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PMID:26445 | Characterization of receptors mediating 5-hydroxytryptamine- and catecholamine-induced platelet aggregation, assessed by the actions of alpha- and beta-blockers, butyrophenones, 5-HT antagonists and chlorpromazine. | 1 Blood platelets from normal human volunteers were isolated and aggregated in vitro with 5-hydroxytryptamine (5-HT), noradrenaline (NA), dopamine and N-dimethyldopamine (DMDA). 2 The effects of 5-HT antagonists, alpha- and beta-adrenoceptor blocking agents, butyrophenones and chlorpromazine upon aggregation induced by the four amines were investigated. 3 Only the the 5-HT antagonists, chlorpromazine and spiroperidol were potent inhibitors of 5-HT-induced aggregation, and only phentolamine was a potent inhibitor of the catecholamine-induced aggregation. 4 Evidence was obtained for two populations of receptors, one for 5-HT and one for the three catecholamines. | Characterization of receptors mediating 5-hydroxytryptamine- and catecholamine-induced platelet aggregation, assessed by the actions of alpha- and beta-blockers, butyrophenones, 5-HT antagonists and chlorpromazine. 1 Blood platelets from normal human volunteers were isolated and aggregated in vitro with 5-hydroxytryptamine (5-HT), noradrenaline (NA), dopamine and N-dimethyldopamine (DMDA). 2 The effects of 5-HT antagonists, alpha- and beta-adrenoceptor blocking agents, butyrophenones and chlorpromazine upon aggregation induced by the four amines were investigated. 3 Only the the 5-HT antagonists, chlorpromazine and spiroperidol were potent inhibitors of 5-HT-induced aggregation, and only phentolamine was a potent inhibitor of the catecholamine-induced aggregation. 4 Evidence was obtained for two populations of receptors, one for 5-HT and one for the three catecholamines. | [
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PMID:26446 | Biochemical evidence for the dual action of labetalol on alpha- and beta-adrenoceptors. | 1 Labetalol (AH 5158A) inhibited the adrenaline-stimulated adenylate cyclase activity of rat liver and heart. This drug had no effect on basal or guanosine triphosphate (GTP)-activated adenylate cyclase activities. 2 Labetalol displaced the binding of the specific ligands [3H]-dihydroergocryptine and (-)-[3H]-dihydroalprenolol from their respective alpha and beta-adrenoceptors in rat heart and liver. The affinity of labetalol was 10 fold higher for the beta- than for the alpha-adrenoceptor. It appeared to be 10 to 100 times less potent than phentolamine in blocking alpha-adrenoceptors and 5 to 10 times less potent than propranolol in blocking beta-receptors. 3 It is concluded that labetalol exerts its dual alpha- and beta-antagonism by acting directly on the plasma membranes, where it binds competitively to alpha- and beta-adrenoceptors. | Biochemical evidence for the dual action of labetalol on alpha- and beta-adrenoceptors. 1 Labetalol (AH 5158A) inhibited the adrenaline-stimulated adenylate cyclase activity of rat liver and heart. This drug had no effect on basal or guanosine triphosphate (GTP)-activated adenylate cyclase activities. 2 Labetalol displaced the binding of the specific ligands [3H]-dihydroergocryptine and (-)-[3H]-dihydroalprenolol from their respective alpha and beta-adrenoceptors in rat heart and liver. The affinity of labetalol was 10 fold higher for the beta- than for the alpha-adrenoceptor. It appeared to be 10 to 100 times less potent than phentolamine in blocking alpha-adrenoceptors and 5 to 10 times less potent than propranolol in blocking beta-receptors. 3 It is concluded that labetalol exerts its dual alpha- and beta-antagonism by acting directly on the plasma membranes, where it binds competitively to alpha- and beta-adrenoceptors. | [
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PMID:26447 | The treatment of frigidity: a comparative study of group and individual desensitization. | Forty patients took part in this study. Twenty patients treated by group desensitization were compared with twenty treated by individual desensitization. Group desensitization appeared the more effective treatment if outcome was measured on the patients' self-rating scale, but the less effective if outcome was measured by the sexual interest questionnaire. Of the two, the group method took longer to administer, but more patients treated in this way completed the course of treatment. | The treatment of frigidity: a comparative study of group and individual desensitization. Forty patients took part in this study. Twenty patients treated by group desensitization were compared with twenty treated by individual desensitization. Group desensitization appeared the more effective treatment if outcome was measured on the patients' self-rating scale, but the less effective if outcome was measured by the sexual interest questionnaire. Of the two, the group method took longer to administer, but more patients treated in this way completed the course of treatment. | [
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PMID:26450 | Antibiotic resistance in Streptococcus pneumoniae and Haemophilus influenzae. Report of a study group on bacterial resistance. | Twenty laboratories in England and Scotland took part in 1977 in a survey of antibiotic resistance in Streptococcus pneumoniae and Haemophilus influenzae. In Str pneumoniae 59 (6.8%) of the 866 strains studied were resistant to tetracycline and three to chloramphenicol, and one strain showed a decreased susceptibility to penicillin. The prevalence of resistance to tetracycline was lower than that found in a similar study performed in 1975. Nine hundred and fifty-two strains of H influenzae were examined: 15 (1.6%) were resistant to ampicillin (all were beta-lactamase producers) and 26 (2.7%) to tetracycline. Only two strains were resistant to chloramphenicol and two to trimethoprim. Sixty-three H influenzae strains were capsulated. Thirty-four of these were of Pittman type b, and antibiotic resistance, particularly to ampicillin, was more common in these than in other serotypes or non-typable strains. Some variation was seen in the resistance rate of both H influenzae and Str pneumoniae to tetracycline in strains from different centres, but too few were isolated to assess whether this represented a true geographical difference. | Antibiotic resistance in Streptococcus pneumoniae and Haemophilus influenzae. Report of a study group on bacterial resistance. Twenty laboratories in England and Scotland took part in 1977 in a survey of antibiotic resistance in Streptococcus pneumoniae and Haemophilus influenzae. In Str pneumoniae 59 (6.8%) of the 866 strains studied were resistant to tetracycline and three to chloramphenicol, and one strain showed a decreased susceptibility to penicillin. The prevalence of resistance to tetracycline was lower than that found in a similar study performed in 1975. Nine hundred and fifty-two strains of H influenzae were examined: 15 (1.6%) were resistant to ampicillin (all were beta-lactamase producers) and 26 (2.7%) to tetracycline. Only two strains were resistant to chloramphenicol and two to trimethoprim. Sixty-three H influenzae strains were capsulated. Thirty-four of these were of Pittman type b, and antibiotic resistance, particularly to ampicillin, was more common in these than in other serotypes or non-typable strains. Some variation was seen in the resistance rate of both H influenzae and Str pneumoniae to tetracycline in strains from different centres, but too few were isolated to assess whether this represented a true geographical difference. | [
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PMID:26452 | Recurrent genital candidosis in women and the effect of intermittent prophylactic treatment. | A study of clotrimazole for the treatment of recurrent genital candidosis unexpectedly showed that symptoms and infection can be dissociated. The aim of the study was to see if intermittent antifungal treatment would reduce symptoms in women constantly distressed by recurrent genital candidosis. Forty women seriously affected by the condition were initially given oral and local antifungal treatment. When the patients were symptom-free and the vagina was free of yeasts, they were entered into a double-blind clinical trial and were treated prophylactically for four months with either intermittent clotrimazole pessaries and cream or a placebo. The prophylactic treatment kept symptoms below a critical level but did not affect the return of the yeasts to the vagina. This dissociation between symptoms and vaginal yeasts was unexpected. Rectal yeast carriage was unaffected by prophylactic vaginal treatment. Male contacts and patients both showed a high incidence of non-specific genital infection. This association has seldom been reported. A few patients cultured yeasts from their homes but this environment was not considered a major source of reinfection. The vaginal pH did not appear to be altered by the presence of yeasts. The results of the study suggested that symptoms in women with recurrent genital candidosis were not caused by yeasts alone, and possibly the reason for recurrences might lie not in constant reinfection by yeasts, but in failure to recognise and remove a primary underlying factor, perhaps infection with other sexually transmitted agents. The question of a synergistic action between yeasts and other organisms is discussed. | Recurrent genital candidosis in women and the effect of intermittent prophylactic treatment. A study of clotrimazole for the treatment of recurrent genital candidosis unexpectedly showed that symptoms and infection can be dissociated. The aim of the study was to see if intermittent antifungal treatment would reduce symptoms in women constantly distressed by recurrent genital candidosis. Forty women seriously affected by the condition were initially given oral and local antifungal treatment. When the patients were symptom-free and the vagina was free of yeasts, they were entered into a double-blind clinical trial and were treated prophylactically for four months with either intermittent clotrimazole pessaries and cream or a placebo. The prophylactic treatment kept symptoms below a critical level but did not affect the return of the yeasts to the vagina. This dissociation between symptoms and vaginal yeasts was unexpected. Rectal yeast carriage was unaffected by prophylactic vaginal treatment. Male contacts and patients both showed a high incidence of non-specific genital infection. This association has seldom been reported. A few patients cultured yeasts from their homes but this environment was not considered a major source of reinfection. The vaginal pH did not appear to be altered by the presence of yeasts. The results of the study suggested that symptoms in women with recurrent genital candidosis were not caused by yeasts alone, and possibly the reason for recurrences might lie not in constant reinfection by yeasts, but in failure to recognise and remove a primary underlying factor, perhaps infection with other sexually transmitted agents. The question of a synergistic action between yeasts and other organisms is discussed. | [
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PMID:26455 | [Nycthemeral plasma and testicular androgen contents in guinea pigs at puberty]. | A study based upon transversal sampling involving 13 series of 7 animals each does not show a significant circadian rhythm of testosterone and delta4 androstenedione concentrations in the plasma and testis of the guinea-pig at the age of puberty. | [Nycthemeral plasma and testicular androgen contents in guinea pigs at puberty]. A study based upon transversal sampling involving 13 series of 7 animals each does not show a significant circadian rhythm of testosterone and delta4 androstenedione concentrations in the plasma and testis of the guinea-pig at the age of puberty. | [
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PMID:26456 | Energy-driven uptake of humic acids by Aspergillus niger. | The uptake of humic acids by mycelia of Aspergillus niger was demonstrated to be energy-dependent with a sensitivity to sodium azide and to 2,4-dinitrophenol. Greater uptake of humic acids by submerged mycelium occurred at pH 3.0 and at 32 degrees C. The rate of uptake was influenced by the concentration of humic acids with an apparent Km of 0.2 grams/ml and with a Vmax of 0.13 mg humic acids per gram mycelial dry weight.10 min-1. In the absence of added energy source, Vmax of 0.05 mg humic acids per gram mycelial dry wt.10 min-1 was obtained; however, the affinity for humic acids by this uptake system was the same as for the energy-driven process. Apparent binding of humic acids to cell structures was indicated because only 41.8% of the humic acids taken up by the energy-dependent system could be recovered. | Energy-driven uptake of humic acids by Aspergillus niger. The uptake of humic acids by mycelia of Aspergillus niger was demonstrated to be energy-dependent with a sensitivity to sodium azide and to 2,4-dinitrophenol. Greater uptake of humic acids by submerged mycelium occurred at pH 3.0 and at 32 degrees C. The rate of uptake was influenced by the concentration of humic acids with an apparent Km of 0.2 grams/ml and with a Vmax of 0.13 mg humic acids per gram mycelial dry weight.10 min-1. In the absence of added energy source, Vmax of 0.05 mg humic acids per gram mycelial dry wt.10 min-1 was obtained; however, the affinity for humic acids by this uptake system was the same as for the energy-driven process. Apparent binding of humic acids to cell structures was indicated because only 41.8% of the humic acids taken up by the energy-dependent system could be recovered. | [
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PMID:26457 | Induction of autolysis in Bacillus subtilis by ochratoxin A. | Ochratoxin A (OTA) added during the exponential growth phase at a concentration higher than 12 microgram/ml caused autolysis of Bacillus subtilis. Optical density of cultures decreased, and at higher concentrations the cultures became sterile. Optimum OTA-induced lysis was about pH 5. At concentrations below 10 microgram/ml, protein synthesis was inhibited more strongly than RNA synthesis. Cell wall synthesis was also strongly inhibited. A fraction extracted from the lysates had the property of a lysis inhibitor. The relevance of this fraction in respect to autolysis is discussed. | Induction of autolysis in Bacillus subtilis by ochratoxin A. Ochratoxin A (OTA) added during the exponential growth phase at a concentration higher than 12 microgram/ml caused autolysis of Bacillus subtilis. Optical density of cultures decreased, and at higher concentrations the cultures became sterile. Optimum OTA-induced lysis was about pH 5. At concentrations below 10 microgram/ml, protein synthesis was inhibited more strongly than RNA synthesis. Cell wall synthesis was also strongly inhibited. A fraction extracted from the lysates had the property of a lysis inhibitor. The relevance of this fraction in respect to autolysis is discussed. | [
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PMID:26458 | Antifungal properties of 2-alkynoic acids and their methyl esters. | Thirteen 2-alkynoic acids and their methyl esters (C3--C12, C14, C16, and C18) were tested against Aspergillus niger, Trichoderma viride, and Myrothecium verrucaria in Sabouraud dextrose agar at pH 4.0 and 5.6. Toxicity to Candida albicans, Trichophyton mentagrophytes, and Mucro mucedo was determined in the same medium at pH 5.6 and 7.0 in the absence and presence of 10% beef serum. The fungitoxicity of the acids was influenced by chain length, pH of the medium, and absence or presence of adsorbents. The toxicity of the esters was influenced primarily by chain length and to a lesser extent by the pH of the medium and the presence of beef serum. The order of activity of the 2-alkynoic acids is C10=C11=C12 greater than C14=C16 greater than C9 greater than C8 greater than C7. When compared with other fatty acid analogs, the order of fungitoxicity on a weight basis is 2-alkynoic acids greater than 2-alkenoic acids greater than alkanoic acids greater than 2-bromoalkanoic acids greater than 2-fluoroalkanoic acids. There is an inverse relationship between chain length and pKa of the acids, suggesting that partition behavior is a fundamental determinant of fungitoxicity along with the effect of adsorbents. | Antifungal properties of 2-alkynoic acids and their methyl esters. Thirteen 2-alkynoic acids and their methyl esters (C3--C12, C14, C16, and C18) were tested against Aspergillus niger, Trichoderma viride, and Myrothecium verrucaria in Sabouraud dextrose agar at pH 4.0 and 5.6. Toxicity to Candida albicans, Trichophyton mentagrophytes, and Mucro mucedo was determined in the same medium at pH 5.6 and 7.0 in the absence and presence of 10% beef serum. The fungitoxicity of the acids was influenced by chain length, pH of the medium, and absence or presence of adsorbents. The toxicity of the esters was influenced primarily by chain length and to a lesser extent by the pH of the medium and the presence of beef serum. The order of activity of the 2-alkynoic acids is C10=C11=C12 greater than C14=C16 greater than C9 greater than C8 greater than C7. When compared with other fatty acid analogs, the order of fungitoxicity on a weight basis is 2-alkynoic acids greater than 2-alkenoic acids greater than alkanoic acids greater than 2-bromoalkanoic acids greater than 2-fluoroalkanoic acids. There is an inverse relationship between chain length and pKa of the acids, suggesting that partition behavior is a fundamental determinant of fungitoxicity along with the effect of adsorbents. | [
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PMID:26459 | Prescribing of psychoactive drugs for chronically ill elderly patients. | The prescribing of psychoactive drugs for 1431 chronically ill elderly patients being assessed for long-term institutional or community care was surveyed. Psychoactive drugs had been prescribed for about one quarter of the patients; benzodiazepines were the most frequently prescribed group. Judging from the extensive prescribing of flurazepam and chloral hydrate, commonly used hypnotics, the main reason psychoactive drugs were prescribed was to provide night-time sedation. Antidepressants and drugs promoted as useful in improving cognitive function were infrequently prescribed. Commendable prescribing practices included the infrequent use of "cerebral vasodilators" and barbiturates. Questionable prescribing practices included the infrequent use of tricyclic antidepressants in severely depressed patients and the use of tranquilizers in patients described by their attending physician as markedly or extremely withdrawn. | Prescribing of psychoactive drugs for chronically ill elderly patients. The prescribing of psychoactive drugs for 1431 chronically ill elderly patients being assessed for long-term institutional or community care was surveyed. Psychoactive drugs had been prescribed for about one quarter of the patients; benzodiazepines were the most frequently prescribed group. Judging from the extensive prescribing of flurazepam and chloral hydrate, commonly used hypnotics, the main reason psychoactive drugs were prescribed was to provide night-time sedation. Antidepressants and drugs promoted as useful in improving cognitive function were infrequently prescribed. Commendable prescribing practices included the infrequent use of "cerebral vasodilators" and barbiturates. Questionable prescribing practices included the infrequent use of tricyclic antidepressants in severely depressed patients and the use of tranquilizers in patients described by their attending physician as markedly or extremely withdrawn. | [
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PMID:26460 | Clinical pharmacology and therapeutics of benzodiazepines. | Benzodiazepines are among the most commonly prescribed drugs in the world. In contrast to their extensive use, the therapeutic indications and potential of benzodiazepines are limited. All benzodiazepine derivatives available in Canada are similar structurally and in their pharmacologic actions. Few have specific advantages over any others. For example, no benzodiazepine has been shown to be superior to chlordiazepoxide in the treatment of acute anxiety, chronic anxiety neurosis or insomnia. Barbiturates should not be prescribed for these problems since benzodiazepines are just as effective and are safer. Persons more than 70 years old should receive initial doses of benzodiazepines 50% less than those prescribed for younger persons, and individuals with cirrhosis should receive chlordiazepoxide or diazepam in one third the usual dose; oxazepam or lorazepam should be considered for these two groups of patients. Diazepam and chlordiazepoxide should not be given intramuscularly. Benzodiazepines should be prescribed only when clearly indicated and only for the necessary length of time. | Clinical pharmacology and therapeutics of benzodiazepines. Benzodiazepines are among the most commonly prescribed drugs in the world. In contrast to their extensive use, the therapeutic indications and potential of benzodiazepines are limited. All benzodiazepine derivatives available in Canada are similar structurally and in their pharmacologic actions. Few have specific advantages over any others. For example, no benzodiazepine has been shown to be superior to chlordiazepoxide in the treatment of acute anxiety, chronic anxiety neurosis or insomnia. Barbiturates should not be prescribed for these problems since benzodiazepines are just as effective and are safer. Persons more than 70 years old should receive initial doses of benzodiazepines 50% less than those prescribed for younger persons, and individuals with cirrhosis should receive chlordiazepoxide or diazepam in one third the usual dose; oxazepam or lorazepam should be considered for these two groups of patients. Diazepam and chlordiazepoxide should not be given intramuscularly. Benzodiazepines should be prescribed only when clearly indicated and only for the necessary length of time. | [
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PMID:26462 | Heat fractionation and thermotolerance: a review. | A rational approach to the design of clinical protocols combining fractionated hyperthermia plus X-irradiation or hyperthermia plus chemotherapy requires an understanding of the biology of fractionated heat alone. Mammalian cells growing in vitro can dramatically increase their tolerance to thermal damage (i.e., reduce the cellular inactivation rate) after prior heat conditioning. Although the mechanism(s) for this cellular thermotolerance is still unknown, it is apparent that the thermal history, the heat fractionation interval, and the recovery conditions all modify significantly the degree of thermotolerance subsequently exhibited. At the tissue level, the role of cellular thermotolerance is further complicated by host physiological mechanisms. Few data are available on heat fractionation in vivo, and the relative importance of physiological versus cellular effects remains to be defined. | Heat fractionation and thermotolerance: a review. A rational approach to the design of clinical protocols combining fractionated hyperthermia plus X-irradiation or hyperthermia plus chemotherapy requires an understanding of the biology of fractionated heat alone. Mammalian cells growing in vitro can dramatically increase their tolerance to thermal damage (i.e., reduce the cellular inactivation rate) after prior heat conditioning. Although the mechanism(s) for this cellular thermotolerance is still unknown, it is apparent that the thermal history, the heat fractionation interval, and the recovery conditions all modify significantly the degree of thermotolerance subsequently exhibited. At the tissue level, the role of cellular thermotolerance is further complicated by host physiological mechanisms. Few data are available on heat fractionation in vivo, and the relative importance of physiological versus cellular effects remains to be defined. | [
