinking diet soda, or other beverages containing artificial sweetener, before urine play will have the dual effect of diluting the urine and sweetening it. However, if the taste of sugar is detected in an individual's urine, and it is known that artificial sweetener has not been consumed, this may be a sign of diabetes and a doctor should be consulted. Asparagus, on the other hand, gives urine an unpleasant smell with about 40%-79% of people.
The participants should use caution or avoid drinking urine if one or both of them are taking vitamin or mineral supplements or medication, since many of these are excreted in urine.
Urine of persons who are ill, or regularly take medication, should generally not be consumed. In special cases (e.g. chronic illness of the partner), a medical doctor should be consulted to clarify whether the urine of the chronically ill or medicated person may be consumed without endangering one's health, or not.
If put through a house hold water filter, the urine will become odorless and taste much like water.
# Survival
It has been suggested that when a person is in desert survival or surrounded by salt water and devoid of drinking water that the person must resort to drinking his/her own urine if it is the only liquid available. As it tends to cause further dehydration due to the salts in it, drinking urine for survival is advised against by the US Army Field Manual, the head of the Texas Urological Society, and numerous survival instructors and guides
while the Discovery Channel advises it
Aron Ralston claims to have used the technique when trapped for several days with his arm under a boulder.
Bear Grylls of the Discovery Channel's Man vs. Wild supposedly drank his own urine while he was in the Outback of Australia.
Alternatively Les Stroud drank water evaporated from urine that he made to collect on plastic wrap and drip into a cup.
# Alternative medicine/Practices
In countries such as India and China, it is considered normal by some groups to drink your own urine for health and cosmetic purposes. This health branch of drinking urine is considered to be labeled as Urine therapy. Also, an old method of teeth-whitening during the Renaissance involved the consumption of urine, though it needn't be, and wasn't always necessarily, that of the user.
## Teeth whitening
In Roman times, there was a tradition among the Gauls to use urine to whiten teeth. A famous poem by the Roman poet Catullus, criticizing a Gaul named Egnatius, reads:
Egnatius, because he has snow-white teeth,
smiles all the time. If you’re a defendant
in court, when the counsel draws tears,
he smiles: if you’re in grief at the pyre
-f pious sons, the lone lorn mother weeping,
he smiles. Whatever it is, wherever it is,
whatever he’s doing, he smiles: he’s got a disease,
neither polite, I would say, nor charming.
So a reminder to you, from me, good Egnatius.
If you were a Sabine or Tiburtine
-r a fat Umbrian, or plump Etruscan,
-r dark toothy Lanuvian, or from north of the Po,
and I’ll mention my own Veronese too,
-r whoever else clean their teeth religiously,
I’d still not want you to smile all the time:
there’s nothing more foolish than foolishly smiling.
Now you’re Spanish: in the country of Spain
what each man pisses, he’s used to brushing
his teeth and red gums with, every morning,
so the fact that your teeth are so polished
just shows you’re the more full of piss.
# Ceremonial
The Koryak people of Siberia drink urine in conjunction with their ceremonial use of the psychoactive Amanita muscaria (commonly known as fly agaric) mushroom. The active alkaloids are unchanged as they pass through the human body, allowing the urine to prolong the intoxicating effects of the mushroom. | Urophagia
# Overview
Urophagia is the consumption of urine.
# Health issues
Urophagia is generally considered harmless, as the urine of healthy individuals is sterile. However, a small risk exists if there is a disease present, or bacterial infection of the urethra. There may also be secondary effects, such as skin rashes in individuals sensitive to urine.
The main dangers are the high salt and mineral content. The high salt content usually does not pose a problem if the urine is sufficiently diluted and not consumed in mass quantities. The effect of the high salt may be mitigated by drinking some water after consuming urine. The urine may be diluted if the person whose urine will be consumed drinks some water (or diet soda, see below) an hour or so before the act. Many people into BDSM drink beer before the act because it dilutes any unpleasant chemicals in the urine, and alcohol acts as a diuretic, stimulating the body to excrete more urine than it normally would.[1]
Since artificial sweeteners are excreted in urine, consuming artificial sweetener before urine play can lend a sweet taste to the urine. Drinking diet soda, or other beverages containing artificial sweetener, before urine play will have the dual effect of diluting the urine and sweetening it. However, if the taste of sugar is detected in an individual's urine, and it is known that artificial sweetener has not been consumed, this may be a sign of diabetes and a doctor should be consulted. Asparagus, on the other hand, gives urine an unpleasant smell with about 40%-79% of people. [2]
The participants should use caution or avoid drinking urine if one or both of them are taking vitamin or mineral supplements or medication, since many of these are excreted in urine.
Urine of persons who are ill, or regularly take medication, should generally not be consumed. In special cases (e.g. chronic illness of the partner), a medical doctor should be consulted to clarify whether the urine of the chronically ill or medicated person may be consumed without endangering one's health, or not.
If put through a house hold water filter, the urine will become odorless and taste much like water.
# Survival
It has been suggested that when a person is in desert survival or surrounded by salt water and devoid of drinking water that the person must resort to drinking his/her own urine if it is the only liquid available.[3] As it tends to cause further dehydration due to the salts in it, drinking urine for survival is advised against by the US Army Field Manual[1], the head of the Texas Urological Society[2], and numerous survival instructors and guides [3][4][5][6][7][8]
while the Discovery Channel advises it [9]
Aron Ralston claims to have used the technique when trapped for several days with his arm under a boulder.[4]
Bear Grylls of the Discovery Channel's Man vs. Wild supposedly drank his own urine while he was in the Outback of Australia. [5]
Alternatively Les Stroud drank water evaporated from urine that he made to collect on plastic wrap and drip into a cup.
# Alternative medicine/Practices
In countries such as India and China, it is considered normal by some groups to drink your own urine for health and cosmetic purposes. This health branch of drinking urine is considered to be labeled as Urine therapy. Also, an old method of teeth-whitening during the Renaissance involved the consumption of urine, though it needn't be, and wasn't always necessarily, that of the user.
## Teeth whitening
In Roman times, there was a tradition among the Gauls to use urine to whiten teeth. A famous poem by the Roman poet Catullus, criticizing a Gaul named Egnatius, reads:
Egnatius, because he has snow-white teeth,
smiles all the time. If you’re a defendant
in court, when the counsel draws tears,
he smiles: if you’re in grief at the pyre
of pious sons, the lone lorn mother weeping,
he smiles. Whatever it is, wherever it is,
whatever he’s doing, he smiles: he’s got a disease,
neither polite, I would say, nor charming.
So a reminder to you, from me, good Egnatius.
If you were a Sabine or Tiburtine
or a fat Umbrian, or plump Etruscan,
or dark toothy Lanuvian, or from north of the Po,
and I’ll mention my own Veronese too,
or whoever else clean their teeth religiously,
I’d still not want you to smile all the time:
there’s nothing more foolish than foolishly smiling.
Now you’re Spanish: in the country of Spain
what each man pisses, he’s used to brushing
his teeth and red gums with, every morning,
so the fact that your teeth are so polished
just shows you’re the more full of piss.
[10][11]
# Ceremonial
The Koryak people of Siberia drink urine in conjunction with their ceremonial use of the psychoactive Amanita muscaria (commonly known as fly agaric) mushroom. The active alkaloids are unchanged as they pass through the human body, allowing the urine to prolong the intoxicating effects of the mushroom. | https://www.wikidoc.org/index.php/Urophagia | |
8d7a6e07a41aab5349c050b7d394c3926f2991e8 | wikidoc | Valproate | Valproate
For patient information about Valproic acid, click here.
Synonyms / Brand Names:
- Valproic Acid / Depakene, Stavzor
- Sodium Valproate, Valproate Sodium / Depacon
- Divalproex Sodium, Valproate Semisodium / Depakote, Depakote ER, Depakote Sprinkles
# Overview
Valproate, an acidic chemical compound, has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches. VPA is a liquid at room temperature, but it can be reacted with a base such as sodium hydroxide to form the salt sodium valproate, which is a solid. The acid, salt, or a mixture of the two (valproate semisodium) are marketed under the various brand names Depakote, Depakote ER, Depakene, Depakine, Depakine Crono (extended release in Spain), Depacon, Dépakine, Valparin, and Stavzor.
Approved uses of the various formulations vary by country; e.g., valproate semisodium is used as a mood stabilizer and also in the US as an anticonvulsant.
Valproate is a histone deacetylase inhibitor and is under investigation for treatment of HIV and various cancers.
# Formulations
- Depakene: 250 mg
- Generic: 250 mg
- Stavzor: 125 mg, 250 mg, 500 mg
- Depacon: 100 mg/mL (5 mL)
- Generic: 100 mg/mL (5 mL)
- Generic: 100 mg/mL (5 mL); 500 mg/5 mL (5 mL); 100 mg/mL (5 mL)
- Generic: 250 mg/5 mL (473 mL)
- Generic: 250 mg/5 mL (5 mL, 10 mL, 473 mL)
- Depakote Sprinkles: 125 mg
- Generic: 125 mg
- Depakote: 125 mg
- Depakote: 250 mg
- Depakote: 500 mg
- Generic: 125 mg, 250 mg, 500 mg
- Depakote ER: 250 mg, 500 mg
- Generic: 250 mg, 500 mg
# Uses
As an anticonvulsant, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, juvenile myoclonic epilepsy, and the seizures associated with Lennox-Gastaut syndrome. It is also used in treatment of myoclonus. In some countries, parenteral preparations of valproate are used also as second-line treatment of status epilepticus, as an alternative to phenytoin. Valproate is one of the most common drugs used to treat post-traumatic epilepsy. It is more recently being used to treat neuropathic pain, as a second-line agent, particularly lancinating pain from A delta fibers.
In the United States, valproic acid is approved by the Food and Drug Administration only for the treatment of manic episodes associated with bipolar disorder, adjunctive therapy in multiple seizure types (including epilepsy), and prophylaxis of migraine headaches.
Valproic acid is also used off-label for controlling behavioral disturbances in dementia patients.
Some randomized controlled studies have repeatedly indicated that sodium valproate and valproic acid, in borderline personality disorder and antisocial personality disorder, may have some slight to moderate mood-stabilizing advantage over no drug treatment or placebo. This is because it is believed to help reduce impulsive aggressive behavioral episodes and improving interpersonal sensitivity. These improvements would likely be somewhat better when used along with the standard psychotherapeutic regimen for these disorders- which often incorporates, among other elements, individual intensive one-on-one cognitive behavioral therapy, perhaps in a secure setting. However, these two personality disorders are widely known to still normally be lifelong and quite treatment-resistant, with a significant recidivism rate.
## Investigational
### HIV
The enzyme histone deacetylase 1 (HDAC1) is needed for HIV to remain latent, or dormant, in infected cells. When the virus is latent, it cannot be destroyed by anti-HIV drugs. A study published in August 2005 found that three of four patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a mean 75% reduction in latent HIV infection. The idea was that valproic acid, by inhibiting HDAC1, forced HIV out of latency (reactivation) and into its replicative cycle. The highly active antiretroviral drugs could then stop the virus, whilst the immune system could destroy the infected cell. Flushing out all latent virus in this manner would potentially cure HIV patients. Subsequent trials, however, found no long-term benefits of valproic acid in HIV infection.
### Other diseases
Three distinct formulations of valproic acid have been investigated in clinical trials for the treatment of colorectal polyps in familial adenomatous polyposis patients; treatment of hyperproliferative skin diseases (e.g., basal cell carcinoma); and treatment of inflammatory skin diseases (e.g., acne) by TopoTarget. The current names for these therapeutics are Savicol, Baceca and Avugane, respectively.
### Stem cells
Valproic acid's function as an HDAC inhibitor has also led to its use in direct reprogramming in generation of induced pluripotent stem (iPS) cells, where it has been shown that addition of VPA allows for reprogramming of human fibroblasts to iPS cells without addition of genetic factors Klf4 and c-myc. This function has also been investigated as an epigenetic therapy for treatment of lupus.
### Learning
In a single small study, adult men who took valproate learned to identify pitch better than those taking placebo. It is believed that the drug affects the "plasticity" of the human brain, though the mechanisms of how are not fully understood.
# History
Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian. It has two propyl groups, hence the name "val.pro~ic". Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine prophylaxis and bipolar disorder.
# Mechanism of Action
Valproate is believed to affect the function of the neurotransmitter GABA in the human brain, making it an alternative to lithium salts in treatment of bipolar disorder. Its mechanism of action includes enhanced neurotransmission of GABA (by inhibiting GABA transaminase, which breaks down GABA). However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.
Valproic acid also blocks voltage-gated sodium channels and T-type calcium channels. These mechanisms make valproic acid a broad-spectrum anticonvulsant drug.
Valproic acid is an inhibitor of the enzyme histone deacetylase 1 (HDAC1), hence it is a histone deacetylase inhibitor.
# Dosing
Dosing depends on which disease is being treated and whether valproic acid is being treated for maintenance or acute application. For maintenance of bipolar disorder type 1 the dose range can be tested through blood serum testing or by mg per kilogram of weight: minimum of 250 mg a day of Depakote up to 3000 mg a day. For acute treatment of bipolar type 1 the minimum dose would be 1000 mg a day.
## Combination therapy
Valproic acid or valproate are synergistic with lithium, with combination therapy proving more efficacious than monotherapy with valproic acid or valproate alone. This is true at least for glutamate excitotoxicity, amyotrophic lateral sclerosis, Huntington's disease, and bipolar disorder.
# Safety
## Contraindications
### Safety in pregnancy
Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major anomalies as usual, mainly spina bifida and, more rarely, with several other defects, possibly including a "valproate syndrome". Characteristics of this valproate syndrome include facial features that tend to evolve with age, including trigonocephaly, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.
Women who intend to become pregnant should switch to a different drug if possible. Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although vaproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have even worse consequences.) They should take high-dose folic acid and be offered antenatal screening (alpha-fetoprotein and second-trimester ultrasound scans), although screening and scans do not find all birth defects.
Valproate is a folate antagonist, which can cause neural tube defects. Thus, folic acid supplements may alleviate the teratogenic problems. A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower IQs.
Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring. Exposure of the human embryo to valproic acid is associated with risk of autism, and it is possible to duplicate features characteristic of autism by exposing rat embryos to valproic acid at the time of neural tube closure. Valproate exposure on embryonic day 11.5 led to significant local recurrent connectivity in the juvenile rat neocortex, consistent with the underconnectivity theory of autism.
A 2009 study found that the 3 year old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.
## Adverse effects
Adverse effects are dosage-related.
The foremost and most severe concern for anyone taking valproic acid is its potential for sudden and severe, possibly fatal, fulminating impairments in liver and impairments of hematopoietic or pancreatic function, especially in those just starting the medication. This particular warning is the first one listed on any drug adverse effect listing when one receives the drug at the pharmacy.
In rare reports, individuals having used valproic acid for a long time (chronic users) have suffered renal impairment, usually as a result of having been injured or ill or on a drug regimen already and, so, having been overwhelmed.
Valproate is also cautioned against in many patients because it can cause weight gain.
Absolute contraindications are pre-existing severe hepatic (liver) or renal (kidney) damage and certain cases of metastatic cancer, severe hepatitis or pancreatitis, end-stage AIDS HIV infection, marked bone marrow depression, urea cycle disorders, and coagulation hematological disorders that have caused impairment. Some patients with symptomatic but manageable AIDS, cancer, and hepatic or renal disease are kept on the medication (usually at a reduced dose with more frequent blood tests) to avoid having to manipulate the drug regimen for as long as possible.
Common side effects are dyspepsia or weight gain. Less common are fatigue, peripheral edema, acne, feelings of feeling cold or chills, blurred vision, burning of the eyes, dizziness, drowsiness, hair loss, headaches, nausea, sedation, and tremors. Valproic acid also causes hyperammonemia, an increase of ammonia levels in the blood, which can lead to vomiting and sluggishness, and ultimately to mental changes and brain damage. Valproate levels within the normal range are capable of causing hyperammonemia and ensuing encephalopathy. Lactulose has been used on a temporary basis to alleviate the hyperammonemia caused by valproic acid. L-Carnitine is used for hyperammonemia caused by valproic acid toxicity. There have been reports of the development of brain encephalopathy without hyperammonemia or elevated valproate levels.
In rare circumstances, valproic acid can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation (clotting) times due to a lack of blood cells. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies that resemble fetal alcohol syndrome, with a possibility of cognitive impairment. Due to these side effects, most doctors will try to continue the medication, but will ask for blood tests, initially as often as once a week and then once every two months (those taking it for a long period may go six months before being retested; if a pregnant woman and her doctor decide to keep using the drug and to keep the pregnancy, then frequent blood testing, and possibly a higher frequency of diagnostic ultrasounds to identify fetal problems, is a must). Temporary liver enzyme increase has been reported in 20% of cases during the first few months of taking the drug. Inflammation of the liver (hepatitis), the first symptom of which is jaundice, is found in rare cases.
Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome.
Valproate use in women with epilepsy or bipolar disorder is associated with an increased prevalence of polycystic ovary syndrome.
Cognitive dysfunction, Parkinsonian symptoms, and even reversible pseudoatrophic brain changes have been reported in long-term treatment with valproic acid.
According to the information provided with a prescription of this drug, some individuals have become depressed or had a suicidal ideation while on the drug; those taking it should be monitored for this side effect.
## Overdose and toxicity
Excessive amounts of valproic acid can result in tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. Overdosage in children is usually of an accidental nature, whereas with adults it is more likely to be an intentional act. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/l during controlled therapy, but may reach 150–1500 mg/l following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.
In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly than L-carnitine.
## Interactions
Valproic acid may interact with carbamazepine, as valproates inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide (the main active metabolite of carbamazepine) into inactive metabolites. By inhibiting mEH, valproic acid causes a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.
Valproic acid also decreases the clearance of amitriptyline and nortriptyline.
Aspirin may decrease the clearance of valproic acid, leading to higher-than-intended serum levels of the anticonvulsant. Also, combining valproic acid with the benzodiazepine clonazepam can lead to profound sedation and increases the risk of absence seizures in patients susceptible to them.
Valproic acid and sodium valproate reduce the apparent clearance of lamotrigine (Lamictal). In most patients, the lamotrigine dosage for coadministration with valproate must be reduced to half the monotherapy dosage.
Valproic acid is contraindicated in pregnancy, as it decreases the intestinal reabsorption of folate (folic acid), which leads to neural tube defects. Because of a decrease in folate, megaloblastic anemia may also result. Phenytoin also decreases folate absorption, which may lead to the same adverse effects as valproic acid.
# Chemistry
Valproic acid, 2-propylvaleric acid, is synthesized by the alkylation of ethyl cyanoacetate with two moles of propyl bromide, to give dipropylcyanoacetic ester. Hydrolysis and decarboxylation of the carboethoxy group gives 2-propylpentanenitrile, which is hydrolyzed into valproic acid. | Valproate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
For patient information about Valproic acid, click here.
Synonyms / Brand Names:
- Valproic Acid / Depakene, Stavzor
- Sodium Valproate, Valproate Sodium / Depacon
- Divalproex Sodium, Valproate Semisodium / Depakote, Depakote ER, Depakote Sprinkles
# Overview
Valproate, an acidic chemical compound, has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches. VPA is a liquid at room temperature, but it can be reacted with a base such as sodium hydroxide to form the salt sodium valproate, which is a solid. The acid, salt, or a mixture of the two (valproate semisodium) are marketed under the various brand names Depakote, Depakote ER, Depakene, Depakine, Depakine Crono (extended release in Spain), Depacon, Dépakine, Valparin, and Stavzor.
Approved uses of the various formulations vary by country; e.g., valproate semisodium is used as a mood stabilizer and also in the US as an anticonvulsant.
Valproate is a histone deacetylase inhibitor and is under investigation for treatment of HIV and various cancers.[1]
# Formulations
- Depakene: 250 mg
- Generic: 250 mg
- Stavzor: 125 mg, 250 mg, 500 mg [contains fd&c yellow #6 (sunset yellow)]
- Depacon: 100 mg/mL (5 mL)
- Generic: 100 mg/mL (5 mL)
- Generic: 100 mg/mL (5 mL); 500 mg/5 mL (5 mL); 100 mg/mL (5 mL)
- Generic: 250 mg/5 mL (473 mL)
- Generic: 250 mg/5 mL (5 mL, 10 mL, 473 mL)
- Depakote Sprinkles: 125 mg [contains brilliant blue fcf (fd&c blue #1)]
- Generic: 125 mg
- Depakote: 125 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]
- Depakote: 250 mg [contains fd&c yellow #6 (sunset yellow)]
- Depakote: 500 mg [contains fd&c blue #2 (indigotine)]
- Generic: 125 mg, 250 mg, 500 mg
- Depakote ER: 250 mg, 500 mg
- Generic: 250 mg, 500 mg
# Uses
As an anticonvulsant, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, juvenile myoclonic epilepsy, and the seizures associated with Lennox-Gastaut syndrome. It is also used in treatment of myoclonus. In some countries, parenteral preparations of valproate are used also as second-line treatment of status epilepticus, as an alternative to phenytoin. Valproate is one of the most common drugs used to treat post-traumatic epilepsy.[2] It is more recently being used to treat neuropathic pain, as a second-line agent, particularly lancinating pain from A delta fibers.
In the United States, valproic acid is approved by the Food and Drug Administration only for the treatment of manic episodes associated with bipolar disorder, adjunctive therapy in multiple seizure types (including epilepsy), and prophylaxis of migraine headaches.[3][4]
Valproic acid is also used off-label for controlling behavioral disturbances in dementia patients.[4]
Some randomized controlled studies have repeatedly indicated that sodium valproate and valproic acid, in borderline personality disorder and antisocial personality disorder, may have some slight to moderate mood-stabilizing advantage over no drug treatment or placebo. This is because it is believed to help reduce impulsive aggressive behavioral episodes and improving interpersonal sensitivity. These improvements would likely be somewhat better when used along with the standard psychotherapeutic regimen for these disorders- which often incorporates, among other elements, individual intensive one-on-one cognitive behavioral therapy, perhaps in a secure setting. However, these two personality disorders are widely known to still normally be lifelong and quite treatment-resistant, with a significant recidivism rate.[5]
## Investigational
### HIV
The enzyme histone deacetylase 1 (HDAC1) is needed for HIV to remain latent, or dormant, in infected cells. When the virus is latent, it cannot be destroyed by anti-HIV drugs. A study published in August 2005 found that three of four patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a mean 75% reduction in latent HIV infection.[6] The idea was that valproic acid, by inhibiting HDAC1, forced HIV out of latency (reactivation) and into its replicative cycle. The highly active antiretroviral drugs could then stop the virus, whilst the immune system could destroy the infected cell. Flushing out all latent virus in this manner would potentially cure HIV patients. Subsequent trials, however, found no long-term benefits of valproic acid in HIV infection.[7]
### Other diseases
Three distinct formulations of valproic acid have been investigated in clinical trials for the treatment of colorectal polyps in familial adenomatous polyposis patients; treatment of hyperproliferative skin diseases (e.g., basal cell carcinoma); and treatment of inflammatory skin diseases (e.g., acne) by TopoTarget. The current names for these therapeutics are Savicol, Baceca and Avugane, respectively.[8]
### Stem cells
Valproic acid's function as an HDAC inhibitor has also led to its use in direct reprogramming in generation of induced pluripotent stem (iPS) cells, where it has been shown that addition of VPA allows for reprogramming of human fibroblasts to iPS cells without addition of genetic factors Klf4 and c-myc.[9] This function has also been investigated as an epigenetic therapy for treatment of lupus.[10]
### Learning
In a single small study, adult men who took valproate learned to identify pitch better than those taking placebo. It is believed that the drug affects the "plasticity" of the human brain, though the mechanisms of how are not fully understood.[11]
# History
Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian.[12] It has two propyl groups, hence the name "val.pro~ic". Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats.[13] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[14] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[15]
# Mechanism of Action
Valproate is believed to affect the function of the neurotransmitter GABA in the human brain, making it an alternative to lithium salts in treatment of bipolar disorder. Its mechanism of action includes enhanced neurotransmission of GABA (by inhibiting GABA transaminase, which breaks down GABA). However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.[16]
Valproic acid also blocks voltage-gated sodium channels and T-type calcium channels. These mechanisms make valproic acid a broad-spectrum anticonvulsant drug.
Valproic acid is an inhibitor of the enzyme histone deacetylase 1 (HDAC1), hence it is a histone deacetylase inhibitor.
# Dosing
Dosing depends on which disease is being treated and whether valproic acid is being treated for maintenance or acute application. For maintenance of bipolar disorder type 1 the dose range can be tested through blood serum testing or by mg per kilogram of weight: minimum of 250 mg a day of Depakote up to 3000 mg a day. For acute treatment of bipolar type 1 the minimum dose would be 1000 mg a day.
## Combination therapy
Valproic acid[17][18] or valproate[19][20] are synergistic with lithium, with combination therapy proving more efficacious than monotherapy with valproic acid or valproate alone. This is true at least for glutamate excitotoxicity,[17] amyotrophic lateral sclerosis,[18] Huntington's disease,[19] and bipolar disorder.[20][21]
# Safety
## Contraindications
### Safety in pregnancy
Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major anomalies as usual, mainly spina bifida and, more rarely, with several other defects, possibly including a "valproate syndrome".[22] Characteristics of this valproate syndrome include facial features that tend to evolve with age, including trigonocephaly, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.[23]
Women who intend to become pregnant should switch to a different drug if possible.[24] Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although vaproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have even worse consequences.) They should take high-dose folic acid and be offered antenatal screening (alpha-fetoprotein and second-trimester ultrasound scans), although screening and scans do not find all birth defects.[25]
Valproate is a folate antagonist,[26] which can cause neural tube defects. Thus, folic acid supplements may alleviate the teratogenic problems. A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower IQs.[27][28]
Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring.[29] Exposure of the human embryo to valproic acid is associated with risk of autism, and it is possible to duplicate features characteristic of autism by exposing rat embryos to valproic acid at the time of neural tube closure.[30] Valproate exposure on embryonic day 11.5 led to significant local recurrent connectivity in the juvenile rat neocortex, consistent with the underconnectivity theory of autism.[31]
A 2009 study found that the 3 year old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.[32][33][34]
## Adverse effects
Adverse effects are dosage-related.
The foremost and most severe concern for anyone taking valproic acid is its potential for sudden and severe, possibly fatal, fulminating impairments in liver and impairments of hematopoietic or pancreatic function, especially in those just starting the medication. This particular warning is the first one listed on any drug adverse effect listing when one receives the drug at the pharmacy.
In rare reports, individuals having used valproic acid for a long time (chronic users) have suffered renal impairment, usually as a result of having been injured or ill or on a drug regimen already and, so, having been overwhelmed.
Valproate is also cautioned against in many patients because it can cause weight gain.[35]
Absolute contraindications are pre-existing severe hepatic (liver) or renal (kidney) damage and certain cases of metastatic cancer, severe hepatitis or pancreatitis, end-stage AIDS HIV infection, marked bone marrow depression, urea cycle disorders, and coagulation hematological disorders that have caused impairment. Some patients with symptomatic but manageable AIDS, cancer, and hepatic or renal disease are kept on the medication (usually at a reduced dose with more frequent blood tests) to avoid having to manipulate the drug regimen for as long as possible.