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PMID:26464 | Purification and properties of acid ribonucleases in human serum and leukocytes. | Acid RNase was purified from normal human serum about 2400-fold by chromatography on phosphocellulose and Sephadex G-75 and rechromatography on Sephadex G-75. Assayed with yeast RNA as substrate, the enzyme showed the maximal activity at about pH 6.5 with sodium phosphate buffer. The reaction was activated by Na+, K+, and spermine, but it was not affected greatly by Mg2+, Co2+, and EDTA. Ca2+, Fe2+, Zn2+, and Cu2+ inhibited the reaction. Among the synthetic substrates examined, the enzyme preferentially hydrolyzed pyrimidine nucleotides, with a higher affinity for polycytidylate than for polyuridylate. The enzyme was thermolabile, but it stabilized with bovine plasma albumin. The molecular weight was approximately 15,000, estimated gel filtration on Sephadex G-75, and its isoelectric pH was above 11.0. From normal human leukocytes, acid RNase was purified about 400-fold by the same procedure described previously except that rechromatography on Sephadex G-75 was omitted. The properties of leukocytic RNase were found to be similar to those of serum acid RNase, but the latter enzyme differed in substrate specificity substantially from leukocytic RNase, preferring polyuridylate to polycytidylate. This evidence shows that serum RNase is not of leukocytic origin under normal physiological conditions. | Purification and properties of acid ribonucleases in human serum and leukocytes. Acid RNase was purified from normal human serum about 2400-fold by chromatography on phosphocellulose and Sephadex G-75 and rechromatography on Sephadex G-75. Assayed with yeast RNA as substrate, the enzyme showed the maximal activity at about pH 6.5 with sodium phosphate buffer. The reaction was activated by Na+, K+, and spermine, but it was not affected greatly by Mg2+, Co2+, and EDTA. Ca2+, Fe2+, Zn2+, and Cu2+ inhibited the reaction. Among the synthetic substrates examined, the enzyme preferentially hydrolyzed pyrimidine nucleotides, with a higher affinity for polycytidylate than for polyuridylate. The enzyme was thermolabile, but it stabilized with bovine plasma albumin. The molecular weight was approximately 15,000, estimated gel filtration on Sephadex G-75, and its isoelectric pH was above 11.0. From normal human leukocytes, acid RNase was purified about 400-fold by the same procedure described previously except that rechromatography on Sephadex G-75 was omitted. The properties of leukocytic RNase were found to be similar to those of serum acid RNase, but the latter enzyme differed in substrate specificity substantially from leukocytic RNase, preferring polyuridylate to polycytidylate. This evidence shows that serum RNase is not of leukocytic origin under normal physiological conditions. | [
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PMID:26465 | Serum acid ribonuclease in myelogenous leukemia. | Acid and alkaline RNase activities in serum were measured with yeast RNA as the substrate in normal subjects and in leukemic patients pretreatment and posttreatment, and the acid/alkaline ratios of activities were 0.63 +/- 0.08 (S.D.) (N, 12), 2.28 +/- 0.82 (N, 8), and 0.60 +/- 0.13 (N, 9), respectively. The mean value for the ratio in the pretreated leukemia was significantly higher than that in the other 2 groups (p less than 0.01). By separating these acid and alkaline RNases from normal and leukemic sera by phosphocellulose chromatography, it was further confirmed that acid RNase alone increased markedly in leukemic serum. From serum and leukocytes of leukemic patients, acid RNases were purified about 2000-fold and 300-fold, respectively, by phosphocellulose and Sephadex G-75 chromatography. Both enzymes displayed properties nearly identical with those of normal serum and leukocytes, except that leukemic serum acid RNase had about a 2.4-fold greater affinity for polyuridylate than for polycytidylate as substrate, in contrast to normal serum acid RNase that degraded polycytidylate exclusively. On the other hand acid RNases from serum leukocytes of leukemia showed a similar substrate preference. These results suggest that the high RNase levels of leukemic sera are due to an excessive leakage of acid RNase into the blood stream from abnormal leukocytes. | Serum acid ribonuclease in myelogenous leukemia. Acid and alkaline RNase activities in serum were measured with yeast RNA as the substrate in normal subjects and in leukemic patients pretreatment and posttreatment, and the acid/alkaline ratios of activities were 0.63 +/- 0.08 (S.D.) (N, 12), 2.28 +/- 0.82 (N, 8), and 0.60 +/- 0.13 (N, 9), respectively. The mean value for the ratio in the pretreated leukemia was significantly higher than that in the other 2 groups (p less than 0.01). By separating these acid and alkaline RNases from normal and leukemic sera by phosphocellulose chromatography, it was further confirmed that acid RNase alone increased markedly in leukemic serum. From serum and leukocytes of leukemic patients, acid RNases were purified about 2000-fold and 300-fold, respectively, by phosphocellulose and Sephadex G-75 chromatography. Both enzymes displayed properties nearly identical with those of normal serum and leukocytes, except that leukemic serum acid RNase had about a 2.4-fold greater affinity for polyuridylate than for polycytidylate as substrate, in contrast to normal serum acid RNase that degraded polycytidylate exclusively. On the other hand acid RNases from serum leukocytes of leukemia showed a similar substrate preference. These results suggest that the high RNase levels of leukemic sera are due to an excessive leakage of acid RNase into the blood stream from abnormal leukocytes. | [
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PMID:26467 | Changes in small vessel blood content of the rat heart induced by hypercapnic, hyperoxic or asphyxic conditions. | The small vessel blood content (SVBC) of the ventricular walls of the heart of anesthetized closed chest rats was determined using 59FeC13 to label the plasma siderophilin. SVBC was measured breathing air, 100% O2, 5% CO2 in 21% O2 and during asphyxia. The average SVBC could be ranked: air less than 100% O2 less than 5% CO2 less than asphyxia. Only the '100% O2' values were not significantly above the 'air' values. Under control conditions, SVBC of the rat heart averaged 6.77 +/-(SE) 0.23 ml blood/100 g tissue. Inhalation of 5% CO2 increased this to 8.68 +/- 0.34, while asphyxia produced a maximal response to 14.40 +/- 0.77. Comparison of SVBC were made between various regions of the ventricular walls. The only significant difference was that the right side of the septum had a lower SVBC than the left ventricular subepicardium under all conditions except CO2. These differences in SVBC are related to the number of open capillaries in the myocardium. Thus inhalation of CO2 decreases intercapillary distance while 100% O2 has no effect. | Changes in small vessel blood content of the rat heart induced by hypercapnic, hyperoxic or asphyxic conditions. The small vessel blood content (SVBC) of the ventricular walls of the heart of anesthetized closed chest rats was determined using 59FeC13 to label the plasma siderophilin. SVBC was measured breathing air, 100% O2, 5% CO2 in 21% O2 and during asphyxia. The average SVBC could be ranked: air less than 100% O2 less than 5% CO2 less than asphyxia. Only the '100% O2' values were not significantly above the 'air' values. Under control conditions, SVBC of the rat heart averaged 6.77 +/-(SE) 0.23 ml blood/100 g tissue. Inhalation of 5% CO2 increased this to 8.68 +/- 0.34, while asphyxia produced a maximal response to 14.40 +/- 0.77. Comparison of SVBC were made between various regions of the ventricular walls. The only significant difference was that the right side of the septum had a lower SVBC than the left ventricular subepicardium under all conditions except CO2. These differences in SVBC are related to the number of open capillaries in the myocardium. Thus inhalation of CO2 decreases intercapillary distance while 100% O2 has no effect. | [
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PMID:26479 | [Purification of rat brain guanylate cyclase]. | The purification of guanylate cyclase has been achieved. After electrophoresis on polyacrylamide gel only one protein band was observed. The low factor of purification must therefore be ascribed to the loss of an activator of guanylate cyclase. Stimulation of the activity by nitroprusside is also lost during purification. The purified enzyme follows Michaelis--Menten kinetics, it is activated by Mn++ ions and inhibited by triphospho nucleotides. | [Purification of rat brain guanylate cyclase]. The purification of guanylate cyclase has been achieved. After electrophoresis on polyacrylamide gel only one protein band was observed. The low factor of purification must therefore be ascribed to the loss of an activator of guanylate cyclase. Stimulation of the activity by nitroprusside is also lost during purification. The purified enzyme follows Michaelis--Menten kinetics, it is activated by Mn++ ions and inhibited by triphospho nucleotides. | [
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PMID:26481 | Isolation of gamma-glutamyltransferase from human liver, and comparison with the enzyme from human kidney. | We isolated gamma-glutamyltransferase [(gamma-glutamyl)-peptide:amino acid gamma-glutamyltransferase, EC 2.3.2.2] from human liver and compared some of its properties with the same enzyme prepared from human kidney. The enzymes from these two sources are very similar with respect to initial velocity kinetic constants, pH optima of the transpeptidation and autotransfer reactions, heat stability, competitive inhibition by glutathione of the colorimetric assay in which gamma-glutamyl-4-nitroanilide is substrate, stability of catalytic activity to trypsinization, and relative rates of transfer of the gamma-glutamyl moiety from gamma-glutamyl-4-nitroanilide and L-[glycine-2-3/]glutathione to some amino acids and small peptides. The kidney enzyme is inhibited more by the gamma-glutamyl acceptor substrate, glycylglycine, as reflected in a sevenfold lower value for the inhibition constant KiA. Major differences were observed in the lectin-binding properties of liver gamma-glutamyltransferase compared to the kidney enzyme. Lectin-binding property differences are retained for the trypsinized form of the liver and kidney enzymes, although the degree of precipitation was less for certain lectins as compared to the untreated enzyme. Lectin-binding properties were reversed by carbohydrates specific for each lectin. We adapted the histochemical staining technique of Rutenberg et al. [J. Histochem. Cytochem. 17, 517 (1969)] to the detection of gamma-glutamyltransferase activity in acrylamide gels; diffusion artifacts are minimized and the color produced is stable for several days. Untreated and trypsinized forms of the liver enzyme both migrated faster in acrylamide gels (as single bands) than did the corresponding forms of the kidney enzyme. | Isolation of gamma-glutamyltransferase from human liver, and comparison with the enzyme from human kidney. We isolated gamma-glutamyltransferase [(gamma-glutamyl)-peptide:amino acid gamma-glutamyltransferase, EC 2.3.2.2] from human liver and compared some of its properties with the same enzyme prepared from human kidney. The enzymes from these two sources are very similar with respect to initial velocity kinetic constants, pH optima of the transpeptidation and autotransfer reactions, heat stability, competitive inhibition by glutathione of the colorimetric assay in which gamma-glutamyl-4-nitroanilide is substrate, stability of catalytic activity to trypsinization, and relative rates of transfer of the gamma-glutamyl moiety from gamma-glutamyl-4-nitroanilide and L-[glycine-2-3/]glutathione to some amino acids and small peptides. The kidney enzyme is inhibited more by the gamma-glutamyl acceptor substrate, glycylglycine, as reflected in a sevenfold lower value for the inhibition constant KiA. Major differences were observed in the lectin-binding properties of liver gamma-glutamyltransferase compared to the kidney enzyme. Lectin-binding property differences are retained for the trypsinized form of the liver and kidney enzymes, although the degree of precipitation was less for certain lectins as compared to the untreated enzyme. Lectin-binding properties were reversed by carbohydrates specific for each lectin. We adapted the histochemical staining technique of Rutenberg et al. [J. Histochem. Cytochem. 17, 517 (1969)] to the detection of gamma-glutamyltransferase activity in acrylamide gels; diffusion artifacts are minimized and the color produced is stable for several days. Untreated and trypsinized forms of the liver enzyme both migrated faster in acrylamide gels (as single bands) than did the corresponding forms of the kidney enzyme. | [
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PMID:26483 | Biochemical characterization of an aryl acetic ester hydrolase isolated from human monocytes. | A carboxylic-ester hydrolase was isolated from the leukocytes of a patient with myelomonocytic leukemia. Its relative molecular mass as estimated by sucrose density-gradient sedimentation is about 70 000. The purified enzyme is specific for acetyl esters of aromatic alcohols. It is inhibited by fluoride, but insensitive to eserine or p-chloromercuriphenylsulfonate. Hydrolysis of 1-naphthyl acetate was optimal above pH 6.0; of o-nitrophenyl acetate, above 8.0. The common catalytic site for the two types of substrates on the enzyme was confirmed by competitive inhibition data. | Biochemical characterization of an aryl acetic ester hydrolase isolated from human monocytes. A carboxylic-ester hydrolase was isolated from the leukocytes of a patient with myelomonocytic leukemia. Its relative molecular mass as estimated by sucrose density-gradient sedimentation is about 70 000. The purified enzyme is specific for acetyl esters of aromatic alcohols. It is inhibited by fluoride, but insensitive to eserine or p-chloromercuriphenylsulfonate. Hydrolysis of 1-naphthyl acetate was optimal above pH 6.0; of o-nitrophenyl acetate, above 8.0. The common catalytic site for the two types of substrates on the enzyme was confirmed by competitive inhibition data. | [
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PMID:26484 | A novel gamma-glutamyl transpeptidase in renal carcinoma in comparison with normal kidney enzyme. | A novel gamma-glutamyl transpeptidase was found in a renal carcinoma tissue. This enzyme electrophoresed more quickly than that of normal kidney, but more slowly than normal liver enzyme. Their Rf values are 0.46, 0.33, and 0.52 for the renal carcinoma, normal kidney and normal liver enzyme, respectively. After treatment of the renal carcinoma and normal kidney enzyme with neuraminidase, the renal carcinoma gamma-glutamyl transpeptidase still electrophoresed slightly faster than that of normal kidney. The catalytic properties of the renal carcinoma gamma-glutamyl transpeptidase were almost the same as those of normal kidney except for molecular weight; the molecular weight for the renal carcinoma was estimated to be about 130 000, while that of normal kidney was about 90 000. These results may mean that the enzyme of the renal carcinoma is different from that of normal kidney in chemical constituents other than sialic acid. Of 10 patients with renal carcinoma examined electrophoretically, 5 posessed this novel enzyme in their renal carcinoma tissues. | A novel gamma-glutamyl transpeptidase in renal carcinoma in comparison with normal kidney enzyme. A novel gamma-glutamyl transpeptidase was found in a renal carcinoma tissue. This enzyme electrophoresed more quickly than that of normal kidney, but more slowly than normal liver enzyme. Their Rf values are 0.46, 0.33, and 0.52 for the renal carcinoma, normal kidney and normal liver enzyme, respectively. After treatment of the renal carcinoma and normal kidney enzyme with neuraminidase, the renal carcinoma gamma-glutamyl transpeptidase still electrophoresed slightly faster than that of normal kidney. The catalytic properties of the renal carcinoma gamma-glutamyl transpeptidase were almost the same as those of normal kidney except for molecular weight; the molecular weight for the renal carcinoma was estimated to be about 130 000, while that of normal kidney was about 90 000. These results may mean that the enzyme of the renal carcinoma is different from that of normal kidney in chemical constituents other than sialic acid. Of 10 patients with renal carcinoma examined electrophoretically, 5 posessed this novel enzyme in their renal carcinoma tissues. | [
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PMID:26485 | A simple radioimmunoassay for plasma cortisol. | A simple radioimmunoassay (RIA) for plasma cortisol is described which combines the advantages of (i) direct analysis of untreated plasma samples, (ii) use of solid-coupled anti-cortisol antibodies and (iii) use of a gamma-labelled radioligand. The reagents are relatively easily prepared and stable, and the analysis can be completed in 4 h. Inter-assay precision (C.V.) is 8-11%. Critical examination of specificity using high pressure liquid chromatography showed that 23-35% of the immunoassayable material in plasma was not cortisol. RIA results on samples collected under basal conditions were on average 40 nmol/l lower than fluorimetric results, while in insulin hypoglycaemia and synacthen (ACTH) stimulation tests, this difference increased to over 100 nmol/l. The RIA is technically more simple than fluorimetric, competitive-protein-binding, and many RIA methods, and can be used with advantage in the routine investigation of adrenocortical function. However, using the present antiserum, the RIA is not applicable to investigations on patients receiving metyrapone, nor in suspected cases of congenital adrenal hyperplasia. | A simple radioimmunoassay for plasma cortisol. A simple radioimmunoassay (RIA) for plasma cortisol is described which combines the advantages of (i) direct analysis of untreated plasma samples, (ii) use of solid-coupled anti-cortisol antibodies and (iii) use of a gamma-labelled radioligand. The reagents are relatively easily prepared and stable, and the analysis can be completed in 4 h. Inter-assay precision (C.V.) is 8-11%. Critical examination of specificity using high pressure liquid chromatography showed that 23-35% of the immunoassayable material in plasma was not cortisol. RIA results on samples collected under basal conditions were on average 40 nmol/l lower than fluorimetric results, while in insulin hypoglycaemia and synacthen (ACTH) stimulation tests, this difference increased to over 100 nmol/l. The RIA is technically more simple than fluorimetric, competitive-protein-binding, and many RIA methods, and can be used with advantage in the routine investigation of adrenocortical function. However, using the present antiserum, the RIA is not applicable to investigations on patients receiving metyrapone, nor in suspected cases of congenital adrenal hyperplasia. | [
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PMID:26486 | Purification and serological studies of human alpha-L-fucosidase in the normal and fucosidosis states. | An antiserum has been raised to purified alpha-L-fucosidase. Levels of cross-reaction with serum of two unrelated fucosidosis patients and normal individuals with low activity are consistent with the presence of very low amounts of normal enzyme. Similarly no cross-reacting material could be found in cultured fibroblasts from fucosidosis patients. It is deduced that in these cases there is no production of mutant enzyme in quantities comparable to normal levels. Some observations on the interrelations of fucosidases I and II are reported. | Purification and serological studies of human alpha-L-fucosidase in the normal and fucosidosis states. An antiserum has been raised to purified alpha-L-fucosidase. Levels of cross-reaction with serum of two unrelated fucosidosis patients and normal individuals with low activity are consistent with the presence of very low amounts of normal enzyme. Similarly no cross-reacting material could be found in cultured fibroblasts from fucosidosis patients. It is deduced that in these cases there is no production of mutant enzyme in quantities comparable to normal levels. Some observations on the interrelations of fucosidases I and II are reported. | [
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PMID:26487 | Sphingomyelinase activity levels in human peripheral blood leukocytes, using [3H]sphingomyelin as substrate: study of heterozygotes and homozygotes for Niemann-Pick disease variants. | Patients and heterozygous carriers of Niemann-Pick disease types A and B as well as the primary (genetic) sea-blue histiocyte syndrome were investigated for their leukocyte sphingomyelinase activity. In parallel, glucocerebrosidase activity was determined in all cases studied. [3H]Sphingomyelin and [14C]glucocerebroside served as substrates for sphingomyelinase and glucocerebrosidase activity measurements, respectively. Conditions for these enzymes' assays are discussed. Sphingomyelinase activity was completely absent in three cases of Niemann-Pick disease type A and significantly diminished in one patient with Niemann-Pick disease type B and two with the sea-blue histiocyte syndrome. Sphingomyelinase activity in obligatory heterozygotes of all variants investigated represented about 40 to 70% of normal activity. Nevertheless, some overlapping with normal values occasionally occurred. Interestingly, glucocerbrosidase activity was elevated in patients with Niemann-Pick disease variants. | Sphingomyelinase activity levels in human peripheral blood leukocytes, using [3H]sphingomyelin as substrate: study of heterozygotes and homozygotes for Niemann-Pick disease variants. Patients and heterozygous carriers of Niemann-Pick disease types A and B as well as the primary (genetic) sea-blue histiocyte syndrome were investigated for their leukocyte sphingomyelinase activity. In parallel, glucocerebrosidase activity was determined in all cases studied. [3H]Sphingomyelin and [14C]glucocerebroside served as substrates for sphingomyelinase and glucocerebrosidase activity measurements, respectively. Conditions for these enzymes' assays are discussed. Sphingomyelinase activity was completely absent in three cases of Niemann-Pick disease type A and significantly diminished in one patient with Niemann-Pick disease type B and two with the sea-blue histiocyte syndrome. Sphingomyelinase activity in obligatory heterozygotes of all variants investigated represented about 40 to 70% of normal activity. Nevertheless, some overlapping with normal values occasionally occurred. Interestingly, glucocerbrosidase activity was elevated in patients with Niemann-Pick disease variants. | [
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PMID:26488 | Serum alanine assay with an enzymic micromethod (L-alanine dehydrogenase). | L-Alanine was measured by an enzymic micromethod in serum after treatment with perchloric acid, as well as after ultrafiltration through collodium membrane filters. Serum L-alanine was also determined by an automated column chromatographic technique. Using the enzymic method, spuriously increased L-alanine levels could be obtained due to the absorbent reaction between hydrazine and NAD-containing reagents. It could be shown that this absorbent reaction depends on the pH value of the test solution. In contrast to supernatant diluted by perchloric acid, ultrafiltrates gave L-alanine data equivalent to those by column chromatography, since conditions of reaction time and pH value could be kept identical for blank, standard and ultrafiltrate solutions. | Serum alanine assay with an enzymic micromethod (L-alanine dehydrogenase). L-Alanine was measured by an enzymic micromethod in serum after treatment with perchloric acid, as well as after ultrafiltration through collodium membrane filters. Serum L-alanine was also determined by an automated column chromatographic technique. Using the enzymic method, spuriously increased L-alanine levels could be obtained due to the absorbent reaction between hydrazine and NAD-containing reagents. It could be shown that this absorbent reaction depends on the pH value of the test solution. In contrast to supernatant diluted by perchloric acid, ultrafiltrates gave L-alanine data equivalent to those by column chromatography, since conditions of reaction time and pH value could be kept identical for blank, standard and ultrafiltrate solutions. | [
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PMID:26489 | Interaction of [14C]acetylsalicylic acid with normal human peripheral blood lymphocytes. | Therapeutic concentrations of acetylsalicylic acid (ASA) have strikingly inhibited in vitro and in vivo mitogen- and antigen-induced blastogenesis by human lymphocytes. These observations may be pertinent to the anti-inflammatory actions of ASA. To investigate further the possible effects of ASA on cellular responses, we studied the in vitro interaction of [14C]ASA with lymphocytes. Results indicated that the [14C]ASA association with cells was (a) proportional to ASA concentrations, (b) non-saturable at high concentrations of ASA, (c) dependent on pH, (d) independent of temperature, (e) dependent on cell concentration, (f) not consistently displaced by unlabelled ASA or other drugs, (g) rapid and unchanged over 1 min to 72 hr incubations and (h) reversed by repeated cell washing. These data confirmed that ASA indeed interacted with lymphocytes. The association was rapid, reversible, pH-dependent and not demonstrably specific under these experimental conditions. | Interaction of [14C]acetylsalicylic acid with normal human peripheral blood lymphocytes. Therapeutic concentrations of acetylsalicylic acid (ASA) have strikingly inhibited in vitro and in vivo mitogen- and antigen-induced blastogenesis by human lymphocytes. These observations may be pertinent to the anti-inflammatory actions of ASA. To investigate further the possible effects of ASA on cellular responses, we studied the in vitro interaction of [14C]ASA with lymphocytes. Results indicated that the [14C]ASA association with cells was (a) proportional to ASA concentrations, (b) non-saturable at high concentrations of ASA, (c) dependent on pH, (d) independent of temperature, (e) dependent on cell concentration, (f) not consistently displaced by unlabelled ASA or other drugs, (g) rapid and unchanged over 1 min to 72 hr incubations and (h) reversed by repeated cell washing. These data confirmed that ASA indeed interacted with lymphocytes. The association was rapid, reversible, pH-dependent and not demonstrably specific under these experimental conditions. | [
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PMID:26493 | Clorazepate kinetics in treated epileptics. | Clorazepate is decarboxylated to form desmethyldiazepam and is a convenient way of administering it. Its kinetics were investigated in epileptic patients after single oral and multiple oral doses. Peak serum concentrations of demethyldiazepam occurred in 0.5 to 1 hr. There appeared to be a brief lag before rapid absorption. Because of the rapid absorption with resulting high serum levels, daily doses should be divided. Serum concentration/time curves were best fitted by the two-compartment open model. The apparent t1/2 of the distribution phase was 1.28 +/- 0.44 hr and the t1/2 of the disposition phase was 40.8 +/- 9.96 hr. Serum concentrations rose after meals. Whole body apparent volume of distribution (VB/F) was 1.63 +/- 0.24 L/kg. Total plasma clearance was 34.4 +/- 7.2 ml/min, which is greater than clearance levels for desmethyldiazepam in normals and reflects the greater hepatic metabolism which occurs in treated epileptics. The discrepancy illustrates the hazards of extrapolating data collected in normals to patients with multiple drug exposures. | Clorazepate kinetics in treated epileptics. Clorazepate is decarboxylated to form desmethyldiazepam and is a convenient way of administering it. Its kinetics were investigated in epileptic patients after single oral and multiple oral doses. Peak serum concentrations of demethyldiazepam occurred in 0.5 to 1 hr. There appeared to be a brief lag before rapid absorption. Because of the rapid absorption with resulting high serum levels, daily doses should be divided. Serum concentration/time curves were best fitted by the two-compartment open model. The apparent t1/2 of the distribution phase was 1.28 +/- 0.44 hr and the t1/2 of the disposition phase was 40.8 +/- 9.96 hr. Serum concentrations rose after meals. Whole body apparent volume of distribution (VB/F) was 1.63 +/- 0.24 L/kg. Total plasma clearance was 34.4 +/- 7.2 ml/min, which is greater than clearance levels for desmethyldiazepam in normals and reflects the greater hepatic metabolism which occurs in treated epileptics. The discrepancy illustrates the hazards of extrapolating data collected in normals to patients with multiple drug exposures. | [
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PMID:26494 | Barbiturate physical dependence in mice: effects of neuroleptics and diazepam on the withdrawal syndrome. | Diazepam (8 mg/kg) quickly and effectively reduced the incidence of withdrawal symptoms in phenobarbital dependent C57BL/6J male mice. In contrast, the neuroleptic agents employed (chlorpormazine, haloperidol, or reserpine) or alpha-methyl-p-tyrosine tended to exacerbate the withdrawal syndrome. Chlorpromazine and haloperidol were approximately equally potent in their effects; this would suggest that their antidopaminergic effects were not the primary mechanism of action for the increased incidence of withdrawal symptoms. | Barbiturate physical dependence in mice: effects of neuroleptics and diazepam on the withdrawal syndrome. Diazepam (8 mg/kg) quickly and effectively reduced the incidence of withdrawal symptoms in phenobarbital dependent C57BL/6J male mice. In contrast, the neuroleptic agents employed (chlorpormazine, haloperidol, or reserpine) or alpha-methyl-p-tyrosine tended to exacerbate the withdrawal syndrome. Chlorpromazine and haloperidol were approximately equally potent in their effects; this would suggest that their antidopaminergic effects were not the primary mechanism of action for the increased incidence of withdrawal symptoms. | [
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PMID:26490 | The cardiovascular effects of intraventricular 5,6-dihydroxytryptamine in conscious hypertensive rats. | 1. Conscious experimental hypertensive rats injected intraventricularly with 5,6-dihydroxytryptamine (50 microgram) responded with a rapid and long-lasting (4 days) fall in blood pressure and this was accompanied by a bradycardia of similar duration. 2. The acute actions of 5,6-dihydroxytryptamine on the cardiovascular system were not modified by pretreatment with bromolysergide (0.5 mg/kg, i.p.), methysergide (2.5 mg/kg, i.p.) or intraventricular phentolamine (200 microgram). 3. The results suggest that central serotonergic neurones play an important role in the regulation of blood pressure. However, the site of action remains to be investigated. | The cardiovascular effects of intraventricular 5,6-dihydroxytryptamine in conscious hypertensive rats. 1. Conscious experimental hypertensive rats injected intraventricularly with 5,6-dihydroxytryptamine (50 microgram) responded with a rapid and long-lasting (4 days) fall in blood pressure and this was accompanied by a bradycardia of similar duration. 2. The acute actions of 5,6-dihydroxytryptamine on the cardiovascular system were not modified by pretreatment with bromolysergide (0.5 mg/kg, i.p.), methysergide (2.5 mg/kg, i.p.) or intraventricular phentolamine (200 microgram). 3. The results suggest that central serotonergic neurones play an important role in the regulation of blood pressure. However, the site of action remains to be investigated. | [
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PMID:26516 | Comparative trial of two antihistamines, mequitazine and brompheniramine. | A double-blind trial was carried out in 48 patients with allergic disorders to compare the efficacy and tolerance of mequitazine and brompheniramine. Patients received either 10 mg mequitazine or 24 mg brompheniramine daily, divided into 2 doses, for 14 days. The results, analyzed from patients' answers to a questionnaire recorded on a daily basis, showed that mequitazine was at least as effective as brompheniramine and caused significantly less drowsiness throughout the trial period. Few other side-effects were reported. | Comparative trial of two antihistamines, mequitazine and brompheniramine. A double-blind trial was carried out in 48 patients with allergic disorders to compare the efficacy and tolerance of mequitazine and brompheniramine. Patients received either 10 mg mequitazine or 24 mg brompheniramine daily, divided into 2 doses, for 14 days. The results, analyzed from patients' answers to a questionnaire recorded on a daily basis, showed that mequitazine was at least as effective as brompheniramine and caused significantly less drowsiness throughout the trial period. Few other side-effects were reported. | [
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PMID:26517 | Comparative trial of an antihistamine, mequitazine, and placebo. | Forty patients suffering from a dermatological condition suitable for treatment with an antihistamine were studied in a double-blind randomized trial to compare the effectiveness and tolerance of mequitazine and placebo. Over a period of 2 weeks, patients received either 5 mg mequitazine twice daily or placebo. Where justified, patients were also given concomitant topical treatment but only with a hydrating cream or ichthyol paste. Patients' overall response to treatment was significantly better in the mequitazine group, whether the results were analyzed for all patients or those receiving just the trial drugs without topical treatment. Few side-effects were reported and there was no significant difference between the levels of drowsiness experienced with mequitazine compared with placebo. | Comparative trial of an antihistamine, mequitazine, and placebo. Forty patients suffering from a dermatological condition suitable for treatment with an antihistamine were studied in a double-blind randomized trial to compare the effectiveness and tolerance of mequitazine and placebo. Over a period of 2 weeks, patients received either 5 mg mequitazine twice daily or placebo. Where justified, patients were also given concomitant topical treatment but only with a hydrating cream or ichthyol paste. Patients' overall response to treatment was significantly better in the mequitazine group, whether the results were analyzed for all patients or those receiving just the trial drugs without topical treatment. Few side-effects were reported and there was no significant difference between the levels of drowsiness experienced with mequitazine compared with placebo. | [
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PMID:26518 | Double-blind clinical comparison between a gastrin-receptor antagonist, proglumide, and a histamine H2-blocker, cimetidine. | A double-blind trial was carried out in 30 patients with peptic ulcers to assess the effects of treatment with a gastrin-receptor antagonist, proglumide, compared with a histamine H2-blocker, cimetidine. Patients received either 1200 mg proglumide or 1200 mg cimetidine per day for 28 days. The results showed that both drugs significantly reduced clinical symptoms and gastric secretion. In patients treated with cimetidine there was a significant increase in blood gastrin levels and marked hypertrophy and hyperplasia of the antral mucosa was observed in almost all patients. No such changes were found in the patients treated with proglumide. | Double-blind clinical comparison between a gastrin-receptor antagonist, proglumide, and a histamine H2-blocker, cimetidine. A double-blind trial was carried out in 30 patients with peptic ulcers to assess the effects of treatment with a gastrin-receptor antagonist, proglumide, compared with a histamine H2-blocker, cimetidine. Patients received either 1200 mg proglumide or 1200 mg cimetidine per day for 28 days. The results showed that both drugs significantly reduced clinical symptoms and gastric secretion. In patients treated with cimetidine there was a significant increase in blood gastrin levels and marked hypertrophy and hyperplasia of the antral mucosa was observed in almost all patients. No such changes were found in the patients treated with proglumide. | [
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PMID:26519 | Dose-ranging study of the new beta-adrenergic antagonist nadolol in the treatment of essential hypertension. | A preliminary, single-blind, dose-ranging study was carried out in 30 patients with essential hypertension to assess the efficacy of nadolol, a new beta-adrenoceptor blocking agent without intrinsic sympathomimetic action and with an extremely long plasma half-life. After a 2-week period on placebo, patients were treated for 14 weeks with daily doses of 40 mg nadolol (20 mg twice daily). Dosage was increased every second week up to a maximum of 560 mg daily or until the patient was stabilized at an effective normotensive dose level. The results showed that at the end of the trial period there was a significant reduction in both systolic and diastolic blood pressure (approximately 34/21 mmHg) at an average daily dose of 110 mg nadolol. Apart from a tendency to bradycardia, explained by the drug's lack of sympathomimetic action, no other side-effects attributable to treatment were reported and no patient complained of sleep disturbance. | Dose-ranging study of the new beta-adrenergic antagonist nadolol in the treatment of essential hypertension. A preliminary, single-blind, dose-ranging study was carried out in 30 patients with essential hypertension to assess the efficacy of nadolol, a new beta-adrenoceptor blocking agent without intrinsic sympathomimetic action and with an extremely long plasma half-life. After a 2-week period on placebo, patients were treated for 14 weeks with daily doses of 40 mg nadolol (20 mg twice daily). Dosage was increased every second week up to a maximum of 560 mg daily or until the patient was stabilized at an effective normotensive dose level. The results showed that at the end of the trial period there was a significant reduction in both systolic and diastolic blood pressure (approximately 34/21 mmHg) at an average daily dose of 110 mg nadolol. Apart from a tendency to bradycardia, explained by the drug's lack of sympathomimetic action, no other side-effects attributable to treatment were reported and no patient complained of sleep disturbance. | [
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PMID:26520 | Comparison of the new beta-adrenoceptor antagonist, nadolol, and propranolol in the treatment of angina pectoris. | A randomized, double-blind study was carried out in 24 patients with stable angina pectoris to compare the efficacy of nadolol, a new beta-adrenoceptor antagonist, and propranolol. After a period on placebo, 14 patients received nadolol once daily and 10 patients propranolol 4-times daily over a 10-week dose-ranging period followed by a maintenance period of 4 weeks. Optimal daily dosage for nadolol was 100 mg, and 112 mg for propranolol. Parameters used for evaluation of therapeutic effects included the number of anginal attacks, number of nitroglycerine tablets needed, time before onset of chest pain during exercise test, exercise time, and overall clinical impression of response. The results indicated that nadolol given once daily was equally as effective as propranolol 4-times daily in treating angina pectoris. | Comparison of the new beta-adrenoceptor antagonist, nadolol, and propranolol in the treatment of angina pectoris. A randomized, double-blind study was carried out in 24 patients with stable angina pectoris to compare the efficacy of nadolol, a new beta-adrenoceptor antagonist, and propranolol. After a period on placebo, 14 patients received nadolol once daily and 10 patients propranolol 4-times daily over a 10-week dose-ranging period followed by a maintenance period of 4 weeks. Optimal daily dosage for nadolol was 100 mg, and 112 mg for propranolol. Parameters used for evaluation of therapeutic effects included the number of anginal attacks, number of nitroglycerine tablets needed, time before onset of chest pain during exercise test, exercise time, and overall clinical impression of response. The results indicated that nadolol given once daily was equally as effective as propranolol 4-times daily in treating angina pectoris. | [
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PMID:26522 | Cutaneous vasculitis. | Cutaneous vasculitis is a common but confusing clinical syndrome. We report three illustrative cases demonstrating the variable nature of the process. Renal disease is generally a poor prognostic sign; therefore, the renal status should be evaluated early. The process probably represents an immune complex disorder. Although various therapies have been used, an aggressive corticosteroid regimen is the preferred mode of treatment at the current time. | Cutaneous vasculitis. Cutaneous vasculitis is a common but confusing clinical syndrome. We report three illustrative cases demonstrating the variable nature of the process. Renal disease is generally a poor prognostic sign; therefore, the renal status should be evaluated early. The process probably represents an immune complex disorder. Although various therapies have been used, an aggressive corticosteroid regimen is the preferred mode of treatment at the current time. | [
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PMID:26523 | Metabolism of 5-isopropyl-1-methyl-2-nitro-1H-imidazole. Identification of some urinary metabolites in the dog. | The metabolism of 5-isopropyl-1-methyl-2-nitro-1H-[2-14C] imidazole in dogs has been investigated after oral administration of 50 mg/kg. Three main metabolites, still containing the nitro group and accounting for about 50% of the total radiocarbon, together with a small amount of the unchanged drug, were isolated from the urine within 48 hr. The structures were determined by mass, infrared, and nuclear magnetic resonance spectroscopy. The biotransformations giving rise to the metabolites isolated involve the isopropyl chain of the molecule, either at the tertiary carbon atom or at one of the two methyl groups, or both. Thus, the metabolic behavior of this 2-nitroimidazole derivative appears to be similar to that previously demonstrated for the class of the isomeric 5-nitroimidazoles. | Metabolism of 5-isopropyl-1-methyl-2-nitro-1H-imidazole. Identification of some urinary metabolites in the dog. The metabolism of 5-isopropyl-1-methyl-2-nitro-1H-[2-14C] imidazole in dogs has been investigated after oral administration of 50 mg/kg. Three main metabolites, still containing the nitro group and accounting for about 50% of the total radiocarbon, together with a small amount of the unchanged drug, were isolated from the urine within 48 hr. The structures were determined by mass, infrared, and nuclear magnetic resonance spectroscopy. The biotransformations giving rise to the metabolites isolated involve the isopropyl chain of the molecule, either at the tertiary carbon atom or at one of the two methyl groups, or both. Thus, the metabolic behavior of this 2-nitroimidazole derivative appears to be similar to that previously demonstrated for the class of the isomeric 5-nitroimidazoles. | [
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PMID:26524 | Formation of sulfone metabolites from chlorpromazine and perazine in man. | Didesmethylchlorpromazine sulfone [gamma-(2-chlorophenothiazinyl-10)-propylamine sulfone] has been isolated from the urine of a patient under continuous chlorpromazine therapy and identified by mass spectrometry. The same compound was present in organs of rats after injection of the corresponding sulfide. The Cl-free analogue, gamma-(phenothiazinyl-10)-propylamine sulfone, was excreted by patients receiving perazine and by a volunteer after ingestion of the primary amine sulfoxide. | Formation of sulfone metabolites from chlorpromazine and perazine in man. Didesmethylchlorpromazine sulfone [gamma-(2-chlorophenothiazinyl-10)-propylamine sulfone] has been isolated from the urine of a patient under continuous chlorpromazine therapy and identified by mass spectrometry. The same compound was present in organs of rats after injection of the corresponding sulfide. The Cl-free analogue, gamma-(phenothiazinyl-10)-propylamine sulfone, was excreted by patients receiving perazine and by a volunteer after ingestion of the primary amine sulfoxide. | [
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PMID:26525 | Comparison of biliary excretory function and bile composition in male, female, and lactating female rats. | The rates of excretion of phenol-3,6-dibromphthalein disulfonate, ouabain, indocyanine green, and amaranth into the bile of male and female rats were found to be similar. The rates of bile production in male and female rats were also similar whereas that of lactating rats was 50% greater. The increase in bile production occurred during pregnancy and decreased rapidly after removal of the pups from the dam. The increased bile production was of canalicular origin and was due to an increase in both the bile salt-dependent and independent fractions. The lactating rats tended to excrete some xenobiotics more rapidly than did the other rats, but no difference in the biliary excretion was observed in male and female rats. | Comparison of biliary excretory function and bile composition in male, female, and lactating female rats. The rates of excretion of phenol-3,6-dibromphthalein disulfonate, ouabain, indocyanine green, and amaranth into the bile of male and female rats were found to be similar. The rates of bile production in male and female rats were also similar whereas that of lactating rats was 50% greater. The increase in bile production occurred during pregnancy and decreased rapidly after removal of the pups from the dam. The increased bile production was of canalicular origin and was due to an increase in both the bile salt-dependent and independent fractions. The lactating rats tended to excrete some xenobiotics more rapidly than did the other rats, but no difference in the biliary excretion was observed in male and female rats. | [
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PMID:26527 | Dihydropyrimidinase. Stereochemistry of the metabolism of some 5-alkylhydantoins. | The (R)- and (S)-isomers of 5-methylhydantoin (5-MH) and of 5-isopropylhydantoin (5-IPH) were synthesized, and incubations of the individual isomers with a rat liver dihydropyrimidinase preparation (100,000g supernatant fraction) were carried out. Only the (R)-isomer of 5-MH or 5-IPH was ring-opened by the enzyme. Reversibility of the enzymatic ring-opening reaction could be demonstrated with only the (R)-isomer of 2-methylhydantoic acid (2-MHA) or 2-isopropylhydantoic acid (2-IPHA). The results of the present investigation show that the replacement in 5-phenylhydantoin of the phenyl group with an alkyl group does not alter the stereospecificity of the hydantoin substrates in the ring-opening reaction. The results are used to form the concept that (R)-dihydrothymine, the optical isomer previously postulated as the natural substrate to the enzyme, may have a different type of binding at the active site of the enzyme. | Dihydropyrimidinase. Stereochemistry of the metabolism of some 5-alkylhydantoins. The (R)- and (S)-isomers of 5-methylhydantoin (5-MH) and of 5-isopropylhydantoin (5-IPH) were synthesized, and incubations of the individual isomers with a rat liver dihydropyrimidinase preparation (100,000g supernatant fraction) were carried out. Only the (R)-isomer of 5-MH or 5-IPH was ring-opened by the enzyme. Reversibility of the enzymatic ring-opening reaction could be demonstrated with only the (R)-isomer of 2-methylhydantoic acid (2-MHA) or 2-isopropylhydantoic acid (2-IPHA). The results of the present investigation show that the replacement in 5-phenylhydantoin of the phenyl group with an alkyl group does not alter the stereospecificity of the hydantoin substrates in the ring-opening reaction. The results are used to form the concept that (R)-dihydrothymine, the optical isomer previously postulated as the natural substrate to the enzyme, may have a different type of binding at the active site of the enzyme. | [
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PMID:26528 | Dihydropyrimidinase. Metabolism of some cyclic imides of different ring size. | The ability of dihydropyrimidinase (EC 3.5.2.2) to hydrolyze cyclic imides of different ring size was investigated. Succinimide, glutarimide, and adipimide are five-, six-, and seven-membered cyclic imides, respectively. The ring-opened compounds that correspond to these cyclic imides are, respectively, succinamic, glutaramic, and adipamic acid. In incubations of cyclic imides (pH 8, 1 hr) with a rat liver dihydropyrimidinase preparation from which omega-amidase had been removed, adipimide was classed as a good substrate and succinimide and glutarimide were classed as very poor but definite substrates. alpha-Phenylsuccinimide, the N-demethylated metabolite of phensuximide, was a much better substrate than succinimide. alpha-Phenylglutarimide was not a substrate. The in vitro studies of the present investigation were in agreement with observations made in previous in vivo studies. | Dihydropyrimidinase. Metabolism of some cyclic imides of different ring size. The ability of dihydropyrimidinase (EC 3.5.2.2) to hydrolyze cyclic imides of different ring size was investigated. Succinimide, glutarimide, and adipimide are five-, six-, and seven-membered cyclic imides, respectively. The ring-opened compounds that correspond to these cyclic imides are, respectively, succinamic, glutaramic, and adipamic acid. In incubations of cyclic imides (pH 8, 1 hr) with a rat liver dihydropyrimidinase preparation from which omega-amidase had been removed, adipimide was classed as a good substrate and succinimide and glutarimide were classed as very poor but definite substrates. alpha-Phenylsuccinimide, the N-demethylated metabolite of phensuximide, was a much better substrate than succinimide. alpha-Phenylglutarimide was not a substrate. The in vitro studies of the present investigation were in agreement with observations made in previous in vivo studies. | [