Common side effects are dyspepsia or weight gain. Less common are fatigue, peripheral edema, acne, feelings of feeling cold or chills, blurred vision, burning of the eyes, dizziness, drowsiness, hair loss, headaches, nausea, sedation, and tremors. Valproic acid also causes hyperammonemia, an increase of ammonia levels in the blood, which can lead to vomiting and sluggishness, and ultimately to mental changes and brain damage.[36] Valproate levels within the normal range are capable of causing hyperammonemia and ensuing encephalopathy. Lactulose has been used on a temporary basis to alleviate the hyperammonemia caused by valproic acid.[37] L-Carnitine is used for hyperammonemia caused by valproic acid toxicity. There have been reports of the development of brain encephalopathy without hyperammonemia or elevated valproate levels.[38]
In rare circumstances, valproic acid can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation (clotting) times due to a lack of blood cells. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies that resemble fetal alcohol syndrome, with a possibility of cognitive impairment. Due to these side effects, most doctors will try to continue the medication, but will ask for blood tests, initially as often as once a week and then once every two months (those taking it for a long period may go six months before being retested; if a pregnant woman and her doctor decide to keep using the drug and to keep the pregnancy, then frequent blood testing, and possibly a higher frequency of diagnostic ultrasounds to identify fetal problems, is a must). Temporary liver enzyme increase has been reported in 20% of cases during the first few months of taking the drug. Inflammation of the liver (hepatitis), the first symptom of which is jaundice, is found in rare cases.
Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome.[39][40]
Valproate use in women with epilepsy[41][42] or bipolar disorder[42] is associated with an increased prevalence of polycystic ovary syndrome.
Cognitive dysfunction, Parkinsonian symptoms,[43] and even reversible pseudoatrophic brain changes have been reported[44] in long-term treatment with valproic acid.
According to the information provided with a prescription of this drug, some individuals have become depressed or had a suicidal ideation while on the drug; those taking it should be monitored for this side effect.
## Overdose and toxicity
Excessive amounts of valproic acid can result in tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. Overdosage in children is usually of an accidental nature, whereas with adults it is more likely to be an intentional act. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/l during controlled therapy, but may reach 150–1500 mg/l following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.[45]
In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[46][47] Supplemental L-carnitine is indicated in patients having an acute overdose[48][49] and also prophylactically[49] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[50] than L-carnitine.
## Interactions
Valproic acid may interact with carbamazepine, as valproates inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide (the main active metabolite of carbamazepine) into inactive metabolites.[51] By inhibiting mEH, valproic acid causes a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.
Valproic acid also decreases the clearance of amitriptyline and nortriptyline.[52]
Aspirin may decrease the clearance of valproic acid, leading to higher-than-intended serum levels of the anticonvulsant. Also, combining valproic acid with the benzodiazepine clonazepam can lead to profound sedation and increases the risk of absence seizures in patients susceptible to them.[52]
Valproic acid and sodium valproate reduce the apparent clearance of lamotrigine (Lamictal). In most patients, the lamotrigine dosage for coadministration with valproate must be reduced to half the monotherapy dosage.
Valproic acid is contraindicated in pregnancy, as it decreases the intestinal reabsorption of folate (folic acid), which leads to neural tube defects. Because of a decrease in folate, megaloblastic anemia may also result. Phenytoin also decreases folate absorption, which may lead to the same adverse effects as valproic acid.
# Chemistry
Valproic acid, 2-propylvaleric acid, is synthesized by the alkylation of ethyl cyanoacetate with two moles of propyl bromide, to give dipropylcyanoacetic ester. Hydrolysis and decarboxylation of the carboethoxy group gives 2-propylpentanenitrile, which is hydrolyzed into valproic acid.[53][54][55][56] | https://www.wikidoc.org/index.php/Valproate | |
ed80e310650f6f5a812eca1305991414c6a4bd91 | wikidoc | Vasectomy | Vasectomy
# Overview
Vasectomy is a surgical procedure in which the vasa deferentia of a male mammal are cut for the purpose of sterilization. There are some variations on the procedure such as no-scalpel (keyhole) vasectomies, in which a surgical hook, rather than a scalpel, is used to enter the scrotum.
After vasectomy, the testes remain in the scrotum where Leydig cells continue to produce testosterone and other male hormones that continue to be secreted into the bloodstream. Some studies find that sexual desire (libido) is unaffected in over 90% of vasectomized men
whereas other studies find higher rates of diminished sexual desire.
The sperm-filled fluid from the testes contributes about 10% to the volume of an ejaculation (in men who are not vasectomized) and does not significantly affect the appearance, texture, or taste of the ejaculate.
When the vasectomy is complete, sperm can no longer exit the body through the penis. They are broken down and absorbed by the body. Much fluid content is absorbed by membranes in the epididymis, and much solid content is broken down by macrophages and re-absorbed via the blood stream. Sperm is matured in the epididymis for about a month once it leaves the testicles. Approximately 50% of the sperm produced never make it to ejaculation in a non-vasectomized man. After vasectomy, the membranes increase in size to absorb more fluid, and more macrophages are recruited to break down and re-absorb more of the solid content. The fraction of sperms that exceed the digestive capabilities of macrophages exit into the scrotum as sperm granulomas.
# Effectiveness
Early failure rates, i.e. pregnancy within a few months after vasectomy, are below 1%, but the effectiveness of the operation and rates of complications vary with the level of experience of the surgeon performing the operation and the surgical technique used.
Although late failure, i.e. pregnancy after recanalization of the vasa deferentia, is very rare, it has been documented.
# Popularity
How popular vasectomy is as a birth control method varies by age and nationality. Men in their mid 30s to mid 40s are most likely to have a vasectomy.
## Compared to tubal ligations
The rate of vasectomies to tubal ligations worldwide is extremely variable, and the statistics are mostly based on questionnaire studies rather than actual counts of procedures performed. In the U.S. in 2005, the CDC published state by state details of birth control usage by method and age group. Overall, tubal ligation is ahead of vasectomy but not by a large factor. In Britain vasectomy is more popular than tubal ligation, though this statistic may be as a result of the data-gathering methodology.
Couples who opt for tubal ligation do so for a number of reasons, including:
- Convenience of coupling the procedure with delivery at a hospital
- Fear of side effects in the man
- Fear of surgery in the man
Couples who choose vasectomy are motivated by, among other factors:
- The lower cost of vasectomy
- The simplicity of the surgical procedure
- The lower mortality of vasectomy
- Fear of surgery in the woman
# Complications
Short-term complications include temporary bruising and bleeding, known as hematoma. The primary long-term complication is a permanent feeling of pain - chronic post-vasectomy Pain.
Animal and human data indicate that vasectomy does not increase atherosclerosis and that increases in circulating immune complexes after vasectomy are transient. Furthermore, the weight of the evidence regarding prostate and testicular cancer suggests that men with vasectomy are not at increased risk of these cancers.
## Post-Vasectomy Pain Syndrome
Post-Vasectomy Pain Syndrome (PVPS), genital pain of varying intensity that may last for a lifetime, is estimated to appear in between 5% and 33% of vasectomized men, depending on the severity of pain that qualifies for the particular study In one study, vasectomy reversal was found to be 69% effective for reducing the symptoms of chronic post-vasectomy pain. Treatment options for 31% of patients whose pain did not respond to vasectomy reversal were limited. The study was very small, only evaluating 13 patients, making it difficult to draw solid conclusions. In severe cases orchiectomy has been resorted to.
## Possible Vasectomy-Dementia Link
Researchers reported in February 2007 that a survey of a small number of men with a rare form of dementia found that more than twice as many as would be expected had undergone vasectomies. The study has not yet been verified by other researchers, and the authors say larger studies are needed to better understand the issue.
# Reversal
Although men considering vasectomies should not think of them as reversible, and most men and their spouses are satisfied with the operation, there is a procedure to reverse vasectomies using vasovasostomy (a form of microsurgery first performed by Earl Owen in 1971). Vasovasostomy is effective at achieving pregnancy in only 50%-70% of cases, and it is very costly, with total out-of-pocket costs in the United States ranging from $7,000 to more than $35,000. The rate of pregnancy depends on such factors as the method used for the vasectomy and the length of time that has passed since the vasectomy was performed. The reversal procedures are frequently impermanent, with occlusion of the vas recurring two or more years after the operation. Sperm counts are rarely at pre-vasectomy levels. There is evidence that men who have had a vasectomy may produce more abnormal sperm, which would explain why even a mechanically successful reversal does not always restore fertility. The higher rates of aneuploidy and diploidy in the sperms of men who have undergone vasectomy reversal may lead to a higher rate of birth defects .
In order to allow a possibility of reproduction (via artificial insemination) after vasectomy, some men opt for cryostorage of sperm before sterilization.
Various reversible male contraceptives are in research and development, but none are available. Many of these involve the implantation of micro-valves.
# Availability
- In the UK vasectomy is often available free of charge through the National Health Service upon referral by one's GP. However, some PCTs do not fund the procedure. There are private clinics (such as Marie Stopes International) who perform the operation with short waiting times. | Vasectomy
Template:BirthControl infobox
# Overview
Vasectomy is a surgical procedure in which the vasa deferentia of a male mammal are cut for the purpose of sterilization. There are some variations on the procedure such as no-scalpel (keyhole) vasectomies, [1] in which a surgical hook, rather than a scalpel, is used to enter the scrotum.
After vasectomy, the testes remain in the scrotum where Leydig cells continue to produce testosterone and other male hormones that continue to be secreted into the bloodstream. Some studies find that sexual desire (libido) is unaffected in over 90% of vasectomized men
[2]
whereas other studies find higher rates of diminished sexual desire.
[3]
The sperm-filled fluid from the testes contributes about 10% to the volume of an ejaculation (in men who are not vasectomized) and does not significantly affect the appearance, texture, or taste of the ejaculate.
When the vasectomy is complete, sperm can no longer exit the body through the penis. They are broken down and absorbed by the body. Much fluid content is absorbed by membranes in the epididymis, and much solid content is broken down by macrophages and re-absorbed via the blood stream. Sperm is matured in the epididymis for about a month once it leaves the testicles. Approximately 50% of the sperm produced never make it to ejaculation in a non-vasectomized man. After vasectomy, the membranes increase in size to absorb more fluid, and more macrophages are recruited to break down and re-absorb more of the solid content. The fraction of sperms that exceed the digestive capabilities of macrophages exit into the scrotum as sperm granulomas.
# Effectiveness
Early failure rates, i.e. pregnancy within a few months after vasectomy, are below 1%, but the effectiveness of the operation and rates of complications vary with the level of experience of the surgeon performing the operation and the surgical technique used.
Although late failure, i.e. pregnancy after recanalization of the vasa deferentia, is very rare, it has been documented.[4]
# Popularity
How popular vasectomy is as a birth control method varies by age and nationality. Men in their mid 30s to mid 40s are most likely to have a vasectomy.
## Compared to tubal ligations
The rate of vasectomies to tubal ligations worldwide is extremely variable, and the statistics are mostly based on questionnaire studies rather than actual counts of procedures performed. In the U.S. in 2005, the CDC published state by state details of birth control usage by method and age group.[5] Overall, tubal ligation is ahead of vasectomy but not by a large factor. In Britain vasectomy is more popular than tubal ligation, though this statistic may be as a result of the data-gathering methodology.
Couples who opt for tubal ligation do so for a number of reasons, including:
- Convenience of coupling the procedure with delivery at a hospital
- Fear of side effects in the man
- Fear of surgery in the man
Couples who choose vasectomy are motivated by, among other factors:[6]
- The lower cost of vasectomy
- The simplicity of the surgical procedure
- The lower mortality of vasectomy
- Fear of surgery in the woman
# Complications
Short-term complications include temporary bruising and bleeding, known as hematoma. The primary long-term complication is a permanent feeling of pain - chronic post-vasectomy Pain.
Animal and human data indicate that vasectomy does not increase atherosclerosis and that increases in circulating immune complexes after vasectomy are transient. Furthermore, the weight of the evidence regarding prostate and testicular cancer suggests that men with vasectomy are not at increased risk of these cancers.[7]
## Post-Vasectomy Pain Syndrome
Post-Vasectomy Pain Syndrome (PVPS), genital pain of varying intensity that may last for a lifetime, is estimated to appear in between 5% and 33% of vasectomized men, depending on the severity of pain that qualifies for the particular study[8] [9] [10] [11] In one study, vasectomy reversal was found to be 69% effective for reducing the symptoms of chronic post-vasectomy pain. Treatment options for 31% of patients whose pain did not respond to vasectomy reversal were limited. The study was very small, only evaluating 13 patients, making it difficult to draw solid conclusions. [12] In severe cases orchiectomy has been resorted to.
[13]
## Possible Vasectomy-Dementia Link
Researchers reported in February 2007 that a survey of a small number of men with a rare form of dementia found that more than twice as many as would be expected had undergone vasectomies. The study has not yet been verified by other researchers, and the authors say larger studies are needed to better understand the issue.[14]
# Reversal
Although men considering vasectomies should not think of them as reversible, and most men and their spouses are satisfied with the operation, [15][16][17] there is a procedure to reverse vasectomies using vasovasostomy (a form of microsurgery first performed by Earl Owen in 1971[18][19]). Vasovasostomy is effective at achieving pregnancy in only 50%-70% of cases, and it is very costly, with total out-of-pocket costs in the United States ranging from $7,000 [20] to more than $35,000. The rate of pregnancy depends on such factors as the method used for the vasectomy and the length of time that has passed since the vasectomy was performed. The reversal procedures are frequently impermanent, with occlusion of the vas recurring two or more years after the operation. Sperm counts are rarely at pre-vasectomy levels. There is evidence that men who have had a vasectomy may produce more abnormal sperm, which would explain why even a mechanically successful reversal does not always restore fertility.[21][22] The higher rates of aneuploidy and diploidy in the sperms of men who have undergone vasectomy reversal may lead to a higher rate of birth defects [23].
In order to allow a possibility of reproduction (via artificial insemination) after vasectomy, some men opt for cryostorage of sperm before sterilization.[24]
Various reversible male contraceptives are in research and development, but none are available. Many of these involve the implantation of micro-valves.
# Availability
- In the UK vasectomy is often available free of charge through the National Health Service upon referral by one's GP. However, some PCTs do not fund the procedure. There are private clinics (such as Marie Stopes International) who perform the operation with short waiting times. | https://www.wikidoc.org/index.php/Vasectomy | |
cca4e067c6633d118404cc6de3a69e2958ac1482 | wikidoc | Venus Hum | Venus Hum
Synonyms and keywords:Nun's murmur, Bruit de diable
# Pathology
- Venous hum is a benign phenomena, which is caused by blood flow over jugular veins.
- At rest approximately 20% of Cardiac out put pass through internal carotid and vertebral bodies.
- It may result in a continuous humming noise.
- Typically it is heard in upper chest near clavicle.
- It can be differentiated from cardiac murmurs only by placing a finger on jugular vein which abolish or change the murmur however cardiac born murmurs will not change by this maneuver.
- the murmur is also position dependent and can change in intensity if the patient lies in supine form or turn their head to one side. | Venus Hum
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ramyar Ghandriz MD[2]
Synonyms and keywords:Nun's murmur, Bruit de diable
# Pathology
- Venous hum is a benign phenomena, which is caused by blood flow over jugular veins.[1]
- At rest approximately 20% of Cardiac out put pass through internal carotid and vertebral bodies.
- It may result in a continuous humming noise.
- Typically it is heard in upper chest near clavicle.
- It can be differentiated from cardiac murmurs only by placing a finger on jugular vein which abolish or change the murmur however cardiac born murmurs will not change by this maneuver.
- the murmur is also position dependent and can change in intensity if the patient lies in supine form or turn their head to one side.[2] | https://www.wikidoc.org/index.php/Venus_Hum | |
d81c5100568d838bffc22e5c1b336efb7055eed1 | wikidoc | VerifyNow | VerifyNow
# Overview
The VerifyNow system (Accumetrics, San Diego, Ca, USA; ) is a bedside test that allows for monitoring of the efficacy of thienopyridines, aspirin, and glycoprotein IIbIIIa inhibitors.
Formerly known as the Ultegra rapid platelet function analyzer, the VerifyNow system is a turbidimetric based optical detection system which measures platelet induced aggregation as an increase in light transmittance.
This system is a point-of-care and consists of an instrument, a disposable assay device and controls. The assay device contains a lyophilized preparation of human fibrinogen-coated beads, platelet agonist, preservative and buffer.
Three assays are currently available, which differ according to the platelet agonist contained in the mixing chamber:
After activation, the GP IIb/IIIa receptors on platelets will bind to the fibrinogen-coated microbeads and cross link to other microbeads resulting in a clearing of the beads and platelets within the detection well. The instrument uses light transmittance to measure the rate at which this clearing occurs.
The main advantage of this test is that the patient sample is a low sample volume of 3.2% citrated whole blood, which is automatically dispensed from the blood collection tube into the assay device by the instrument, with no blood handling required by the user. Another advantage is that the instrument provides the results in minutes. | VerifyNow
Associate Editors-in-Chief: Davide Capodanno, M.D. [1]
# Overview
The VerifyNow system (Accumetrics, San Diego, Ca, USA; [2]) is a bedside test that allows for monitoring of the efficacy of thienopyridines, aspirin, and glycoprotein IIbIIIa inhibitors.
Formerly known as the Ultegra rapid platelet function analyzer, the VerifyNow system is a turbidimetric based optical detection system which measures platelet induced aggregation as an increase in light transmittance.
This system is a point-of-care and consists of an instrument, a disposable assay device and controls. The assay device contains a lyophilized preparation of human fibrinogen-coated beads, platelet agonist, preservative and buffer.
Three assays are currently available, which differ according to the platelet agonist contained in the mixing chamber:
After activation, the GP IIb/IIIa receptors on platelets will bind to the fibrinogen-coated microbeads and cross link to other microbeads resulting in a clearing of the beads and platelets within the detection well. The instrument uses light transmittance to measure the rate at which this clearing occurs.
The main advantage of this test is that the patient sample is a low sample volume of 3.2% citrated whole blood, which is automatically dispensed from the blood collection tube into the assay device by the instrument, with no blood handling required by the user. Another advantage is that the instrument provides the results in minutes.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/VerifyNow | |
5c5473e98a826d3b1e23b1117e8a87dbdee3c9a1 | wikidoc | Vero cell | Vero cell
Vero cells are lineages of cells used in cell cultures.
The Vero lineage was isolated from kidney epithelial cells extracted from African green monkey (Cercopithecus aethiops). The lineage was developed on 27 Mar 1962, by Yasumura and Kawakita at the Chiba University in Chiba, Japan. The original cell line was named after an acronym of "Verda Reno" and was matched to the word "Vero", which means "green kidney" and "truth" in esperanto, respectively.
Vero cells are used for many purposes, including:
- screening for the toxin of E. coli, first named Vero toxin after this cell line, and later called Shiga-like toxin due to its similarity to Shiga toxin isolated from Shigella dysenteriae.
- as host cells for growing virus; for example, to measure replication in the presence or absence of a research pharmaceutical, or testing for the presence of rabies virus.
- as host cells for eukaryotic parasites, specially of the Trypanosomatids.
The Vero cell lineage is continuous and aneuploid. A continuous cell lineage can be replicated through many cycles of division and not become senescent. Aneuploidy is the characteristic of having an abnormal number of chromosomes.
# Lineages
- Vero (ATCC No. CCL-81)
- Vero 76 (ATCC No. CRL-1587)
- Vero E6 (ATCC No. CRL-1586)
- Research strains transfected with viral genes: | Vero cell
Vero cells are lineages of cells used in cell cultures.[1]
The Vero lineage was isolated from kidney epithelial cells extracted from African green monkey (Cercopithecus aethiops). The lineage was developed on 27 Mar 1962, by Yasumura and Kawakita at the Chiba University in Chiba, Japan. [2] The original cell line was named after an acronym of "Verda Reno" and was matched to the word "Vero", which means "green kidney" and "truth" in esperanto, respectively.[3]
Vero cells are used for many purposes, including:
- screening for the toxin of E. coli, first named Vero toxin after this cell line, and later called Shiga-like toxin due to its similarity to Shiga toxin isolated from Shigella dysenteriae.
- as host cells for growing virus; for example, to measure replication in the presence or absence of a research pharmaceutical, or testing for the presence of rabies virus.
- as host cells for eukaryotic parasites, specially of the Trypanosomatids.
The Vero cell lineage is continuous and aneuploid. A continuous cell lineage can be replicated through many cycles of division and not become senescent.[4] Aneuploidy is the characteristic of having an abnormal number of chromosomes.
# Lineages
- Vero (ATCC No. CCL-81)
- Vero 76 (ATCC No. CRL-1587)
- Vero E6 (ATCC No. CRL-1586)
- Research strains transfected with viral genes: | https://www.wikidoc.org/index.php/Vero_cell | |
13c07a35bd862800bb153ae3c8a6be909e5beb70 | wikidoc | Vestibule | Vestibule
Vestibule or Vestibulum can have the following meanings, each primarily based upon a common origin, from early 17th century French, derived from Latin vestibulum, -i n. "entrance court".
# Anatomy
In general, vestibule is a small space or cavity at the beginning of a canal.
- The vulval vestibule is the anatomical name for the entrance to the vagina (it is the boundary between the external genitalia (vulva) and internal genitalia (vagina), where the Bartholin's glands are located).
- The nasal vestibule is the anatomical name for the nostrils. It is simply lined with an extension of skin epithelium. The nasal cavity on the other hand, is lined with respiratory epithelium.
- The vestibule of the ear refers to the central part of the labyrinth, as used in the vestibular system.
- The vestibule of the larynx is between the epiglottis and rima glottidis.
- The aortic vestibule is the part of the left ventricle of the heart just below the aortic valve.
- The vestibule of mouth
# Architecture
See: Vestibule (architecture)
- a large entrance
- a lobby, entrance hall, or passage between the outer door and the interior of a building
- an enclosed area between two rail cars
- a reception area
- a footstool
- a toilet
- a bar-stool
- an antechamber
- an entry room
- a laundry shoot in an American apartment building
- a passageway acting as an airlock between two environments
Related:
- a covered section between the outer opening and inner opening of a tent, typically used for the storage of boots, packs and small equipment.
# Music
- Vestibule (Texas band), a Christian worship/rock band in North and South Texas.
- Vestibule (Oxford band), a Rock/Post-rock band from Oxford, UK.
- A song by They Might Be Giants
# Other
- The Vestibules (formerly known as Radio Free Vestibule), a Canadian comedy troupe.
- An IGN message board
- Vestibulum (wasp), a wasp genus | Vestibule
Vestibule or Vestibulum can have the following meanings, each primarily based upon a common origin, from early 17th century French, derived from Latin vestibulum, -i n. "entrance court".
# Anatomy
In general, vestibule is a small space or cavity at the beginning of a canal.
- The vulval vestibule is the anatomical name for the entrance to the vagina (it is the boundary between the external genitalia (vulva) and internal genitalia (vagina), where the Bartholin's glands are located).
- The nasal vestibule is the anatomical name for the nostrils. It is simply lined with an extension of skin epithelium. The nasal cavity on the other hand, is lined with respiratory epithelium.
- The vestibule of the ear refers to the central part of the labyrinth, as used in the vestibular system.
- The vestibule of the larynx is between the epiglottis and rima glottidis.
- The aortic vestibule is the part of the left ventricle of the heart just below the aortic valve.
- The vestibule of mouth
# Architecture
See: Vestibule (architecture)
- a large entrance
- a lobby, entrance hall, or passage between the outer door and the interior of a building
- an enclosed area between two rail cars
- a reception area
- a footstool
- a toilet
- a bar-stool
- an antechamber
- an entry room
- a laundry shoot in an American apartment building
- a passageway acting as an airlock between two environments
Related:
- a covered section between the outer opening and inner opening of a tent, typically used for the storage of boots, packs and small equipment.
# Music
- Vestibule (Texas band), a Christian worship/rock band in North and South Texas.[1]
- Vestibule (Oxford band), a Rock/Post-rock band from Oxford, UK.[2]
- A song by They Might Be Giants
# Other
- The Vestibules (formerly known as Radio Free Vestibule), a Canadian comedy troupe.
- An IGN message board
- Vestibulum (wasp), a wasp genus | https://www.wikidoc.org/index.php/Vestibule | |
6331887b9418389eb853366f6788206475831cab | wikidoc | Vibration | Vibration
Vibration refers to mechanical oscillations about an equilibrium point . The oscillations may be periodic such as the motion of a pendulum or random such as the movement of a tire on a gravel road.
Vibration is occasionally "desirable". For example the motion of a tuning fork, the reed in a woodwind instrument or harmonica, or the cone of a loudspeaker is desirable vibration, necessary for the correct functioning of the various devices.
More often, vibration is undesirable, wasting energy and creating unwanted sound -- noise. For example, the vibrational motions of engines, electric motors, or any mechanical device in operation are typically unwanted. Such vibrations can be caused by imbalances in the rotating parts, uneven friction, the meshing of gear teeth, etc. Careful designs usually minimize unwanted vibrations.
The study of sound and vibration are closely related. Sound, or "pressure waves", are generated by vibrating structures (e.g. vocal cords); these pressure waves can also induce the vibration of structures (e.g. ear drum). Hence, when trying to reduce noise it is often a problem in trying to reduce vibration.
# Types of vibration
Free vibration occurs when a mechanical system is set off with an initial input and then allowed to vibrate freely. Examples of this type of vibration are pulling a child back on a swing and then letting go or hitting a tuning fork and letting it ring. The mechanical system will then vibrate at one or more of its "natural frequencies" and damp down to zero.
Forced vibration is when an alternating force or motion is applied to a mechanical system. Examples of this type of vibration include a shaking washing machining due to an imbalance, transportation vibration (caused by truck engine, springs, road, etc), or the vibration of a building during an earthquake. In forced vibration the frequency of the vibration is the frequency of the force or motion applied, with order of magnitude being dependent on the actual mechanical system.
# Vibration testing
Vibration testing is accomplished by introducing a forcing function into a structure, usually with some type of shaker. Generally, one or more points on the structure are kept at a specified vibration level. Two typical types of vibration tests performed are random- and sine test. Sine tests are performed to survey the structural response of the device under test (DUT). A random test is generally conducted to replicate a real world environment.
# Vibration analysis
The fundamentals of vibration analysis can be understood by studying the simple mass-spring-damper model. Indeed, even a complex structure such as an automobile body can be modeled as a "summation" of simple mass-spring-damper models. The mass-spring-damper model is an example of a simple harmonic oscillator. The mathematics used to describe its behavior is identical to other simple harmonic oscillators such as the RLC circuit.
Note: In this article the step by step mathematical derivations will not be included, but will focus on the major equations and concepts in vibration analysis. Please refer to the references at the end of the article for detailed derivations.
## Free vibration without damping
To start the investigation of the mass-spring-damper we will assume the damping is negligible and that there is no external force applied to the mass (i.e. free vibration).