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PMID:26529 | Metabolism and tissue distribution of mono-2-ethylhexyl phthalate in the rat. | The absorption, distribution and metabolic excretion of mono-2-ethylhexyl [7-14C]phthalate (MEHP) were studied in the rat. This compound was readily absorbed from the gastrointestinal tract. Radioactivity following intravenous administration of 14C-MEHP was rapidly distributed in all tissues, with the highest levels occurring in the liver, kidney, and urinary bladder. Excretion of radioactivity was rapid and approximately 80% of the dose was eliminated 24 hr after oral administration, 72% in the urine and 8% in feces. MEHP was extensively metabolized after oral administration, and the major urinary metabolites were identified as an alcohol, a ketone, and an acid resulting from the side-chain oxidation of MEHP. A trace of o-phthalic acid was also identified. | Metabolism and tissue distribution of mono-2-ethylhexyl phthalate in the rat. The absorption, distribution and metabolic excretion of mono-2-ethylhexyl [7-14C]phthalate (MEHP) were studied in the rat. This compound was readily absorbed from the gastrointestinal tract. Radioactivity following intravenous administration of 14C-MEHP was rapidly distributed in all tissues, with the highest levels occurring in the liver, kidney, and urinary bladder. Excretion of radioactivity was rapid and approximately 80% of the dose was eliminated 24 hr after oral administration, 72% in the urine and 8% in feces. MEHP was extensively metabolized after oral administration, and the major urinary metabolites were identified as an alcohol, a ketone, and an acid resulting from the side-chain oxidation of MEHP. A trace of o-phthalic acid was also identified. | [
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PMID:26530 | Species, sex, and developmental differences in the O- and N-dealkylation of ethylmorphine by hepatic microsomes. | 3-O-[1'-14C]Ethylmorphine and ethylmorphine, respectively, were used to measure O- and N-dealkylase activities of hepatic microsomes. The well-known sex difference in the rate of N-delakylation in mature rats was not observed with O-dealkylation, nor did O-dealkylase activity increase as male rats reached maturity, as is the case with N-dealkylase activity. Accordingly, O-dealkylation represents only about 20% of the total dealkylase activity (O- + N-) in mature male rats, but about 50% in mature female rats. A comparison of the O- and N-dealkylating activities of hepatic microsomes from rats, mice, guinea pigs, and rabbits showed that both the rates of O- and N-dealkylation and the ratio of the two reactions vary greatly among animal species. These studies contribute to the evidence that different cytochrome P-450-dependent mono-oxygenase systems are involved in the O- and N-dealkylation of opium alkaloids. | Species, sex, and developmental differences in the O- and N-dealkylation of ethylmorphine by hepatic microsomes. 3-O-[1'-14C]Ethylmorphine and ethylmorphine, respectively, were used to measure O- and N-dealkylase activities of hepatic microsomes. The well-known sex difference in the rate of N-delakylation in mature rats was not observed with O-dealkylation, nor did O-dealkylase activity increase as male rats reached maturity, as is the case with N-dealkylase activity. Accordingly, O-dealkylation represents only about 20% of the total dealkylase activity (O- + N-) in mature male rats, but about 50% in mature female rats. A comparison of the O- and N-dealkylating activities of hepatic microsomes from rats, mice, guinea pigs, and rabbits showed that both the rates of O- and N-dealkylation and the ratio of the two reactions vary greatly among animal species. These studies contribute to the evidence that different cytochrome P-450-dependent mono-oxygenase systems are involved in the O- and N-dealkylation of opium alkaloids. | [
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PMID:26532 | Levodopa pharmacokinetics. Alterations after benserazide, a decarboxylase inhibitor. | Plasma levodopa decay curves appeared to be triexponential up to 6 hr after single intravenous injections of levodopa in rats, rabbits, and dogs. After pretreatment of each of these three species with benserazide (Ro-4-4602), a decarboxylase inhibitor, plasma levodopa concentrations declined biexponentially. Administration of benserazide decreased both total plasma clearance and apparent volume of distribution of levodopa, but did not change the rate constant of the terminal phase of the plasma levodopa decay curve. Thus, decarboxylase inhibition failed to alter the plasma half-life of levodopa. | Levodopa pharmacokinetics. Alterations after benserazide, a decarboxylase inhibitor. Plasma levodopa decay curves appeared to be triexponential up to 6 hr after single intravenous injections of levodopa in rats, rabbits, and dogs. After pretreatment of each of these three species with benserazide (Ro-4-4602), a decarboxylase inhibitor, plasma levodopa concentrations declined biexponentially. Administration of benserazide decreased both total plasma clearance and apparent volume of distribution of levodopa, but did not change the rate constant of the terminal phase of the plasma levodopa decay curve. Thus, decarboxylase inhibition failed to alter the plasma half-life of levodopa. | [
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PMID:26533 | Biotransformation products of 3,4,4'-trichlorocarbanilide in rat, monkey, and man. | 3,4,4'-Trichlorocarbanilide (TCC), uniformly labeled with 14C in the monochloro ring, was administered to rats, rhesus monkeys, and humans. Radioactive materials in the plasma and urine of all three species and in the bile of rats and monkeys were separated by high performance liquid chromatography. The chromatography showed great similarity between the monkey and the human. Principal metabolites common to all species were the sulfate and glucuronide conjugates of 2'-, 3'-, and 6-hydroxy-TCC. The rat also produced the glucuronide and sulfate conjugates of 2',6-dihydroxy-TCC. The major urinary excretion products found in humans and monkeys were the N- and N'-TCC glucuronides. | Biotransformation products of 3,4,4'-trichlorocarbanilide in rat, monkey, and man. 3,4,4'-Trichlorocarbanilide (TCC), uniformly labeled with 14C in the monochloro ring, was administered to rats, rhesus monkeys, and humans. Radioactive materials in the plasma and urine of all three species and in the bile of rats and monkeys were separated by high performance liquid chromatography. The chromatography showed great similarity between the monkey and the human. Principal metabolites common to all species were the sulfate and glucuronide conjugates of 2'-, 3'-, and 6-hydroxy-TCC. The rat also produced the glucuronide and sulfate conjugates of 2',6-dihydroxy-TCC. The major urinary excretion products found in humans and monkeys were the N- and N'-TCC glucuronides. | [
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PMID:26534 | The absorption, excretion, and biotransformation of 3,4,4'-trichlorocarbanilide in humans. | The metabolism and disposition of 14C-TCC (3,4,4'-trichlorocarbanilide) have been evaluated in humans following oral exposure to 2.2 mumol/kg body wt. Fecal elimination (70% of dose) was complete 120 hr after dosing and the urinary excretion (27% of dose) was completed in 80 hr. The maximum plasma level occurred 2.8 hr after dosing and was 3.7 nmol-equivalents of TCC per g of plasma (approximately 1.2 ppm). Biotransformation of TCC was rapid but did not appear to involve splitting of the basic TCC structure. The major plasma metabolites were N- and N'-glucuronides of TCC which were eliminated with t1/2 approximately 2 hr to the urine and 2'-hydroxy-TCC sulfate and 6-hydroxy-TCC sulfate (the o-hydroxy-TCC sulfates) which were removed with t1/2 approximately 20 hr (presumably into the bile). It is concluded that a nonradioactive analytical method based on the urinary excretion of the N-glucuronides would be suitable for the determination of TCC absorption in humans. | The absorption, excretion, and biotransformation of 3,4,4'-trichlorocarbanilide in humans. The metabolism and disposition of 14C-TCC (3,4,4'-trichlorocarbanilide) have been evaluated in humans following oral exposure to 2.2 mumol/kg body wt. Fecal elimination (70% of dose) was complete 120 hr after dosing and the urinary excretion (27% of dose) was completed in 80 hr. The maximum plasma level occurred 2.8 hr after dosing and was 3.7 nmol-equivalents of TCC per g of plasma (approximately 1.2 ppm). Biotransformation of TCC was rapid but did not appear to involve splitting of the basic TCC structure. The major plasma metabolites were N- and N'-glucuronides of TCC which were eliminated with t1/2 approximately 2 hr to the urine and 2'-hydroxy-TCC sulfate and 6-hydroxy-TCC sulfate (the o-hydroxy-TCC sulfates) which were removed with t1/2 approximately 20 hr (presumably into the bile). It is concluded that a nonradioactive analytical method based on the urinary excretion of the N-glucuronides would be suitable for the determination of TCC absorption in humans. | [
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PMID:26535 | Metabolism of cyclobenzaprine in the dog. | Ten metabolites of cyclobenzaprine, accounting for approximately 50% of the urinary radioactivity, were identified in the urine of dogs to which the labeled drug had been given orally. These included the 1,2-dihydrodiol, three phenolic derivatives, the N-oxide, the 10,11-epoxide, the 10,11-glycol, desmethylcyclobenzaprine, and the glucuronide conjugates of desmethylcyclobenzaprine and cyclobenzaprine. The metabolites were excreted in both the free and conjugated states. Unchanged cyclobenzaprine was present in only minor amounts. | Metabolism of cyclobenzaprine in the dog. Ten metabolites of cyclobenzaprine, accounting for approximately 50% of the urinary radioactivity, were identified in the urine of dogs to which the labeled drug had been given orally. These included the 1,2-dihydrodiol, three phenolic derivatives, the N-oxide, the 10,11-epoxide, the 10,11-glycol, desmethylcyclobenzaprine, and the glucuronide conjugates of desmethylcyclobenzaprine and cyclobenzaprine. The metabolites were excreted in both the free and conjugated states. Unchanged cyclobenzaprine was present in only minor amounts. | [
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PMID:26536 | Pharmacokinetic model of presystemic metabolism. | A pharmacokinetic perfusion model is presented that describes the disposition of drugs that are subject to both first-pass hepatic and intestinal epithelial metabolism. Equations are developed to estimate hepatic and intestinal epithelial clearances by determining drug concentrations as a function of time in both portal and peripheral vein blood after oral and iv administration, and by determining or estimating the flow rate of blood perfusing the gastrointestinal tissues. A method that can be used, under the stated conditions, to approximate the systemic availability after oral administration of drugs subject to presystemic metabolism is also developed. | Pharmacokinetic model of presystemic metabolism. A pharmacokinetic perfusion model is presented that describes the disposition of drugs that are subject to both first-pass hepatic and intestinal epithelial metabolism. Equations are developed to estimate hepatic and intestinal epithelial clearances by determining drug concentrations as a function of time in both portal and peripheral vein blood after oral and iv administration, and by determining or estimating the flow rate of blood perfusing the gastrointestinal tissues. A method that can be used, under the stated conditions, to approximate the systemic availability after oral administration of drugs subject to presystemic metabolism is also developed. | [
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PMID:26538 | Studies on metabolism of bromazepam. VI. Reduction of 2-(2-amino-5-bromobenzoyl)pyridine, a metabolite of bromazepam, in the rabbit, rat, and guinea pig. | Three urinary metabolites that were formed by cleavage of the benzodiazepine ring of bromazepam, 2-(2-amino-5-bromobenzoyl)pyridine (ABBP), 2-(2-amino-5-bromo-3-hydroxybenzoyl)pyridine (3-OH-ABBP), and 2-amino-5-bromo-2'-azabenzhydrol (ABAB), were measured in urine of rabbits, rats, and guinea pigs. The major metabolite was 3-OH-ABBP in all animals given bromazepam orally. ABAB was also excreted in major amounts in the guinea pig, but was excreted in minor amounts in the rabbit and rat. Moreover, ABAB was excreted in the urine of all animals given ABBP orally. It may be concluded that ABAB was formed by reduction of the carbonyl group of ABBP. ABBP reduction was catalyzed by NADPH-dependent enzymes occurring in rabbit liver cytoplasm, and rat liver microsomes, and guinea pig liver cytoplasm and microsomes. The reductases were inhibited by sulfhydryl group reagents. The optimum pH of the cytoplasmic enzyme ranged from 7.2 to 7.8, and that of the microsomal enzyme was 6.5. The apparent KM value for the reduction of ABBP by guinea pig liver microsomes was the lowest among all of the liver preparations. | Studies on metabolism of bromazepam. VI. Reduction of 2-(2-amino-5-bromobenzoyl)pyridine, a metabolite of bromazepam, in the rabbit, rat, and guinea pig. Three urinary metabolites that were formed by cleavage of the benzodiazepine ring of bromazepam, 2-(2-amino-5-bromobenzoyl)pyridine (ABBP), 2-(2-amino-5-bromo-3-hydroxybenzoyl)pyridine (3-OH-ABBP), and 2-amino-5-bromo-2'-azabenzhydrol (ABAB), were measured in urine of rabbits, rats, and guinea pigs. The major metabolite was 3-OH-ABBP in all animals given bromazepam orally. ABAB was also excreted in major amounts in the guinea pig, but was excreted in minor amounts in the rabbit and rat. Moreover, ABAB was excreted in the urine of all animals given ABBP orally. It may be concluded that ABAB was formed by reduction of the carbonyl group of ABBP. ABBP reduction was catalyzed by NADPH-dependent enzymes occurring in rabbit liver cytoplasm, and rat liver microsomes, and guinea pig liver cytoplasm and microsomes. The reductases were inhibited by sulfhydryl group reagents. The optimum pH of the cytoplasmic enzyme ranged from 7.2 to 7.8, and that of the microsomal enzyme was 6.5. The apparent KM value for the reduction of ABBP by guinea pig liver microsomes was the lowest among all of the liver preparations. | [
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PMID:26539 | Metabolism of levorotary 4,5-dihydrodiazepam in the rat. | The metabolism of (-)-4,5-dihydrodiazepam (7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-2H-1,4-benzo[2-14C]diazepin-2-one) (I) was investigated in rats. Metabolites from urine and bile extracts purified by thin-layer chromatography were identified by mass spectrometry. Diazepam and its main metabolites were found among the biotransformation products of I. Based on these findings, the most important identified metabolic route of the compound studied appears to be the formation of an unsaturated bond between the N4 and C5 atoms, and further transformation of the diazepam formed. | Metabolism of levorotary 4,5-dihydrodiazepam in the rat. The metabolism of (-)-4,5-dihydrodiazepam (7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-2H-1,4-benzo[2-14C]diazepin-2-one) (I) was investigated in rats. Metabolites from urine and bile extracts purified by thin-layer chromatography were identified by mass spectrometry. Diazepam and its main metabolites were found among the biotransformation products of I. Based on these findings, the most important identified metabolic route of the compound studied appears to be the formation of an unsaturated bond between the N4 and C5 atoms, and further transformation of the diazepam formed. | [
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PMID:26541 | Microsomal N-hydroxylation of trans-4'-alkoxy-4-acetamidostilbenes. | Hamster liver microsomes catalyze the N-hydroxylation of the 4'-OCH3, 4'-OCH2CH3, 4'-O(CH2)2CH3, and 4'-O(CH2)3CH3 analogs of trans-4-acetamidostilbene. Other metabolites which were identified were the O-deethylation product of the 4'-OCH2CH3 analog as well as the alpha,beta-epoxides of the 4'-OCH2CH3 and 4'-O(CH2)2CH3 compounds and the (omega-1)-hydroxylation product of trans-4'-n-butoxy-4-acetamidostilbene. The kinetics of metabolism of the 4'-O(CH2)3CH3 analog were determined, but the rates of formation of the metabolites of the other members of the series were not linearly related to substrate concentration. | Microsomal N-hydroxylation of trans-4'-alkoxy-4-acetamidostilbenes. Hamster liver microsomes catalyze the N-hydroxylation of the 4'-OCH3, 4'-OCH2CH3, 4'-O(CH2)2CH3, and 4'-O(CH2)3CH3 analogs of trans-4-acetamidostilbene. Other metabolites which were identified were the O-deethylation product of the 4'-OCH2CH3 analog as well as the alpha,beta-epoxides of the 4'-OCH2CH3 and 4'-O(CH2)2CH3 compounds and the (omega-1)-hydroxylation product of trans-4'-n-butoxy-4-acetamidostilbene. The kinetics of metabolism of the 4'-O(CH2)3CH3 analog were determined, but the rates of formation of the metabolites of the other members of the series were not linearly related to substrate concentration. | [
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PMID:26542 | Microsomal mixed-function amine oxidase. Oxidation products of piperazine-substituted phenothiazine drugs. | Oxidation products of fluphenazide, thioproperazine, and trifluoperazine obtained in reactions catalyzed by homogeneous preparations of the microsomal mixed-function amine oxidase have been isolated and identified. Approximately 0.5 g of metabolite of each piperazine-substituted phenothiazine drug was prepared in reactors containing, as catalyst, the purified oxidase covalently attached to glass beads. Nuclear magnetic resonance spectra of the isolated products indicated that with all three substrates the enzyme preferentially catalyzes N-oxidation of the piperazine nitrogen furthest from the phenothiazine nitrogen atom. The enzyme-catalyzed oxidation is quite specific and oxidation of the sulfur or nitrogen atoms in the phenothiazine ring could not be detected. Concentrations of piperazine-substituted phenothiazines required to half-saturate the amine oxidase were in the micromolar range and at pH 8.3 and 37 degrees C, all those tested were oxidized at approximately 2 mumol/min/mg of enzyme. Kinetic constants for the piperazine-substituted phenothiazines were very similar to those obtained with phenothiazines containing a dimethylaminopropyl sidechain. | Microsomal mixed-function amine oxidase. Oxidation products of piperazine-substituted phenothiazine drugs. Oxidation products of fluphenazide, thioproperazine, and trifluoperazine obtained in reactions catalyzed by homogeneous preparations of the microsomal mixed-function amine oxidase have been isolated and identified. Approximately 0.5 g of metabolite of each piperazine-substituted phenothiazine drug was prepared in reactors containing, as catalyst, the purified oxidase covalently attached to glass beads. Nuclear magnetic resonance spectra of the isolated products indicated that with all three substrates the enzyme preferentially catalyzes N-oxidation of the piperazine nitrogen furthest from the phenothiazine nitrogen atom. The enzyme-catalyzed oxidation is quite specific and oxidation of the sulfur or nitrogen atoms in the phenothiazine ring could not be detected. Concentrations of piperazine-substituted phenothiazines required to half-saturate the amine oxidase were in the micromolar range and at pH 8.3 and 37 degrees C, all those tested were oxidized at approximately 2 mumol/min/mg of enzyme. Kinetic constants for the piperazine-substituted phenothiazines were very similar to those obtained with phenothiazines containing a dimethylaminopropyl sidechain. | [
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PMID:26544 | Influence of pregnancy and folic acid on phenytoin metabolism by rat liver microsomes. | Liver microsomal suspensions from pregnant and nonpregnant Sprague-Dawley rats were assayed for NADPH-dependent metabolism of phenytoin to the hydroxylated products, 5-(rho-hydroxyphenyl)-5-phenylhydantoin (rhoHPPH) and 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)5-phenylhydantoin (H2DIOL). UDP-glucuronic acid-dependent glucuronyltransferase activity for conjugating rhoHPPH was also measured. The specific activity for formation of rhoHPPH decreased by 35% in 21-day pregnant rats compared with nonpregnant rats, whereas specific activity for production of H2DIOL was increased approximately 2-fold on the 7th and 14th but not the 21st day of pregnancy. Because of a 25% increase in liver weight during pregnancy, the total hepatic phenytoin hydroxylase activity in pregnant rats (day 21) was not significantly different from that of nonpregnant controls. Folic acid treatment during pregnancy prevented the decrease in phenytoin hydroxylase specific activity. The KM for production of either rhoHPPH or H2DIOL was similar (90 micrometer) in pregnant (day 21) and nonpregnant animals. Thus, overall hepatic microsomal enzyme activity for metabolizing phenytoin was not significantly reduced during pregnancy in rats, although the ratio of H2DIOL to rhoHPPH was increased during the first two weeks. Folic acid may play a role in pregnancy-associated changes in phenytoin hydroxylase activity. | Influence of pregnancy and folic acid on phenytoin metabolism by rat liver microsomes. Liver microsomal suspensions from pregnant and nonpregnant Sprague-Dawley rats were assayed for NADPH-dependent metabolism of phenytoin to the hydroxylated products, 5-(rho-hydroxyphenyl)-5-phenylhydantoin (rhoHPPH) and 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)5-phenylhydantoin (H2DIOL). UDP-glucuronic acid-dependent glucuronyltransferase activity for conjugating rhoHPPH was also measured. The specific activity for formation of rhoHPPH decreased by 35% in 21-day pregnant rats compared with nonpregnant rats, whereas specific activity for production of H2DIOL was increased approximately 2-fold on the 7th and 14th but not the 21st day of pregnancy. Because of a 25% increase in liver weight during pregnancy, the total hepatic phenytoin hydroxylase activity in pregnant rats (day 21) was not significantly different from that of nonpregnant controls. Folic acid treatment during pregnancy prevented the decrease in phenytoin hydroxylase specific activity. The KM for production of either rhoHPPH or H2DIOL was similar (90 micrometer) in pregnant (day 21) and nonpregnant animals. Thus, overall hepatic microsomal enzyme activity for metabolizing phenytoin was not significantly reduced during pregnancy in rats, although the ratio of H2DIOL to rhoHPPH was increased during the first two weeks. Folic acid may play a role in pregnancy-associated changes in phenytoin hydroxylase activity. | [
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PMID:26550 | Quantitation of N-demethylantipyrine in biological samples and isolation and characterization of its glucuronic acid conjugate. | An improved method for quantitating N-demethylantipyrine (N-DEM-AP) in urine by gas chromatography or gas chromatography-mass spectrometry has been developed. Recovery of greater than 90% of N-DEM-AP was achieved by extraction of the sample at pH 1 after addition of 3-amino-1-phenyl-2-pyrazolin-5-one. The coefficient of variation of replicate analyses was 8%. N-DEM-AP was excreted in the urine as a glucuronic acid conjugate. This conjugate was isolated from the urine of an individual receiving antipyrine and purified. The NMR and mass-spectral data are consistent with the conjugate being an O-glucuronide of N-DEM-AP in its enol form. | Quantitation of N-demethylantipyrine in biological samples and isolation and characterization of its glucuronic acid conjugate. An improved method for quantitating N-demethylantipyrine (N-DEM-AP) in urine by gas chromatography or gas chromatography-mass spectrometry has been developed. Recovery of greater than 90% of N-DEM-AP was achieved by extraction of the sample at pH 1 after addition of 3-amino-1-phenyl-2-pyrazolin-5-one. The coefficient of variation of replicate analyses was 8%. N-DEM-AP was excreted in the urine as a glucuronic acid conjugate. This conjugate was isolated from the urine of an individual receiving antipyrine and purified. The NMR and mass-spectral data are consistent with the conjugate being an O-glucuronide of N-DEM-AP in its enol form. | [
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PMID:26549 | Alterations in the pharmacokinetics of 3H-delta9-tetrahydrocannabinol in mice by bacterial endotoxin. | Mice were pretreated with either bacterial endotoxin (3 mg/kg, ip) or saline 3 hr prior to an ip injection of 100 mg of 3H-delta9-tetrahydrocannabinol (3H-delta9-THC) per kg, a combination that results in synergistic lethality. Five hours after the injection of 3H-delta9-THC, the endotoxin-pretreated mice contained a significantly greater amount of radioactivity in kidney, liver, heart, plasma, urine, and brain than those without pretreatment. However, the plasma and brain levels of the animals tested with both endotoxin and 3H-delta9-THC (100 mg/kg) were significantly less than those in mice treated only with 200 mg of 3H-delta9-THC per kg, a sublethal dose. The percentage of radioactivity corresponding to unchanged 3H-delta9-THC in extracts of livers and brains was significantly greater in the endotoxin-pretreatment group than in controls. The brain level of 3H-delta9-THC in the endotoxin-pretreated mice was 50% higher than that in the saline-pretreated mice 5 hr after 3H-delta9-THC (100 mg/kg) administration. However, the brain levels of 3H-delta9-THC in the mice treated with endotoxin and 3H-delta9-THC (100 mg/kg) was one-third of that in brains of mice receiving the LD50 of 3H-delta9-THC (300 mg/kg). | Alterations in the pharmacokinetics of 3H-delta9-tetrahydrocannabinol in mice by bacterial endotoxin. Mice were pretreated with either bacterial endotoxin (3 mg/kg, ip) or saline 3 hr prior to an ip injection of 100 mg of 3H-delta9-tetrahydrocannabinol (3H-delta9-THC) per kg, a combination that results in synergistic lethality. Five hours after the injection of 3H-delta9-THC, the endotoxin-pretreated mice contained a significantly greater amount of radioactivity in kidney, liver, heart, plasma, urine, and brain than those without pretreatment. However, the plasma and brain levels of the animals tested with both endotoxin and 3H-delta9-THC (100 mg/kg) were significantly less than those in mice treated only with 200 mg of 3H-delta9-THC per kg, a sublethal dose. The percentage of radioactivity corresponding to unchanged 3H-delta9-THC in extracts of livers and brains was significantly greater in the endotoxin-pretreatment group than in controls. The brain level of 3H-delta9-THC in the endotoxin-pretreated mice was 50% higher than that in the saline-pretreated mice 5 hr after 3H-delta9-THC (100 mg/kg) administration. However, the brain levels of 3H-delta9-THC in the mice treated with endotoxin and 3H-delta9-THC (100 mg/kg) was one-third of that in brains of mice receiving the LD50 of 3H-delta9-THC (300 mg/kg). | [
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PMID:26552 | The metabolism of (2-cyclopentyl-6,7-dichloro-2-methyl-1-oxo-5-indanyloxy)acetic acid in chimpanzee and man. | The metabolism of the polyvalent saluretic agent (2-cyclopentyl-6,7-dichloro-2-methyl-1-oxo-5-indanyloxy)acetic acid was studied in chimpanzee and man. The drug was well absorbed and extensively metabolized by man. Peak levels of drug (5--8 microgram/ml) occurred within 1.5--4.5 hr of drug administration. The plasma half-life was estimated to be 2 hr; a similar half-life was observed in the chimpanzee. Little unchanged drug (less than 10%) was excreted in the urine of either species. Similar metabolic profiles were obtained for man and chimpanzee. The major urinary metabolites resulted from hydroxylation of the cyclopentyl moiety, giving rise to a number of diastereomers. The alcohol metabolites were subsequently oxidized to the ketone. The excretion of the metabolites coincided with maximal excretion of sodium and chloride ions. The hydroxylated metabolites have intrinsic pharmacological activity. | The metabolism of (2-cyclopentyl-6,7-dichloro-2-methyl-1-oxo-5-indanyloxy)acetic acid in chimpanzee and man. The metabolism of the polyvalent saluretic agent (2-cyclopentyl-6,7-dichloro-2-methyl-1-oxo-5-indanyloxy)acetic acid was studied in chimpanzee and man. The drug was well absorbed and extensively metabolized by man. Peak levels of drug (5--8 microgram/ml) occurred within 1.5--4.5 hr of drug administration. The plasma half-life was estimated to be 2 hr; a similar half-life was observed in the chimpanzee. Little unchanged drug (less than 10%) was excreted in the urine of either species. Similar metabolic profiles were obtained for man and chimpanzee. The major urinary metabolites resulted from hydroxylation of the cyclopentyl moiety, giving rise to a number of diastereomers. The alcohol metabolites were subsequently oxidized to the ketone. The excretion of the metabolites coincided with maximal excretion of sodium and chloride ions. The hydroxylated metabolites have intrinsic pharmacological activity. | [
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PMID:26551 | Urinary metabolites of 3,5-di-(1-[13C]methyl-1-methylethyl)4-hydroxytoluene (BHT-13C) in man. | Butylated hydroxytoluene (BHT) containing the stable isotope 13C was synthesized from 2-[13C]methylpropan-2-ol. A minor constituent of urine following ingestion of BHT-13C by a human volunteer was identified as 3,5-di-(1-[13C]methyl-1-methylethyl)-4-hydroxybenzoic acid, The major metabolite detected was 13C-labeled 5-carboxy-7-(1-carboxy-1-methylethyl)-3,3-dimethyl-2-hydroxy-2,3-dihydrobenzofuran. Detailed spectral analysis provided the basis for structural assignment. No evidence was found for intermediate metabolites leading from BHT-13C to the above compounds. Analysis of one fraction indicated the presence of traces of S-(3,5-di-(1-[13C]methyl-1-methylethyl-4-hydroxy-benzyl)-N-acetylcysteine. Analysis of serum samples by gas chromatography detected only trace quantities of unchanged BHT. No evidence was found for the presence of other nonpolar or unconjugated metabolites. | Urinary metabolites of 3,5-di-(1-[13C]methyl-1-methylethyl)4-hydroxytoluene (BHT-13C) in man. Butylated hydroxytoluene (BHT) containing the stable isotope 13C was synthesized from 2-[13C]methylpropan-2-ol. A minor constituent of urine following ingestion of BHT-13C by a human volunteer was identified as 3,5-di-(1-[13C]methyl-1-methylethyl)-4-hydroxybenzoic acid, The major metabolite detected was 13C-labeled 5-carboxy-7-(1-carboxy-1-methylethyl)-3,3-dimethyl-2-hydroxy-2,3-dihydrobenzofuran. Detailed spectral analysis provided the basis for structural assignment. No evidence was found for intermediate metabolites leading from BHT-13C to the above compounds. Analysis of one fraction indicated the presence of traces of S-(3,5-di-(1-[13C]methyl-1-methylethyl-4-hydroxy-benzyl)-N-acetylcysteine. Analysis of serum samples by gas chromatography detected only trace quantities of unchanged BHT. No evidence was found for the presence of other nonpolar or unconjugated metabolites. | [
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PMID:26554 | Elimination of radioactivity following administration of [15,16-3H]naltrexone to rats and guinea pigs. | The elimination of radioactivity after [15,16-3H]naltrexone administration was studied in rats and guinea pigs. An average of 42% of the dose was eliminated in urine and 55% in feces following administration of 1 mg/kg iv to each of three rats. Analysis of radioactivity in the excreta of one rat that received the same dose im yielded similar results. On the other hand, four guinea pigs that received 1 mg/kg iv excreted only 14% of the dose in feces and 84% in urine. Similar results were obtained following im administration to guinea pigs at 1 and 20 mg/kg doses. In guinea pig excreta, an average of 64% of the dose corresponded to naltrexone and conjugates, 19% to beta-naltrexol and conjugates, and 2% to alpha-naltrexol and conjugates. In urine, the radioactivity corresponding to alpha-naltrexol and naltrexone was present mainly in conjugated form, whereas apparent beta-naltrexol was mainly unconjugated. The radioactivity in feces corresponded principally to unconjugated naltrexone and beta-naltrexol. | Elimination of radioactivity following administration of [15,16-3H]naltrexone to rats and guinea pigs. The elimination of radioactivity after [15,16-3H]naltrexone administration was studied in rats and guinea pigs. An average of 42% of the dose was eliminated in urine and 55% in feces following administration of 1 mg/kg iv to each of three rats. Analysis of radioactivity in the excreta of one rat that received the same dose im yielded similar results. On the other hand, four guinea pigs that received 1 mg/kg iv excreted only 14% of the dose in feces and 84% in urine. Similar results were obtained following im administration to guinea pigs at 1 and 20 mg/kg doses. In guinea pig excreta, an average of 64% of the dose corresponded to naltrexone and conjugates, 19% to beta-naltrexol and conjugates, and 2% to alpha-naltrexol and conjugates. In urine, the radioactivity corresponding to alpha-naltrexol and naltrexone was present mainly in conjugated form, whereas apparent beta-naltrexol was mainly unconjugated. The radioactivity in feces corresponded principally to unconjugated naltrexone and beta-naltrexol. | [
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PMID:26555 | Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man. | With the aim of developing anticancer compounds which overcome some of the clinical limitations of the polar dihydrofolate reductase inhibitor, methotrexate, the physicochemical properties, kinetics, and metabolism of a series of lipid-soluble 2,4-diamino-5-phenylpyrimidine folate antagonists have been studied. Metoprine and etoprine, potent inhibitors of mammalian dihydrofolate reductase, were compared with pyrimethamine, a widely used antimalarial drug. The development of assay procedures in our laboratory and the synthesis of radiolabeled compounds have enabled a comparison of the kinetic characteristics and tissue distribution of these compounds in several species. The relative lipophilicities as indicated by the octanol/water partition coefficient are: etoprine (log P = 3.19) greater than metoprine (log P = 2.82) greater than pyrimethamine (log P = 2.69). Etoprine has the greatest affinity for plasma proteins, but all three compounds are bound to human plasma protein by 87% or more at therapeutic concentrations. Pharmacokinetic studies in the mouse, rat, dog, and man indicate that metoprine has the longest plasma half-life in all four species. The mean plasma half-lives in man are: pyrimethamine, 85 hr; metoprine, 216 hr; etoprine, 176 hr. | Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man. With the aim of developing anticancer compounds which overcome some of the clinical limitations of the polar dihydrofolate reductase inhibitor, methotrexate, the physicochemical properties, kinetics, and metabolism of a series of lipid-soluble 2,4-diamino-5-phenylpyrimidine folate antagonists have been studied. Metoprine and etoprine, potent inhibitors of mammalian dihydrofolate reductase, were compared with pyrimethamine, a widely used antimalarial drug. The development of assay procedures in our laboratory and the synthesis of radiolabeled compounds have enabled a comparison of the kinetic characteristics and tissue distribution of these compounds in several species. The relative lipophilicities as indicated by the octanol/water partition coefficient are: etoprine (log P = 3.19) greater than metoprine (log P = 2.82) greater than pyrimethamine (log P = 2.69). Etoprine has the greatest affinity for plasma proteins, but all three compounds are bound to human plasma protein by 87% or more at therapeutic concentrations. Pharmacokinetic studies in the mouse, rat, dog, and man indicate that metoprine has the longest plasma half-life in all four species. The mean plasma half-lives in man are: pyrimethamine, 85 hr; metoprine, 216 hr; etoprine, 176 hr. | [
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PMID:26559 | [Assessment of vigilance]. | Two aspects of vigilance are to be distinguished: the quantitative one refers to sleep-wakefulness dimension and the qualitative one refers to focusing of attention. Their combination leads to a curvilinear relationship between activation and performances. After describing the psychometric characteristics of vigilance tests, some examples are given of simple paper-pencil or more sophisticated methods. Physiological indices are also approached. The sources of variation influencing vigilance measurement are presented and also some useful experimental designs. At last some remarks are made on statistical exploitation and interpretation of results. | [Assessment of vigilance]. Two aspects of vigilance are to be distinguished: the quantitative one refers to sleep-wakefulness dimension and the qualitative one refers to focusing of attention. Their combination leads to a curvilinear relationship between activation and performances. After describing the psychometric characteristics of vigilance tests, some examples are given of simple paper-pencil or more sophisticated methods. Physiological indices are also approached. The sources of variation influencing vigilance measurement are presented and also some useful experimental designs. At last some remarks are made on statistical exploitation and interpretation of results. | [
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PMID:26556 | Pharmacokinetics and steady-state myocardial uptake of disopyramide in the dog. | The pharmacokinetics and steady-state myocardial uptake of the antiarrhythmic drug disopyramide (DP) were determined in dogs after oral or intravenous administration of [14C]disopyramide phosphate. DP was absorbed rapidly and its absolute oral bioavailability was about 70%. Significant dose-dependent kinetics were not apparent after 7.5- to 30-mg/kg po doses. Plasma half-lives of DP were about 2.9 and 1.2 hr after the po and iv doses, respectively. DP and its N-dealkylated metabolites were largely excreted in the urine and their composition was qualitatively similar after the po and iv doses. Marked differences in the protein binding of DP in human and dog plasma were found. In the papillary muscle, ventricular septum, and ventricles of one dog, the steady-state concentrations of DP and its less active mono-N-dealkylated metabolite were about twice those in plasma, whereas in the atria and tricuspid and mitral valves they were similar to those in plasma. | Pharmacokinetics and steady-state myocardial uptake of disopyramide in the dog. The pharmacokinetics and steady-state myocardial uptake of the antiarrhythmic drug disopyramide (DP) were determined in dogs after oral or intravenous administration of [14C]disopyramide phosphate. DP was absorbed rapidly and its absolute oral bioavailability was about 70%. Significant dose-dependent kinetics were not apparent after 7.5- to 30-mg/kg po doses. Plasma half-lives of DP were about 2.9 and 1.2 hr after the po and iv doses, respectively. DP and its N-dealkylated metabolites were largely excreted in the urine and their composition was qualitatively similar after the po and iv doses. Marked differences in the protein binding of DP in human and dog plasma were found. In the papillary muscle, ventricular septum, and ventricles of one dog, the steady-state concentrations of DP and its less active mono-N-dealkylated metabolite were about twice those in plasma, whereas in the atria and tricuspid and mitral valves they were similar to those in plasma. | [
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PMID:26560 | [Influence of pipotiazine on schizophrenia]. | This study is an account of thirty cases of schizophrenia treated experimentally in open with Pipotiazine (19366 R.P.), these cases, of the Kraepelin's Dementia Praecox type, in serious or complicated forms necessitating important measures of hospital care. The quantitative and qualitative therapeutic results, very favourable and original, consist in the transformation of these serious forms into simple or latent forms of schizophrenia. The undesirable effects, rare and always regressive, were all the smaller in the measure as the favourable effects were greater, which indicates a precise impact on certain determinants (central control of affectivity and the representation of the autonomous body). Pipotiazine develops a curative process in the personality characterized mainly by the emergence of lucidity, narcissistic euphoria (anti-persecutory and anti-splintering) and by the apprehension of intrapsychic splitting, setting in motion the necessary psychological task of reconstruction. | [Influence of pipotiazine on schizophrenia]. This study is an account of thirty cases of schizophrenia treated experimentally in open with Pipotiazine (19366 R.P.), these cases, of the Kraepelin's Dementia Praecox type, in serious or complicated forms necessitating important measures of hospital care. The quantitative and qualitative therapeutic results, very favourable and original, consist in the transformation of these serious forms into simple or latent forms of schizophrenia. The undesirable effects, rare and always regressive, were all the smaller in the measure as the favourable effects were greater, which indicates a precise impact on certain determinants (central control of affectivity and the representation of the autonomous body). Pipotiazine develops a curative process in the personality characterized mainly by the emergence of lucidity, narcissistic euphoria (anti-persecutory and anti-splintering) and by the apprehension of intrapsychic splitting, setting in motion the necessary psychological task of reconstruction. | [
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PMID:26561 | Chorismate mutase/prephenate dehydratase from Escherichia coli K12. Effect of phenylalanine, NaCl and pH on the protein conformation. | The effects of phenylalanine, NaCl and pH on the conformation of chorismate mutase/prephenate dehydratase have been investigated, using measurements of far and near-ultraviolet circular dichroic spectra and ultraviolet difference spectra. At pH 8.2 in 20 mM Tris-Cl buffer the enzyme was found to contain 10-20% helix and 40-50% beta-structure. There was little or no change in these values on the addition of 1 mM phenylalanine (the allosteric effector) or 0.4 M NaCl or by decreasing the pH to 7.4. Both phenylalanine and NaCl caused significant changes in the conformation of the enzyme. The most prominent of these was the movement of a tryptophan residue into a more hydrophobic environment. There was also a slight perturbation of this tryptophan when the pH was decreased to 7.4. The conformational changes can explain sigmoidal kinetic behaviour observed previously [Gething et al. (1976) Eur. J. Biochem. 71, 317-325]. | Chorismate mutase/prephenate dehydratase from Escherichia coli K12. Effect of phenylalanine, NaCl and pH on the protein conformation. The effects of phenylalanine, NaCl and pH on the conformation of chorismate mutase/prephenate dehydratase have been investigated, using measurements of far and near-ultraviolet circular dichroic spectra and ultraviolet difference spectra. At pH 8.2 in 20 mM Tris-Cl buffer the enzyme was found to contain 10-20% helix and 40-50% beta-structure. There was little or no change in these values on the addition of 1 mM phenylalanine (the allosteric effector) or 0.4 M NaCl or by decreasing the pH to 7.4. Both phenylalanine and NaCl caused significant changes in the conformation of the enzyme. The most prominent of these was the movement of a tryptophan residue into a more hydrophobic environment. There was also a slight perturbation of this tryptophan when the pH was decreased to 7.4. The conformational changes can explain sigmoidal kinetic behaviour observed previously [Gething et al. (1976) Eur. J. Biochem. 71, 317-325]. | [
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PMID:26562 | Chorismate mutase/prephenate dehydratase from Escherichia coli K12. Binding studies with the allosteric effector phenylalanine. | The binding of phenylalanine to the allosteric site of chorismate mutase/prephenate dehydratase has been studied by steady-state dialysis. Under most of the experimental conditions examined positive co-operativity was observed for the binding of ligand up to 50% saturation and negative co-operativity above 50% saturation. In the presence of 0.4 M NaCl at pH 8.2 the co-operativity was positive at all phenylalanine concentrations and the maximal stoichiometry of 1 mol of phenylalanine/mol of enzyme subunit was observed. It was concluded that there is a single phenylalanine-binding site per subunit which is associated with the regulation of each of the mutase and dehydratase activities. The effects of enzyme concentration, NaCl, temperature and pH on the binding of phenylalanine have been investigated. Neither tyrosine nor tryptophan bound to the allosteric site of the enzyme. Enzyme that was desensitized to inhibition by phenylalanine following modification of three sulphydryl groups with 5,5'-dithio-bis (2-nitrobenzoic acid) did not bind phenylalanine. The mechanism of co-operativity, the binding of the enzyme to Sepharosyl-phenylalanine and the physiological significance of the inhibition of the enzyme by phenylalanine are discussed in terms of the results obtained. | Chorismate mutase/prephenate dehydratase from Escherichia coli K12. Binding studies with the allosteric effector phenylalanine. The binding of phenylalanine to the allosteric site of chorismate mutase/prephenate dehydratase has been studied by steady-state dialysis. Under most of the experimental conditions examined positive co-operativity was observed for the binding of ligand up to 50% saturation and negative co-operativity above 50% saturation. In the presence of 0.4 M NaCl at pH 8.2 the co-operativity was positive at all phenylalanine concentrations and the maximal stoichiometry of 1 mol of phenylalanine/mol of enzyme subunit was observed. It was concluded that there is a single phenylalanine-binding site per subunit which is associated with the regulation of each of the mutase and dehydratase activities. The effects of enzyme concentration, NaCl, temperature and pH on the binding of phenylalanine have been investigated. Neither tyrosine nor tryptophan bound to the allosteric site of the enzyme. Enzyme that was desensitized to inhibition by phenylalanine following modification of three sulphydryl groups with 5,5'-dithio-bis (2-nitrobenzoic acid) did not bind phenylalanine. The mechanism of co-operativity, the binding of the enzyme to Sepharosyl-phenylalanine and the physiological significance of the inhibition of the enzyme by phenylalanine are discussed in terms of the results obtained. | [
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PMID:26564 | Kinetics of the interaction of alpha-chymotrypsin with trypsin kallikrein inhibitor (Kunitz) in which the reactive-site peptide bond Lys-15--Ala-16 is split. | Modified trypsin kallikrein inhibitor (I*), with the reactive-site peptide bond Lys-15--Ala-16 split, reacts with alpha-chymotrypsin (E) via an intermediate X to the stable tetrahedral complex C:E + I in equilibrium X leads to C. Formation X constitutes a fast pre-equilibrium (equilibrium constant Kx = 7 X 10(-5) M, association rate constant kx = 4 X 10(3)M-1s-1) to the slow reaction X leads to C (rate constant kc = 2 X 10(-3) s-1), all values at pH 7.5. No intermediate X is observed when alpha-chymotrypsin reacts with I*-OMe in which the carboxyl group of Lys-15 is esterified by methanol. This observation as well as the different pH dependence of the overall association rate constants in the case of I* and I*-OMe indicate tha formation of X precedes formation of the acyl enzyme in the catalytic pathway. The data are compared to the similar results obtained with beta-trypsin and I* or I*-OMe. | Kinetics of the interaction of alpha-chymotrypsin with trypsin kallikrein inhibitor (Kunitz) in which the reactive-site peptide bond Lys-15--Ala-16 is split. Modified trypsin kallikrein inhibitor (I*), with the reactive-site peptide bond Lys-15--Ala-16 split, reacts with alpha-chymotrypsin (E) via an intermediate X to the stable tetrahedral complex C:E + I in equilibrium X leads to C. Formation X constitutes a fast pre-equilibrium (equilibrium constant Kx = 7 X 10(-5) M, association rate constant kx = 4 X 10(3)M-1s-1) to the slow reaction X leads to C (rate constant kc = 2 X 10(-3) s-1), all values at pH 7.5. No intermediate X is observed when alpha-chymotrypsin reacts with I*-OMe in which the carboxyl group of Lys-15 is esterified by methanol. This observation as well as the different pH dependence of the overall association rate constants in the case of I* and I*-OMe indicate tha formation of X precedes formation of the acyl enzyme in the catalytic pathway. The data are compared to the similar results obtained with beta-trypsin and I* or I*-OMe. | [