The force applied to the mass by the spring is proportional to the amount the spring is stretched "x" (we will assume the spring is already compressed due to the weight of the mass). The proportionality constant, k, is the stiffness of the spring and has units of force/distance (e.g. lbf/in or N/m)
F_s=- k x \!
The force generated by the mass is proportional to the acceleration of the mass as given by Newton’s second law of motion.
\Sigma\ F = ma = m \ddot{x} = m \frac{d^2x}{dt^2}
The sum of the forces on the mass then generates this ordinary differential equation:
If we assume that we start the system to vibrate by stretching the spring by the distance of A and letting go, the solution to the above equation that describes the motion of mass is:
x(t) = A \cos (2 \pi f_n t) \!
This solution says that it will oscillate with simple harmonic motion that has an amplitude of A and a frequency of f_n. The number f_n is one of the most important quantities in vibration analysis and is called the undamped natural frequency. For the simple mass-spring system, f_n is defined as:
f_n = {1\over {2 \pi}} \sqrt{k \over m} \!
Note: Angular frequency \omega (\omega=2 \pi f) with the units of radians per second is often used in equations because it simplifies the equations, but is normally converted to “standard” frequency (units of Hz or equivalently cycles per second) when stating the frequency of a system.
If you know the mass and stiffness of the system you can determine the frequency at which the system will vibrate once it is set in motion by an initial disturbance using the above stated formula. Every vibrating system has one or more natural frequencies that it will vibrate at once it is disturbed. This simple relation can be used to understand in general what will happen to a more complex system once we add mass or stiffness. For example, the above formula explains why when a car or truck is fully loaded the suspension will feel “softer” than unloaded because the mass has increased and therefore reduced the natural frequency of the system.
### What causes the system to vibrate under no force?
These formulas describe the resulting motion, but they do not explain why the system oscillates. The reason for the oscillation is due to the conservation of energy. In the above example we have extended the spring by a value of A and therefore have stored potential energy (\tfrac {1}{2} k x^2) in the spring. Once we let go of the spring, the spring tries to return to its un-stretched state and in the process accelerates the mass. At the point where the spring has reached its un-stretched state it no longer has energy stored, but the mass has reached its maximum speed and hence all the energy has been transformed into kinetic energy (\tfrac {1}{2} m v^2). The mass then begins to decelerate because it is now compressing the spring and in the process transferring the kinetic energy back to its potential. This transferring back and forth of the kinetic energy in the mass and the potential energy in the spring causes the mass to oscillate.
In our simple model the mass will continue to oscillate forever at the same magnitude, but in a real system there is always something called damping that dissipates the energy and therefore the system eventually bringing it to rest.
## Free vibration with damping
We now add a "viscous" damper to the model that outputs a force that is proportional to the velocity of the mass. The damping is called viscous because it models the effects of an object within a fluid. The proportionality constant c is called the damping coefficient and has units of Force over velocity (lbf s/ in or N s/m).
F_d = - c v = - c \dot{x} = - c \frac{dx}{dt} \!
By summing the forces on the mass we get the following ordinary differential equation:
The solution to this equation depends on the amount of damping. If the damping is small enough the system will still vibrate, but eventually, over time, will stop vibrating. This case is called underdamping--this case is of most interest in vibration analysis. If we increase the damping just to the point where the system no longer oscillates we reach the point of critical damping (if the damping is increased past critical damping the system is called overdamped). The value that the damping coefficient needs to reach for critical damping in the mass spring damper model is:
To characterize the amount of damping in a system a ratio called the damping ratio (also known as damping factor and % critical damping) is used. This damping ratio is just a ratio of the actual damping over the amount of damping required to reach critical damping. The formula for the damping ratio (\zeta ) of the mass spring damper model is:
For example, metal structures (e.g. airplane fuselage, engine crankshaft) will have damping factors less than 0.05 while automotive suspensions in the range of 0.2-0.3.
The solution to the underdamped system for the mass spring damper model is the following:
The value of X, the initial magnitude, and \phi , the phase shift, are determined by the amount the spring is stretched. The formulas for these values can be found in the references.
The major points to note from the solution are the exponential term and the cosine function. The exponential term defines how quickly the system “damps” down – the larger the damping ratio, the quicker it damps to zero. The cosine function is the oscillating portion of the solution, but the frequency of the oscillations is different from the undamped case.
The frequency in this case is called the "damped natural frequency", f_d , and is related to the undamped natural frequency by the following formula:
The damped natural frequency is less than the undamped natural frequency, but for many practical cases the damping ratio is relatively small and hence the difference is negligible. Therefore the damped and undamped description are often dropped when stating the natural frequency (e.g. with 0.1 damping ratio, the damped natural frequency is only 1% less than the undamped).
The plots to the side present how 0.1 and 0.3 damping ratios effect how the system will “ring” down over time. What is often done in practice is to experimentally measure the free vibration after an impact (for example by a hammer) and then determine the natural frequency of the system by measuring the rate of oscillation as well as the damping ratio by measuring the rate of decay. The natural frequency and damping ratio are not only important in free vibration, but also characterize how a system will behave under forced vibration.
## Forced vibration with damping
In this section we will look at the behavior of the spring mass damper model when we add a harmonic force in the form below. A force of this type could, for example, be generated by a rotating imbalance.
If we again sum the forces on the mass we get the following ordinary differential equation:
The steady state solution of this problem can be written as:
The result states that the mass will oscillate at the same frequency, f, of the applied force, but with a phase shift \phi .
The amplitude of the vibration “X” is defined by the following formula.
Where “r” is defined as the ratio of the harmonic force frequency over the undamped natural frequency of the mass-spring-damper model.
The phase shift , \phi, is defined by following formula.
Forced Vibration Response
The plot of these functions, called "the frequency response of the system", presents one of the most important features in forced vibration. In a lightly damped system when the forcing frequency nears the natural frequency (r \approx 1 ) the amplitude of the vibration can get extremely high. This phenomenon is called resonance (subsequently the natural frequency of a system is often referred to as the resonant frequency). In rotor bearing systems any rotational speed that excites a resonant frequency is referred to as a critical speed.
If resonance occurs in a mechanical system it can be very harmful-- leading to eventual failure of the system. Consequently, one of the major reasons for vibration analysis is to predict when this type of resonance may occur and then to determine what steps to take to prevent it from occurring. As the amplitude plot shows, adding damping can significantly reduce the magnitude of the vibration. Also, the magnitude can be reduced if the natural frequency can be shifted away from the forcing frequency by changing the stiffness or mass of the system. If the system cannot be changed, perhaps the forcing frequency can be shifted (for example, changing the speed of the machine generating the force).
The following are some other points in regards to the forced vibration shown in the frequency response plots.
- At a given frequency ratio, the amplitude of the vibration, X, is directly proportional to the amplitude of the force F_0 (e.g. If you double the force, the vibration doubles)
- With little or no damping, the vibration is in phase with the forcing frequency when the frequency ratio r 1
- When rF_0 . This deflection is called the static deflection \delta_{st}. Hence, when r<<1 the effects of the damper and the mass are minimal.
- When r>>1 the amplitude of the vibration is actually less than the static deflection \delta_{st}. In this region the force generated by the mass (F=ma) is dominating because the acceleration seen by the mass increases with the frequency. Since the deflection seen in the spring, X, is reduced in this region, the force transmitted by the spring (F=kx) to the base is reduced. Therefore the mass-spring-damper system is isolating the harmonic force from the mounting base—referred to as vibration isolation. Interestingly, more damping actually reduces the effects of vibration isolation when r>>1 because the damping force (F=cv) is also transmitted to the base.
### What causes resonance?
Resonance is simple to understand if you view the spring and mass as energy storage elements--with the mass storing kinetic energy and the spring storing potential energy. As discussed earlier, when the mass and spring have no force acting on them they transfer energy back forth at a rate equal to the natural frequency. In other words, if energy is to be efficiently pumped into both the mass and spring the energy source needs to feed the energy in at a rate equal to the natural frequency. Applying a force to the mass and spring is similar to pushing a child on swing, you need to push at the correct moment if you want the swing to get higher and higher. As in the case of the swing, the force applied does not necessarily have to be high to get large motions; the pushes just need to keep adding energy into the system.
The damper, instead of storing energy, dissipates energy. Since the damping force is proportional to the velocity, the more the motion the more the damper dissipates the energy. Therefore a point will come when the energy dissipated by the damper will equal the energy being fed in by the force. At this point, the system has reached its maximum amplitude and will continue to vibrate at this level as long as the force applied stays the same. If no damping exists, there is nothing to dissipate the energy and therefore theoretically the motion will continue to grow on into infinity.
### Applying "complex" forces to the mass-spring-damper model
In a previous section only a simple harmonic force was applied to the model, but this can be extended considerably using two powerful mathematical tools. The first is the Fourier transform that takes a signal as a function of time (time domain) and breaks it down into its harmonic components as a function of frequency (frequency domain). For example, let us apply a force to the mass-spring-damper model that repeats the following cycle--a force equal to 1 newton for 0.5 second and then no force for 0.5 second. This type of force has the shape of a 1 Hz square wave.
The Fourier transform of the square wave generates a frequency spectrum that presents the magnitude of the harmonics that make up the square wave (the phase is also generated, but is typically of less concern and therefore is often not plotted). The Fourier transform can also be used to analyze non-periodic functions such as transients (e.g. impulses) and random functions. With the advent of the modern computer the Fourier transform is almost always computed using the Fast Fourier Transform (FFT) computer algorithm in combination with a window function.
In the case of our square wave force, the first component is actually a constant force of 0.5 newton and is represented by a value at "0" Hz in the frequency spectrum. The next component is a 1 Hz sine wave with an amplitude of 0.64. This is shown by the line at 1 Hz. The remaining components are at odd frequencies and it takes an infinite amount of sine waves to generate the perfect square wave. Hence, the Fourier transform allows you to interpret the force as a sum of sinusoidal forces being applied instead of a more "complex" force (e.g. a square wave).
In the previous section, the vibration solution was given for a single harmonic force, but the Fourier transform will in general give multiple harmonic forces. The second mathematical tool, "the principle of superposition", allows you to sum the solutions from multiple forces if the system is linear. In the case of the spring-mass-damper model, the system is linear if the spring force is proportional to the displacement and the damping is proportional to the velocity over the range of motion of interest. Hence, the solution to the problem with a square wave is summing the predicted vibration from each one of the harmonic forces found in the frequency spectrum of the square wave.
### Frequency response model
We can view the solution of a vibration problem as an input/output relation--where the force is the input and the output is the vibration. If we represent the force and vibration in the frequency domain (magnitude and phase) we can write the following relation:
H(\omega) is called the frequency response function (also referred to the transfer function, but not technically as accurate) and has both a magnitude and phase component (if represented as a complex number, a real and imaginary component). The magnitude of the frequency response function (FRF) was presented earlier for the mass-spring-damper system.
The phase of the FRF was also presented earlier as:
For example, let us calculate the FRF for a mass-spring-damper system with a mass of 1 kg, spring stiffness of 1.93 N/mm and a damping ratio of 0.1. The values of the spring and mass give a natural frequency of 7 Hz for this specific system. If we apply the 1 Hz square wave from earlier we can calculate the predicted vibration of the mass. The figure illustrates the resulting vibration. It happens in this example that the fourth harmonic of the square wave falls at 7 Hz. The frequency response of the mass-spring-damper therefore outputs a high 7 Hz vibration even though the input force had a relatively low 7 Hz harmonic. This example highlights that the resulting vibration is dependent on both the forcing function and the system that the force is applied.
The figure also shows the time domain representation of the resulting vibration. This is done by performing an inverse Fourier Transform that converts frequency domain data to time domain. In practice, this is rarely done because the frequency spectrum provides all the necessary information.
The frequency response function (FRF) does not necessarily have to be calculated from the knowledge of the mass, damping, and stiffness of the system, but can be measured experimentally. For example, if you apply a known force and sweep the frequency and then measure the resulting vibration you can calculate the frequency response function and then characterize the system. This technique is used in the field of experimental modal analysis to determine the vibration characteristics of a structure.
# Multiple degrees of freedom systems and mode shapes
The simple mass-spring damper model is the foundation of vibration analysis, but what about more complex systems? The mass-spring-damper model described above is called a single degree of freedom (DOF) model since we have assumed the mass only moves up and down. In the case of more complex systems we need to discretize the system into more masses and allow them to move in more than one direction--adding degrees of freedom. The major concepts of multiple degrees of freedom (MDOF) can be understood by looking at just a 2 degree of freedom model as shown in the figure.
The equations of motion of the 2DOF system are found to be:
m_1 \ddot{x_1} + { (c_1+c_2) } \dot{x_1} - { c_2 } \dot{x_2}+ { (k_1+k_2) } x_1 -{ k_2 } x_2= f_1
m_2 \ddot{x_2} - { c_2 } \dot{x_1}+ { (c_2+c_3) } \dot{x_2} - { c_3 } \dot{x_3} - { k_2 } x_1+ { (k_2+k_3) } x_2 -{ k_3 } x_3= f_2 \!
We can rewrite this in matrix format:
\begin{bmatrix}m_1 & 0\\ 0 & m_2\end{bmatrix}\begin{Bmatrix}\ddot{x_1}\\ \ddot{x_2}\end{Bmatrix}+\begin{bmatrix}c_1+c_2 & -c_2\\ -c_2 & c_2+c_3\end{bmatrix}\begin{Bmatrix}\dot{x_1}\\ \dot{x_2}\end{Bmatrix}+\begin{bmatrix}k_1+k_2 & -k_2\\ -k_2 & k_2+k_3\end{bmatrix}\begin{Bmatrix} x_1\\ x_2\end{Bmatrix}=\begin{Bmatrix} f_1\\ f_2\end{Bmatrix}
A more compact form of this matrix equation can be written as:
\begin{bmatrix}M\end{bmatrix}\begin{Bmatrix}\ddot{x}\end{Bmatrix}+\begin{bmatrix}C\end{bmatrix}\begin{Bmatrix}\dot{x}\end{Bmatrix}+\begin{bmatrix}K\end{bmatrix}\begin{Bmatrix} x\end{Bmatrix}=\begin{Bmatrix} f \end{Bmatrix} \!
where \begin{bmatrix}M\end{bmatrix}, \begin{bmatrix}C\end{bmatrix}, and \begin{bmatrix}K\end{bmatrix} are symmetric matrices referred respectively as the mass, damping, and stiffness matrices. The matrices are NxN square matrices where N is the number of degrees of freedom of the system.
In the following analysis we will consider the case where there is no damping and no applied forces (i.e. free vibration). The solution of a viscously damped system is somewhat more complicated and is shown in Maia, Silva. .
This differential equation can be solved by assuming the following type of solution:
\begin{Bmatrix} x\end{Bmatrix}=\begin{Bmatrix} X\end{Bmatrix}e^{i\omega t}
Note: Using the exponential solution of \begin{Bmatrix} X\end{Bmatrix}e^{i\omega t} is a mathematical trick used to solve linear differential equations. If we use Euler's formula and take only the real part of the solution it is the same cosine solution for the 1 DOF system. The exponential solution is only used because it easier to manipulate mathematically.
The equation then becomes:
Since e^{i\omega t}=0 cannot equal zero the equation reduces to the following.
## Eigenvalue problem
This is referred to an eigenvalue problem in mathematics and can be put in the standard format by pre-multiplying the equation by \begin{bmatrix}M\end{bmatrix}^{-1}
and if we let \begin{bmatrix}M\end{bmatrix}^{-1}\begin{bmatrix}K\end{bmatrix}=\begin{bmatrix}A\end{bmatrix} and \lambda=\omega^2 \,
The solution to the problem results in N eigenvalues (ie. \omega_1^2,\omega_2^2,..\omega_N^2), where N corresponds to the number of degrees of freedom. The eigenvalues provide the natural frequencies of the system. When these eigenvalues are substituted back into the original set of equations, the values of \begin{Bmatrix}X\end{Bmatrix} that correspond to each eigenvalue are called the eigenvectors. These eigenvectors represent the mode shapes of the system. The solution of an eigenvalue problem can be quite cumbersome (especially for problems with many degrees of freedom), but fortunately most math analysis programs have eigenvalue routines.
The eigenvalues and eigenvectors are often written in the following matrix format and describe the modal model of the system:
A simple example using our 2 DOF model can help illustrate the concepts. Let both masses have a mass of 1 kg and the stiffness of all three springs equal 1000 N/m. The mass and stiffness matrix for this problem are then:
Then \begin{bmatrix}A\end{bmatrix}=\begin{bmatrix}2000 & -1000\\ -1000 & 2000\end{bmatrix}.
The eigenvalues for this problem given by an eigenvalue routine will be:
The natural frequencies in the units of hertz are then (remembering \omega=2 \pi f) f_1=31.62 Hz and f_2=54.77 Hz.
The two mode shapes for the respective natural frequencies are given as:
Since the system is a 2 DOF system, there are two modes with their respective natural frequencies and shapes. The mode shape vectors are not the absolute motion, but just describe relative motion of the degrees of freedom. In our case the first mode shape vector is saying that the masses are moving together in phase since they have the same value and sign. In the case of the second mode shape vector, each mass is moving in opposite direction at the same rate.
## Illustration of a multiple DOF problem
When there are many degrees of freedom, the best method of visualizing the mode shapes is by animating them. An example of animated mode shapes is shown in the figure below for a cantilevered I-beam. In this case, a finite element model was used to generate the mass and stiffness matrices and solve the eigenvalue problem. Even this relatively simple model has over a 100 degrees of freedom and hence as many natural frequencies and mode shapes. In general only the first few modes are important.
## Multiple DOF problem converted to a single DOF problem
The eigenvectors have very important properties called orthoganility properties. These properties can be used to greatly simplify the solution of multi-degree of freedom models. It can be shown that the eigenvectors have the following properties:
\begin{bmatrix} ^\diagdown m_{r\diagdown} \end{bmatrix} and \begin{bmatrix} ^\diagdown k_{r\diagdown} \end{bmatrix} are diagonal matrices that contain the modal mass and stiffness values for each one of the modes. (Note: Since the eigenvectors (mode shapes) can be arbitrarily scaled, the orthogonality properties are often used to scale the eigenvectors so the modal mass value for each mode is equal to 1. The modal mass matrix is therefore an identity matrix)
These properties can be used to greatly simplify the solution of multi-degree of freedom models by making the following the coordinate transformation.
If we use this coordinate transformation in our original free vibration differential equation we get the following equation.
We can take advantage of the orthogonality properties by premultiplying this equation by \begin{bmatrix}\Psi\end{bmatrix}^{T}
The orthogonality properties then simplify this equation to:
This equation is the foundation of vibration analysis for multiple degree of freedom systems. A similar type of result can be derived for damped systems. . The key is that the modal and stiffness matrices are diagonal matrices and therefore we have "decoupled" the equations. In other words, we have transformed our problem from a large unwieldy multiple degree of freedom problem into many single degree of freedom problems that can be solved using the same methods outlined above.
Instead of solving for x we are instead solving for q, referred to as the modal coordinates or modal participation factors.
It may be clearer to understand if we write \begin{Bmatrix} x \end{Bmatrix}= \begin{bmatrix} \Psi \end{bmatrix} \begin{Bmatrix} q \end{Bmatrix} as:
Written in this form we can see that the vibration at each of the degrees of freedom is just a linear sum of the mode shapes. Furthermore, how much each mode "participates" in the final vibration is defined by q, its modal participation factor. | Vibration
Vibration refers to mechanical oscillations about an equilibrium point . The oscillations may be periodic such as the motion of a pendulum or random such as the movement of a tire on a gravel road.
Vibration is occasionally "desirable". For example the motion of a tuning fork, the reed in a woodwind instrument or harmonica, or the cone of a loudspeaker is desirable vibration, necessary for the correct functioning of the various devices.
More often, vibration is undesirable, wasting energy and creating unwanted sound -- noise. For example, the vibrational motions of engines, electric motors, or any mechanical device in operation are typically unwanted. Such vibrations can be caused by imbalances in the rotating parts, uneven friction, the meshing of gear teeth, etc. Careful designs usually minimize unwanted vibrations.
The study of sound and vibration are closely related. Sound, or "pressure waves", are generated by vibrating structures (e.g. vocal cords); these pressure waves can also induce the vibration of structures (e.g. ear drum). Hence, when trying to reduce noise it is often a problem in trying to reduce vibration.
# Types of vibration
Free vibration occurs when a mechanical system is set off with an initial input and then allowed to vibrate freely. Examples of this type of vibration are pulling a child back on a swing and then letting go or hitting a tuning fork and letting it ring. The mechanical system will then vibrate at one or more of its "natural frequencies" and damp down to zero.
Forced vibration is when an alternating force or motion is applied to a mechanical system. Examples of this type of vibration include a shaking washing machining due to an imbalance, transportation vibration (caused by truck engine, springs, road, etc), or the vibration of a building during an earthquake. In forced vibration the frequency of the vibration is the frequency of the force or motion applied, with order of magnitude being dependent on the actual mechanical system.
# Vibration testing
Vibration testing is accomplished by introducing a forcing function into a structure, usually with some type of shaker. Generally, one or more points on the structure are kept at a specified vibration level. Two typical types of vibration tests performed are random- and sine test. Sine tests are performed to survey the structural response of the device under test (DUT). A random test is generally conducted to replicate a real world environment.
# Vibration analysis
The fundamentals of vibration analysis can be understood by studying the simple mass-spring-damper model. Indeed, even a complex structure such as an automobile body can be modeled as a "summation" of simple mass-spring-damper models. The mass-spring-damper model is an example of a simple harmonic oscillator. The mathematics used to describe its behavior is identical to other simple harmonic oscillators such as the RLC circuit.
Note: In this article the step by step mathematical derivations will not be included, but will focus on the major equations and concepts in vibration analysis. Please refer to the references at the end of the article for detailed derivations.
## Free vibration without damping
To start the investigation of the mass-spring-damper we will assume the damping is negligible and that there is no external force applied to the mass (i.e. free vibration).
The force applied to the mass by the spring is proportional to the amount the spring is stretched "x" (we will assume the spring is already compressed due to the weight of the mass). The proportionality constant, k, is the stiffness of the spring and has units of force/distance (e.g. lbf/in or N/m)
F_s=- k x \!
</math>
The force generated by the mass is proportional to the acceleration of the mass as given by Newton’s second law of motion.
\Sigma\ F = ma = m \ddot{x} = m \frac{d^2x}{dt^2}
</math>
The sum of the forces on the mass then generates this ordinary differential equation:
If we assume that we start the system to vibrate by stretching the spring by the distance of A and letting go, the solution to the above equation that describes the motion of mass is:
x(t) = A \cos (2 \pi f_n t) \!
</math>
This solution says that it will oscillate with simple harmonic motion that has an amplitude of A and a frequency of <math>f_n.</math> The number <math>f_n</math> is one of the most important quantities in vibration analysis and is called the undamped natural frequency. For the simple mass-spring system, <math>f_n</math> is defined as:
f_n = {1\over {2 \pi}} \sqrt{k \over m} \!
</math>
Note: Angular frequency <math>\omega</math> (<math>\omega=2 \pi f</math>) with the units of radians per second is often used in equations because it simplifies the equations, but is normally converted to “standard” frequency (units of Hz or equivalently cycles per second) when stating the frequency of a system.
If you know the mass and stiffness of the system you can determine the frequency at which the system will vibrate once it is set in motion by an initial disturbance using the above stated formula. Every vibrating system has one or more natural frequencies that it will vibrate at once it is disturbed. This simple relation can be used to understand in general what will happen to a more complex system once we add mass or stiffness. For example, the above formula explains why when a car or truck is fully loaded the suspension will feel “softer” than unloaded because the mass has increased and therefore reduced the natural frequency of the system.
### What causes the system to vibrate under no force?
These formulas describe the resulting motion, but they do not explain why the system oscillates. The reason for the oscillation is due to the conservation of energy. In the above example we have extended the spring by a value of A and therefore have stored potential energy (<math>\tfrac {1}{2} k x^2</math>) in the spring. Once we let go of the spring, the spring tries to return to its un-stretched state and in the process accelerates the mass. At the point where the spring has reached its un-stretched state it no longer has energy stored, but the mass has reached its maximum speed and hence all the energy has been transformed into kinetic energy (<math>\tfrac {1}{2} m v^2</math>). The mass then begins to decelerate because it is now compressing the spring and in the process transferring the kinetic energy back to its potential. This transferring back and forth of the kinetic energy in the mass and the potential energy in the spring causes the mass to oscillate.
In our simple model the mass will continue to oscillate forever at the same magnitude, but in a real system there is always something called damping that dissipates the energy and therefore the system eventually bringing it to rest.
## Free vibration with damping
We now add a "viscous" damper to the model that outputs a force that is proportional to the velocity of the mass. The damping is called viscous because it models the effects of an object within a fluid. The proportionality constant c is called the damping coefficient and has units of Force over velocity (lbf s/ in or N s/m).
F_d = - c v = - c \dot{x} = - c \frac{dx}{dt} \!
</math>
By summing the forces on the mass we get the following ordinary differential equation:
The solution to this equation depends on the amount of damping. If the damping is small enough the system will still vibrate, but eventually, over time, will stop vibrating. This case is called underdamping--this case is of most interest in vibration analysis. If we increase the damping just to the point where the system no longer oscillates we reach the point of critical damping (if the damping is increased past critical damping the system is called overdamped). The value that the damping coefficient needs to reach for critical damping in the mass spring damper model is:
To characterize the amount of damping in a system a ratio called the damping ratio (also known as damping factor and % critical damping) is used. This damping ratio is just a ratio of the actual damping over the amount of damping required to reach critical damping. The formula for the damping ratio (<math>\zeta </math>) of the mass spring damper model is:
For example, metal structures (e.g. airplane fuselage, engine crankshaft) will have damping factors less than 0.05 while automotive suspensions in the range of 0.2-0.3.
The solution to the underdamped system for the mass spring damper model is the following:
The value of X, the initial magnitude, and <math> \phi </math>, the phase shift, are determined by the amount the spring is stretched. The formulas for these values can be found in the references.
The major points to note from the solution are the exponential term and the cosine function. The exponential term defines how quickly the system “damps” down – the larger the damping ratio, the quicker it damps to zero. The cosine function is the oscillating portion of the solution, but the frequency of the oscillations is different from the undamped case.
The frequency in this case is called the "damped natural frequency", <math> f_d </math>, and is related to the undamped natural frequency by the following formula:
The damped natural frequency is less than the undamped natural frequency, but for many practical cases the damping ratio is relatively small and hence the difference is negligible. Therefore the damped and undamped description are often dropped when stating the natural frequency (e.g. with 0.1 damping ratio, the damped natural frequency is only 1% less than the undamped).
The plots to the side present how 0.1 and 0.3 damping ratios effect how the system will “ring” down over time. What is often done in practice is to experimentally measure the free vibration after an impact (for example by a hammer) and then determine the natural frequency of the system by measuring the rate of oscillation as well as the damping ratio by measuring the rate of decay. The natural frequency and damping ratio are not only important in free vibration, but also characterize how a system will behave under forced vibration.
## Forced vibration with damping
In this section we will look at the behavior of the spring mass damper model when we add a harmonic force in the form below. A force of this type could, for example, be generated by a rotating imbalance.