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PMID:26567 | Cycloheximide causes increased accumulation of translatable mRNA for tyrosine aminotransferase and tryptophan oxygenase in livers of cortisol-treated rats. | Messenger RNA activities for two cortisol-inducible enzymes, tyrosine aminotransferase and tryptophan oxygenase, have been determined by translation in a wheat germ system. The effects of cycloheximide on the two mRNA activities have been evaluated. Cortisol leads to an increase of the translatable mRNAs for tyrosine aminotransferase and tryptophan oxygenase with a maximum at approximately 6 h. Cycloheximide was administered 4 h after treatment with cortisol; 2 h later, the activities of tyrosine aminotransferase and tryptophan oxygenase mRNA had increased five-fold and two-fold, respectively, compared to the activities reached with cortisol alone. Thereafter the amount of the two translatable mRNAs declined, though 14 h after cortisol administration the mRNA activities were still several fold higher than in control animals. Application of alpha-amanitin together with cycloheximide did not prevent an increased accumulation of specific translatable mRNAs. The increase in tyrosine aminotransferase and tryptophan oxygenase activity by cortisol was immediately blocked by cycloheximide. Whereas tryptophan oxygenase activity rapidly declined after cycloheximide application, tyrosine aminotransferase activity remained at the same level. Approximately 4 h thereafter, both enzyme activities increased again. | Cycloheximide causes increased accumulation of translatable mRNA for tyrosine aminotransferase and tryptophan oxygenase in livers of cortisol-treated rats. Messenger RNA activities for two cortisol-inducible enzymes, tyrosine aminotransferase and tryptophan oxygenase, have been determined by translation in a wheat germ system. The effects of cycloheximide on the two mRNA activities have been evaluated. Cortisol leads to an increase of the translatable mRNAs for tyrosine aminotransferase and tryptophan oxygenase with a maximum at approximately 6 h. Cycloheximide was administered 4 h after treatment with cortisol; 2 h later, the activities of tyrosine aminotransferase and tryptophan oxygenase mRNA had increased five-fold and two-fold, respectively, compared to the activities reached with cortisol alone. Thereafter the amount of the two translatable mRNAs declined, though 14 h after cortisol administration the mRNA activities were still several fold higher than in control animals. Application of alpha-amanitin together with cycloheximide did not prevent an increased accumulation of specific translatable mRNAs. The increase in tyrosine aminotransferase and tryptophan oxygenase activity by cortisol was immediately blocked by cycloheximide. Whereas tryptophan oxygenase activity rapidly declined after cycloheximide application, tyrosine aminotransferase activity remained at the same level. Approximately 4 h thereafter, both enzyme activities increased again. | [
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PMID:26570 | Formation of complexes between microsomal cytochrome P-450-Fe(II) and nitrosoarenes obtained by oxidation of arylhydroxylamines or reduction of nitroarenes in situ. | A cytochrome P-450 complex exhibiting a Soret peak at 454 nm is formed by direct interaction of nitrosobenzene with NADPH-reduced rat liver microsomes in anaerobic conditions, by reaction of phenylhydroxylamine with aerobic microsomes or during nitrobenzene reduction by NADPH-reduced or dithionite-reduced microsomes. In the latter conditions, the complex formation is only transient as it is unstable to dithionite. Analogous reactions with myoglobin lead to the previously described myoglobin-Fe(II)-nitrosobenzene complex which has similar properties to those of the 454-nm-absorbing cytochrome P-450 complex. This analogy, together with the various conditions of its formation, strongly indicates that it is a cytochrome-P-450-Fe(II)-nitrosobenzene complex. The corresponding complex with the 4-chloro-nitrosobenzene ligand is formed in similar conditions. Cytochrome P-450-Fe(II) complexes with nitrosoarenes seem less stable than the previously described complexes with nitrosoalkanes. | Formation of complexes between microsomal cytochrome P-450-Fe(II) and nitrosoarenes obtained by oxidation of arylhydroxylamines or reduction of nitroarenes in situ. A cytochrome P-450 complex exhibiting a Soret peak at 454 nm is formed by direct interaction of nitrosobenzene with NADPH-reduced rat liver microsomes in anaerobic conditions, by reaction of phenylhydroxylamine with aerobic microsomes or during nitrobenzene reduction by NADPH-reduced or dithionite-reduced microsomes. In the latter conditions, the complex formation is only transient as it is unstable to dithionite. Analogous reactions with myoglobin lead to the previously described myoglobin-Fe(II)-nitrosobenzene complex which has similar properties to those of the 454-nm-absorbing cytochrome P-450 complex. This analogy, together with the various conditions of its formation, strongly indicates that it is a cytochrome-P-450-Fe(II)-nitrosobenzene complex. The corresponding complex with the 4-chloro-nitrosobenzene ligand is formed in similar conditions. Cytochrome P-450-Fe(II) complexes with nitrosoarenes seem less stable than the previously described complexes with nitrosoalkanes. | [
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PMID:26572 | Neurotransmittor changes in the rat brain after portacaval anastomosis. | Portacaval anastomosis in rats elevated the brain serotonin content by about 30%, the greatest increase being noted in the brain stem. A minor increase in norepinephrine content but no change in dopamine concentration was also noted. Low dose L-dopa treatment reversed the serotonin changes but did not affect catecholamine concentrations. Protein load tended to lower most transmittor concentrations without clinically affecting the animals. The formation of 5-HT from tryptophane in vitro in rat cortical slices was reduced by about 35% whereas the formation of 5-HIAA in the same slices was increased with about 60%. This in vitro study indicates a change in the activity of serotonin neurons caused by the protacaval shunt. The findings suggest that changes in brain serotonin metabolism and brain serotonin neurons may be an explanation of hepatic encephalopathy. | Neurotransmittor changes in the rat brain after portacaval anastomosis. Portacaval anastomosis in rats elevated the brain serotonin content by about 30%, the greatest increase being noted in the brain stem. A minor increase in norepinephrine content but no change in dopamine concentration was also noted. Low dose L-dopa treatment reversed the serotonin changes but did not affect catecholamine concentrations. Protein load tended to lower most transmittor concentrations without clinically affecting the animals. The formation of 5-HT from tryptophane in vitro in rat cortical slices was reduced by about 35% whereas the formation of 5-HIAA in the same slices was increased with about 60%. This in vitro study indicates a change in the activity of serotonin neurons caused by the protacaval shunt. The findings suggest that changes in brain serotonin metabolism and brain serotonin neurons may be an explanation of hepatic encephalopathy. | [
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PMID:26573 | Effect of capsule colour and order of administration of hypnotic treatments. | Ninety-six hospitalized insomniac patients were asked to compare by a daily questionnaire the effect on sleep of the colour of the capsules and the order of administration of two treatments--heptabarbital and placebo. A balanced incomplete-block design was used; sleep onset time and sleep duration time were the main criteria of assessment. There was a significant interaction of colour and order of administration with sex. The placebo response was positive in 36% of instances. | Effect of capsule colour and order of administration of hypnotic treatments. Ninety-six hospitalized insomniac patients were asked to compare by a daily questionnaire the effect on sleep of the colour of the capsules and the order of administration of two treatments--heptabarbital and placebo. A balanced incomplete-block design was used; sleep onset time and sleep duration time were the main criteria of assessment. There was a significant interaction of colour and order of administration with sex. The placebo response was positive in 36% of instances. | [
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PMID:26575 | Subpopulations of mouse T lymphocytes. II. Suppression of graft-vs.-host reactions by naturally proliferating splenic T cells. | The immunological role of a naturally proliferating subpopulation of splenic T cells was investigated using the graft-vs.-host (GvH) reaction on the mouse. Normal parental spleen cells, purified splenic T cells or lymph node cells were pulse-treated for one hour in vitro with tritiated thymidine of high specific activity ([3H]dThd, "thymidine suicide"). The treatment specifically and selectively kills proliferating cells which are actively synthesizing DNA, i.e. cells in S phase. Following treatment, the cells were transferred to F1 recipients and the GvH reaction measured by the splenomegaly assay. The results showed that the GvH effector cells in the donor spleen and lymph node are nonproliferating T cells. Furthermore, donor spleen cells treated with [3H]dThd consistently had enhanced GvH reactivity when compared to the controls, while the phytohemagglutinin response of these same treated cell suspensions was significantly inhibited. When purified splenic T cells were used, treatment with [3H]dThd also caused an increase in the GvH reaction, showing that a T cell population was being affected by the cycleactive agent. These results indicated that some naturally proliferating T cells have suppressor functions, and their specific inactivation allows nonproliferating effector T cells to mount a more vigourous GvH reaction. | Subpopulations of mouse T lymphocytes. II. Suppression of graft-vs.-host reactions by naturally proliferating splenic T cells. The immunological role of a naturally proliferating subpopulation of splenic T cells was investigated using the graft-vs.-host (GvH) reaction on the mouse. Normal parental spleen cells, purified splenic T cells or lymph node cells were pulse-treated for one hour in vitro with tritiated thymidine of high specific activity ([3H]dThd, "thymidine suicide"). The treatment specifically and selectively kills proliferating cells which are actively synthesizing DNA, i.e. cells in S phase. Following treatment, the cells were transferred to F1 recipients and the GvH reaction measured by the splenomegaly assay. The results showed that the GvH effector cells in the donor spleen and lymph node are nonproliferating T cells. Furthermore, donor spleen cells treated with [3H]dThd consistently had enhanced GvH reactivity when compared to the controls, while the phytohemagglutinin response of these same treated cell suspensions was significantly inhibited. When purified splenic T cells were used, treatment with [3H]dThd also caused an increase in the GvH reaction, showing that a T cell population was being affected by the cycleactive agent. These results indicated that some naturally proliferating T cells have suppressor functions, and their specific inactivation allows nonproliferating effector T cells to mount a more vigourous GvH reaction. | [
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PMID:26576 | Investigation of cardiac beta-adrenoceptors using 125I-labelled 1-(4-iodophenoxy)-3-isopropylaminopropan-2-ol. | 1-(4-iodophenoxy)-3-isopropylaminopropan-2-ol (IIP) is a potent beta-adrenergic antagonist which has been labelled to high specific activity with 125I and used to bind to rat myocardial membranes. The characteristics of binding were consistent with the known properties of beta-receptors. Thus, binding was highly stereospecific for the L-stereoisomer since L-propranolol was two orders of magnitude more potent than the D-isomer in competing for these sites. The beta-adrenergic agonists isoproterenol, epinephrine and norepinephrine competed for binding with potencies paralleling their pharmacological potencies as beta-adrenergic effectors. The dissociation constant for binding of IIP was 4--5 nM as measured either by direct binding studies or by its inhibition of isoproterenol stimulated adenylate cyclase. Binding was saturable with 0.06 pmoles of IIP per mg of membrane protein binding at saturation. 125IIP is a high affinity, high specific activity ligand suitable for use as a selective probe for the detection and quantitation of cardiac beta-receptors. Its introduction should help solve the problems involved in the investigation of myocardial beta-adrenergic receptors. | Investigation of cardiac beta-adrenoceptors using 125I-labelled 1-(4-iodophenoxy)-3-isopropylaminopropan-2-ol. 1-(4-iodophenoxy)-3-isopropylaminopropan-2-ol (IIP) is a potent beta-adrenergic antagonist which has been labelled to high specific activity with 125I and used to bind to rat myocardial membranes. The characteristics of binding were consistent with the known properties of beta-receptors. Thus, binding was highly stereospecific for the L-stereoisomer since L-propranolol was two orders of magnitude more potent than the D-isomer in competing for these sites. The beta-adrenergic agonists isoproterenol, epinephrine and norepinephrine competed for binding with potencies paralleling their pharmacological potencies as beta-adrenergic effectors. The dissociation constant for binding of IIP was 4--5 nM as measured either by direct binding studies or by its inhibition of isoproterenol stimulated adenylate cyclase. Binding was saturable with 0.06 pmoles of IIP per mg of membrane protein binding at saturation. 125IIP is a high affinity, high specific activity ligand suitable for use as a selective probe for the detection and quantitation of cardiac beta-receptors. Its introduction should help solve the problems involved in the investigation of myocardial beta-adrenergic receptors. | [
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PMID:26577 | Benzodiazepines: potentiation of a GABA inhibitory response in the dorsal raphe nucleus. | Based on evidence that the dorsal raphe nucleus (DR) has specific and independent receptors for 5HT, GABA and glycine (Gallager and Aghajanian, 1976; Wang and Aghajanian, 1977), alterations in the firing rate of DR neurons following the administration of benzodiazepines (BZ) were evaluated to determine whether they were the result of a direct interaction with 5HT receptors or due to interactions of these drugs with GABA and/or glycine. The effects of BZs after both direct and systemic application were tested in rats using microiotophoretic and single-cell recording techniques. Although the BZs did not alter the spontaneous firing rate of the DR, both the systemic and iontophoretic administration of these drugs were found to potentiate the inhibitory response produced by GABA. The data suggest that this potentiation is mediated postsynaptically. Since the effects of BZs on the spontaneous activity of the DR are only apparent following pretreatments with AOAA, it is speculated that these drugs may only have pronounced effects when GABAergic input is prominent. | Benzodiazepines: potentiation of a GABA inhibitory response in the dorsal raphe nucleus. Based on evidence that the dorsal raphe nucleus (DR) has specific and independent receptors for 5HT, GABA and glycine (Gallager and Aghajanian, 1976; Wang and Aghajanian, 1977), alterations in the firing rate of DR neurons following the administration of benzodiazepines (BZ) were evaluated to determine whether they were the result of a direct interaction with 5HT receptors or due to interactions of these drugs with GABA and/or glycine. The effects of BZs after both direct and systemic application were tested in rats using microiotophoretic and single-cell recording techniques. Although the BZs did not alter the spontaneous firing rate of the DR, both the systemic and iontophoretic administration of these drugs were found to potentiate the inhibitory response produced by GABA. The data suggest that this potentiation is mediated postsynaptically. Since the effects of BZs on the spontaneous activity of the DR are only apparent following pretreatments with AOAA, it is speculated that these drugs may only have pronounced effects when GABAergic input is prominent. | [
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PMID:26578 | 2,5-Dimethoxy-4-methylamphetamine (DOM)- a central component of its cardiovascular effects in rats; involvement of serotonin. | The hallucinogen DOM produces a rise in blood pressure and heart rate when injected into the cerebral ventricles of anesthetized rats. These effects are abolished in rats with transected spinal cords but are unaffected by prior treatment with hexamethonium. Central but not peripheral administration of the serotonin antagonist BOL reduces the response. Tachyphylaxis to the response develops rapidly and is accompanied by a decrease in the ability of 5-HT to induce a centrally mediated cardiovascular change. It is concluded that the response is mediated by direct stimulation of central 5HT receptors. Tachyphylaxis may be the result of irreversible binding of DOM to 5-HT receptors or to 5-HT receptor densensitization. | 2,5-Dimethoxy-4-methylamphetamine (DOM)- a central component of its cardiovascular effects in rats; involvement of serotonin. The hallucinogen DOM produces a rise in blood pressure and heart rate when injected into the cerebral ventricles of anesthetized rats. These effects are abolished in rats with transected spinal cords but are unaffected by prior treatment with hexamethonium. Central but not peripheral administration of the serotonin antagonist BOL reduces the response. Tachyphylaxis to the response develops rapidly and is accompanied by a decrease in the ability of 5-HT to induce a centrally mediated cardiovascular change. It is concluded that the response is mediated by direct stimulation of central 5HT receptors. Tachyphylaxis may be the result of irreversible binding of DOM to 5-HT receptors or to 5-HT receptor densensitization. | [
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PMID:26579 | Biphasic effect of chlorpromazine on rat paradoxical sleep: a study of dose-related mechanisms. | The experiments reported here investigated the effect of chlorpromazine (CPZ) alone or after inhibition of catecholamine (CA) synthesis on paradoxical sleep (PS) in the rat. The dose--response curve for CPZ was biphasic with enhancement of PS after low doses, and depression of PS after higher doses. In contrast, low doses of CPZ after inhibition of CA synthesis markedly decreased PS. This decrease was greater after tyrosine hydroxylase inhibition than after dopamine-beta-hydroxylase inhibition. These results support the view that low doses of CPZ produce increased activity in brain CA synapses, and that both dopamine and noradrenaline participate in the control of PS in the rat. | Biphasic effect of chlorpromazine on rat paradoxical sleep: a study of dose-related mechanisms. The experiments reported here investigated the effect of chlorpromazine (CPZ) alone or after inhibition of catecholamine (CA) synthesis on paradoxical sleep (PS) in the rat. The dose--response curve for CPZ was biphasic with enhancement of PS after low doses, and depression of PS after higher doses. In contrast, low doses of CPZ after inhibition of CA synthesis markedly decreased PS. This decrease was greater after tyrosine hydroxylase inhibition than after dopamine-beta-hydroxylase inhibition. These results support the view that low doses of CPZ produce increased activity in brain CA synapses, and that both dopamine and noradrenaline participate in the control of PS in the rat. | [
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PMID:26580 | Studies on the mechanism of the vasodilator effects of prazosin in dogs and rabbits. | In pentobarbital (35.0 mg/kg) anaesthetised dogs, bolus injections of prazosin into the femoral artery (3.0--300.0 microgram) provoked a dose-related fall in the vascular resistance of the innervated hind limb. In contrast to papaverine, prazosin failed to produce the same effect in dogs under spinal anaesthesia even when the intrinsic femoral vascular tone was increased with vasopressin. However, vasodilator effects of prazosin were again observed when the tone of the limb was elevated by either stimulating the sympathetic lumbar chain or by infusing alpha-adrenoceptor agonists. A significant reduction of both aortic blood pressure and pressor response to bilateral carotid artery occlusion was noted in a group of normotensive dogs anaesthetised 12 h after the last dose of prazosin given twice daily at 0.5 mg/kg, p.o., for 3 day period. This short-term treatment modified neither the resting heart rate nor the positive chronotropic effect induced by either intravenous noradrenaline or electrical stimulation of pre- and post-ganglionic nerve fibres of the right stellate ganglion. However, it prevented the larger increase in heart rate in response to bilateral carotid occlusion in placebo-treated dogs after section of the vagi. A decrease in baseline sympathetic tone of the perfused hind limb as well as vasoconstrictor effects produced by i.a. injections of several alpha-adrenoceptor agonists and electrical stimulation of the lumbar sympathetic chain was observed in prazosin-treated animals. The dose--pressor response profiles to these alpha-adrenoceptor stimulants after prazosin were not parallel to those obtained in the control group. The vasoconstrictor response to angiotensin II was not changed by prazosin. In rabbit aortic strips, prazosin (0.1--3.0 micrometer) produced competitive antagonism of the contractile responses induced by cirazoline, noradrenaline and phenylephrine. In contrast to papaverine, prazosin in concentrations up to 100.0 micrometer neither relaxed the aortic strips contracted by potassium ions nor modified the concentration-response curve to calcium ions. These studies indicate that blood pressure lowering effects of prazosin given acutely or for three days can be accounted for by a clear-cut functional impairment of vascular postsynaptic alpha-adrenoceptors. No evidence for a direct myorelaxant property of prazosin could be obtained in these studies. | Studies on the mechanism of the vasodilator effects of prazosin in dogs and rabbits. In pentobarbital (35.0 mg/kg) anaesthetised dogs, bolus injections of prazosin into the femoral artery (3.0--300.0 microgram) provoked a dose-related fall in the vascular resistance of the innervated hind limb. In contrast to papaverine, prazosin failed to produce the same effect in dogs under spinal anaesthesia even when the intrinsic femoral vascular tone was increased with vasopressin. However, vasodilator effects of prazosin were again observed when the tone of the limb was elevated by either stimulating the sympathetic lumbar chain or by infusing alpha-adrenoceptor agonists. A significant reduction of both aortic blood pressure and pressor response to bilateral carotid artery occlusion was noted in a group of normotensive dogs anaesthetised 12 h after the last dose of prazosin given twice daily at 0.5 mg/kg, p.o., for 3 day period. This short-term treatment modified neither the resting heart rate nor the positive chronotropic effect induced by either intravenous noradrenaline or electrical stimulation of pre- and post-ganglionic nerve fibres of the right stellate ganglion. However, it prevented the larger increase in heart rate in response to bilateral carotid occlusion in placebo-treated dogs after section of the vagi. A decrease in baseline sympathetic tone of the perfused hind limb as well as vasoconstrictor effects produced by i.a. injections of several alpha-adrenoceptor agonists and electrical stimulation of the lumbar sympathetic chain was observed in prazosin-treated animals. The dose--pressor response profiles to these alpha-adrenoceptor stimulants after prazosin were not parallel to those obtained in the control group. The vasoconstrictor response to angiotensin II was not changed by prazosin. In rabbit aortic strips, prazosin (0.1--3.0 micrometer) produced competitive antagonism of the contractile responses induced by cirazoline, noradrenaline and phenylephrine. In contrast to papaverine, prazosin in concentrations up to 100.0 micrometer neither relaxed the aortic strips contracted by potassium ions nor modified the concentration-response curve to calcium ions. These studies indicate that blood pressure lowering effects of prazosin given acutely or for three days can be accounted for by a clear-cut functional impairment of vascular postsynaptic alpha-adrenoceptors. No evidence for a direct myorelaxant property of prazosin could be obtained in these studies. | [
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PMID:26581 | Positive chronotropic and inotropic responses to guanosine in the isolated dog atrium. | The effects of guanosine on chronotropism and inotropism in isolated dog atria were studied in spontaneously beating preparations which were suspended in a bath perfused with arterial blood from a carotid artery of a heparinized support dog. Guanosine administered into the cannulated sinus node artery in a dose range of 30 microgram to 3 mg produced a dose-related positive inotropic and chronotropic effect. The positive responses to guanosine were not inhibited by treatment with propranolol or a non-depressant beta-blocker, carteolol, in doses which blocked responses to norepinephrine. From these results, it is concluded that guanosine has a direct effect on atrial rate and contractility. | Positive chronotropic and inotropic responses to guanosine in the isolated dog atrium. The effects of guanosine on chronotropism and inotropism in isolated dog atria were studied in spontaneously beating preparations which were suspended in a bath perfused with arterial blood from a carotid artery of a heparinized support dog. Guanosine administered into the cannulated sinus node artery in a dose range of 30 microgram to 3 mg produced a dose-related positive inotropic and chronotropic effect. The positive responses to guanosine were not inhibited by treatment with propranolol or a non-depressant beta-blocker, carteolol, in doses which blocked responses to norepinephrine. From these results, it is concluded that guanosine has a direct effect on atrial rate and contractility. | [
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PMID:26584 | Graft versus leukemia. VIII. Selective reduction in antihost reactivity without loss of antileukemic reactivity by treatment of donor mice with lipopolysaccharide. | Spleen and lymph node cells from DBA/2 (H-2d) donor mice treated with multiple injections of bacterial lipopolysaccharide (LPS) were tested in vivo for reactivity against normal tissues of host AKR (H-2k) mice against an AKR long-passage, acute lymphoblastic leukemia (BW5147). LPS treatment of donor mice resulted in a reduction in graft-versus-host (GVH) reactivity without loss of graft-versus-leukemia (GVL) reactivity. Immunocompetent cells from LPS treated DBA/2 donors were effective when used for adoptive immunotherapy (in combination with chemoradiotherapy) of BW5147 leukemia. GVH associated mortality decreased as the dose of spleen cells from LPS treated histoincompatible donors was increased as much as four times the number necessary to eliminate leukemia. The mechanism by which LPS reduced GVH reactivity without eliminating GVL reactivity is unclear; however, it does not appear to be the result of a dilution in the number of GVH reactive cells by nonlymphoid elements in the donor spleen nor of the adjuvant effects of LPS on resistance to bacterial infections. | Graft versus leukemia. VIII. Selective reduction in antihost reactivity without loss of antileukemic reactivity by treatment of donor mice with lipopolysaccharide. Spleen and lymph node cells from DBA/2 (H-2d) donor mice treated with multiple injections of bacterial lipopolysaccharide (LPS) were tested in vivo for reactivity against normal tissues of host AKR (H-2k) mice against an AKR long-passage, acute lymphoblastic leukemia (BW5147). LPS treatment of donor mice resulted in a reduction in graft-versus-host (GVH) reactivity without loss of graft-versus-leukemia (GVL) reactivity. Immunocompetent cells from LPS treated DBA/2 donors were effective when used for adoptive immunotherapy (in combination with chemoradiotherapy) of BW5147 leukemia. GVH associated mortality decreased as the dose of spleen cells from LPS treated histoincompatible donors was increased as much as four times the number necessary to eliminate leukemia. The mechanism by which LPS reduced GVH reactivity without eliminating GVL reactivity is unclear; however, it does not appear to be the result of a dilution in the number of GVH reactive cells by nonlymphoid elements in the donor spleen nor of the adjuvant effects of LPS on resistance to bacterial infections. | [
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PMID:26587 | Acid release at meiotic maturation of oocytes in the polychaete annelid Sabellaria alveolata. | ABout 1 pmole of acid per egg is released when prophasic oocytes undergo maturation under the action of sperm, proteases or ionophore A 23187. No similar acid release occurs at fertilization of matured oocytes. These findings are compared with data on Urechis and sea urchin. | Acid release at meiotic maturation of oocytes in the polychaete annelid Sabellaria alveolata. ABout 1 pmole of acid per egg is released when prophasic oocytes undergo maturation under the action of sperm, proteases or ionophore A 23187. No similar acid release occurs at fertilization of matured oocytes. These findings are compared with data on Urechis and sea urchin. | [
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PMID:26588 | [Effect of tropaphene and fentolamin on the spasmogenic effects of adrenaline, noradrenaline, serotonin and other biologically active substances]. | Tests conducted in vitro and in vivo demonstrated that tropaphen, tropine ether of alpha-phenyl-beta-(p-acetoxyphenyl)-propionic acid, an original alpha-adrenoblocking agent, display a marked antiserotonin activity exceeding that of phentolamine. Moreover, tropaphen is more active that phenolamine by its inhibiting influence on the spasmogenous effects of histamine, angiotensin, bradykinine and prostaglandin E2. In doses of 0.1 and 0.25 mg/kg both drugs had no effect on changes of the arterial pressure in anesthetized rats, caused by the above mentioned biologically active substances. | [Effect of tropaphene and fentolamin on the spasmogenic effects of adrenaline, noradrenaline, serotonin and other biologically active substances]. Tests conducted in vitro and in vivo demonstrated that tropaphen, tropine ether of alpha-phenyl-beta-(p-acetoxyphenyl)-propionic acid, an original alpha-adrenoblocking agent, display a marked antiserotonin activity exceeding that of phentolamine. Moreover, tropaphen is more active that phenolamine by its inhibiting influence on the spasmogenous effects of histamine, angiotensin, bradykinine and prostaglandin E2. In doses of 0.1 and 0.25 mg/kg both drugs had no effect on changes of the arterial pressure in anesthetized rats, caused by the above mentioned biologically active substances. | [
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PMID:26589 | [Comparative assessment of the effect of sympatholytics and beta-adrenoblockaders on carbohydrate-phosphorus metabolic indices in the myocardium of growing rats]. | The sympatholyitic ornide and beta-adrenoblocking agent alpheprol were introduced intraperitoneally in single doses of 5 and 1 mg/kg, respectively to 7--30 day and 3--5-month old adult rats. The content of ATP, ADP, AMP, inorganic phosphorus glycogen and also active P32 incorporation were determined. The 7-day old rattlings are shown to be more sensitive to ornide than to alpheprol by comparison with older animals. | [Comparative assessment of the effect of sympatholytics and beta-adrenoblockaders on carbohydrate-phosphorus metabolic indices in the myocardium of growing rats]. The sympatholyitic ornide and beta-adrenoblocking agent alpheprol were introduced intraperitoneally in single doses of 5 and 1 mg/kg, respectively to 7--30 day and 3--5-month old adult rats. The content of ATP, ADP, AMP, inorganic phosphorus glycogen and also active P32 incorporation were determined. The 7-day old rattlings are shown to be more sensitive to ornide than to alpheprol by comparison with older animals. | [
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PMID:26591 | [Metabolic effects of ethyl alcohol the ways to correct them]. | Tests conducted on albino male-rats demonstrated that with its intragastric administration in a dose of 3 g/kg ethanol produces a hypoxy-like situation in the organism, i.e. the oxygen tension in the liver and skeletal muscles decreases and the redox potential is activation during the 1st hour with succinate-cytochrome-c-oxidase of the liver mitochondria with concomitantly activated oxidation of succinic acid. The activity of NAD-dependent dehydrogenases goes down and in the blood occur acidotic shifts in the acid-base equilibrium (ABE). Twenty four hours after a single administration of ethanol the activity of all the study liver enzymes declines with the acidotic ABE shifts remaining unchanged. The used mixture of glutamate and sodium succinate appreciably decreases the blood ethanol level, corrects metabolic effects of ethanol and increases the survival of rats receiving lethal doses of ethanol. | [Metabolic effects of ethyl alcohol the ways to correct them]. Tests conducted on albino male-rats demonstrated that with its intragastric administration in a dose of 3 g/kg ethanol produces a hypoxy-like situation in the organism, i.e. the oxygen tension in the liver and skeletal muscles decreases and the redox potential is activation during the 1st hour with succinate-cytochrome-c-oxidase of the liver mitochondria with concomitantly activated oxidation of succinic acid. The activity of NAD-dependent dehydrogenases goes down and in the blood occur acidotic shifts in the acid-base equilibrium (ABE). Twenty four hours after a single administration of ethanol the activity of all the study liver enzymes declines with the acidotic ABE shifts remaining unchanged. The used mixture of glutamate and sodium succinate appreciably decreases the blood ethanol level, corrects metabolic effects of ethanol and increases the survival of rats receiving lethal doses of ethanol. | [
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PMID:26594 | [Ethological analysis of the action of medazepam and diazepam on the zoosocial behavior of isolated mice]. | Tests set up with isolated mice of two groups (aggressive and "fearful") evidenced that diazepam and medazepam weaken the behavioral manifestations of the partner's avoidance, increase sociability in "fearful" mice and help to regain the ability for elementary intraspecies contacts. These drugs have a biphasic action on the behavior of aggressive mice, small doses (medazepam 0.1 mg/kg) facilitating aggression and large one (medazepam, diazepam--5 mg/kg) suppressing it. | [Ethological analysis of the action of medazepam and diazepam on the zoosocial behavior of isolated mice]. Tests set up with isolated mice of two groups (aggressive and "fearful") evidenced that diazepam and medazepam weaken the behavioral manifestations of the partner's avoidance, increase sociability in "fearful" mice and help to regain the ability for elementary intraspecies contacts. These drugs have a biphasic action on the behavior of aggressive mice, small doses (medazepam 0.1 mg/kg) facilitating aggression and large one (medazepam, diazepam--5 mg/kg) suppressing it. | [
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PMID:26590 | [Effect of a new central adrenolytic on cardiac metabolic indices in neurogenic damage]. | It is shown that in rabbits subjected to an electric stimulation of the aortic arch there developed concurrently with depletion of tissular norepinephrine reserves in the myocardium also gross metabolic disorders. A preliminary introduction of the drug izm-611 by blocking central alpha-adrenoreseptors at the same time prevented depletion of the tissular norepinephrine reserves and development of disturbances of the energy exchange in the myocardium caused by its neurogenic damage. | [Effect of a new central adrenolytic on cardiac metabolic indices in neurogenic damage]. It is shown that in rabbits subjected to an electric stimulation of the aortic arch there developed concurrently with depletion of tissular norepinephrine reserves in the myocardium also gross metabolic disorders. A preliminary introduction of the drug izm-611 by blocking central alpha-adrenoreseptors at the same time prevented depletion of the tissular norepinephrine reserves and development of disturbances of the energy exchange in the myocardium caused by its neurogenic damage. | [
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] |
PMID:26595 | [Action of analeptics in acute alcoholic intoxication]. | Tests conducted on rabbits in a state of acute ethanol poisoning (2.5 g/kg per os) of a medium degree demonstrated that caffein (10 mg/kg) and bemegride (5 mg/kg) introduced one time intravenously at the height of alcoholic intoxication raise the activity of aerobic oxidative processes, but fail to eliminate metabolic acidosis and do not accelerate the excretion of ethanol. Unlike caffein, bemegride shows a tendency toward respiratory compensation of metabolic acidosis and lowers the activity of the alcohol-dehydrogenase. | [Action of analeptics in acute alcoholic intoxication]. Tests conducted on rabbits in a state of acute ethanol poisoning (2.5 g/kg per os) of a medium degree demonstrated that caffein (10 mg/kg) and bemegride (5 mg/kg) introduced one time intravenously at the height of alcoholic intoxication raise the activity of aerobic oxidative processes, but fail to eliminate metabolic acidosis and do not accelerate the excretion of ethanol. Unlike caffein, bemegride shows a tendency toward respiratory compensation of metabolic acidosis and lowers the activity of the alcohol-dehydrogenase. | [
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PMID:26596 | [Pharmacokinetics of the new Soviet, tritium-labelled, antihistamine preparation, phencarol]. | As evidenced no less than 45 per cent of tritium-labelled antihistaminic drug phencarol (quinuclidine-3-diphenylcarbinol hydrochloride) introduced intragastrically to rats is absorbed. The maximal radioactivity in various organs is reached in 1--3 hours, with high specific radioactivity being recorded in the lungs and liver and low--in the brain. The drug or radioactive products of its tranformation are eliminated largely via the gastrointestinal tract and kidneys. | [Pharmacokinetics of the new Soviet, tritium-labelled, antihistamine preparation, phencarol]. As evidenced no less than 45 per cent of tritium-labelled antihistaminic drug phencarol (quinuclidine-3-diphenylcarbinol hydrochloride) introduced intragastrically to rats is absorbed. The maximal radioactivity in various organs is reached in 1--3 hours, with high specific radioactivity being recorded in the lungs and liver and low--in the brain. The drug or radioactive products of its tranformation are eliminated largely via the gastrointestinal tract and kidneys. | [
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PMID:26597 | [Effect of amisyl and spasmolytin on the blood supply and oxygen metabolism of the brain]. | The effect of benactyzine and spasmolytin adiphenine on the blood circulation in the oxygen consumption by the brain were investigated in experiments on dogs. The resulting data point to a biphasic action of benacyzine and spasmolytin on the blood supply of the brain (after a short-lived increase of the blood flow a clearcut decline of it is noted). The oxygen intake from the blood varies irregularly. In chlorophos-poisoned dogs the oxygen absorption by the brain changes under the effect of benactyzine and rises after administration of spasmolytin. The cerebral circulation then changes non-uniformly under the effect of benactyzine, while following spasmolytin injections it dicreases in the majority of experiments. | [Effect of amisyl and spasmolytin on the blood supply and oxygen metabolism of the brain]. The effect of benactyzine and spasmolytin adiphenine on the blood circulation in the oxygen consumption by the brain were investigated in experiments on dogs. The resulting data point to a biphasic action of benacyzine and spasmolytin on the blood supply of the brain (after a short-lived increase of the blood flow a clearcut decline of it is noted). The oxygen intake from the blood varies irregularly. In chlorophos-poisoned dogs the oxygen absorption by the brain changes under the effect of benactyzine and rises after administration of spasmolytin. The cerebral circulation then changes non-uniformly under the effect of benactyzine, while following spasmolytin injections it dicreases in the majority of experiments. | [
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] |
PMID:26598 | [Possible neuropharmacological regulation of chemical carcinogenesis caused by diethylnitrosamine]. | The effect of a number of neurotropic drugs on diethylnitrosoamine (DENA)-induced chemical carcinogenesis was studied by applying pharmacological, morphological and biochemical techniques. Atropine stimulated significantly the rat liver and esophagus carcinogenesis, whereas the alpha-adrenoblocking agent, a pyrrhoxane analogue, and, particularly, proserine inhibited these processes. All animals treated with DENA demonstrated a significant increase of liver mitochondrial monoaminoxidase activity. These findings as well as the evidence of a stimulating effect of exogenous norepinephrine on carcionogenesis, together with the literature sources on carcinogenic and modifying carcinogenesis action of neurotropics allow the authors to formulate a concet of the trigger role played by catecholamines in the DENA-induced cell transformation and carcinogenesis. | [Possible neuropharmacological regulation of chemical carcinogenesis caused by diethylnitrosamine]. The effect of a number of neurotropic drugs on diethylnitrosoamine (DENA)-induced chemical carcinogenesis was studied by applying pharmacological, morphological and biochemical techniques. Atropine stimulated significantly the rat liver and esophagus carcinogenesis, whereas the alpha-adrenoblocking agent, a pyrrhoxane analogue, and, particularly, proserine inhibited these processes. All animals treated with DENA demonstrated a significant increase of liver mitochondrial monoaminoxidase activity. These findings as well as the evidence of a stimulating effect of exogenous norepinephrine on carcionogenesis, together with the literature sources on carcinogenic and modifying carcinogenesis action of neurotropics allow the authors to formulate a concet of the trigger role played by catecholamines in the DENA-induced cell transformation and carcinogenesis. | [
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PMID:26606 | The pathophysiology of hyperprolactinemic states and the role of newer ergot compounds in their treatment. | Studies of prolactin secretion in humans have confirmed the concept, derived originally from animal investigations, that prolactin is predominantly controlled by tonic inhibition from the hypothalamus. The locus of action of dopamine and dopaminergic agents such as the ergot alkaloids inhibiting prolactin secretion appears to be primarily at the pituitary level, though a hypothalamic action to increase secretion of prolactin inhibitory factor may also contribute. Prolactin hypersecretion, through any of several possible mechanisms, is frequently but not always found in patients with galactorrhea. Recent studies have shown that hyperprolactinemia is considerably more common than was previously appreciated among patients without galactorrhea. It is present in at least two-thirds of all patients with pituitary tumors and in a significant minority of patients with secondary amenorrhea. Its clinical measurement in these conditions is therefore of considerable diagnostic importance. Whatever the pathophysiology of its production, hyperprolactinemia of all forms is responsive to treatment with the newer ergot alkaloids. The potential use of these agents for therapeutic purposes, particularly in the treatment of infertility, appears to be wider than was originally anticipated. | The pathophysiology of hyperprolactinemic states and the role of newer ergot compounds in their treatment. Studies of prolactin secretion in humans have confirmed the concept, derived originally from animal investigations, that prolactin is predominantly controlled by tonic inhibition from the hypothalamus. The locus of action of dopamine and dopaminergic agents such as the ergot alkaloids inhibiting prolactin secretion appears to be primarily at the pituitary level, though a hypothalamic action to increase secretion of prolactin inhibitory factor may also contribute. Prolactin hypersecretion, through any of several possible mechanisms, is frequently but not always found in patients with galactorrhea. Recent studies have shown that hyperprolactinemia is considerably more common than was previously appreciated among patients without galactorrhea. It is present in at least two-thirds of all patients with pituitary tumors and in a significant minority of patients with secondary amenorrhea. Its clinical measurement in these conditions is therefore of considerable diagnostic importance. Whatever the pathophysiology of its production, hyperprolactinemia of all forms is responsive to treatment with the newer ergot alkaloids. The potential use of these agents for therapeutic purposes, particularly in the treatment of infertility, appears to be wider than was originally anticipated. | [
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PMID:26609 | Evaluation of testicular function in prepubertal boys by means of the luteinizing hormone-releasing hormone test. | Luteinizing hormone (LH)-releasing hormone (LH-RH) tests (50 microgram/sq m intravenously) were performed in 112 prepubertal boys ages 13/12 to 11 years (mean +/- standard deviation, 75/12 +/- 16/12 years) suspected of having a testicular disorder because of improperly located testes (77 boys) or hypogonadism (35 boys). Four of the patients were retested within a period ranging from 6 to 16 months. Of the 112 boys tested, 17% were found to have high basal levels of follicle-stimulating hormone (FSH) and 23% were found to have an abnormally high release of FSH after LH-RH administration. Only three patients had abnormally high basal levels of LH and/or elevated LH responses to LH-RH. The basal plasma testosterone levels were found to be normal in all 112 bosy. The fact that plasma FSH levels were elevated more often than LH levels suggests that the tubular elements are damaged more frequently than are the Leydig cells. The surprisingly high incidence of an abnormal response of plasma FSH to LH-RH in boys with mobile testes calls for an increased awareness of the importance of regular examination of these patients until full puberty has been achieved. It is concluded that determination of basal plasma FSH levels and the response to LH-RH stimulation is a useful diagnostic tool for evaluating testicular function in prepubertal boys with suspected pathology of the testes. | Evaluation of testicular function in prepubertal boys by means of the luteinizing hormone-releasing hormone test. Luteinizing hormone (LH)-releasing hormone (LH-RH) tests (50 microgram/sq m intravenously) were performed in 112 prepubertal boys ages 13/12 to 11 years (mean +/- standard deviation, 75/12 +/- 16/12 years) suspected of having a testicular disorder because of improperly located testes (77 boys) or hypogonadism (35 boys). Four of the patients were retested within a period ranging from 6 to 16 months. Of the 112 boys tested, 17% were found to have high basal levels of follicle-stimulating hormone (FSH) and 23% were found to have an abnormally high release of FSH after LH-RH administration. Only three patients had abnormally high basal levels of LH and/or elevated LH responses to LH-RH. The basal plasma testosterone levels were found to be normal in all 112 bosy. The fact that plasma FSH levels were elevated more often than LH levels suggests that the tubular elements are damaged more frequently than are the Leydig cells. The surprisingly high incidence of an abnormal response of plasma FSH to LH-RH in boys with mobile testes calls for an increased awareness of the importance of regular examination of these patients until full puberty has been achieved. It is concluded that determination of basal plasma FSH levels and the response to LH-RH stimulation is a useful diagnostic tool for evaluating testicular function in prepubertal boys with suspected pathology of the testes. | [
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PMID:26611 | [Modulation of autonomic correlates of emotional stress and adaptive responses]. | The character and dynamics of the cardio-vascular response to psychogenic stress (confrontation of cat and dog) depends on active or passive type of behavioral response. Tranquilizers inhibit long-lasting hypertension otherwise occurring after the stress stimulus. Adaptive cardio-vascular responses and baroreceptor reflexes did not alter after tranquilizers administration. Effects of psychotropic drugs correspond to the type of individual behavioral response. | [Modulation of autonomic correlates of emotional stress and adaptive responses]. The character and dynamics of the cardio-vascular response to psychogenic stress (confrontation of cat and dog) depends on active or passive type of behavioral response. Tranquilizers inhibit long-lasting hypertension otherwise occurring after the stress stimulus. Adaptive cardio-vascular responses and baroreceptor reflexes did not alter after tranquilizers administration. Effects of psychotropic drugs correspond to the type of individual behavioral response. | [