If we again sum the forces on the mass we get the following ordinary differential equation:
The steady state solution of this problem can be written as:
The result states that the mass will oscillate at the same frequency, f, of the applied force, but with a phase shift <math> \phi </math>.
The amplitude of the vibration “X” is defined by the following formula.
Where “r” is defined as the ratio of the harmonic force frequency over the undamped natural frequency of the mass-spring-damper model.
The phase shift , <math>\phi</math>, is defined by following formula.
Forced Vibration Response
The plot of these functions, called "the frequency response of the system", presents one of the most important features in forced vibration. In a lightly damped system when the forcing frequency nears the natural frequency (<math>r \approx 1 </math>) the amplitude of the vibration can get extremely high. This phenomenon is called resonance (subsequently the natural frequency of a system is often referred to as the resonant frequency). In rotor bearing systems any rotational speed that excites a resonant frequency is referred to as a critical speed.
If resonance occurs in a mechanical system it can be very harmful-- leading to eventual failure of the system. Consequently, one of the major reasons for vibration analysis is to predict when this type of resonance may occur and then to determine what steps to take to prevent it from occurring. As the amplitude plot shows, adding damping can significantly reduce the magnitude of the vibration. Also, the magnitude can be reduced if the natural frequency can be shifted away from the forcing frequency by changing the stiffness or mass of the system. If the system cannot be changed, perhaps the forcing frequency can be shifted (for example, changing the speed of the machine generating the force).
The following are some other points in regards to the forced vibration shown in the frequency response plots.
- At a given frequency ratio, the amplitude of the vibration, X, is directly proportional to the amplitude of the force <math>F_0 </math> (e.g. If you double the force, the vibration doubles)
- With little or no damping, the vibration is in phase with the forcing frequency when the frequency ratio r < 1 and 180 degrees out of phase when the frequency ratio r >1
- When r<<1 the amplitude is just the deflection of the spring under the static force <math>F_0 </math>. This deflection is called the static deflection <math>\delta_{st}</math>. Hence, when r<<1 the effects of the damper and the mass are minimal.
- When r>>1 the amplitude of the vibration is actually less than the static deflection <math>\delta_{st}</math>. In this region the force generated by the mass (F=ma) is dominating because the acceleration seen by the mass increases with the frequency. Since the deflection seen in the spring, X, is reduced in this region, the force transmitted by the spring (F=kx) to the base is reduced. Therefore the mass-spring-damper system is isolating the harmonic force from the mounting base—referred to as vibration isolation. Interestingly, more damping actually reduces the effects of vibration isolation when r>>1 because the damping force (F=cv) is also transmitted to the base.
### What causes resonance?
Resonance is simple to understand if you view the spring and mass as energy storage elements--with the mass storing kinetic energy and the spring storing potential energy. As discussed earlier, when the mass and spring have no force acting on them they transfer energy back forth at a rate equal to the natural frequency. In other words, if energy is to be efficiently pumped into both the mass and spring the energy source needs to feed the energy in at a rate equal to the natural frequency. Applying a force to the mass and spring is similar to pushing a child on swing, you need to push at the correct moment if you want the swing to get higher and higher. As in the case of the swing, the force applied does not necessarily have to be high to get large motions; the pushes just need to keep adding energy into the system.
The damper, instead of storing energy, dissipates energy. Since the damping force is proportional to the velocity, the more the motion the more the damper dissipates the energy. Therefore a point will come when the energy dissipated by the damper will equal the energy being fed in by the force. At this point, the system has reached its maximum amplitude and will continue to vibrate at this level as long as the force applied stays the same. If no damping exists, there is nothing to dissipate the energy and therefore theoretically the motion will continue to grow on into infinity.
### Applying "complex" forces to the mass-spring-damper model
In a previous section only a simple harmonic force was applied to the model, but this can be extended considerably using two powerful mathematical tools. The first is the Fourier transform that takes a signal as a function of time (time domain) and breaks it down into its harmonic components as a function of frequency (frequency domain). For example, let us apply a force to the mass-spring-damper model that repeats the following cycle--a force equal to 1 newton for 0.5 second and then no force for 0.5 second. This type of force has the shape of a 1 Hz square wave.
The Fourier transform of the square wave generates a frequency spectrum that presents the magnitude of the harmonics that make up the square wave (the phase is also generated, but is typically of less concern and therefore is often not plotted). The Fourier transform can also be used to analyze non-periodic functions such as transients (e.g. impulses) and random functions. With the advent of the modern computer the Fourier transform is almost always computed using the Fast Fourier Transform (FFT) computer algorithm in combination with a window function.
In the case of our square wave force, the first component is actually a constant force of 0.5 newton and is represented by a value at "0" Hz in the frequency spectrum. The next component is a 1 Hz sine wave with an amplitude of 0.64. This is shown by the line at 1 Hz. The remaining components are at odd frequencies and it takes an infinite amount of sine waves to generate the perfect square wave. Hence, the Fourier transform allows you to interpret the force as a sum of sinusoidal forces being applied instead of a more "complex" force (e.g. a square wave).
In the previous section, the vibration solution was given for a single harmonic force, but the Fourier transform will in general give multiple harmonic forces. The second mathematical tool, "the principle of superposition", allows you to sum the solutions from multiple forces if the system is linear. In the case of the spring-mass-damper model, the system is linear if the spring force is proportional to the displacement and the damping is proportional to the velocity over the range of motion of interest. Hence, the solution to the problem with a square wave is summing the predicted vibration from each one of the harmonic forces found in the frequency spectrum of the square wave.
### Frequency response model
We can view the solution of a vibration problem as an input/output relation--where the force is the input and the output is the vibration. If we represent the force and vibration in the frequency domain (magnitude and phase) we can write the following relation:
<math>H(\omega)</math> is called the frequency response function (also referred to the transfer function, but not technically as accurate) and has both a magnitude and phase component (if represented as a complex number, a real and imaginary component). The magnitude of the frequency response function (FRF) was presented earlier for the mass-spring-damper system.
The phase of the FRF was also presented earlier as:
For example, let us calculate the FRF for a mass-spring-damper system with a mass of 1 kg, spring stiffness of 1.93 N/mm and a damping ratio of 0.1. The values of the spring and mass give a natural frequency of 7 Hz for this specific system. If we apply the 1 Hz square wave from earlier we can calculate the predicted vibration of the mass. The figure illustrates the resulting vibration. It happens in this example that the fourth harmonic of the square wave falls at 7 Hz. The frequency response of the mass-spring-damper therefore outputs a high 7 Hz vibration even though the input force had a relatively low 7 Hz harmonic. This example highlights that the resulting vibration is dependent on both the forcing function and the system that the force is applied.
The figure also shows the time domain representation of the resulting vibration. This is done by performing an inverse Fourier Transform that converts frequency domain data to time domain. In practice, this is rarely done because the frequency spectrum provides all the necessary information.
The frequency response function (FRF) does not necessarily have to be calculated from the knowledge of the mass, damping, and stiffness of the system, but can be measured experimentally. For example, if you apply a known force and sweep the frequency and then measure the resulting vibration you can calculate the frequency response function and then characterize the system. This technique is used in the field of experimental modal analysis to determine the vibration characteristics of a structure.
# Multiple degrees of freedom systems and mode shapes
The simple mass-spring damper model is the foundation of vibration analysis, but what about more complex systems? The mass-spring-damper model described above is called a single degree of freedom (DOF) model since we have assumed the mass only moves up and down. In the case of more complex systems we need to discretize the system into more masses and allow them to move in more than one direction--adding degrees of freedom. The major concepts of multiple degrees of freedom (MDOF) can be understood by looking at just a 2 degree of freedom model as shown in the figure.
The equations of motion of the 2DOF system are found to be:
m_1 \ddot{x_1} + { (c_1+c_2) } \dot{x_1} - { c_2 } \dot{x_2}+ { (k_1+k_2) } x_1 -{ k_2 } x_2= f_1
</math>
m_2 \ddot{x_2} - { c_2 } \dot{x_1}+ { (c_2+c_3) } \dot{x_2} - { c_3 } \dot{x_3} - { k_2 } x_1+ { (k_2+k_3) } x_2 -{ k_3 } x_3= f_2 \!
</math>
We can rewrite this in matrix format:
\begin{bmatrix}m_1 & 0\\ 0 & m_2\end{bmatrix}\begin{Bmatrix}\ddot{x_1}\\ \ddot{x_2}\end{Bmatrix}+\begin{bmatrix}c_1+c_2 & -c_2\\ -c_2 & c_2+c_3\end{bmatrix}\begin{Bmatrix}\dot{x_1}\\ \dot{x_2}\end{Bmatrix}+\begin{bmatrix}k_1+k_2 & -k_2\\ -k_2 & k_2+k_3\end{bmatrix}\begin{Bmatrix} x_1\\ x_2\end{Bmatrix}=\begin{Bmatrix} f_1\\ f_2\end{Bmatrix}
</math>
A more compact form of this matrix equation can be written as:
\begin{bmatrix}M\end{bmatrix}\begin{Bmatrix}\ddot{x}\end{Bmatrix}+\begin{bmatrix}C\end{bmatrix}\begin{Bmatrix}\dot{x}\end{Bmatrix}+\begin{bmatrix}K\end{bmatrix}\begin{Bmatrix} x\end{Bmatrix}=\begin{Bmatrix} f \end{Bmatrix} \!
</math>
where <math>\begin{bmatrix}M\end{bmatrix}</math>, <math>\begin{bmatrix}C\end{bmatrix}</math>, and <math>\begin{bmatrix}K\end{bmatrix}</math> are symmetric matrices referred respectively as the mass, damping, and stiffness matrices. The matrices are NxN square matrices where N is the number of degrees of freedom of the system.
In the following analysis we will consider the case where there is no damping and no applied forces (i.e. free vibration). The solution of a viscously damped system is somewhat more complicated and is shown in Maia, Silva. [1].
This differential equation can be solved by assuming the following type of solution:
\begin{Bmatrix} x\end{Bmatrix}=\begin{Bmatrix} X\end{Bmatrix}e^{i\omega t}
</math>
Note: Using the exponential solution of <math> \begin{Bmatrix} X\end{Bmatrix}e^{i\omega t}</math> is a mathematical trick used to solve linear differential equations. If we use Euler's formula and take only the real part of the solution it is the same cosine solution for the 1 DOF system. The exponential solution is only used because it easier to manipulate mathematically.
The equation then becomes:
Since <math>e^{i\omega t}=0</math> cannot equal zero the equation reduces to the following.
## Eigenvalue problem
This is referred to an eigenvalue problem in mathematics and can be put in the standard format by pre-multiplying the equation by <math>\begin{bmatrix}M\end{bmatrix}^{-1}</math>
and if we let <math>\begin{bmatrix}M\end{bmatrix}^{-1}\begin{bmatrix}K\end{bmatrix}=\begin{bmatrix}A\end{bmatrix}</math> and <math>\lambda=\omega^2 \,</math>
The solution to the problem results in N eigenvalues (ie. <math>\omega_1^2,\omega_2^2,..\omega_N^2</math>), where N corresponds to the number of degrees of freedom. The eigenvalues provide the natural frequencies of the system. When these eigenvalues are substituted back into the original set of equations, the values of <math>\begin{Bmatrix}X\end{Bmatrix}</math> that correspond to each eigenvalue are called the eigenvectors. These eigenvectors represent the mode shapes of the system. The solution of an eigenvalue problem can be quite cumbersome (especially for problems with many degrees of freedom), but fortunately most math analysis programs have eigenvalue routines.
The eigenvalues and eigenvectors are often written in the following matrix format and describe the modal model of the system:
A simple example using our 2 DOF model can help illustrate the concepts. Let both masses have a mass of 1 kg and the stiffness of all three springs equal 1000 N/m. The mass and stiffness matrix for this problem are then:
Then <math>\begin{bmatrix}A\end{bmatrix}=\begin{bmatrix}2000 & -1000\\ -1000 & 2000\end{bmatrix}</math>.
The eigenvalues for this problem given by an eigenvalue routine will be:
The natural frequencies in the units of hertz are then (remembering <math>\omega=2 \pi f</math>) <math>f_1=31.62 Hz</math> and <math>f_2=54.77 Hz</math>.
The two mode shapes for the respective natural frequencies are given as:
Since the system is a 2 DOF system, there are two modes with their respective natural frequencies and shapes. The mode shape vectors are not the absolute motion, but just describe relative motion of the degrees of freedom. In our case the first mode shape vector is saying that the masses are moving together in phase since they have the same value and sign. In the case of the second mode shape vector, each mass is moving in opposite direction at the same rate.
## Illustration of a multiple DOF problem
When there are many degrees of freedom, the best method of visualizing the mode shapes is by animating them. An example of animated mode shapes is shown in the figure below for a cantilevered I-beam. In this case, a finite element model was used to generate the mass and stiffness matrices and solve the eigenvalue problem. Even this relatively simple model has over a 100 degrees of freedom and hence as many natural frequencies and mode shapes. In general only the first few modes are important.
## Multiple DOF problem converted to a single DOF problem
The eigenvectors have very important properties called orthoganility properties. These properties can be used to greatly simplify the solution of multi-degree of freedom models. It can be shown that the eigenvectors have the following properties:
<math>\begin{bmatrix} ^\diagdown m_{r\diagdown} \end{bmatrix}</math> and <math>\begin{bmatrix} ^\diagdown k_{r\diagdown} \end{bmatrix}</math> are diagonal matrices that contain the modal mass and stiffness values for each one of the modes. (Note: Since the eigenvectors (mode shapes) can be arbitrarily scaled, the orthogonality properties are often used to scale the eigenvectors so the modal mass value for each mode is equal to 1. The modal mass matrix is therefore an identity matrix)
These properties can be used to greatly simplify the solution of multi-degree of freedom models by making the following the coordinate transformation.
If we use this coordinate transformation in our original free vibration differential equation we get the following equation.
We can take advantage of the orthogonality properties by premultiplying this equation by <math>\begin{bmatrix}\Psi\end{bmatrix}^{T}</math>
The orthogonality properties then simplify this equation to:
This equation is the foundation of vibration analysis for multiple degree of freedom systems. A similar type of result can be derived for damped systems. [2]. The key is that the modal and stiffness matrices are diagonal matrices and therefore we have "decoupled" the equations. In other words, we have transformed our problem from a large unwieldy multiple degree of freedom problem into many single degree of freedom problems that can be solved using the same methods outlined above.
Instead of solving for x we are instead solving for q, referred to as the modal coordinates or modal participation factors.
It may be clearer to understand if we write <math>\begin{Bmatrix} x \end{Bmatrix}= \begin{bmatrix} \Psi \end{bmatrix} \begin{Bmatrix} q \end{Bmatrix} </math> as:
Written in this form we can see that the vibration at each of the degrees of freedom is just a linear sum of the mode shapes. Furthermore, how much each mode "participates" in the final vibration is defined by q, its modal participation factor. | https://www.wikidoc.org/index.php/Vibration | |
5d2e4e2b7876a24719a22a80863397cfe8b77502 | wikidoc | Vipassanā | Vipassanā
Vipassanā (Pāli) or vipaśyanā (विपश्यना) in (Sanskrit) means "insight" into the impermanent nature or anicca of mind and body. Vipassana is one of India's most ancient techniques of meditation, rediscovered by Gautama Buddha 2500 years ago. It is a way of self-transformation through self-observation and introspection. It focuses on the deep interconnection between mind and body, which can be experienced directly by disciplined attention to the physical sensations that form the life of the body, and that continuously interconnect and condition the life of the mind . Vipassanā meditation is often referred to by Buddhists and non-Buddhists alike simply as "insight meditation". While it is a type of Buddhist meditation as taught by the Buddha, it is essentially non-sectarian in character and has universal application. One need not convert to Buddhism to practice vipassanā meditation. While the practice of vipassana meditation varies from school to school, the underlying principle is the investigation of phenomena as they manifest in the four Foundations of Mindfulness highlighted in the Satipatthana Sutta; namely: kaya (body or breath), vedana (feeling or sensation), citta (mind), and dhamma (mind objects). These phenomena differ from the khandas (aggregates) because the citta factor is not connected to any aggregate, as it is the basic mood of the mind-body aggregate, while the dhamma encompasses all mind objects that are fruits of kamma (i.e., the vinnana, sanna and sankhara aggregates), and also all mind objects that are not a fruit of kamma, such as the Four Noble Truths.
In a broader sense, vipassanā has been used as one of two poles for the categorization of types of Buddhist meditation, the other being samatha (Pāli) or śamatha (Sanskrit). Samatha is a focusing, pacifying and calming meditation, common to many traditions in the world, notably yoga. It is used as a preparation for vipassanā, pacifying the mind and strengthening the concentration in order to allow the work of insight. This dichotomy is also sometimes discussed as "stopping and seeing." In Buddhist practice it is said that, while samatha can calm the mind, only insight can reveal how the mind was disturbed to start with, which leads to prajñā (Pāli: paññā, wisdom) and jñāna (Pāli: ñāṇa, knowledge) and thus understanding, preventing it from being disturbed again.
The term is also used to refer to the Buddhist vipassana movement (modeled after Theravāda Buddhism meditation practices), which employs vipassanā and ānāpāna meditation as its primary techniques and places emphasis on the teachings of the Satipaṭṭhāna Sutta. Vedanā (sensation/feeling) is the primary initial subject of investigation.
# Etymology
Vipassanā is a Pali word from the Sanskrit prefix "vi-" and verbal root √paś. It is often translated as "insight" or "clear-seeing," though, the "in-" prefix may be misleading; "vi" in Indo-Aryan languages is equivalent to our (Latin) "dis." The "vi" in vipassanā may then mean to see apart, or discern. Alternatively, the "vi" can function as an intensive, and thus vipassanā may mean "seeing deeply". In any case, this is used metaphorically for a particularly powerful mental self-perception.
A synonym for "Vipassanā" is paccakkha (Pāli; Sanskrit: Template:IAST), "before the eyes," which refers to direct experiential perception. Thus, the type of seeing denoted by "vipassanā" is that of direct perception, as opposed to knowledge derived from reasoning or argument.
In Tibetan, vipashyana is lhagthong. The semantic field of "lhag" means "higher", "superior", "greater"; the semantic field of "thong" is "view" or "to see". So together, lhagthong may be rendered into English as "superior seeing" or "great vision". This may be interpreted as a "superior manner of seeing, and also as "seeing that which is the essential nature". Its nature is a lucidity, a clarity of mind.
# Practice of vipassanā
Vipassanā meditation is a simple technique which depends on direct experience and observation. It can be related to the three trainings taught by the Buddha as the basis of a spiritual path: adherence to a sīla (Sanskrit: śīla) (abstinence from killing, stealing, lying, sexual misconduct and intoxication), which is not an end in itself but a requirement for the second part, concentration of the mind (samādhi). With this concentrated mind, the third training, in the context of this technique (paññā, Sanskrit prajñā), is detached observation of the reality of the mind and body from moment to moment.
The actual instructions for Vipassana meditation are not often published in clear terms in public venues. This is simply to avoid confusion and prevent incorrect technique. The instructions are not esoteric or difficult but basically involve retraining the mind to avoid its innate conditioned response to most stimuli. In order to obtain maximum benefit, it is recommended that this be learned from a legitimate source as it does have deep cleansing effects. Although Vipassana includes body awareness as part of the practice, it is not a "body scan" technique. The purpose is also not to release past trauma, but to bring full awareness of the mind, body and all sensations and be fully present. This practice is thought to develop a deep, experiential understanding of the impermanence of all phenomena and also brings to the surface and dissolves deep-seated complexes and tensions. The technique fosters development of insight and needs to be continued as a way of life in order to having lasting effects.
Put another way, Vipassanā meditation consists of the experiential observation of mind and matter (nāma and rūpa) in their aspects of impermanence, unsatisfactoriness and lack of an inherent, independent essence or self.
To see through the mode of impermanence means to examine things to determine whether they are permanent. To see through the mode of unsatisfactoriness means to examine things to determine whether they are satisfactory or are imbued with suffering. To see through the mode of non-self means to examine meditation objects to see whether they are permanent, isolated, and enduring entities. In other words, to see through non-self relates to having a sense of non-doership and a sense of non-possessorship while examining things.
In Vipassanā meditation, the meditation object is one's own consciousness, although it can be further refined to be one's consciousness while observing, say, the breath, as in anapanasati meditation. In this context, the modes of seeing refers to focusing on those aspects of consciousness which appear to have (or not have) these characteristics.
Some steps are described as vipassanā jhānas, or simply as knowledges.
# Vipassanā today
Today, the term "Vipassanā" also refers to a series of meditation techniques used by many branches of modern Theravāda Buddhism, for example in modern Sri Lanka, Burma, Laos and Thailand, and to a specific branch of Buddhism popularized by S. N. Goenka and his mentor U Ba Khin as a nonsectarian form of Buddhism, and also by Americans Joseph Goldstein, Sharon Salzberg, and Jack Kornfield (who were inspired by the monks Mahasi Sayadaw and Ajahn Chah) under the rubric "insight meditation."
# Famous masters
- U Ba Khin
- Mahasi Sayadaw
- Ledi Sayadaw
- Ajahn Chah Subhatto
# Living teachers
- Ajahn Tong Sirimangalo
- Lakshman Attanayake
- Ajahn Sumedho
- Ajahn Sobin S. Namto
- Bhante Henepola Gunaratana (schedule)
- Bhikkhu Bodhi
- Bhikkhu Sri Matara Nyanarama (steps)
- Bhikkhu Katukurunde Nyanananda (analysis)
- Christopher Titmuss
- Gil Fronsdal (schedule)
- Jack Kornfield
- Joseph Goldstein
- Larry Rosenberg
- Matthew Flickstein
- Rodney Smith
- S. N. Goenka (schedule)
- Sayadaw U Pandita
- Shaila Catherine (schedule)
- Sharon Salzberg (schedule)
- Shinzen Young (schedule)
- Sujin Boriharnwanaket (books)
- Khenchen Thrangu Rinpoche
# Vipassanā in the Theravāda, Mahāyāna and Vajrayāna
## In the Theravāda
Vipassanā as practiced in the Theravāda is the understanding of the Four Noble Truths that were taught by the Buddha. It is understanding the transitory nature of phenomena and the selflessness of persons, that the conceptual consciousness, "I" does not exist.
Most of Theravāda's teachers refer to knowledges evolving during practice. The meditator gradually improve his perception of the three marks of existence until he reaches the step sensations constantly disappear, which is called Template:IAST (Sanskrit: Template:IAST), knowledge of dissolution.
The yogi will then experience fear and ceasing of attachment, and eventually will reach the step of Template:IAST (Sanskrit: Template:IAST): knowledge of equanimity of formations. This step leads to the attainment of nibbāna.
In practice one can use various methods to do Vipassanā Meditation. For example one method is that there are 40 topics that can be concentrated by the meditator such as anitya (Pāli anicca, impermanence), ] (Pāli dukkha, suffering), roga (illness), and so on. The meditator can meditate on one of these until he sees the truth in everything in the universe.
## In the Mahāyāna
Mahāyāna Vipaśyanā consists of meditating on the two truths: conventional truth and absolute truth. One realizes that phenomena likewise have a lack of inherent existence, and have the nature of emptiness (śūnyatā). This is determined by the inferential path of reasoning and direct observation through meditation.
Gradualism or Subitism and the realisation is a debate in the Mahāyāna. Nevertheless, Huineng, sixth patriarch of the Zen, considered the practice cannot be described as gradualistic nor subitist, but implies people with more or less clear minds.
## In the Vajrayāna
Mahāmudrā and Dzogchen use Vipaśyana extensively, though in a different manner than in the Theravāda. In the Vajrayāna (tantric) path, the true nature of mind is pointed out by the guru, and the practitioner takes the path of direct experience.
"In the Sūtra path (Theravāda) one proceeds by examining and analyzing phenomena, using reasoning. One recognizes that all phenomena lack any true existence and that all appearances are merely interdependently related and are without any inherent nature. They are empty yet apparent, apparent yet empty. The path of Mahāmudrā is different in that one proceeds using the instructions concerning the nature of mind that are given by one's guru. This is called taking direct perception or direct experiences as the path. The fruition of śamatha is purity of mind, a mind undisturbed by false conception or emotional afflictions. The fruition of vipaśyanā is knowledge (prajnā) and pure wisdom (jñāna). Jñāna is called the wisdom of nature of phenomena and it comes about through the realization of the true nature of phenomena."
-Thrangu Rinpoche, Looking Directly at Mind : The Moonlight of Mahāmudrā
Dzogchen Pönlop Rinpoche clearly charts the developmental relationship of the sadhanas of shamatha and vipashyana:
The ways these two aspects of meditation are practiced is that one begins with the practice of shamatha; on the basis of that, it becomes possible to practice vipashyana or lhagthong. Through one's practrice of vipashyana being based on and carried on in the midst of shamatha, one eventually ends up practicing a unification of shamatha and vipashyana. The unification leads to a very clear and direct experience of the nature of all things. This brings one very close to what is called the absolute truth.
Dzogchen Pönlop Rinpoche evokes an extended poetic metaphor from Milarepa to qualify vipashyana (as qualitatively different to shamatha) as having the propensity to "eradicate" klesha:
Insight, or vipashyana (lhagthong), is extremely important because it can eradicate the mental afflications, whereas tranquility alone cannot. That is why we want to be able to practice tranquility and insight in a unified manner. This unified practice has three steps; first, we practice tranquility; then we practice insight; and then we bring the two together. Doing this will eradicate the cause of samsara (which is mental afflictions), thereby eradicating the result of samsara (which is suffering). For this reason, it is improper to become too attached to the delight or pleasure of tranquility, because tranquility alone is not enough. As was said by Lord Milarepa in a song:
# Vipassanā in prisons
Vipassana is a practice often taken up in prison, especially in Burma. In 1993, Kiran Bedi, a reformist Inspector General of India's prisons, learned of the success of Vipassanā in a jail in Jainpur, Rajasthan. A 10-day course involved officials and inmates alike. In India's largest prison, Tihar Jail, near New Delhi, another attempt was made. This program was said to have dramatically changed the behavior of inmates and jailers alike. It was actually found that inmates who completed the 10-day course were less violent and had a lower recidivism rate than other inmates. This project was documented in the television documentary, Doing Time, Doing Vipassana. So successful was this program that it was adopted by correctional facilities in the United States and other countries as well. Unfortunately, the prisoners involved in the study were a biased sample, however, due to the fact that they volunteered for the program, while many who were told they would miss the Super-Bowl if they joined the program chose not to participate. Therefore, it is possible that only prisoners who were willing to make a significant personal sacrifice to "improve" themselves participated in the study. A less biased study would have taken this self-electing prisoner pool and randomly assigned them to either Vipassana training or a "placebo" meditation training and evaluated the results according to a double blind protocol.
# Notes
- ↑ Ray, Reginald A. (Ed.)(2004). In the Presence of Masters: Wisdom from 30 Contemporary Tibetan Buddhist Teachers. Boston, Massachusetts, USA: Shambala. ISBN 1-57062-849-1 (pbk.: alk. paper) p.74.
- ↑ Ray, Reginald A. (Ed.)(2004). In the Presence of Masters: Wisdom from 30 Contemporary Tibetan Buddhist Teachers. Boston, Massachusetts, USA: Shambala. ISBN 1-57062-849-1 (pbk.: alk. paper) p.76.
- ↑ Ray, Reginald A. (Ed.)(2004). In the Presence of Masters: Wisdom from 30 Contemporary Tibetan Buddhist Teachers. Boston, Massachusetts, USA: Shambala. ISBN 1-57062-849-1 (pbk.: alk. paper) p.76. | Vipassanā
Template:Buddhism
Vipassanā (Pāli) or vipaśyanā (विपश्यना) in (Sanskrit) means "insight" into the impermanent nature or anicca of mind and body. Vipassana is one of India's most ancient techniques of meditation, rediscovered by Gautama Buddha 2500 years ago. It is a way of self-transformation through self-observation and introspection. It focuses on the deep interconnection between mind and body, which can be experienced directly by disciplined attention to the physical sensations that form the life of the body, and that continuously interconnect and condition the life of the mind [1]. Vipassanā meditation is often referred to by Buddhists and non-Buddhists alike simply as "insight meditation". While it is a type of Buddhist meditation as taught by the Buddha, it is essentially non-sectarian in character and has universal application. One need not convert to Buddhism to practice vipassanā meditation. While the practice of vipassana meditation varies from school to school, the underlying principle is the investigation of phenomena as they manifest in the four Foundations of Mindfulness highlighted in the Satipatthana Sutta; namely: kaya (body or breath), vedana (feeling or sensation), citta (mind), and dhamma (mind objects). These phenomena differ from the khandas (aggregates) because the citta factor is not connected to any aggregate, as it is the basic mood of the mind-body aggregate, while the dhamma encompasses all mind objects that are fruits of kamma (i.e., the vinnana, sanna and sankhara aggregates), and also all mind objects that are not a fruit of kamma, such as the Four Noble Truths.
In a broader sense, vipassanā has been used as one of two poles for the categorization of types of Buddhist meditation, the other being samatha (Pāli) or śamatha (Sanskrit). Samatha is a focusing, pacifying and calming meditation, common to many traditions in the world, notably yoga. It is used as a preparation for vipassanā, pacifying the mind and strengthening the concentration in order to allow the work of insight. This dichotomy is also sometimes discussed as "stopping and seeing." In Buddhist practice it is said that, while samatha can calm the mind, only insight can reveal how the mind was disturbed to start with, which leads to prajñā (Pāli: paññā, wisdom) and jñāna (Pāli: ñāṇa, knowledge) and thus understanding, preventing it from being disturbed again.
The term is also used to refer to the Buddhist vipassana movement (modeled after Theravāda Buddhism meditation practices), which employs vipassanā and ānāpāna meditation as its primary techniques and places emphasis on the teachings of the Satipaṭṭhāna Sutta. Vedanā (sensation/feeling) is the primary initial subject of investigation.
# Etymology
Vipassanā is a Pali word from the Sanskrit prefix "vi-" and verbal root √paś. It is often translated as "insight" or "clear-seeing," though, the "in-" prefix may be misleading; "vi" in Indo-Aryan languages is equivalent to our (Latin) "dis." The "vi" in vipassanā may then mean to see apart, or discern. Alternatively, the "vi" can function as an intensive, and thus vipassanā may mean "seeing deeply". In any case, this is used metaphorically for a particularly powerful mental self-perception.
A synonym for "Vipassanā" is paccakkha (Pāli; Sanskrit: Template:IAST), "before the eyes," which refers to direct experiential perception. Thus, the type of seeing denoted by "vipassanā" is that of direct perception, as opposed to knowledge derived from reasoning or argument.
In Tibetan, vipashyana is lhagthong. The semantic field of "lhag" means "higher", "superior", "greater"; the semantic field of "thong" is "view" or "to see". So together, lhagthong may be rendered into English as "superior seeing" or "great vision". This may be interpreted as a "superior manner of seeing, and also as "seeing that which is the essential nature". Its nature is a lucidity, a clarity of mind.[1]
# Practice of vipassanā
Vipassanā meditation is a simple technique which depends on direct experience and observation. It can be related to the three trainings taught by the Buddha as the basis of a spiritual path: adherence to a sīla (Sanskrit: śīla) (abstinence from killing, stealing, lying, sexual misconduct and intoxication), which is not an end in itself but a requirement for the second part, concentration of the mind (samādhi). With this concentrated mind, the third training, in the context of this technique (paññā, Sanskrit prajñā), is detached observation of the reality of the mind and body from moment to moment.
The actual instructions for Vipassana meditation are not often published in clear terms in public venues. This is simply to avoid confusion and prevent incorrect technique. The instructions are not esoteric or difficult but basically involve retraining the mind to avoid its innate conditioned response to most stimuli. In order to obtain maximum benefit, it is recommended that this be learned from a legitimate source as it does have deep cleansing effects. Although Vipassana includes body awareness as part of the practice, it is not a "body scan" technique. The purpose is also not to release past trauma, but to bring full awareness of the mind, body and all sensations and be fully present. This practice is thought to develop a deep, experiential understanding of the impermanence of all phenomena and also brings to the surface and dissolves deep-seated complexes and tensions. The technique fosters development of insight and needs to be continued as a way of life in order to having lasting effects.
Put another way, Vipassanā meditation consists of the experiential observation of mind and matter (nāma and rūpa) in their aspects of impermanence, unsatisfactoriness and lack of an inherent, independent essence or self.
To see through the mode of impermanence means to examine things to determine whether they are permanent. To see through the mode of unsatisfactoriness means to examine things to determine whether they are satisfactory or are imbued with suffering. To see through the mode of non-self means to examine meditation objects to see whether they are permanent, isolated, and enduring entities. In other words, to see through non-self relates to having a sense of non-doership and a sense of non-possessorship while examining things.
In Vipassanā meditation, the meditation object is one's own consciousness, although it can be further refined to be one's consciousness while observing, say, the breath, as in anapanasati meditation. In this context, the modes of seeing refers to focusing on those aspects of consciousness which appear to have (or not have) these characteristics.
Some steps are described as vipassanā jhānas, or simply as knowledges.
# Vipassanā today
Today, the term "Vipassanā" also refers to a series of meditation techniques used by many branches of modern Theravāda Buddhism, for example in modern Sri Lanka, Burma, Laos and Thailand, and to a specific branch of Buddhism popularized by S. N. Goenka and his mentor U Ba Khin as a nonsectarian form of Buddhism, and also by Americans Joseph Goldstein, Sharon Salzberg, and Jack Kornfield (who were inspired by the monks Mahasi Sayadaw and Ajahn Chah) under the rubric "insight meditation."
# Famous masters
- U Ba Khin
- Mahasi Sayadaw
- Ledi Sayadaw
- Ajahn Chah Subhatto
# Living teachers
- Ajahn Tong Sirimangalo
- Lakshman Attanayake
- Ajahn Sumedho
- Ajahn Sobin S. Namto
- Bhante Henepola Gunaratana (schedule)
- Bhikkhu Bodhi
- Bhikkhu Sri Matara Nyanarama (steps)
- Bhikkhu Katukurunde Nyanananda (analysis)
- Christopher Titmuss
- Gil Fronsdal (schedule)
- Jack Kornfield
- Joseph Goldstein
- Larry Rosenberg
- Matthew Flickstein
- Rodney Smith
- S. N. Goenka (schedule)
- Sayadaw U Pandita
- Shaila Catherine (schedule)
- Sharon Salzberg (schedule)
- Shinzen Young (schedule)
- Sujin Boriharnwanaket (books)
- Khenchen Thrangu Rinpoche
# Vipassanā in the Theravāda, Mahāyāna and Vajrayāna
## In the Theravāda
Vipassanā as practiced in the Theravāda is the understanding of the Four Noble Truths that were taught by the Buddha. It is understanding the transitory nature of phenomena and the selflessness of persons, that the conceptual consciousness, "I" does not exist.
Most of Theravāda's teachers refer to knowledges evolving during practice. The meditator gradually improve his perception of the three marks of existence until he reaches the step sensations constantly disappear, which is called Template:IAST (Sanskrit: Template:IAST), knowledge of dissolution.
The yogi will then experience fear and ceasing of attachment, and eventually will reach the step of Template:IAST (Sanskrit: Template:IAST): knowledge of equanimity of formations. This step leads to the attainment of nibbāna.
In practice one can use various methods to do Vipassanā Meditation. For example one method is that there are 40 topics that can be concentrated by the meditator such as anitya (Pāli anicca, impermanence), [[dukkha|Template:IAST]] (Pāli dukkha, suffering), roga (illness), and so on. The meditator can meditate on one of these until he sees the truth in everything in the universe.
## In the Mahāyāna
Mahāyāna Vipaśyanā consists of meditating on the two truths: conventional truth and absolute truth. One realizes that phenomena likewise have a lack of inherent existence, and have the nature of emptiness (śūnyatā). This is determined by the inferential path of reasoning and direct observation through meditation.
Gradualism or Subitism and the realisation is a debate in the Mahāyāna. Nevertheless, Huineng, sixth patriarch of the Zen, considered the practice cannot be described as gradualistic nor subitist, but implies people with more or less clear minds.
## In the Vajrayāna
Mahāmudrā and Dzogchen use Vipaśyana extensively, though in a different manner than in the Theravāda. In the Vajrayāna (tantric) path, the true nature of mind is pointed out by the guru, and the practitioner takes the path of direct experience.
"In the Sūtra path (Theravāda) one proceeds by examining and analyzing phenomena, using reasoning. One recognizes that all phenomena lack any true existence and that all appearances are merely interdependently related and are without any inherent nature. They are empty yet apparent, apparent yet empty. The path of Mahāmudrā is different in that one proceeds using the instructions concerning the nature of mind that are given by one's guru. This is called taking direct perception or direct experiences as the path. The fruition of śamatha is purity of mind, a mind undisturbed by false conception or emotional afflictions. The fruition of vipaśyanā is knowledge (prajnā) and pure wisdom (jñāna). Jñāna is called the wisdom of nature of phenomena and it comes about through the realization of the true nature of phenomena."
-Thrangu Rinpoche, Looking Directly at Mind : The Moonlight of Mahāmudrā
Dzogchen Pönlop Rinpoche clearly charts the developmental relationship of the sadhanas of shamatha and vipashyana:
The ways these two aspects of meditation are practiced is that one begins with the practice of shamatha; on the basis of that, it becomes possible to practice vipashyana or lhagthong. Through one's practrice of vipashyana being based on and carried on in the midst of shamatha, one eventually ends up practicing a unification of shamatha and vipashyana. The unification leads to a very clear and direct experience of the nature of all things. This brings one very close to what is called the absolute truth.[2]
Dzogchen Pönlop Rinpoche evokes an extended poetic metaphor from Milarepa to qualify vipashyana (as qualitatively different to shamatha) as having the propensity to "eradicate" klesha:
Insight, or vipashyana (lhagthong), is extremely important because it can eradicate the mental afflications, whereas tranquility [shamatha] alone cannot. That is why we want to be able to practice tranquility and insight in a unified manner. This unified practice has three steps; first, we practice tranquility; then we practice insight; and then we bring the two together. Doing this will eradicate the cause of samsara (which is mental afflictions), thereby eradicating the result of samsara (which is suffering). For this reason, it is improper to become too attached to the delight or pleasure of tranquility, because tranquility alone is not enough. As was said by Lord Milarepa in a song:
# Vipassanā in prisons
Vipassana is a practice often taken up in prison, especially in Burma.[2] In 1993, Kiran Bedi, a reformist Inspector General of India's prisons, learned of the success of Vipassanā in a jail in Jainpur, Rajasthan. A 10-day course involved officials and inmates alike. In India's largest prison, Tihar Jail, near New Delhi, another attempt was made. This program was said to have dramatically changed the behavior of inmates and jailers alike. It was actually found that inmates who completed the 10-day course were less violent and had a lower recidivism rate than other inmates. This project was documented in the television documentary, Doing Time, Doing Vipassana. So successful was this program that it was adopted by correctional facilities in the United States and other countries as well. Unfortunately, the prisoners involved in the study were a biased sample, however, due to the fact that they volunteered for the program, while many who were told they would miss the Super-Bowl if they joined the program chose not to participate. Therefore, it is possible that only prisoners who were willing to make a significant personal sacrifice to "improve" themselves participated in the study. A less biased study would have taken this self-electing prisoner pool and randomly assigned them to either Vipassana training or a "placebo" meditation training and evaluated the results according to a double blind protocol.
# Notes
- ↑ Ray, Reginald A. (Ed.)(2004). In the Presence of Masters: Wisdom from 30 Contemporary Tibetan Buddhist Teachers. Boston, Massachusetts, USA: Shambala. ISBN 1-57062-849-1 (pbk.: alk. paper) p.74.
- ↑ Ray, Reginald A. (Ed.)(2004). In the Presence of Masters: Wisdom from 30 Contemporary Tibetan Buddhist Teachers. Boston, Massachusetts, USA: Shambala. ISBN 1-57062-849-1 (pbk.: alk. paper) p.76.
- ↑ Ray, Reginald A. (Ed.)(2004). In the Presence of Masters: Wisdom from 30 Contemporary Tibetan Buddhist Teachers. Boston, Massachusetts, USA: Shambala. ISBN 1-57062-849-1 (pbk.: alk. paper) p.76. | https://www.wikidoc.org/index.php/Vipassana | |
5c008632da7fd42e204f8a37d1f1fea3897571e6 | wikidoc | Viperidae | Viperidae
The Viperidae are a family of venomous snakes commonly referred to as vipers, although the term viperids is more specific and distinguishes them from the viperines (subfamily Viperinae). These snakes are found all over the world, except in Australia and Madagascar. All have relatively long hinged fangs that permit deep penetration and injection of venom. Four subfamilies are currently recognized.
# Description
All viperids have a pair of relatively long solenoglyphous (hollow) fangs, that are used to inject venom from glands located towards the rear of the upper jaws. Each of the two fangs is at the front of the mouth on a short maxillary bone that can rotate back and forth. When not in use, the fangs fold back against the roof of the mouth and are enclosed in a membranous sheath. The left and right fangs can be rotated together or independently. During a strike, the mouth can open nearly 180° and the maxilla rotates forward, erecting the fang. The jaws close on impact and powerful muscles that surround the venom glands contract to inject the venom as the fangs penetrate. This action is very fast; in defensive strikes it can be more a stab than a bite. Viperids use this mechanism both to immobilize their prey and in self-defense.
Almost all vipers have keeled scales, a stocky build with a short tail, and, due to the location of the venom glands, a triangular-shaped head distinct from the neck. Their eyes have vertically elliptical, or slit-shaped, pupils that can open wide to cover most of the eye or close almost completely, which helps them to see in a wide range of light levels. Typically, vipers are nocturnal and ambush their prey.
Compared to many other snakes, vipers often appear rather sluggish. Most are ovoviviparous, giving birth to live young, but a few lay eggs; the word "viper" is derived from Latin vivo = "I live" and pario = "I give birth".
# Behavior
Experiments have shown that these snakes are capable of making decisions on how much venom to inject depending on the circumstances. In all cases, the most important determinant of venom expenditure is generally the size of the snake, with larger specimens being capable of delivering much more venom. Also, the species is important, since some are likely to inject more than others, how much venom is available, the accuracy of the strike, and the number of bites already delivered in a short space of time. In predatory bites, factors that influence the amount of venom injected include the size of the prey, the species of prey, and whether the prey item is held or released. The need to label prey for chemosensory relocation after a bite and release may also play a role. In defensive bites, the amount of venom injected may be determined by the size or species of the predator (or antagonist), as well as the assessed level of threat, although larger assailants and higher threat levels may not necessarily lead to larger amounts of venom being injected.
# Venom
Viperid venoms typically contain an abundance of protein-degrading enzymes, called proteases, that produce symptoms such as pain, strong local swelling and necrosis, blood loss from cardiovascular damage complicated by coagulopathy, and disruption of the blood clotting system. Death is usually caused by collapse in blood pressure. This is in contrast to elapid venoms that generally contain neurotoxins that disable muscle contraction and cause paralysis. Death from elapid bites usually results from asphyxiation because the diaphragm can no longer contract. However, this rule does not always apply: some elapid bites include proteolytic symptoms typical of viperid bites, while some viperid bites produce neurotoxic symptoms.
Proteolytic venom is also dual-purpose: it is used for defense and to immobilize prey, as with neurotoxic venoms, and also many of the enzymes have a digestive function, breaking down molecules in prey items, such as lipids, nucleic acids, and proteins. This is important, as many vipers have weak digestive systems.
Due to the nature of proteolytic venom, a viperid bite is often a very painful experience and should always be taken seriously, even though it is not necessarily fatal. Even with prompt and proper treatment, a bite can still result in a permanent scar, and in the worst cases the affected limb may even have to be amputated. A victim's fate is impossible to predict as this depends on many factors, including (but not limited to) the species and size of the snake involved, how much venom was injected (if any), and the size and condition of the patient before being bitten. The patient may also be allergic to the venom and/or the antivenin.
# Subfamilies
Type genus = Vipera - Laurenti, 1768
# Taxonomy
That Viperidae is attributed to Oppel (1811), as opposed to Laurenti (1768) or Gray (1825), is subject to some interpretation. However, the consensus among leading experts is that Laurenti used viperae as the plural of vipera (Latin for "viper", "adder", or "snake") and did not intend for it to indicate a a family group taxon. Rather, it is attributed to Oppel, based on his Viperini as a distinct family group name, despite the fact that Gray was the first to use the form Viperinae. | Viperidae
The Viperidae are a family of venomous snakes commonly referred to as vipers, although the term viperids is more specific and distinguishes them from the viperines (subfamily Viperinae). These snakes are found all over the world, except in Australia and Madagascar. All have relatively long hinged fangs that permit deep penetration and injection of venom. Four subfamilies are currently recognized.[2]
# Description
All viperids have a pair of relatively long solenoglyphous (hollow) fangs, that are used to inject venom from glands located towards the rear of the upper jaws. Each of the two fangs is at the front of the mouth on a short maxillary bone that can rotate back and forth. When not in use, the fangs fold back against the roof of the mouth and are enclosed in a membranous sheath. The left and right fangs can be rotated together or independently. During a strike, the mouth can open nearly 180° and the maxilla rotates forward, erecting the fang. The jaws close on impact and powerful muscles that surround the venom glands contract to inject the venom as the fangs penetrate. This action is very fast; in defensive strikes it can be more a stab than a bite. Viperids use this mechanism both to immobilize their prey and in self-defense.
Almost all vipers have keeled scales, a stocky build with a short tail, and, due to the location of the venom glands, a triangular-shaped head distinct from the neck. Their eyes have vertically elliptical, or slit-shaped, pupils that can open wide to cover most of the eye or close almost completely, which helps them to see in a wide range of light levels. Typically, vipers are nocturnal and ambush their prey.
Compared to many other snakes, vipers often appear rather sluggish. Most are ovoviviparous, giving birth to live young, but a few lay eggs; the word "viper" is derived from Latin vivo = "I live" and pario = "I give birth".[3]
# Behavior
Experiments have shown that these snakes are capable of making decisions on how much venom to inject depending on the circumstances. In all cases, the most important determinant of venom expenditure is generally the size of the snake, with larger specimens being capable of delivering much more venom. Also, the species is important, since some are likely to inject more than others, how much venom is available, the accuracy of the strike, and the number of bites already delivered in a short space of time. In predatory bites, factors that influence the amount of venom injected include the size of the prey, the species of prey, and whether the prey item is held or released. The need to label prey for chemosensory relocation after a bite and release may also play a role. In defensive bites, the amount of venom injected may be determined by the size or species of the predator (or antagonist), as well as the assessed level of threat, although larger assailants and higher threat levels may not necessarily lead to larger amounts of venom being injected.[4]
# Venom
Viperid venoms typically contain an abundance of protein-degrading enzymes, called proteases, that produce symptoms such as pain, strong local swelling and necrosis, blood loss from cardiovascular damage complicated by coagulopathy, and disruption of the blood clotting system. Death is usually caused by collapse in blood pressure. This is in contrast to elapid venoms that generally contain neurotoxins that disable muscle contraction and cause paralysis. Death from elapid bites usually results from asphyxiation because the diaphragm can no longer contract. However, this rule does not always apply: some elapid bites include proteolytic symptoms typical of viperid bites, while some viperid bites produce neurotoxic symptoms.[5]
Proteolytic venom is also dual-purpose: it is used for defense and to immobilize prey, as with neurotoxic venoms, and also many of the enzymes have a digestive function, breaking down molecules in prey items, such as lipids, nucleic acids, and proteins.[5] This is important, as many vipers have weak digestive systems.[6]
Due to the nature of proteolytic venom, a viperid bite is often a very painful experience and should always be taken seriously, even though it is not necessarily fatal. Even with prompt and proper treatment, a bite can still result in a permanent scar, and in the worst cases the affected limb may even have to be amputated. A victim's fate is impossible to predict as this depends on many factors, including (but not limited to) the species and size of the snake involved, how much venom was injected (if any), and the size and condition of the patient before being bitten. The patient may also be allergic to the venom and/or the antivenin.
# Subfamilies
Type genus = Vipera - Laurenti, 1768[1]
# Taxonomy
That Viperidae is attributed to Oppel (1811), as opposed to Laurenti (1768) or Gray (1825), is subject to some interpretation. However, the consensus among leading experts is that Laurenti used viperae as the plural of vipera (Latin for "viper", "adder", or "snake") and did not intend for it to indicate a a family group taxon. Rather, it is attributed to Oppel, based on his Viperini as a distinct family group name, despite the fact that Gray was the first to use the form Viperinae.[1] | https://www.wikidoc.org/index.php/Viper | |
c834ff88c444db3a9efad3dde453563b17b48737 | wikidoc | Virulence | Virulence
# Overview
Virulence refers to the degree of pathogenicity of a microbe, or in other words the relative ability of a microbe to cause disease.
The word virulent, which is the adjective for virulence, derives from the Latin word virulentus, which means "full of poison." From an ecological point of view, virulence can be defined as the host's parasite induced loss of fitness.
# Virulent bacteria
The ability of bacteria to cause disease is described in terms of the number of infecting bacteria, the route of entry into the body, the effects of host defense mechanisms, and intrinsic characteristics of the bacteria called virulence factors. Host-mediated pathogenesis is often important because the host can respond aggressively to infection with the result that host defense mechanisms do damage to host tissues while the infection is being countered.
The virulence factors of bacteria are typically proteins or other molecules that are synthesized by protein enzymes. These proteins are coded for by genes in chromosomal DNA, bacteriophage DNA or plasmids.
Methods by which pathogens cause disease
- Adhesion. Many bacteria must first bind to host cell surfaces. Many bacterial and host molecules that are involved in the adhesion of bacteria to host cells have been identified. Often, the host cell receptors for bacteria are essential proteins for other functions.
- Colonization. Some virulent bacteria produce special proteins that allow them to colonize parts of the host body. Helicobacter pylori is able to survive in the acidic environment of the human stomach by producing the enzyme urease. Colonization of the stomach lining by this bacterium can lead to Gastric ulcer and cancer. The virulence of various strains of Helicobacter pylori tends to corellate with the level of production of urease.
- Invasion. Some virulent bacteria produce proteins that either disrupt host cell membranes or stimulate endocytosis into host cells. These virulence factors allow the bacteria to enter host cells and facilitate entry into the body across epithelial tissue layers at the body surface.
- Immune response inhibitors. Many bacteria produce virulence factors that inhibit the host's immune system defenses. For example, a common bacterial strategy is to produce proteins that bind host antibodies. The polysaccharide capsule of Streptococcus pneumoniae inhibits phagocytosis of the bacterium by host immune cells.
- Toxins. Many virulence factors are proteins made by bacteria that poison host cells and cause tissue damage. For example, there are many food poisoning toxins produced by bacteria that can contaminate human foods. Some of these can remain in "spoiled" food even after cooking and cause illness when the contaminated food is consumed. Some bacterial toxins are chemically altered and inactivated by the heat of cooking.
# Virulent virus
Viral virulence factors determine whether infection occurs and how severe the resulting viral disease symptoms are. Viruses often require receptor proteins on host cells to which they specifically bind. Typically, these host cell proteins are endocytosed and the bound virus then enters the host cell. Virulent viruses such as the AIDS virus (HIV) have mechanisms for evading host defenses. HIV causes a loss of T-cells and immunosuppression. Death results from opportunistic infections secondary to disruption of the immune system caused by the AIDS virus. Some viral virulence factors confer ability to replicate during the defensive inflammation responses of the host such as during virus-induced fever. Many viruses can exist inside a host for long periods during which little damage is done. Extremely virulent strains can eventually evolve by mutation and natural selection within the virus population inside a host.
See also Optimal virulence | Virulence
# Overview
Virulence refers to the degree of pathogenicity of a microbe, or in other words the relative ability of a microbe to cause disease.
The word virulent, which is the adjective for virulence, derives from the Latin word virulentus, which means "full of poison." From an ecological point of view, virulence can be defined as the host's parasite induced loss of fitness.
# Virulent bacteria
The ability of bacteria to cause disease is described in terms of the number of infecting bacteria, the route of entry into the body, the effects of host defense mechanisms, and intrinsic characteristics of the bacteria called virulence factors. Host-mediated pathogenesis is often important because the host can respond aggressively to infection with the result that host defense mechanisms do damage to host tissues while the infection is being countered.
The virulence factors of bacteria are typically proteins or other molecules that are synthesized by protein enzymes. These proteins are coded for by genes in chromosomal DNA, bacteriophage DNA or plasmids.
Methods by which pathogens cause disease
- Adhesion. Many bacteria must first bind to host cell surfaces. Many bacterial and host molecules that are involved in the adhesion of bacteria to host cells have been identified. Often, the host cell receptors for bacteria are essential proteins for other functions.
- Colonization. Some virulent bacteria produce special proteins that allow them to colonize parts of the host body. Helicobacter pylori is able to survive in the acidic environment of the human stomach by producing the enzyme urease. Colonization of the stomach lining by this bacterium can lead to Gastric ulcer and cancer. The virulence of various strains of Helicobacter pylori tends to corellate with the level of production of urease.
- Invasion. Some virulent bacteria produce proteins that either disrupt host cell membranes or stimulate endocytosis into host cells. These virulence factors allow the bacteria to enter host cells and facilitate entry into the body across epithelial tissue layers at the body surface.
- Immune response inhibitors. Many bacteria produce virulence factors that inhibit the host's immune system defenses. For example, a common bacterial strategy is to produce proteins that bind host antibodies. The polysaccharide capsule of Streptococcus pneumoniae inhibits phagocytosis of the bacterium by host immune cells.
- Toxins. Many virulence factors are proteins made by bacteria that poison host cells and cause tissue damage. For example, there are many food poisoning toxins produced by bacteria that can contaminate human foods. Some of these can remain in "spoiled" food even after cooking and cause illness when the contaminated food is consumed. Some bacterial toxins are chemically altered and inactivated by the heat of cooking.
# Virulent virus
Viral virulence factors determine whether infection occurs and how severe the resulting viral disease symptoms are. Viruses often require receptor proteins on host cells to which they specifically bind. Typically, these host cell proteins are endocytosed and the bound virus then enters the host cell. Virulent viruses such as the AIDS virus (HIV) have mechanisms for evading host defenses. HIV causes a loss of T-cells and immunosuppression. Death results from opportunistic infections secondary to disruption of the immune system caused by the AIDS virus. Some viral virulence factors confer ability to replicate during the defensive inflammation responses of the host such as during virus-induced fever. Many viruses can exist inside a host for long periods during which little damage is done. Extremely virulent strains can eventually evolve by mutation and natural selection within the virus population inside a host.
See also Optimal virulence
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Virulence | |
2de2084c77ef1ad5b145a54ad76ebc7bae1689ba | wikidoc | Vitamin A | Vitamin A
# Overview
Vitamin A is an essential human nutrient. It exists not as a single compound, but in several forms. In foods of animal origin, the major form of vitamin A is an alcohol (retinol), but can also exist as an aldehyde (retinal), or as an acid (retinoic acid). Precursors to the vitamin (a provitamin) are present in foods of plant origin as some of the members of the carotenoid family of compounds.
All forms of Vitamin A have a Beta-ionone ring to which an isoprenoid chain is attached. This structure is essential for vitamin activity.
- retinol, the animal form of Vitamin A, is a yellow, fat-soluble, vitamin with importance in vision and bone growth.
- other retinoids, a class of chemical compounds that are related chemically to Vitamin A, are used in medicine.
# Discovery of Vitamin A
The discovery of Vitamin A stemmed from research dating back to 1906, indicating that factors other than carbohydrates, proteins, and fats were necessary to keep cattle healthy. By 1917 one of these substances was independently discovered by Elmer McCollum at the University of Wisconsin-Madison, and Lafayette Mendel and Thomas Osborne at Yale University. Since "water-soluble factor B" (Vitamin B) had recently been discovered, the researchers chose the name "fat-soluble factor A".
# Sources
Vitamin A is found naturally in many foods. Each of the following contains at least 0.15 mg (which is equal to 150 micrograms (mcg). See Recommended Daily Intake below.) of Vitamin A or beta carotene per 1.75-7 oz. (50-200 g): butter, lemon, sweet potatoes, carrots, collard greens, milk, beetroot, pumpkin, spinach, beef, apple, winter squash, apricots, cantaloupe melon, mango, liver, (beef, pork, chicken, turkey, fish) eggs, broccoli, and leafy vegetables.
# Recommended daily intake
Vitamin A US Dietary Reference Intake:
- 900 micrograms for men
- 700 for women.
- Upper limit - 3,000 micrograms.
(Note that the limit refers to retinoid forms of vitamin A. Carotene forms from dietary sources are not toxic.)
# Equivalencies of retinoids and carotenoids
Vitamin A intake is often expressed in international units (IU) or as retinol equivalents (RE), with 1 IU = 0.3 micrograms retinol. Because the production of retinol from provitamins by the human body is regulated by the amount of retinol available to the body, the conversions apply strictly only for Vitamin A deficient humans. The absorption of provitamins also depends greatly on the amount of lipids ingested with the provitamin; lipids increase the uptake of the provitamin.
Conversion of carotenoids into retinol relies on adequate intake of vitamin C, zinc and protein.
# Symptoms of deficiency
Night blindness, corneal drying (xerosis), triangular gray spots on eye (Bitot's spots), corneal degeneration and blindness (xerophthalmia), impaired immunity, hypokeratosis (white lumps at hair follicles), keratosis pilaris, softening of the cornea (keratomalacia).
# Symptoms of overdose
As vitamin A is fat-soluble, disposing of any excesses taken in through diet is a lot harder than with water-soluble vitamins B and C. As such, vitamin A toxicity can result. This can lead to nausea, jaundice, irritability, anorexia (not to be confused with anorexia nervosa, the eating disorder), vomiting, blurry vision, headaches, muscle and abdominal pain and weakness, drowsiness and altered mentality.
In chronic cases, hair loss, drying of the mucous membranes, fever, insomnia, fatigue, weight loss, bone fractures, anemia, and diarrhea can all be evident on top of the symptoms associated with less serious toxicity. | Vitamin A
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Vitamin A is an essential human nutrient. It exists not as a single compound, but in several forms. In foods of animal origin, the major form of vitamin A is an alcohol (retinol), but can also exist as an aldehyde (retinal), or as an acid (retinoic acid). Precursors to the vitamin (a provitamin) are present in foods of plant origin as some of the members of the carotenoid family of compounds.[1]
All forms of Vitamin A have a Beta-ionone ring to which an isoprenoid chain is attached. This structure is essential for vitamin activity.[1]
- retinol, the animal form of Vitamin A, is a yellow, fat-soluble, vitamin with importance in vision and bone growth.
- other retinoids, a class of chemical compounds that are related chemically to Vitamin A, are used in medicine.[2]
# Discovery of Vitamin A
The discovery of Vitamin A stemmed from research dating back to 1906, indicating that factors other than carbohydrates, proteins, and fats were necessary to keep cattle healthy.[3] By 1917 one of these substances was independently discovered by Elmer McCollum at the University of Wisconsin-Madison, and Lafayette Mendel and Thomas Osborne at Yale University. Since "water-soluble factor B" (Vitamin B) had recently been discovered, the researchers chose the name "fat-soluble factor A".[3]
# Sources
Vitamin A is found naturally in many foods. Each of the following contains at least 0.15 mg (which is equal to 150 micrograms (mcg). See Recommended Daily Intake below.) of Vitamin A or beta carotene per 1.75-7 oz. (50-200 g): butter, lemon, sweet potatoes, carrots, collard greens, milk, beetroot, pumpkin, spinach, beef, apple, winter squash, apricots, cantaloupe melon, mango, liver, (beef, pork, chicken, turkey, fish) eggs, broccoli, and leafy vegetables.
# Recommended daily intake
Vitamin A US Dietary Reference Intake:
- 900 micrograms for men
- 700 for women.
- Upper limit - 3,000 micrograms.
(Note that the limit refers to retinoid forms of vitamin A. Carotene forms from dietary sources are not toxic.[4])
# Equivalencies of retinoids and carotenoids
Vitamin A intake is often expressed in international units (IU) or as retinol equivalents (RE), with 1 IU = 0.3 micrograms retinol. Because the production of retinol from provitamins by the human body is regulated by the amount of retinol available to the body, the conversions apply strictly only for Vitamin A deficient humans. The absorption of provitamins also depends greatly on the amount of lipids ingested with the provitamin; lipids increase the uptake of the provitamin.[5]
Conversion of carotenoids into retinol relies on adequate intake of vitamin C, zinc and protein.
# Symptoms of deficiency
Night blindness, corneal drying (xerosis), triangular gray spots on eye (Bitot's spots), corneal degeneration and blindness (xerophthalmia)[6], impaired immunity, hypokeratosis (white lumps at hair follicles), keratosis pilaris, softening of the cornea (keratomalacia).
# Symptoms of overdose
As vitamin A is fat-soluble, disposing of any excesses taken in through diet is a lot harder than with water-soluble vitamins B and C. As such, vitamin A toxicity can result. This can lead to nausea, jaundice, irritability, anorexia (not to be confused with anorexia nervosa, the eating disorder), vomiting, blurry vision, headaches, muscle and abdominal pain and weakness, drowsiness and altered mentality.
In chronic cases, hair loss, drying of the mucous membranes, fever, insomnia, fatigue, weight loss, bone fractures, anemia, and diarrhea can all be evident on top of the symptoms associated with less serious toxicity.[7] | https://www.wikidoc.org/index.php/Vitamin_A | |
b91a911c2aade41d916701080085d15d3ee2753f | wikidoc | Vitamin O | Vitamin O
Vitamin O is a dietary supplement, which has been marketed and sold by Rose Creek Health Products Inc. since 1998. It is not recognized by nutritional science as a vitamin. It has been claimed that taking the supplement has a beneficial effect on a wide variety of ailments, including angina, anaemia, and various forms of cancer, as well as increasing vigour and improving state of mind. The given reason for this is that vitamin O is "a special supplemented oxygen taken in liquid form and produced through electrical-activation with a saline solution from the ocean," and that the substance increases the amount of oxygen present in the blood. This would in turn promote cellular oxygen uptake.
As a result of the Dietary Supplement Health and Education Act, the product could be sold without approval by the Food and Drug Administration, provided claims were never made by the producers of the supplement about its medical efficacy. Rose Creek complied, instead collecting statements from users who attributed wide-ranging benefits to taking it. However, later ads also ran statements from "experts", who provided anecdotal evidence from small-scale clinical trials showing positive results in several patients. Because of this, the Federal Trade Commission filed an injunction in March 1999 against Rose Creek Health Products Inc., stating that the ads being run in both print and online sources, including USA Today, were "blatantly false". Studies run on vitamin O showed it to be composed largely of salt water as well as a small quantity of germanium, which would provide no benefits not attributable to the placebo effect.
On April 28 2000, Donald L. Smyth, CEO of Rose Creek Health Products Inc., agreed to pay a cash settlement of $375,000 for consumer redress, and to abstain from making claims as to the scientific accuracy of beneficial effects attributed to the supplement, or promoting its efficacy in treating life-threatening illnesses. | Vitamin O
Vitamin O is a dietary supplement, which has been marketed and sold by Rose Creek Health Products Inc. since 1998. It is not recognized by nutritional science as a vitamin. It has been claimed that taking the supplement has a beneficial effect on a wide variety of ailments, including angina, anaemia, and various forms of cancer, as well as increasing vigour and improving state of mind. The given reason for this is that vitamin O is "a special supplemented oxygen taken in liquid form and produced through electrical-activation with a saline solution from the ocean,"[1] and that the substance increases the amount of oxygen present in the blood. This would in turn promote cellular oxygen uptake.
As a result of the Dietary Supplement Health and Education Act, the product could be sold without approval by the Food and Drug Administration, provided claims were never made by the producers of the supplement about its medical efficacy. Rose Creek complied, instead collecting statements from users who attributed wide-ranging benefits to taking it. However, later ads also ran statements from "experts", who provided anecdotal evidence from small-scale clinical trials showing positive results in several patients. Because of this, the Federal Trade Commission filed an injunction in March 1999 against Rose Creek Health Products Inc., stating that the ads being run in both print and online sources, including USA Today, were "blatantly false".[2] Studies run on vitamin O showed it to be composed largely of salt water as well as a small quantity of germanium, which would provide no benefits not attributable to the placebo effect.
On April 28 2000, Donald L. Smyth, CEO of Rose Creek Health Products Inc., agreed to pay a cash settlement of $375,000 for consumer redress, and to abstain from making claims as to the scientific accuracy of beneficial effects attributed to the supplement, or promoting its efficacy in treating life-threatening illnesses.[3] | https://www.wikidoc.org/index.php/Vitamin_O | |
af93bc7747045bc5e3a6635387322e9f8adfc9d8 | wikidoc | Voglibose | Voglibose
Voglibose (INN and USAN) is an alpha-glucosidase inhibitor used for lowering post-prandial blood glucose levels in people with diabetes mellitus. It is made in India by Ranbaxy Labs and sold under the trade name Volix.
Glenmark is also producing voglibose under brand name vocarb.
Diabetes is chronic metabolic disorder characterised by hyperglycemia which is due to relative or absolute deficiency of insulin or insulin resistance.
PPHG is termed as Post Prandial Hyperglycemia which is primarily due to first phase insulin secretion. Alpha glucosidase inhibitor is one agent which delays the glucose absorption at the intestine level and thereby prevents sudden surge of glucose post meal.
There are three molecules which belong to this class namely, Acarbose, Miglitol and Voglibose. Voglibose is the latest molecule in this class. Voglibose scores over both Acarbose and MIglitol in terms of potency and side effect profile.
There are several trials supporting the use of Voglibose in the management of PPHG. Also, it has been established that it is PPHG not FPG which is marker of cardiovascular disorders associated with diabetes. So, controlling PPHG is imperative and Voglibose is indicated for the management of PPHG.
Sun Pharmaceuticals launched Voglibose 0.2 / 0.3 mg under the brand name VOLIBO. | Voglibose
Voglibose (INN and USAN) is an alpha-glucosidase inhibitor used for lowering post-prandial blood glucose levels in people with diabetes mellitus. It is made in India by Ranbaxy Labs and sold under the trade name Volix.
Glenmark is also producing voglibose under brand name vocarb.
Diabetes is chronic metabolic disorder characterised by hyperglycemia which is due to relative or absolute deficiency of insulin or insulin resistance.
PPHG is termed as Post Prandial Hyperglycemia which is primarily due to first phase insulin secretion. Alpha glucosidase inhibitor is one agent which delays the glucose absorption at the intestine level and thereby prevents sudden surge of glucose post meal.
There are three molecules which belong to this class namely, Acarbose, Miglitol and Voglibose. Voglibose is the latest molecule in this class. Voglibose scores over both Acarbose and MIglitol in terms of potency and side effect profile.
There are several trials supporting the use of Voglibose in the management of PPHG. Also, it has been established that it is PPHG not FPG which is marker of cardiovascular disorders associated with diabetes. So, controlling PPHG is imperative and Voglibose is indicated for the management of PPHG.
Sun Pharmaceuticals launched Voglibose 0.2 / 0.3 mg under the brand name VOLIBO.
# External links
- voglibose.com
- diabetesincontrol.com
- diabetesjournals.org
- Ranbaxy announcement
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Voglibose | |
128955f54873f087080c2b63cabf111bb753554c | wikidoc | Vorapaxar | Vorapaxar
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Vorapaxar is a platelet aggregation inhibitor that is FDA approved for the prophylaxis of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding, anemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 1 tablet of 2.08 mg PO once daily, with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vorapaxar in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vorapaxar in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Vorapaxar FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vorapaxar in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vorapaxar in pediatric patients.
# Contraindications
### History of Stroke, Transient Ischemic Attack (TIA), or Intracranial Hemorrhage (ICH)
- Vorapaxar is contraindicated in patients with a history of stroke, TIA, or ICH because of an increased risk of ICH in this population.
- Discontinue vorapaxar in patients who experience a stroke, TIA, or ICH.
### Active Pathologic Bleeding
- Vorapaxar is contraindicated in patients with active pathological bleeding such as ICH or peptic ulcer.
# Warnings
### General Risk of Bleeding
- Antiplatelet agents, including vorapaxar, increase the risk of bleeding, including ICHand fatal bleeding.
- Vorapaxar increases the risk of bleeding in proportion to the patient's underlying bleeding risk.
- Consider the underlying risk of bleeding before initiating vorapaxar. General risk factors for bleeding include older age, low body weight, reduced renal or hepatic function, history of bleeding disorders, and use of certain concomitant medications (e.g., anticoagulants, fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs , selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors) increases the risk of bleeding
- Avoid concomitant use of warfarin or other anticoagulants.
- Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), or other surgical procedures.
- Withholding vorapaxar for a brief period will not be useful in managing an acute bleeding event because of its long half-life.
- There is no known treatment to reverse the antiplatelet effect of vorapaxar.
- Significant inhibition of platelet aggregation remains 4 weeks after discontinuation.
### Strong CYP3A Inhibitors or Inducers
- Strong CYP3A inhibitors increase and inducers decrease vorapaxar exposure.
- Avoid concomitant use of vorapaxar with strong CYP3A inhibitors or inducers
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Vorapaxar was evaluated for safety in 13,186 patients, including 2,187 patients treated for more than 3 years, in the Phase 3 study TRA 2°P TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events). The overall study population, patients who had evidence or a history of atherosclerosis involving the coronary (post-MI), cerebral (ischemic stroke), or peripheral vascular (documented history of PAD) systems, was treated once a day with vorapaxar (n=13,186) or placebo (n=13,166). Patients randomized to vorapaxar received treatment for a median of 2.3 years.
The adverse events in the vorapaxar-treated (n=10,059) and placebo-treated (n=10,049) post-MI or PAD patients with no history of stroke or TIA are shown below.
### Bleeding
GUSTO severe bleeding was defined as fatal, intracranial, or bleeding with hemodynamic compromise requiring intervention; GUSTO moderate bleeding was defined as bleeding requiring transfusion of whole blood or packed red blood cells without hemodynamic compromise. (GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries.)
The results for the bleeding endpoints in the post-MI or PAD patients without a history of stroke or TIA are shown in Table 1. Vorapaxar increased GUSTO moderate or severe bleeding by 55%.
The effects of vorapaxar on bleeding were examined in a number of subsets based on demographic and other baseline characteristics. Many of these are shown in Figure 1. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.
In TRA 2°P, 367 post-MI or PAD patients without a history of stroke or TIA underwent CABG surgery. Study investigators were encouraged not to discontinue treatment with study drug (i.e., vorapaxar or placebo) prior to surgery. Approximately 12.3% of patients discontinued vorapaxar more than 30 days prior to CABG. The relative risk for GUSTO moderate or severe bleeding was approximately 1.2 on vorapaxar vs. placebo.
Bleeding events that occurred on vorapaxar were treated in the same manner as for other antiplatelet agents.
### Use in Patients with History of Stroke, TIA, or ICH
In the TRA 2°P study, patients with a history of ischemic stroke had a higher rate for ICH on vorapaxar than on placebo. Vorapaxar is contraindicated in patients with a history of stroke, TIA, or ICH.
### Other Adverse Reactions
Adverse reactions other than bleeding were evaluated in 19,632 patients treated with vorapaxar . Adverse events other than bleeding that occurred at a rate that was at least 2% in the vorapaxar group and also 10% greater than the rate in the placebo group are shown in Table 2.
The following adverse reactions occurred at a rate less than 2% in the vorapaxar group but at least 40% greater than placebo. In descending order of rate in the vorapaxar group: iron deficiency, retinopathy or retinal disorder, and diplopia/oculomotor disturbances.
An increased rate of diplopia and related oculomotor disturbances was observed with vorapaxar treatment (30 subjects, 0.2%) vs. placebo (10 subjects, 0.06%). While some cases resolved during continued treatment, information on resolution of symptoms was not available for some cases.
## Postmarketing Experience
There is limited information regarding Vorapaxar Postmarketing Experience in the drug label.
# Drug Interactions
Vorapaxar is eliminated primarily by metabolism, with contributions from CYP3A4 and CYP2J2.
### Strong CYP3A Inhibitors
Avoid concomitant use of vorapaxar with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan).
### Strong CYP3A Inducers
Avoid concomitant use of vorapaxar with strong inducers of CYP3A (e.g., rifampin, carbamazepine, St. John's Wort and phenytoin).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
There are no adequate and well-controlled studies of vorapaxar use in pregnant women.
Based on data in rats and rabbits, vorapaxar is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background. No embryo/fetal toxicities, malformations or maternal toxicities were observed in rats exposed during gestation to 56 times the human systemic exposure at the recommended human dose (RHD). No embryo/fetal toxicities, malformations or maternal toxicities were observed in rabbits exposed during gestation to 26 times the human systemic exposure at the RHD. The No Adverse Effect Level (NOAEL) for decreased perinatal survival and body weight in off-spring exposed in utero and during lactation was 31 times the human systemic exposure at the RHD. Both male and female pups displayed transient effects on sensory function and neurobehavioral development at weaning at 67 times the human exposure at the RHD, whereas female pups displayed decreased memory at 31 times the human exposure at the RHD. However, animal studies are not always predictive of a human response. Vorapaxar should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of vorapaxar at 0, 5, 25, and 75 mg/kg from implantation to closure of the fetal hard palate (6th to 17th day of gestation). Maternal systemic exposures were approximately 0, 7, 56, and 285 times greater than exposures in women treated at the RHD based on AUC. No embryo/fetal toxicities, malformations, or maternal toxicities were observed in rats receiving exposures up to 56 times the human systemic exposure at the RHD.
In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of vorapaxar at 0, 2, 10, or 20 mg/kg from implantation to closure of the fetal hard palate (7th to 19th day of gestation). The NOAEL for maternal and fetal toxicity was equal to or above the highest dose tested. However, an overall increase in the number of litters with any malformation was observed at the highest dose, where systemic exposures were 89-fold higher than the human exposure at RHD.
The effects of vorapaxar on prenatal and postnatal development were assessed in pregnant rats dosed at 0, 5, 25, or 50 mg/kg/day from implantation through the end of lactation. Rat pups had decreased survival and body weight gain from birth to postnatal day 4 and decreased body weight gain for the overall pre-weaning period at exposures 67 times the human exposure at the RHD. Both male and female pups displayed effects on sensory function (acoustic startle) and neurobehavioral (locomotor assay) development on post-natal day (PND) 20 and 21, but not later (PND 60, 61) in development, whereas decreased memory was observed in female pups on PND 27 at 31 times the human exposure at the RHD. In utero and lactational exposure did not affect fertility or reproductive behavior of offspring at exposures up to 67 times the RHD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vorapaxar in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vorapaxar during labor and delivery.
### Nursing Mothers
It is unknown whether vorapaxar or its metabolites are excreted in human milk, but it is actively secreted in milk of rats. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from vorapaxar, discontinue nursing or discontinue vorapaxar.
### Pediatric Use
The safety and effectiveness of vorapaxar in pediatric patients have not been established.
### Geriatic Use
In TRA 2°P, in post-MI or PAD patients without a history of stroke or TIA, 33% of patients were ≥65 years of age and 9% were ≥75 years of age. The relative risk of bleeding (vorapaxar compared with placebo) was similar across age groups. No overall differences in safety or effectiveness were observed between these patients and younger patients. Vorapaxar increases the risk of bleeding in proportion to a patient's underlying risk. Because older patients are generally at a higher risk of bleeding, consider patient age before initiating vorapaxar
### Gender
There is no FDA guidance on the use of Vorapaxar with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vorapaxar with respect to specific racial populations.
### Renal Impairment
No dose adjustment is required in patients with renal impairment
### Hepatic Impairment
No dose adjustment is required in patients with mild and moderate hepatic impairment. Based on the increased inherent risk of bleeding in patients with severe hepatic impairment, vorapaxar is not recommended in such patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vorapaxar in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vorapaxar in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral, with or without food.
### Monitoring
There is limited information regarding Vorapaxar Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Vorapaxar and IV administrations.
# Overdosage
There is no known treatment to reverse the antiplatelet effect of vorapaxar, and neither dialysis nor platelet transfusion can be expected to be beneficial if bleeding occurs after overdose. Inhibition of platelet aggregation can be expected for weeks after discontinuation of normal dosing. There is no standard test available to assess the risk of bleeding in an overdose situation.
# Pharmacology
## Mechanism of Action
Vorapaxar is a reversible antagonist of the protease-activated receptor-1 (PAR-1) expressed on platelets, but its long half-life makes it effectively irreversible. Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation in in vitro studies. Vorapaxar does not inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen or a thromboxane mimetic and does not affect coagulation parameters ex vivo. PAR-1 receptors are also expressed in a wide variety of cell types, including endothelial cells, neurons, and smooth muscle cells, but the pharmacodynamic effects of vorapaxar in these cell types have not been assessed.
## Structure
The chemical name of vorapaxar sulfate is ethyl ethen-1-yl}-1-methyl-3-oxododecahydronaphthofuran-6-yl]carbamate sulfate. The empirical formula is C29H33FN2O4∙H2SO4, and its molecular weight is 590.7. The structural formula is:
## Pharmacodynamics
At the recommended dose, vorapaxar achieves ≥80% inhibition of TRAP-induced platelet aggregation within one week of initiation of treatment. The duration of platelet inhibition is dose- and concentration-dependent. Inhibition of TRAP-induced platelet aggregation at a level of 50% can be expected at 4 weeks after discontinuation of daily doses of vorapaxar 2.08 mg, consistent with the terminal elimination half-life of vorapaxar.
In healthy volunteer studies, no changes in platelet P-selectin and soluble CD40 ligand (sCD40L) expression or coagulation test parameters (TT, PT, aPTT, ACT, ECT) occurred after single- or multiple- dose (28 days) administration of vorapaxar. No meaningful changes in P-selectin, sCD40L, or hs-CRP concentrations were observed in patients treated with vorapaxar in the phase 2/3 clinical trials.
The effect of vorapaxar on the QTc interval was evaluated in a thorough QT study and in other studies. Vorapaxar had no effect on the QTc interval at single doses up to 48 times the recommended dose.
## Pharmacokinetics
Vorapaxar exposure increases in an approximately dose-proportional manner following single doses up to 16 times the recommended dose. Vorapaxar pharmacokinetics are similar in healthy subjects and patients.
After oral administration of a single vorapaxar 2.08 mg dose under fasted conditions, peak concentrations (Cmax) occur at 1 hour post-dose (range: 1 to 2 h). The mean absolute bioavailability as determined from a microdosing study is approximately 100%.
Ingestion of vorapaxar with a high-fat meal resulted in no meaningful change in AUC with a small (21%) decrease in Cmax and delayed time to peak concentration (45 minutes). Vorapaxar may be taken with or without food.
The mean volume of distribution of vorapaxar is approximately 424 liters (95% CI: 351-512). Vorapaxar and the major circulating active metabolite, M20, are extensively bound (≥99%) to human plasma proteins. Vorapaxar is highly bound to human serum albumin and does not preferentially distribute into red blood cells.
Vorapaxar is eliminated by metabolism via CYP3A4 and CYP2J2. The major active circulating metabolite is M20 (monohydroxy metabolite) and the predominant metabolite identified in excreta is M19 (amine metabolite). The systemic exposure of M20 is ~20% of the exposure to vorapaxar.
The primary route of elimination is through the feces. In a 6-week study, 84% of the administered radiolabeled dose was recovered as total radioactivity with 58% collected in feces and 25% in urine. Vorapaxar is eliminated primarily in the form of metabolites, with no unchanged vorapaxar detected in urine.
Vorapaxar exhibits multi-exponential disposition with an effective half-life of 3-4 days and an apparent terminal elimination half-life of 8 days. Steady-state is achieved by 21 days following once-daily dosing with an accumulation of 5- to 6-fold. The apparent terminal elimination half-life for vorapaxar is approximately 8 days (range 5-13 days) and is similar for the active metabolite. The terminal elimination half-life is important to determine the time to offset the pharmacodynamic effect.
In general, effects on the exposure of vorapaxar based on age, race, gender, weight, and moderate renal insufficiency were modest (20-40%). No dose adjustments are necessary based upon these factors. Because of the inherent bleeding risks in patients with severe hepatic impairment, vorapaxar is not recommended in such patients.
The effects of other drugs on the pharmacokinetics of vorapaxar are presented in Figure 3 as change relative to vorapaxar administered alone (test/reference). Phase 3 data suggest that coadministration of a weak or moderate CYP3A inhibitor with vorapaxar does not increase bleeding risk or alter the efficacy of vorapaxar. No dose adjustment for vorapaxar is required in patients taking weak to moderate inhibitors of CYP3A.
In vitro metabolism studies demonstrate that vorapaxar or M20 is unlikely to cause clinically significant inhibition or induction of major CYP isoforms or inhibition of OATP1B1, OATP1B3, BCRP, OAT1, OAT3, and OCT2 transporters.
Specific in vivo effects on the pharmacokinetics of digoxin, warfarin, rosiglitazone and prasugrel are presented in Figure 4 as a change relative to the interacting drug administered alone (test/reference). Vorapaxar is a weak inhibitor of the intestinal P-glycoprotein (P-gp) transporter. No dosage adjustment of digoxin or vorapaxar is required.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in rats and mice dosed orally with vorapaxar for two years. Male and female rats dosed at 0, 3, 10 or 30 mg/kg/day showed no carcinogenic potential at systemic exposures (AUC) in males and females that were 9- and 29-fold, respectively, the human systemic exposure at the RHD. In male and female mice dosed at 0, 1, 5, and 15 mg/kg/day, vorapaxar showed no carcinogenic potential at systemic exposures (AUC) that were up to 30-fold the human systemic exposure.
Vorapaxar was not mutagenic in the Ames bacterial reverse mutation assay and not clastogenic in an in vitro human peripheral blood lymphocyte assay or an in vivo mouse micronucleus assay after intraperitoneal administration.
Fertility studies in rats showed that vorapaxar had no effect on either male or female fertility at doses up to 50 mg/kg/day, a dose resulting in systemic exposures (AUC) in male and female rats that are 40 and 67 times, respectively, the human systemic exposure at the RHD.
### Animal Pharmacology
Vorapaxar did not increase bleeding time in non-human primates when administered alone. Bleeding time was prolonged slightly with administration of aspirin or aspirin plus vorapaxar. The combination of aspirin, vorapaxar, and clopidogrel produced significant prolongation of bleeding time. Transfusion of human platelet rich plasma normalized bleeding times with partial recovery of ex vivo platelet aggregation induced with arachidonic acid, but not induced with ADP or TRAP. Platelet poor plasma had no effect on bleeding times or platelet aggregation.
# Clinical Studies
The clinical evidence for the effectiveness of vorapaxar is supported by TRA 2°P - TIMI 50. TRA 2°P was a multicenter, randomized, double-blind, placebo-controlled study conducted in patients who had evidence or a history of atherosclerosis involving the coronary (spontaneous MI ≥2 weeks but ≤12 months prior), cerebral (ischemic stroke), or peripheral vascular (documented peripheral arterial disease ) systems. Patients were randomized to receive daily treatment with vorapaxar (n=13,225) or placebo (n=13,224) in addition to standard of care. The study's primary endpoint was the composite of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR). The composite of cardiovascular death, MI, and stroke was assessed as key secondary endpoint. The median follow-up was 2.5 years (up to 4 years).
The findings in all randomized patients for the primary efficacy composite endpoint show a 3-year K-M event rate of 11.2% in the vorapaxar group compared to 12.4% in the placebo group (hazard ratio : 0.88; 95% confidence interval , 0.82 to 0.95; p=0.001).
The findings for the key secondary efficacy endpoint show a 3-year Kaplan-Meier (K-M) event rate of 9.3% in the vorapaxar group compared to 10.5% in placebo group (HR 0.87; 95% CI, 0.80 to 0.94; p<0.001).
Although TRA 2°P was not designed to evaluate the relative benefits and risks of vorapaxar in individual patient subgroups, patients with a history of stroke or TIA showed an increased risk of ICH. Of the patients who comprised the post-MI and PAD strata and had no baseline history of stroke or TIA,10,080 were randomized to treatment with vorapaxar and 10,090 to placebo. These patients were 89% Caucasian, 22% female, and 33% ≥65 years of age, with a median age of 60 years. The population included patients with diabetes (24%) and patients with hypertension (65%). Of the patients who qualified for the trial with MI without a history of stroke or TIA, 98% were receiving aspirin, 78% were receiving a thienopyridine, and 77% were receiving both aspirin and a thienopyridine when they enrolled in the trial. Of the patients who qualified for the trial with PAD without a history of stroke or TIA, 88% were receiving aspirin, 35% were receiving a thienopyridine, and 27% were receiving both aspirin and a thienopyridine when they enrolled.
In post-MI or PAD patients without a history of stroke or TIA the 3-year K-M event rate for the primary efficacy endpoint (composite of time to first CV death, MI, stroke, or UCR) was of 10.1% in the vorapaxar group compared to 11.8% in the placebo group (HR 0.83; 95% CI, 0.76 to 0.90; p<0.001).
The results for the key secondary efficacy endpoint (composite of time to first CV death, MI, or stroke) show a 3-year K-M event rate of 7.9% in the vorapaxar group compared to 9.5% in the placebo group (HR 0.80; 95% CI, 0.73 to 0.89; p<0.001).
The effect of chronic dosing with vorapaxar on the primary and key secondary endpoints was maintained for the duration of the trial (median follow up 2.5 years, up to 4 years).
In post-MI or PAD patients who survived an on-study efficacy event, the incidence of subsequent events was lower with vorapaxar.
The time from the prior MI to randomization had no relationship to the treatment benefit for the primary study outcome.
A range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcomes as shown in Figure 6. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.
# How Supplied
Vorapaxar tablets, 2.08 mg vorapaxar, are yellow, oval-shaped, film-coated tablets with "351" on one side and the Merck logo on the other side.
They are supplied as follows:
- NDC 0006-0351-31 bottles of 30 tablets
- NDC 0006-0351-54 bottles of 90 tablets
- NDC 0006-0351-48 unit dose packages of 100 tablets (one carton containing 10 10-count blister cards)
## Storage
### Storage of bottles
Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). Store tablets in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.
### Storage of blisters
Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). Store in the original package until use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved Patient Labeling (Medication Guide).
### Benefits and Risks
- Summarize the benefits and potential side effects of vorapaxar.
- Tell patients to take vorapaxar exactly as prescribed.
- Inform patients not to discontinue vorapaxar without discussing it with the prescribing physician.
- Tell patients to read the Medication Guide.
### Bleeding
Inform patients that they:
- May bleed and bruise more easily.
- Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine.
### Invasive Procedures
Instruct patients to:
- Inform physicians and dentists that they are taking vorapaxar before any surgery or dental procedure.
- Tell the doctor performing any surgery or dental procedure to talk to the prescribing physician before stopping vorapaxar.
### Concomitant Medications
- Tell patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so that the physician knows about other treatments that may affect bleeding risk.
# Precautions with Alcohol
Alcohol-Vorapaxar interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zontivity
# Look-Alike Drug Names
There is limited information regarding Vorapaxar Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Vorapaxar
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Vorapaxar is a platelet aggregation inhibitor that is FDA approved for the prophylaxis of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding, anemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 1 tablet of 2.08 mg PO once daily, with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vorapaxar in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vorapaxar in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Vorapaxar FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vorapaxar in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vorapaxar in pediatric patients.
# Contraindications
### History of Stroke, Transient Ischemic Attack (TIA), or Intracranial Hemorrhage (ICH)
- Vorapaxar is contraindicated in patients with a history of stroke, TIA, or ICH because of an increased risk of ICH in this population.
- Discontinue vorapaxar in patients who experience a stroke, TIA, or ICH.
### Active Pathologic Bleeding
- Vorapaxar is contraindicated in patients with active pathological bleeding such as ICH or peptic ulcer.
# Warnings
### General Risk of Bleeding
- Antiplatelet agents, including vorapaxar, increase the risk of bleeding, including ICHand fatal bleeding.
- Vorapaxar increases the risk of bleeding in proportion to the patient's underlying bleeding risk.
- Consider the underlying risk of bleeding before initiating vorapaxar. General risk factors for bleeding include older age, low body weight, reduced renal or hepatic function, history of bleeding disorders, and use of certain concomitant medications (e.g., anticoagulants, fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs [NSAIDS], selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors) increases the risk of bleeding
- Avoid concomitant use of warfarin or other anticoagulants.
- Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), or other surgical procedures.
- Withholding vorapaxar for a brief period will not be useful in managing an acute bleeding event because of its long half-life.
- There is no known treatment to reverse the antiplatelet effect of vorapaxar.
- Significant inhibition of platelet aggregation remains 4 weeks after discontinuation.
### Strong CYP3A Inhibitors or Inducers
- Strong CYP3A inhibitors increase and inducers decrease vorapaxar exposure.
- Avoid concomitant use of vorapaxar with strong CYP3A inhibitors or inducers
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Vorapaxar was evaluated for safety in 13,186 patients, including 2,187 patients treated for more than 3 years, in the Phase 3 study TRA 2°P TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events). The overall study population, patients who had evidence or a history of atherosclerosis involving the coronary (post-MI), cerebral (ischemic stroke), or peripheral vascular (documented history of PAD) systems, was treated once a day with vorapaxar (n=13,186) or placebo (n=13,166). Patients randomized to vorapaxar received treatment for a median of 2.3 years.
The adverse events in the vorapaxar-treated (n=10,059) and placebo-treated (n=10,049) post-MI or PAD patients with no history of stroke or TIA are shown below.
### Bleeding
GUSTO severe bleeding was defined as fatal, intracranial, or bleeding with hemodynamic compromise requiring intervention; GUSTO moderate bleeding was defined as bleeding requiring transfusion of whole blood or packed red blood cells without hemodynamic compromise. (GUSTO: Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries.)
The results for the bleeding endpoints in the post-MI or PAD patients without a history of stroke or TIA are shown in Table 1. Vorapaxar increased GUSTO moderate or severe bleeding by 55%.
The effects of vorapaxar on bleeding were examined in a number of subsets based on demographic and other baseline characteristics. Many of these are shown in Figure 1. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.
In TRA 2°P, 367 post-MI or PAD patients without a history of stroke or TIA underwent CABG surgery. Study investigators were encouraged not to discontinue treatment with study drug (i.e., vorapaxar or placebo) prior to surgery. Approximately 12.3% of patients discontinued vorapaxar more than 30 days prior to CABG. The relative risk for GUSTO moderate or severe bleeding was approximately 1.2 on vorapaxar vs. placebo.
Bleeding events that occurred on vorapaxar were treated in the same manner as for other antiplatelet agents.
### Use in Patients with History of Stroke, TIA, or ICH
In the TRA 2°P study, patients with a history of ischemic stroke had a higher rate for ICH on vorapaxar than on placebo. Vorapaxar is contraindicated in patients with a history of stroke, TIA, or ICH.
### Other Adverse Reactions
Adverse reactions other than bleeding were evaluated in 19,632 patients treated with vorapaxar [13,186 patients in the TRA 2°P study and 6,446 patients in the TRA•CER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study]. Adverse events other than bleeding that occurred at a rate that was at least 2% in the vorapaxar group and also 10% greater than the rate in the placebo group are shown in Table 2.
The following adverse reactions occurred at a rate less than 2% in the vorapaxar group but at least 40% greater than placebo. In descending order of rate in the vorapaxar group: iron deficiency, retinopathy or retinal disorder, and diplopia/oculomotor disturbances.
An increased rate of diplopia and related oculomotor disturbances was observed with vorapaxar treatment (30 subjects, 0.2%) vs. placebo (10 subjects, 0.06%). While some cases resolved during continued treatment, information on resolution of symptoms was not available for some cases.
## Postmarketing Experience
There is limited information regarding Vorapaxar Postmarketing Experience in the drug label.
# Drug Interactions
Vorapaxar is eliminated primarily by metabolism, with contributions from CYP3A4 and CYP2J2.
### Strong CYP3A Inhibitors
Avoid concomitant use of vorapaxar with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan).
### Strong CYP3A Inducers
Avoid concomitant use of vorapaxar with strong inducers of CYP3A (e.g., rifampin, carbamazepine, St. John's Wort and phenytoin).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
There are no adequate and well-controlled studies of vorapaxar use in pregnant women.
Based on data in rats and rabbits, vorapaxar is predicted to have a low probability of increasing the risk of adverse developmental outcomes above background. No embryo/fetal toxicities, malformations or maternal toxicities were observed in rats exposed during gestation to 56 times the human systemic exposure at the recommended human dose (RHD). No embryo/fetal toxicities, malformations or maternal toxicities were observed in rabbits exposed during gestation to 26 times the human systemic exposure at the RHD. The No Adverse Effect Level (NOAEL) for decreased perinatal survival and body weight in off-spring exposed in utero and during lactation was 31 times the human systemic exposure at the RHD. Both male and female pups displayed transient effects on sensory function and neurobehavioral development at weaning at 67 times the human exposure at the RHD, whereas female pups displayed decreased memory at 31 times the human exposure at the RHD. However, animal studies are not always predictive of a human response. Vorapaxar should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
In the rat embryo/fetal developmental toxicity study, pregnant rats received daily oral doses of vorapaxar at 0, 5, 25, and 75 mg/kg from implantation to closure of the fetal hard palate (6th to 17th day of gestation). Maternal systemic exposures were approximately 0, 7, 56, and 285 times greater than exposures in women treated at the RHD based on AUC. No embryo/fetal toxicities, malformations, or maternal toxicities were observed in rats receiving exposures up to 56 times the human systemic exposure at the RHD.
In the rabbit embryo/fetal developmental toxicity study, pregnant rabbits received daily oral doses of vorapaxar at 0, 2, 10, or 20 mg/kg from implantation to closure of the fetal hard palate (7th to 19th day of gestation). The NOAEL for maternal and fetal toxicity was equal to or above the highest dose tested. However, an overall increase in the number of litters with any malformation was observed at the highest dose, where systemic exposures were 89-fold higher than the human exposure at RHD.
The effects of vorapaxar on prenatal and postnatal development were assessed in pregnant rats dosed at 0, 5, 25, or 50 mg/kg/day from implantation through the end of lactation. Rat pups had decreased survival and body weight gain from birth to postnatal day 4 and decreased body weight gain for the overall pre-weaning period at exposures 67 times the human exposure at the RHD. Both male and female pups displayed effects on sensory function (acoustic startle) and neurobehavioral (locomotor assay) development on post-natal day (PND) 20 and 21, but not later (PND 60, 61) in development, whereas decreased memory was observed in female pups on PND 27 at 31 times the human exposure at the RHD. In utero and lactational exposure did not affect fertility or reproductive behavior of offspring at exposures up to 67 times the RHD.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vorapaxar in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vorapaxar during labor and delivery.
### Nursing Mothers
It is unknown whether vorapaxar or its metabolites are excreted in human milk, but it is actively secreted in milk of rats. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from vorapaxar, discontinue nursing or discontinue vorapaxar.
### Pediatric Use
The safety and effectiveness of vorapaxar in pediatric patients have not been established.
### Geriatic Use
In TRA 2°P, in post-MI or PAD patients without a history of stroke or TIA, 33% of patients were ≥65 years of age and 9% were ≥75 years of age. The relative risk of bleeding (vorapaxar compared with placebo) was similar across age groups. No overall differences in safety or effectiveness were observed between these patients and younger patients. Vorapaxar increases the risk of bleeding in proportion to a patient's underlying risk. Because older patients are generally at a higher risk of bleeding, consider patient age before initiating vorapaxar
### Gender
There is no FDA guidance on the use of Vorapaxar with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vorapaxar with respect to specific racial populations.
### Renal Impairment
No dose adjustment is required in patients with renal impairment
### Hepatic Impairment
No dose adjustment is required in patients with mild and moderate hepatic impairment. Based on the increased inherent risk of bleeding in patients with severe hepatic impairment, vorapaxar is not recommended in such patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vorapaxar in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vorapaxar in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral, with or without food.
### Monitoring
There is limited information regarding Vorapaxar Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Vorapaxar and IV administrations.
# Overdosage
There is no known treatment to reverse the antiplatelet effect of vorapaxar, and neither dialysis nor platelet transfusion can be expected to be beneficial if bleeding occurs after overdose. Inhibition of platelet aggregation can be expected for weeks after discontinuation of normal dosing. There is no standard test available to assess the risk of bleeding in an overdose situation.
# Pharmacology
## Mechanism of Action
Vorapaxar is a reversible antagonist of the protease-activated receptor-1 (PAR-1) expressed on platelets, but its long half-life makes it effectively irreversible. Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation in in vitro studies. Vorapaxar does not inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen or a thromboxane mimetic and does not affect coagulation parameters ex vivo. PAR-1 receptors are also expressed in a wide variety of cell types, including endothelial cells, neurons, and smooth muscle cells, but the pharmacodynamic effects of vorapaxar in these cell types have not been assessed.
## Structure
The chemical name of vorapaxar sulfate is ethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(1E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethen-1-yl}-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamate sulfate. The empirical formula is C29H33FN2O4∙H2SO4, and its molecular weight is 590.7. The structural formula is:
## Pharmacodynamics
At the recommended dose, vorapaxar achieves ≥80% inhibition of TRAP-induced platelet aggregation within one week of initiation of treatment. The duration of platelet inhibition is dose- and concentration-dependent. Inhibition of TRAP-induced platelet aggregation at a level of 50% can be expected at 4 weeks after discontinuation of daily doses of vorapaxar 2.08 mg, consistent with the terminal elimination half-life of vorapaxar.
In healthy volunteer studies, no changes in platelet P-selectin and soluble CD40 ligand (sCD40L) expression or coagulation test parameters (TT, PT, aPTT, ACT, ECT) occurred after single- or multiple- dose (28 days) administration of vorapaxar. No meaningful changes in P-selectin, sCD40L, or hs-CRP concentrations were observed in patients treated with vorapaxar in the phase 2/3 clinical trials.
The effect of vorapaxar on the QTc interval was evaluated in a thorough QT study and in other studies. Vorapaxar had no effect on the QTc interval at single doses up to 48 times the recommended dose.
## Pharmacokinetics
Vorapaxar exposure increases in an approximately dose-proportional manner following single doses up to 16 times the recommended dose. Vorapaxar pharmacokinetics are similar in healthy subjects and patients.
After oral administration of a single vorapaxar 2.08 mg dose under fasted conditions, peak concentrations (Cmax) occur at 1 hour post-dose (range: 1 to 2 h). The mean absolute bioavailability as determined from a microdosing study is approximately 100%.
Ingestion of vorapaxar with a high-fat meal resulted in no meaningful change in AUC with a small (21%) decrease in Cmax and delayed time to peak concentration (45 minutes). Vorapaxar may be taken with or without food.
The mean volume of distribution of vorapaxar is approximately 424 liters (95% CI: 351-512). Vorapaxar and the major circulating active metabolite, M20, are extensively bound (≥99%) to human plasma proteins. Vorapaxar is highly bound to human serum albumin and does not preferentially distribute into red blood cells.
Vorapaxar is eliminated by metabolism via CYP3A4 and CYP2J2. The major active circulating metabolite is M20 (monohydroxy metabolite) and the predominant metabolite identified in excreta is M19 (amine metabolite). The systemic exposure of M20 is ~20% of the exposure to vorapaxar.
The primary route of elimination is through the feces. In a 6-week study, 84% of the administered radiolabeled dose was recovered as total radioactivity with 58% collected in feces and 25% in urine. Vorapaxar is eliminated primarily in the form of metabolites, with no unchanged vorapaxar detected in urine.
Vorapaxar exhibits multi-exponential disposition with an effective half-life of 3-4 days and an apparent terminal elimination half-life of 8 days. Steady-state is achieved by 21 days following once-daily dosing with an accumulation of 5- to 6-fold. The apparent terminal elimination half-life for vorapaxar is approximately 8 days (range 5-13 days) and is similar for the active metabolite. The terminal elimination half-life is important to determine the time to offset the pharmacodynamic effect.
In general, effects on the exposure of vorapaxar based on age, race, gender, weight, and moderate renal insufficiency were modest (20-40%). No dose adjustments are necessary based upon these factors. Because of the inherent bleeding risks in patients with severe hepatic impairment, vorapaxar is not recommended in such patients.
The effects of other drugs on the pharmacokinetics of vorapaxar are presented in Figure 3 as change relative to vorapaxar administered alone (test/reference). Phase 3 data suggest that coadministration of a weak or moderate CYP3A inhibitor with vorapaxar does not increase bleeding risk or alter the efficacy of vorapaxar. No dose adjustment for vorapaxar is required in patients taking weak to moderate inhibitors of CYP3A.
In vitro metabolism studies demonstrate that vorapaxar or M20 is unlikely to cause clinically significant inhibition or induction of major CYP isoforms or inhibition of OATP1B1, OATP1B3, BCRP, OAT1, OAT3, and OCT2 transporters.
Specific in vivo effects on the pharmacokinetics of digoxin, warfarin, rosiglitazone and prasugrel are presented in Figure 4 as a change relative to the interacting drug administered alone (test/reference). Vorapaxar is a weak inhibitor of the intestinal P-glycoprotein (P-gp) transporter. No dosage adjustment of digoxin or vorapaxar is required.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in rats and mice dosed orally with vorapaxar for two years. Male and female rats dosed at 0, 3, 10 or 30 mg/kg/day showed no carcinogenic potential at systemic exposures (AUC) in males and females that were 9- and 29-fold, respectively, the human systemic exposure at the RHD. In male and female mice dosed at 0, 1, 5, and 15 mg/kg/day, vorapaxar showed no carcinogenic potential at systemic exposures (AUC) that were up to 30-fold the human systemic exposure.
Vorapaxar was not mutagenic in the Ames bacterial reverse mutation assay and not clastogenic in an in vitro human peripheral blood lymphocyte assay or an in vivo mouse micronucleus assay after intraperitoneal administration.
Fertility studies in rats showed that vorapaxar had no effect on either male or female fertility at doses up to 50 mg/kg/day, a dose resulting in systemic exposures (AUC) in male and female rats that are 40 and 67 times, respectively, the human systemic exposure at the RHD.
### Animal Pharmacology
Vorapaxar did not increase bleeding time in non-human primates when administered alone. Bleeding time was prolonged slightly with administration of aspirin or aspirin plus vorapaxar. The combination of aspirin, vorapaxar, and clopidogrel produced significant prolongation of bleeding time. Transfusion of human platelet rich plasma normalized bleeding times with partial recovery of ex vivo platelet aggregation induced with arachidonic acid, but not induced with ADP or TRAP. Platelet poor plasma had no effect on bleeding times or platelet aggregation.
# Clinical Studies
The clinical evidence for the effectiveness of vorapaxar is supported by TRA 2°P - TIMI 50. TRA 2°P was a multicenter, randomized, double-blind, placebo-controlled study conducted in patients who had evidence or a history of atherosclerosis involving the coronary (spontaneous MI ≥2 weeks but ≤12 months prior), cerebral (ischemic stroke), or peripheral vascular (documented peripheral arterial disease [PAD]) systems. Patients were randomized to receive daily treatment with vorapaxar (n=13,225) or placebo (n=13,224) in addition to standard of care. The study's primary endpoint was the composite of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR). The composite of cardiovascular death, MI, and stroke was assessed as key secondary endpoint. The median follow-up was 2.5 years (up to 4 years).
The findings in all randomized patients for the primary efficacy composite endpoint show a 3-year K-M event rate of 11.2% in the vorapaxar group compared to 12.4% in the placebo group (hazard ratio [HR]: 0.88; 95% confidence interval [CI], 0.82 to 0.95; p=0.001).
The findings for the key secondary efficacy endpoint show a 3-year Kaplan-Meier (K-M) event rate of 9.3% in the vorapaxar group compared to 10.5% in placebo group (HR 0.87; 95% CI, 0.80 to 0.94; p<0.001).
Although TRA 2°P was not designed to evaluate the relative benefits and risks of vorapaxar in individual patient subgroups, patients with a history of stroke or TIA showed an increased risk of ICH. Of the patients who comprised the post-MI and PAD strata and had no baseline history of stroke or TIA,10,080 were randomized to treatment with vorapaxar and 10,090 to placebo. These patients were 89% Caucasian, 22% female, and 33% ≥65 years of age, with a median age of 60 years. The population included patients with diabetes (24%) and patients with hypertension (65%). Of the patients who qualified for the trial with MI without a history of stroke or TIA, 98% were receiving aspirin, 78% were receiving a thienopyridine, and 77% were receiving both aspirin and a thienopyridine when they enrolled in the trial. Of the patients who qualified for the trial with PAD without a history of stroke or TIA, 88% were receiving aspirin, 35% were receiving a thienopyridine, and 27% were receiving both aspirin and a thienopyridine when they enrolled.
In post-MI or PAD patients without a history of stroke or TIA the 3-year K-M event rate for the primary efficacy endpoint (composite of time to first CV death, MI, stroke, or UCR) was of 10.1% in the vorapaxar group compared to 11.8% in the placebo group (HR 0.83; 95% CI, 0.76 to 0.90; p<0.001).
The results for the key secondary efficacy endpoint (composite of time to first CV death, MI, or stroke) show a 3-year K-M event rate of 7.9% in the vorapaxar group compared to 9.5% in the placebo group (HR 0.80; 95% CI, 0.73 to 0.89; p<0.001).
The effect of chronic dosing with vorapaxar on the primary and key secondary endpoints was maintained for the duration of the trial (median follow up 2.5 years, up to 4 years).
In post-MI or PAD patients who survived an on-study efficacy event, the incidence of subsequent events was lower with vorapaxar.
The time from the prior MI to randomization had no relationship to the treatment benefit for the primary study outcome.
A range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcomes as shown in Figure 6. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.
# How Supplied
Vorapaxar tablets, 2.08 mg vorapaxar, are yellow, oval-shaped, film-coated tablets with "351" on one side and the Merck logo on the other side.
They are supplied as follows:
- NDC 0006-0351-31 bottles of 30 tablets
- NDC 0006-0351-54 bottles of 90 tablets
- NDC 0006-0351-48 unit dose packages of 100 tablets (one carton containing 10 10-count blister cards)
## Storage
### Storage of bottles
Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). Store tablets in the original package with the bottle tightly closed. Keep the desiccant in the bottle to protect from moisture.
### Storage of blisters
Store at 20-25°C (68-77°F), excursions permitted between 15-30°C (between 59-86°F). Store in the original package until use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved Patient Labeling (Medication Guide).
### Benefits and Risks
- Summarize the benefits and potential side effects of vorapaxar.
- Tell patients to take vorapaxar exactly as prescribed.
- Inform patients not to discontinue vorapaxar without discussing it with the prescribing physician.
- Tell patients to read the Medication Guide.
### Bleeding
Inform patients that they:
- May bleed and bruise more easily.
- Should report any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine.
### Invasive Procedures
Instruct patients to:
- Inform physicians and dentists that they are taking vorapaxar before any surgery or dental procedure.
- Tell the doctor performing any surgery or dental procedure to talk to the prescribing physician before stopping vorapaxar.
### Concomitant Medications
- Tell patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so that the physician knows about other treatments that may affect bleeding risk.
# Precautions with Alcohol
Alcohol-Vorapaxar interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zontivity
# Look-Alike Drug Names
There is limited information regarding Vorapaxar Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Vorapaxar | |
aaa5382e401cb450ba87064280e35ab849ddb28c | wikidoc | Wada test | Wada test
The Wada test, also known as the "intracarotid sodium amobarbital procedure" (ISAP), is used to establish which cerebral functions are localized to which hemisphere.
# Method
The test is conducted with the patient awake. Essentially, a barbiturate (which is usually sodium amobarbital) is introduced into one of the internal carotid arteries via a cannula or intra-arterial catheter from the femoral artery. The drug is injected into one hemisphere at a time. The effect is to shut down any language and/or memory function in that hemisphere in order to evaluate the other hemisphere ("half of the brain"). Then the patient is engaged in a series of language and memory related tests. The memory is evaluated by showing a series of items or pictures to the patient so that within a few minutes as soon as the effect of the medication is dissipated, the ability to recall can be tested.
There is currently great variability in the processes used to administer the test, and so it is difficult to compare results from one patient to the other.
# Uses
The test is usually performed prior to ablative surgery for epilepsy and sometimes prior to tumor resection. The aim is to determine which side of the brain is responsible for certain vital cognitive functions, namely speech and memory. The risk of damaging such structures during surgery can then be assessed, and the need for awake craniotomies can be determined as well.
The Wada test has several interesting side-effects. Drastic personality changes are rarely noted, but disinhibition is common. Also, contralateral hemiplegia, hemineglect and shivering are often seen. During one injection, typically the left hemisphere, the patient will have impaired speech or be completely unable to express or understand language. Although the patient may not be able to talk, sometimes their ability to sing is preserved. This is because music and singing utilizes a different part of your brain than speech and language. Most people with aphasia are able to sing, and even learn new songs (as in the case of Cesero Rota, klawans, 2002).Recovery from the anesthesia is rapid, and EEG recordings and distal grip strength are used to determine when the medication has worn off. Generally, recovery of speech is dysphasic (contains errors in speech or comprehension) after a dominant hemisphere injection. Although generally considered a safe procedure, there are at least minimal risks associated with the angiography procedure used to guide the catheter to the internal carotid artery. As such, efforts to utilize non-invasive means to determine language and memory laterality (e.g. fMRI) are being researched.
# History
The Wada test is named after Canadian neurologist Juhn A. Wada, of the University of British Columbia. He developed the test while a medical resident in Japan just after World War II, when he was receiving training in neurosurgery. Recognizing that there was no available test for cerebral dominance for speech, Wada developed the carotid amytal test. He published the initial description in 1949, in Japanese. During later training at the Montreal Neurological Institute, he introduced the test to the English-speaking world. | Wada test
The Wada test, also known as the "intracarotid sodium amobarbital procedure" (ISAP), is used to establish which cerebral functions are localized to which hemisphere.
# Method
The test is conducted with the patient awake. Essentially, a barbiturate (which is usually sodium amobarbital) is introduced into one of the internal carotid arteries via a cannula or intra-arterial catheter from the femoral artery. The drug is injected into one hemisphere at a time. The effect is to shut down any language and/or memory function in that hemisphere in order to evaluate the other hemisphere ("half of the brain"). Then the patient is engaged in a series of language and memory related tests. The memory is evaluated by showing a series of items or pictures to the patient so that within a few minutes as soon as the effect of the medication is dissipated, the ability to recall can be tested.
There is currently great variability in the processes used to administer the test, and so it is difficult to compare results from one patient to the other.[1]
# Uses
The test is usually performed prior to ablative surgery for epilepsy and sometimes prior to tumor resection. The aim is to determine which side of the brain is responsible for certain vital cognitive functions, namely speech and memory. The risk of damaging such structures during surgery can then be assessed, and the need for awake craniotomies can be determined as well.
The Wada test has several interesting side-effects. Drastic personality changes are rarely noted, but disinhibition is common. Also, contralateral hemiplegia, hemineglect and shivering are often seen. During one injection, typically the left hemisphere, the patient will have impaired speech or be completely unable to express or understand language. Although the patient may not be able to talk, sometimes their ability to sing is preserved. This is because music and singing utilizes a different part of your brain than speech and language. Most people with aphasia are able to sing, and even learn new songs (as in the case of Cesero Rota, klawans, 2002).Recovery from the anesthesia is rapid, and EEG recordings and distal grip strength are used to determine when the medication has worn off. Generally, recovery of speech is dysphasic (contains errors in speech or comprehension) after a dominant hemisphere injection. Although generally considered a safe procedure, there are at least minimal risks associated with the angiography procedure used to guide the catheter to the internal carotid artery. As such, efforts to utilize non-invasive means to determine language and memory laterality (e.g. fMRI) are being researched.
# History
The Wada test is named after Canadian neurologist Juhn A. Wada, of the University of British Columbia.[2][3] He developed the test while a medical resident in Japan just after World War II, when he was receiving training in neurosurgery. Recognizing that there was no available test for cerebral dominance for speech, Wada developed the carotid amytal test. He published the initial description in 1949, in Japanese. During later training at the Montreal Neurological Institute, he introduced the test to the English-speaking world. | https://www.wikidoc.org/index.php/Wada_test | |
67d735bed687e0d45642bbda3d833c4a96beef22 | wikidoc | Water gas | Water gas
Water gas is a synthesis gas, containing carbon monoxide and hydrogen. It is a useful product but requires careful handling because of the risk of carbon monoxide poisoning. The gas is made by passing steam over red-hot coke:
The reaction is endothermic so the coke must be continually re-heated to keep the reaction going. This was usually done by alternating the steam stream with an air stream.
# Variations
Water gas had a lower calorific value than coal gas so the calorific value was often boosted by passing the gas through a heated retort into which oil was sprayed. The resulting mixed gas was called carburetted water gas.
Semi-water gas is a mixture of water gas and producer gas made by passing a mixture of air and steam through heated coke. The heat generated when producer gas is formed keeps the temperature of the coke high enough to allow water gas to be formed.
Pure hydrogen can be obtained from water gas by using the Water gas shift reaction. | Water gas
Water gas is a synthesis gas, containing carbon monoxide and hydrogen. It is a useful product but requires careful handling because of the risk of carbon monoxide poisoning. The gas is made by passing steam over red-hot coke:
The reaction is endothermic so the coke must be continually re-heated to keep the reaction going. This was usually done by alternating the steam stream with an air stream.
# Variations
Water gas had a lower calorific value than coal gas so the calorific value was often boosted by passing the gas through a heated retort into which oil was sprayed. The resulting mixed gas was called carburetted water gas.
Semi-water gas is a mixture of water gas and producer gas made by passing a mixture of air and steam through heated coke. The heat generated when producer gas is formed keeps the temperature of the coke high enough to allow water gas to be formed.
Pure hydrogen can be obtained from water gas by using the Water gas shift reaction. | https://www.wikidoc.org/index.php/Water_gas | |
06550397f8910a3b2b9e0b2580c98035ea905272 | wikidoc | Weak acid | Weak acid
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
A weak acid is an acid that does not ionize in a solution to a significant extent; that is, if the acid was represented by the general formula HA, then in aqueous solution a significant amount of undissociated HA still remains. Weak acids in water dissociate as
\mathrm{ HA_{(aq)} \, \leftrightarrow \, H^+\,_{(aq)} +\, A^-\,_{(aq)} }.
The equilibrium concentrations of reactants and products are related by the Acidity constant expression, (Ka):
\mathrm{ K_a\, =\, \frac {}{} }
The greater the value of Ka, the more the formation of H+ is favored, and the lower the pH of the solution. The Ka of weak acids varies between 1.8×10-16 and 55.5. Acids with a Ka less than 1.8×10-16 are weaker acids than water. Acids with a Ka of greater than 55.5 are strong acids and almost totally dissociate when dissolved in water. The vast majority of acids are weak acids. Organic acids are a large subset of weak acids. Common household weak organic acids include acetic acid found in vinegar, and citric acid found in lemons; weak mineral acids include boric acid used as an antiseptic and eyewash and phosphoric acid that appears in many soft drinks. | Weak acid
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
A weak acid is an acid that does not ionize in a solution to a significant extent; that is, if the acid was represented by the general formula HA, then in aqueous solution a significant amount of undissociated HA still remains. Weak acids in water dissociate as
<math>\mathrm{ HA_{(aq)} \, \leftrightarrow \, H^+\,_{(aq)} +\, A^-\,_{(aq)} }.</math>
The equilibrium concentrations of reactants and products are related by the Acidity constant expression, (Ka):
<math>\mathrm{ K_a\, =\, \frac {[H^+\,][A^-\,]}{[HA]} }</math>
The greater the value of Ka, the more the formation of H+ is favored, and the lower the pH of the solution. The Ka of weak acids varies between 1.8×10-16 and 55.5. Acids with a Ka less than 1.8×10-16 are weaker acids than water. Acids with a Ka of greater than 55.5 are strong acids and almost totally dissociate when dissolved in water. The vast majority of acids are weak acids. Organic acids are a large subset of weak acids. Common household weak organic acids include acetic acid found in vinegar, and citric acid found in lemons; weak mineral acids include boric acid used as an antiseptic and eyewash and phosphoric acid that appears in many soft drinks. | https://www.wikidoc.org/index.php/Weak_acid | |
1bc48d63ee2bdb3cfb5dd8a4ec04ac667d006a7e | wikidoc | Weak base | Weak base
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
In chemistry, a weak base is a chemical base that does not ionize fully in an aqueous solution. As Bronsted-Lowry bases are proton acceptors, a weak base may also be defined as a chemical base in which protonation is incomplete. This results in a relatively low pH level compared to strong bases. Bases range from a pH of greater than 7 (7 is neutral, like pure water) to 14 (though some bases are greater than 14). The pH level has the formula:
Since bases are proton acceptors, the base receives a hydrogen ion from water, H2O, and the remaining H+ concentration in the solution determines the pH level. Weak bases will have a higher H+ concentration because they are less completely protonated than stronger bases and, therefore, more hydrogen ions remain in the solution. If you plug in a higher H+ concentration into the formula, a low pH level results. However, the pH level of bases is usually calculated using the OH- concentration to find the pOH level first. This is done because the H+ concentration is not a part of the reaction, while the OH- concentration is.
By multiplying a conjugate acid (such as NH4+) and a conjugate base (such as NH3) the following is given:
Since {K_w} = then, K_a \times K_b = K_w
By taking logarithms of both sides of the equation, the following is reached:
Finally, multipying throughout the equation by -1, the equation turns into:
After acquiring pOH from the previous pOH formula, pH can be calculated using the formula pH = pKw - pOH where pKw = 14.00.
Weak bases exist in chemical equilibrium much in the same way as weak acids do, with a Base Ionization Constant (Kb) (or the Base Dissociation Constant) indicating the strength of the base. For example, when ammonia is put in water, the following equilibrium is set up:
Bases that have a large Kb will ionize more completely and are thus stronger bases. As stated above, the pH of the solution depends on the H+ concentration, which is related to the OH- concentration by the Ionic Constant of water (Kw = 1.0x10-14) (See article Self-ionization of water.) A strong base has a lower H+ concentration because they are fully protonated and less hydrogen ions remain in the solution. A lower H+ concentration also means a higher OH- concentration and therefore, a larger Kb.
NaOH (s) (sodium hydroxide) is a stronger base than (CH3CH2)2NH (l) (diethylamine) which is a stronger base than NH3 (g) (ammonia). As the bases get weaker, the smaller the Kb values become. The pie-chart representation is as follows:
- purple areas represent the fraction of OH- ions formed
- red areas represent the cation remaining after ionization
- yellow areas represent dissolved but non-ionized molecules.
# Percentage protonated
As seen above, the strength of a base depends primarily on the pH level. To help describe the strengths of weak bases, it is helpful to know the percentage protonated-the percentage of base molecules that have been protonated. A lower percentage will correspond with a lower pH level because both numbers result from the amount of protonation. A weak base is less protonated, leading to a lower pH and a lower percentage protonated.
The typical proton transfer equilibrium appears as such:
B represents the base.
In this formula, initial is the initial molar concentration of the base, assuming that no protonation has occurred.
# A typical pH problem
Calculate the pH and percentage protonation of a .20 M aqueous solution of pyridine, C5H5N. The Kb for C5H5N is 1.8 x 10-9.
First, write the proton transfer equilibrium:
The equilibrium table, with all concentrations in moles per liter, is
This means .0095% of the pyridine is in the protonated form of C5H6N+.
# Examples
- Alanine, C3H5O2NH2
- Ammonia, NH3
- Methylamine, CH3NH2
- Pyridine, C5H5N
Other weak bases are essentially any bases not on the list of strong bases. | Weak base
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
In chemistry, a weak base is a chemical base that does not ionize fully in an aqueous solution. As Bronsted-Lowry bases are proton acceptors, a weak base may also be defined as a chemical base in which protonation is incomplete. This results in a relatively low pH level compared to strong bases. Bases range from a pH of greater than 7 (7 is neutral, like pure water) to 14 (though some bases are greater than 14). The pH level has the formula:
Since bases are proton acceptors, the base receives a hydrogen ion from water, H2O, and the remaining H+ concentration in the solution determines the pH level. Weak bases will have a higher H+ concentration because they are less completely protonated than stronger bases and, therefore, more hydrogen ions remain in the solution. If you plug in a higher H+ concentration into the formula, a low pH level results. However, the pH level of bases is usually calculated using the OH- concentration to find the pOH level first. This is done because the H+ concentration is not a part of the reaction, while the OH- concentration is.
By multiplying a conjugate acid (such as NH4+) and a conjugate base (such as NH3) the following is given:
Since <math>{K_w} = [H_3O^+][OH^-]</math> then, <math>K_a \times K_b = K_w</math>
By taking logarithms of both sides of the equation, the following is reached:
Finally, multipying throughout the equation by -1, the equation turns into:
After acquiring pOH from the previous pOH formula, pH can be calculated using the formula pH = pKw - pOH where pKw = 14.00.
Weak bases exist in chemical equilibrium much in the same way as weak acids do, with a Base Ionization Constant (Kb) (or the Base Dissociation Constant) indicating the strength of the base. For example, when ammonia is put in water, the following equilibrium is set up:
Bases that have a large Kb will ionize more completely and are thus stronger bases. As stated above, the pH of the solution depends on the H+ concentration, which is related to the OH- concentration by the Ionic Constant of water (Kw = 1.0x10-14) (See article Self-ionization of water.) A strong base has a lower H+ concentration because they are fully protonated and less hydrogen ions remain in the solution. A lower H+ concentration also means a higher OH- concentration and therefore, a larger Kb.
NaOH (s) (sodium hydroxide) is a stronger base than (CH3CH2)2NH (l) (diethylamine) which is a stronger base than NH3 (g) (ammonia). As the bases get weaker, the smaller the Kb values become. The pie-chart representation is as follows:
- purple areas represent the fraction of OH- ions formed
- red areas represent the cation remaining after ionization
- yellow areas represent dissolved but non-ionized molecules.
# Percentage protonated
As seen above, the strength of a base depends primarily on the pH level. To help describe the strengths of weak bases, it is helpful to know the percentage protonated-the percentage of base molecules that have been protonated. A lower percentage will correspond with a lower pH level because both numbers result from the amount of protonation. A weak base is less protonated, leading to a lower pH and a lower percentage protonated.
The typical proton transfer equilibrium appears as such:
B represents the base.
In this formula, [B]initial is the initial molar concentration of the base, assuming that no protonation has occurred.
# A typical pH problem
Calculate the pH and percentage protonation of a .20 M aqueous solution of pyridine, C5H5N. The Kb for C5H5N is 1.8 x 10-9.
First, write the proton transfer equilibrium:
The equilibrium table, with all concentrations in moles per liter, is
This means .0095% of the pyridine is in the protonated form of C5H6N+.
# Examples
- Alanine, C3H5O2NH2
- Ammonia, NH3
- Methylamine, CH3NH2
- Pyridine, C5H5N
Other weak bases are essentially any bases not on the list of strong bases. | https://www.wikidoc.org/index.php/Weak_base | |
97c2a089b278e68ceb89eca3cc80460e6a5357ca | wikidoc | White Ash | White Ash
The White Ash (also called Biltmore ash, Biltmore white ash or Cane Ash) (Fraxinus americana) is one of the largest of the ash genus Fraxinus, growing to 35 m (115 ft) tall. It is native to eastern North American hardwood forests, found in mesophytic forests from Quebec to northern Florida. The wood is white, strong, and straight-grained. The name White Ash apparently derives from the glaucous undersides of the leaves. The leaves are 20-30 cm long, pinnately compound with 7 (occasionally 5 or 9) leaflets, 6-13 cm (2-5 in) long. They turn yellow, red, or purple in the fall. Cultivars, which have superior fall color, include 'Autumn Applause' and 'Autumn Purple'.
This tree, like all ashes, is dioecious, with male and female flowers being born on separate trees. Flowering occurs in early spring after 30-55 growing degree days. The fruit when fully formed is a samara 3-5 cm long, the seed 1.5-2 cm long with a pale brown wing 1.5-3 cm long, and can be blown a good distance from the parent tree.
White ash trees have an average natural lifespan of 100 years.
It is the timber of choice for production of baseball bats and tool handles. The wood is also favorable for furniture and flooring. White Ash is also a food plant for the larvae of several Lepidoptera species - see List of Lepidoptera which feed on Ashes.
The White Ash is similar in appearance to the Green Ash, making identification difficult. The lower sides of the leaves of White Ash are lighter-colored than their upper sides, and the outer surface of the twigs of White Ash may be flaky or peeling. Green Ash leaves are similar in color on upper and lower sides, and twigs are smoother. Also, these species tend to occupy different habitat niches, with White Ash found in moist upland sites and Green Ash in wet forests of floodplains or swamps, although there is some overlap in habitat distribution. | White Ash
The White Ash (also called Biltmore ash, Biltmore white ash or Cane Ash) (Fraxinus americana) is one of the largest of the ash genus Fraxinus, growing to 35 m (115 ft) tall. It is native to eastern North American hardwood forests, found in mesophytic forests from Quebec to northern Florida. The wood is white, strong, and straight-grained. The name White Ash apparently derives from the glaucous undersides of the leaves. The leaves are 20-30 cm long, pinnately compound with 7 (occasionally 5 or 9) leaflets, 6-13 cm (2-5 in) long. They turn yellow, red, or purple in the fall. Cultivars, which have superior fall color, include 'Autumn Applause' and 'Autumn Purple'.
This tree, like all ashes, is dioecious, with male and female flowers being born on separate trees. Flowering occurs in early spring after 30-55 growing degree days. The fruit when fully formed is a samara 3-5 cm long, the seed 1.5-2 cm long with a pale brown wing 1.5-3 cm long, and can be blown a good distance from the parent tree.
White ash trees have an average natural lifespan of 100 years.
It is the timber of choice for production of baseball bats and tool handles. The wood is also favorable for furniture and flooring. White Ash is also a food plant for the larvae of several Lepidoptera species - see List of Lepidoptera which feed on Ashes.
The White Ash is similar in appearance to the Green Ash, making identification difficult. The lower sides of the leaves of White Ash are lighter-colored than their upper sides, and the outer surface of the twigs of White Ash may be flaky or peeling. Green Ash leaves are similar in color on upper and lower sides, and twigs are smoother. Also, these species tend to occupy different habitat niches, with White Ash found in moist upland sites and Green Ash in wet forests of floodplains or swamps, although there is some overlap in habitat distribution. | https://www.wikidoc.org/index.php/White_Ash | |
ed7ec6a764ad405bdabc1e042406eb87692d8ea4 | wikidoc | White tea | White tea
White tea is tea manufactured by a process that uses relatively low heat and no rolling. The formative stage is an extended period of withering, during which enzymatic reactions progress under the right temperature, humidity and airflow. The key is to get the fresh leaves to mature properly with minimal oxidation. White tea usually contains buds and young tea leaves, which have been found to contain lower levels of caffeine than older leaves, suggesting that the caffeine content of some white teas may be slightly lower than that of green teas.
White tea is a specialty of the Chinese province Fujian.
The leaves come from a number of varieties of tea cultivars. The most popular are Da Bai (Large White), Xiao Bai (Small White), Narcissus and Chaicha bushes. According to the different standards of picking and selection, white teas can be classified into a number of grades, further described in the varieties section.
# History
In hard times, very poor Chinese people would serve guests boiled water if they could not afford tea. Host and guest would refer to the water as "white tea" and act as if the tradition of serving guests tea had been carried out as usual. This usage is related to plain boiled water being called "white boiled water" in Chinese.
# Varieties of white tea
## Chinese white teas
- Bai Hao Yinzhen (Silver needle): The highest grade of the Bai Hao Yinzhen should be fleshy, bright colored and covered with tiny white hairs. The shape should be very uniform, with no stems or leaves. The very best Yinzhen are picked between March 15 and April 10 when it is not raining and only using undamaged and unopened buds. Fujian Province, China.
- Bai Mu Dan (White Peony): A grade down from Bai Hao Yinzhen tea, incorporating the bud and two leaves which should be covered with a fine, silvery-white down. From Fujian Province, China. (Sometimes spelled Pai Mu Tan.)
- Gong Mei (Tribute Eyebrow): The third grade of white tea, the production uses leaves from the Xiao Bai or "small white" tea trees.
- Shou Mei (Noble, Long Life Eyebrow): A fruity, furry white tea that is a chaotic mix of tips and upper leaf, it has a stronger flavor than other white teas, similar to Oolong. It is the fourth grade of white tea and is plucked later than Bai Mu Dan hence the tea may be darker in color. From Fujian Province and Guangxi Province in China
## Other white teas
- Ceylon White: A highly prized tea grown in Sri Lanka. Ceylon White tea can fetch much higher prices than black tea from the area. The tea has a very light liquoring with notes of pine and honey and a golden coppery infusion.
- Darjeeling White: It has a delicate aroma and brews to a pale golden cup with a mellow taste and a hint of sweetness. This tea is particularly fluffy and light. A tea from Darjeeling, India.
- Assam White: White tea production in the Assam region is rare. Much lighter in body than the traditional black teas, a white Assam yields a refined infusion that is naturally sweet with a distinct malty character.
- White Puerh Tea: Harvested in the spring from plantations found high on remote mountain peaks of Yunnan Province, China. Incredibly labor intensive with each step processed by hand, these luxury whites are wonderfully rich in fragrance, and possess an alluring, sweet nectar-like quality.
# Potential health benefits
## White tea compared to green tea
A study at Pace University in 2004 showed white tea had more anti-viral and anti-bacterial qualities than green tea.
White tea contains higher catechin levels than green tea due to its lack of processing. Catechin concentration is greatest in fresh, unbroken and unfermented tea leaves. Furthermore, one study examining the composition of brewed green and white teas found that white tea contained more gallic acid, theobromine, and caffeine.
White tea contains less fluoride than green tea, since it is made from young leaves only.
# Brewing
Generally, around 2 to 2.5 grams of tea per 200 ml (6 ounces) of water, or about 1.5 teaspoons of white tea per cup, should be used. White teas should be prepared with 80°C (180°F) water (not boiling) and steeped for 2 to 3 minutes. Many tea graders, however, choose to brew this tea for much longer, as long as 10 minutes on the first infusion, to allow the delicate aromas to develop. Finer teas expose more flavor and complexity with no bitterness. Lower grade teas do not always stand this test well and develop bitter flavors or tannins. On successive brews (white teas produce three very good brews and a fourth that is passable), extend the time by several minutes per. The third brew may require as long as 15 minutes to develop well. Temperature is crucial: if it is too hot, the brew will be bitter and the finer flavors will be overpowered. | White tea
White tea is tea manufactured by a process that uses relatively low heat and no rolling. The formative stage is an extended period of withering, during which enzymatic reactions progress under the right temperature, humidity and airflow. The key is to get the fresh leaves to mature properly with minimal oxidation.[1] White tea usually contains buds and young tea leaves, which have been found to contain lower levels of caffeine than older leaves, suggesting that the caffeine content of some white teas may be slightly lower than that of green teas. [2]
White tea is a specialty of the Chinese province Fujian.[3]
The leaves come from a number of varieties of tea cultivars. The most popular are Da Bai (Large White), Xiao Bai (Small White), Narcissus and Chaicha bushes. According to the different standards of picking and selection, white teas can be classified into a number of grades, further described in the varieties section.
# History
Template:Seealso
In hard times, very poor Chinese people would serve guests boiled water if they could not afford tea. Host and guest would refer to the water as "white tea" and act as if the tradition of serving guests tea had been carried out as usual. This usage is related to plain boiled water being called "white boiled water" in Chinese.[4]
# Varieties of white tea
## Chinese white teas
- Bai Hao Yinzhen (Silver needle): The highest grade of the Bai Hao Yinzhen should be fleshy, bright colored and covered with tiny white hairs. The shape should be very uniform, with no stems or leaves. The very best Yinzhen are picked between March 15 and April 10 when it is not raining and only using undamaged and unopened buds. Fujian Province, China.
- Bai Mu Dan (White Peony): A grade down from Bai Hao Yinzhen tea, incorporating the bud and two leaves which should be covered with a fine, silvery-white down. From Fujian Province, China. (Sometimes spelled Pai Mu Tan.)
- Gong Mei (Tribute Eyebrow): The third grade of white tea, the production uses leaves from the Xiao Bai or "small white" tea trees.
- Shou Mei (Noble, Long Life Eyebrow): A fruity, furry white tea that is a chaotic mix of tips and upper leaf, it has a stronger flavor than other white teas, similar to Oolong. It is the fourth grade of white tea and is plucked later than Bai Mu Dan hence the tea may be darker in color. From Fujian Province and Guangxi Province in China
## Other white teas
- Ceylon White: A highly prized tea grown in Sri Lanka. Ceylon White tea can fetch much higher prices than black tea from the area. The tea has a very light liquoring with notes of pine and honey and a golden coppery infusion.
- Darjeeling White: It has a delicate aroma and brews to a pale golden cup with a mellow taste and a hint of sweetness. This tea is particularly fluffy and light. A tea from Darjeeling, India.
- Assam White: White tea production in the Assam region is rare. Much lighter in body than the traditional black teas, a white Assam yields a refined infusion that is naturally sweet with a distinct malty character.
- White Puerh Tea: Harvested in the spring from plantations found high on remote mountain peaks of Yunnan Province, China. Incredibly labor intensive with each step processed by hand, these luxury whites are wonderfully rich in fragrance, and possess an alluring, sweet nectar-like quality.[5]
# Potential health benefits
Template:Seealso
## White tea compared to green tea
A study at Pace University in 2004 showed white tea had more anti-viral and anti-bacterial qualities than green tea. [6]
White tea contains higher catechin levels than green tea due to its lack of processing. [7] Catechin concentration is greatest in fresh, unbroken and unfermented tea leaves. [8] Furthermore, one study examining the composition of brewed green and white teas found that white tea contained more gallic acid, theobromine, and caffeine. [9]
White tea contains less fluoride than green tea, since it is made from young leaves only. [10]
# Brewing
Generally, around 2 to 2.5 grams of tea per 200 ml (6 ounces) of water, or about 1.5 teaspoons of white tea per cup, should be used. White teas should be prepared with 80°C (180°F) water (not boiling) and steeped for 2 to 3 minutes. Many tea graders, however, choose to brew this tea for much longer, as long as 10 minutes on the first infusion, to allow the delicate aromas to develop. Finer teas expose more flavor and complexity with no bitterness. Lower grade teas do not always stand this test well and develop bitter flavors or tannins. On successive brews (white teas produce three very good brews and a fourth that is passable), extend the time by several minutes per. The third brew may require as long as 15 minutes to develop well. Temperature is crucial: if it is too hot, the brew will be bitter and the finer flavors will be overpowered.[11]
Template:Teas | https://www.wikidoc.org/index.php/White_tea |
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