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PMID:26612 | Local graft-versus-host reaction in mice evoked by Peyer's patch and other lymphoid tissue cells tested in a lymphocyte-induced angiogenesis assay. | The competence of murine Peyer's patch cells to evoke a local GVH reaction was compared with that displayed by lymphoid cells of spleen, lymph nodes, thymus, bone marrow, peritoneal cavity and peripheral blood. The local GVH reaction was assessed in a lymphocyte-induced angiogenesis assay in which an intradermal injection of lymphoid cells results in a new blood vessel formation at the injection site, and the number of vessels corresponds to the number of the immunocompetent cells injected. Peyer's patch cells were capable of mounting a local GVH reaction of intensity comparable to that evoked by the corresponding number of thymus cells or a four times lower number of spleen cells. The highest activity was exhibited by lymph node and peripheral blood cells while bone marrow cells were the least active. A striking increase in angiogenic response was observed after X-irradiation of the recipients with 700R. | Local graft-versus-host reaction in mice evoked by Peyer's patch and other lymphoid tissue cells tested in a lymphocyte-induced angiogenesis assay. The competence of murine Peyer's patch cells to evoke a local GVH reaction was compared with that displayed by lymphoid cells of spleen, lymph nodes, thymus, bone marrow, peritoneal cavity and peripheral blood. The local GVH reaction was assessed in a lymphocyte-induced angiogenesis assay in which an intradermal injection of lymphoid cells results in a new blood vessel formation at the injection site, and the number of vessels corresponds to the number of the immunocompetent cells injected. Peyer's patch cells were capable of mounting a local GVH reaction of intensity comparable to that evoked by the corresponding number of thymus cells or a four times lower number of spleen cells. The highest activity was exhibited by lymph node and peripheral blood cells while bone marrow cells were the least active. A striking increase in angiogenic response was observed after X-irradiation of the recipients with 700R. | [
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PMID:26613 | Serum polyphenol oxidase activity (ceruloplasmin) in conventional laboratory animals and man. | The optimum pH for ceruloplasmin as polyphenol oxidase (EC 1.10.3.2) activity was determined in human serum (pH 5.4) and the serum of conventional laboratory animals--the rat (pH 5.2), mouse (pH 5.2), hamster (pH 5.3), guinea pig (pH 5.4), multimammate mouse (pH 5.2) and rabbit (pH 5.4). Determined at the optimum pH in 0.1M acetate buffer polyphenol oxidase activity fell in the sequence: rat--man--rabbit--mouse--multimammate mouse--hamster--guinea pig. Ceruloplasmin polyphenol oxidase activity was inhibited by 0.1M phosphate buffer in the mouse, rat and multimammate mouse, but not in the other species. It was inhibited by 0.05M citrate and 0.1M phthalate buffer in all the species tested. | Serum polyphenol oxidase activity (ceruloplasmin) in conventional laboratory animals and man. The optimum pH for ceruloplasmin as polyphenol oxidase (EC 1.10.3.2) activity was determined in human serum (pH 5.4) and the serum of conventional laboratory animals--the rat (pH 5.2), mouse (pH 5.2), hamster (pH 5.3), guinea pig (pH 5.4), multimammate mouse (pH 5.2) and rabbit (pH 5.4). Determined at the optimum pH in 0.1M acetate buffer polyphenol oxidase activity fell in the sequence: rat--man--rabbit--mouse--multimammate mouse--hamster--guinea pig. Ceruloplasmin polyphenol oxidase activity was inhibited by 0.1M phosphate buffer in the mouse, rat and multimammate mouse, but not in the other species. It was inhibited by 0.05M citrate and 0.1M phthalate buffer in all the species tested. | [
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PMID:26614 | Evaluation of in vitro and in vivo activities of isoantibodies directed against idiotypes and recognition structures for transplantation antigens. | Anti-idiotype sera were prepared by injection of CBA anti-A/JAX serum with or without adjuvant into CBA mice. These sera were tested in allocluster inhibition and passive enhancement-facilitation. While the anti-idiotype sera inhibited allocluster formation, particularly when prepared with complete Freund's adjuvant, they had virtually no effect on enhancement of Sa I grafted in CBA mice except for a marginal prolongation of graft survival in one out of three experiments. Anti-RS serum was prepared by immunizing (CBA X A)F1 mice with CBA thymus or spleen cells. The sera were tested in local graft-versus-host inhibition and passive enhancement. F1 anti-CBA thymus serum inhibited the local graft-versus-host reaction but had no enhancing effect. F1 anti-CBA spleen serum was virtually ineffective in both tests although a slight tendency to graft-versus-host inhibition was noted. The relative contribution of anti-idiotype and/or anti-RS antibodies to transplantation reactions is discussed. | Evaluation of in vitro and in vivo activities of isoantibodies directed against idiotypes and recognition structures for transplantation antigens. Anti-idiotype sera were prepared by injection of CBA anti-A/JAX serum with or without adjuvant into CBA mice. These sera were tested in allocluster inhibition and passive enhancement-facilitation. While the anti-idiotype sera inhibited allocluster formation, particularly when prepared with complete Freund's adjuvant, they had virtually no effect on enhancement of Sa I grafted in CBA mice except for a marginal prolongation of graft survival in one out of three experiments. Anti-RS serum was prepared by immunizing (CBA X A)F1 mice with CBA thymus or spleen cells. The sera were tested in local graft-versus-host inhibition and passive enhancement. F1 anti-CBA thymus serum inhibited the local graft-versus-host reaction but had no enhancing effect. F1 anti-CBA spleen serum was virtually ineffective in both tests although a slight tendency to graft-versus-host inhibition was noted. The relative contribution of anti-idiotype and/or anti-RS antibodies to transplantation reactions is discussed. | [
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PMID:26620 | Interaction of glucocorticoid receptors from lymphoid cell lines with their nuclear acceptor sites. | Procedures have been developed which provide simple means of determining binding constants of steroid receptors for glucocorticoids in mouse lymphoid cell lines and of characterizing the interaction of the steroid--receptor complex with the nucleus. An average of 70% of the steroid--receptor complexes is found associated with the nuclear fraction in three investigated cell lines, whereas 30% of the steroid--receptor complexes is found in the cytosol fraction. This distribution of the steroid-receptor complex within the cell is independent of whether steroid uptake of the cells is performed at low or at high steroid concentration. Part of the binding of the steroid receptor to the nuclear fraction is sensitive to high ionic strength and to high pH. A larger fraction of the steroid--receptor complex binding to the nuclear fraction is insensitive to high ionic strength and pH when the steroid uptake is performed at low steroid concentrations than when performed at high steroid concentrations. Steroid--receptor complex is released from the nuclear fraction by DNAase treatment but not by RNAase treatment. The possible correlation between the sensitivity to ionic strength and pH and the specificity of the binding is discussed. | Interaction of glucocorticoid receptors from lymphoid cell lines with their nuclear acceptor sites. Procedures have been developed which provide simple means of determining binding constants of steroid receptors for glucocorticoids in mouse lymphoid cell lines and of characterizing the interaction of the steroid--receptor complex with the nucleus. An average of 70% of the steroid--receptor complexes is found associated with the nuclear fraction in three investigated cell lines, whereas 30% of the steroid--receptor complexes is found in the cytosol fraction. This distribution of the steroid-receptor complex within the cell is independent of whether steroid uptake of the cells is performed at low or at high steroid concentration. Part of the binding of the steroid receptor to the nuclear fraction is sensitive to high ionic strength and to high pH. A larger fraction of the steroid--receptor complex binding to the nuclear fraction is insensitive to high ionic strength and pH when the steroid uptake is performed at low steroid concentrations than when performed at high steroid concentrations. Steroid--receptor complex is released from the nuclear fraction by DNAase treatment but not by RNAase treatment. The possible correlation between the sensitivity to ionic strength and pH and the specificity of the binding is discussed. | [
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PMID:26626 | Effect of cimetidine on ion fluxes and potential difference across the human stomach. | The H(2)-receptor antagonist, cimetidine, reduces acid output regardless of the means of stimulation. It is not known in man whether this is due entirely to a reduction in acid secretion or whether increased back diffusion of hydrogen ions is also occurring. We studied fluxes of H(+), Na(+), K(+), and Cl(-) ions after acid instillation into the human stomach in six healthy subjects with and without prior administration of 300 mg cimetidine orally. Potential difference across gastric mucosa was measured continuously throughout each study. Cimetidine caused a significant reduction in hydrogen ion secretion (5.05 mEq per 15 minutes controls versus 2.70 cimetidine, p < 0.05), and consequently a significant reduction in net hydrogen flux into the gastric lumen (2.01 mEq per 15 minutes versus 0.02, p < 0.05). There were no significant differences between sodium ion fluxes in control and cimetidine studies, suggesting that the gastric mucosal barrier remained intact. Cimetidine alone caused a highly significant rise in intragastric pH (to 7) and of potential difference (p < 0.001). Addition of intragastric acid (pH < 1.0) did not reverse the rise in potential difference caused by cimetidine, suggesting that factors other than change in intragastric pH were involved. In conclusion, our studies support the concept that reduction in acid output by cimetidine is due to inhibition of acid secretion, and not to increased permeability to hydrogen ion. | Effect of cimetidine on ion fluxes and potential difference across the human stomach. The H(2)-receptor antagonist, cimetidine, reduces acid output regardless of the means of stimulation. It is not known in man whether this is due entirely to a reduction in acid secretion or whether increased back diffusion of hydrogen ions is also occurring. We studied fluxes of H(+), Na(+), K(+), and Cl(-) ions after acid instillation into the human stomach in six healthy subjects with and without prior administration of 300 mg cimetidine orally. Potential difference across gastric mucosa was measured continuously throughout each study. Cimetidine caused a significant reduction in hydrogen ion secretion (5.05 mEq per 15 minutes controls versus 2.70 cimetidine, p < 0.05), and consequently a significant reduction in net hydrogen flux into the gastric lumen (2.01 mEq per 15 minutes versus 0.02, p < 0.05). There were no significant differences between sodium ion fluxes in control and cimetidine studies, suggesting that the gastric mucosal barrier remained intact. Cimetidine alone caused a highly significant rise in intragastric pH (to 7) and of potential difference (p < 0.001). Addition of intragastric acid (pH < 1.0) did not reverse the rise in potential difference caused by cimetidine, suggesting that factors other than change in intragastric pH were involved. In conclusion, our studies support the concept that reduction in acid output by cimetidine is due to inhibition of acid secretion, and not to increased permeability to hydrogen ion. | [
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PMID:26627 | p-Nitrobenzyl p-toluenesulfonyl-L-arginine: a chromogenic substrate for thrombin, plasmin and trypsin. | p-Nitrobenzyl p-toluenesulfonyl-L-arginine is hydrolyzed by thrombin, plasmin, and trypsin to p-nitrobenzyl alcohol and tosyl-L-arginine. The absorption of p-nitrobenzyl alcohol formed is measured at 271 nm (AmM 8.89). With 0.10 mM of the ester in 0.1 M Tris-HCl at pH 8.4 and 30 degrees C, the hydrolysis catalyzed by thrombin, plasmin, and trypsin is linearly proportional to time up to consumption of 60% of the substrate. Km is 14 micron and Vmax is 0.037 mumol/min/NIH unit for bovine thrombin, Km is 78 micron and Vmax is 0.31 mumol/min/CTA unit/ml for human plasmin, and Km is 12 micron and Vmax is 138 mumol/min/mg protein/ml for bovine trypsin. Samples of bovine and human thrombin ranging in specific clotting activity from 59 to 2,133 NIH units/mg protein showed esterase activities ranging from 0.15 to 0.4 mumol p-nitrobenzyl alcohol formed/10 min/NIH unit. Useful ranges for assay of enzymes were (per milliliter): 0.05-0.2 NIH units (thrombin), 0.005-0.02 CTA units (plasmin), and 0.01-0.04 microgram (trypsin). | p-Nitrobenzyl p-toluenesulfonyl-L-arginine: a chromogenic substrate for thrombin, plasmin and trypsin. p-Nitrobenzyl p-toluenesulfonyl-L-arginine is hydrolyzed by thrombin, plasmin, and trypsin to p-nitrobenzyl alcohol and tosyl-L-arginine. The absorption of p-nitrobenzyl alcohol formed is measured at 271 nm (AmM 8.89). With 0.10 mM of the ester in 0.1 M Tris-HCl at pH 8.4 and 30 degrees C, the hydrolysis catalyzed by thrombin, plasmin, and trypsin is linearly proportional to time up to consumption of 60% of the substrate. Km is 14 micron and Vmax is 0.037 mumol/min/NIH unit for bovine thrombin, Km is 78 micron and Vmax is 0.31 mumol/min/CTA unit/ml for human plasmin, and Km is 12 micron and Vmax is 138 mumol/min/mg protein/ml for bovine trypsin. Samples of bovine and human thrombin ranging in specific clotting activity from 59 to 2,133 NIH units/mg protein showed esterase activities ranging from 0.15 to 0.4 mumol p-nitrobenzyl alcohol formed/10 min/NIH unit. Useful ranges for assay of enzymes were (per milliliter): 0.05-0.2 NIH units (thrombin), 0.005-0.02 CTA units (plasmin), and 0.01-0.04 microgram (trypsin). | [
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PMID:26628 | Chromogenic substrate assay of plasma prekallikrein. With a note on its site of biosynthesis. | A method for assaying plasma prekallikrein has been developed applying the chromogenic substrate Chromozym PK. Different variables have been investigated, and the final assay system was found to give a reproducible and reliable assay procedure. A normal value of 99.0 +/- 18% was found, the coefficient of variation being 7.9. Studies on material from patients with various liver diseases indicated that the main site of prekallikrein biosynthesis is the liver. | Chromogenic substrate assay of plasma prekallikrein. With a note on its site of biosynthesis. A method for assaying plasma prekallikrein has been developed applying the chromogenic substrate Chromozym PK. Different variables have been investigated, and the final assay system was found to give a reproducible and reliable assay procedure. A normal value of 99.0 +/- 18% was found, the coefficient of variation being 7.9. Studies on material from patients with various liver diseases indicated that the main site of prekallikrein biosynthesis is the liver. | [
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PMID:26629 | Methods for determination of prekallikrein in plasma, glandular kallikrein and urokinase. | New chromogenic tripeptide substrates have been used for the determination of kallikreins and urokinase. The conditions have been optimized. It is possible to determine prekallikrein in plasma after activation with Cephotest. No significant loss in activity caused by plasma kallikrein inhibitors is observed at the dilutions used. | Methods for determination of prekallikrein in plasma, glandular kallikrein and urokinase. New chromogenic tripeptide substrates have been used for the determination of kallikreins and urokinase. The conditions have been optimized. It is possible to determine prekallikrein in plasma after activation with Cephotest. No significant loss in activity caused by plasma kallikrein inhibitors is observed at the dilutions used. | [
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] |
PMID:26631 | [Regional myocardial blood supply in coronary disease]. | 1. Value and limitations of the precordial Xenon-clearance technique are analyzed. The results of this technique are compared to the scintigraphic display of the initial Xenon distribution and to microsphere scintigraphy (Engel et al. 1976a). 2. The effects of coronary obstructions and of segmental LV dysfunction on regional myocardial blood flow are analyzed (Engel et al. 1977). Independent of coronary obstructions, a clear reduction of regional myocardial blood flow in areas of hypokinesis and akinesis was observed. Thus in coronary disease a decrease of regional myocardial blood flow may represent either a cause or a result of abnormal segmental wall motion. 3. The effects of nitroglycerin, beta-blockade (Atenolol), calcium-antagonists (Nifedipine) and coronary dilatation (Dipyridamole) on regional myocardial blood flow were investigated (Engel et al. 1976b). Regional flow at rest decreased after nitroglycerin and beta-blockade, increased mildly after Nifedipine and markedly after Dipyridamole. | [Regional myocardial blood supply in coronary disease]. 1. Value and limitations of the precordial Xenon-clearance technique are analyzed. The results of this technique are compared to the scintigraphic display of the initial Xenon distribution and to microsphere scintigraphy (Engel et al. 1976a). 2. The effects of coronary obstructions and of segmental LV dysfunction on regional myocardial blood flow are analyzed (Engel et al. 1977). Independent of coronary obstructions, a clear reduction of regional myocardial blood flow in areas of hypokinesis and akinesis was observed. Thus in coronary disease a decrease of regional myocardial blood flow may represent either a cause or a result of abnormal segmental wall motion. 3. The effects of nitroglycerin, beta-blockade (Atenolol), calcium-antagonists (Nifedipine) and coronary dilatation (Dipyridamole) on regional myocardial blood flow were investigated (Engel et al. 1976b). Regional flow at rest decreased after nitroglycerin and beta-blockade, increased mildly after Nifedipine and markedly after Dipyridamole. | [
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PMID:26632 | [On the acute toxicity of labetalol (AH-5158), a combined alpha-and-beta-adrenoceptor-blocking agent (author's transl)]. | Acute toxicity studies in labetalol were performed using mice, rats and rabbits, An oral administration of labetalol produced an increase in salivary secretion due to local irritation. Death followed convulsions by large doses of labetalol. Pathological examinations suggested that the cause of death by labetalol was circulatory disturbances due to the damage of heart muscles and a subsequent respiratory paralysis. Parenteral LD50 showed almost the same values among mice (50 mg/kg iv, 117 mg/kg ip), rats (66 mg/kg iv, 115 mg/kg ip) and rabbits (43 mg/kg iv). However, species difference was seen in oral LD50 values which were enormously large as compared with iv LD50 values. | [On the acute toxicity of labetalol (AH-5158), a combined alpha-and-beta-adrenoceptor-blocking agent (author's transl)]. Acute toxicity studies in labetalol were performed using mice, rats and rabbits, An oral administration of labetalol produced an increase in salivary secretion due to local irritation. Death followed convulsions by large doses of labetalol. Pathological examinations suggested that the cause of death by labetalol was circulatory disturbances due to the damage of heart muscles and a subsequent respiratory paralysis. Parenteral LD50 showed almost the same values among mice (50 mg/kg iv, 117 mg/kg ip), rats (66 mg/kg iv, 115 mg/kg ip) and rabbits (43 mg/kg iv). However, species difference was seen in oral LD50 values which were enormously large as compared with iv LD50 values. | [
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PMID:26633 | Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis. | In order to detect accompanying gastric lesions, we examined 22 patients with familial adenomatosis of the colon belonging to 14 families. Various gastric lesions were confirmed in 15 patients (68.2 per cent) belonging to 13 families. The lesions were found histologically to be adenoma in nine cases, fundic gland polyposis in six, carcinoma in three, and microcarcinoid in two. Fundic gland polyposis consisting of simple hyperplasia of the fundic glands seems to be the gastric lesion specific to familial adenomatosis of the colon and rectum. Familial adenomatosis coli not only affects the colon and rectum, but is also capable of inducing tumorigenicity in other organs. The stomach is one of the organs in which extracolonic lesions occur. | Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis. In order to detect accompanying gastric lesions, we examined 22 patients with familial adenomatosis of the colon belonging to 14 families. Various gastric lesions were confirmed in 15 patients (68.2 per cent) belonging to 13 families. The lesions were found histologically to be adenoma in nine cases, fundic gland polyposis in six, carcinoma in three, and microcarcinoid in two. Fundic gland polyposis consisting of simple hyperplasia of the fundic glands seems to be the gastric lesion specific to familial adenomatosis of the colon and rectum. Familial adenomatosis coli not only affects the colon and rectum, but is also capable of inducing tumorigenicity in other organs. The stomach is one of the organs in which extracolonic lesions occur. | [
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PMID:26634 | Morphologic aspects of bone marrow transplantation in patients with aplastic anemia. | Pre- and post-transplant bone marrow samples from 20 patients with aplastic anemia were studied. Morphologic evidence of marrow reconstitution was noted in 18 patients one to three weeks following transplantation. In most instances the engrafted marrow elements in early weeks appeared as small clusters of erythroid or myeloid precursors. Bone marrow biopsy or clot sections obtained four to eight weeks after transplantation were more cellular with larger clusters of hematopoietic cells, which were most often composed of mixed cellular elements, including megakaryocytes. Two patients with morphologic evidence of engraftment died shortly after transplantation and were excluded from further analysis. In four of the remaining 16 patients grafts were "rejected" three to eight weeks after transplant. A fifth patient who received a marrow graft from his identical twin showed a transient increase in marrow cellularity without clinical improvement. However, the second marrow transplantation in this patient using the same donor after conditioning with cyclophosphamide resulted in moderate clinical improvement. In four of the five patients developing graft "rejection" or failure there was an increase in marrow mast cells in pre- and post-transplant marrow samples. In contrast, only two of 11 patients with successful engraftment had an increase in mast cells. Although the pathophysiologic role of mast cells in marrow transplantation is unclear, the present study suggests a possible inverse correlation between the numbers of marrow mast cells and the likelihood of successful engraftment. Bone marrow samples in patients with graft versus host disease displayed a slight increase in the number of eosinophils, lymphocytes, and plasma cells. | Morphologic aspects of bone marrow transplantation in patients with aplastic anemia. Pre- and post-transplant bone marrow samples from 20 patients with aplastic anemia were studied. Morphologic evidence of marrow reconstitution was noted in 18 patients one to three weeks following transplantation. In most instances the engrafted marrow elements in early weeks appeared as small clusters of erythroid or myeloid precursors. Bone marrow biopsy or clot sections obtained four to eight weeks after transplantation were more cellular with larger clusters of hematopoietic cells, which were most often composed of mixed cellular elements, including megakaryocytes. Two patients with morphologic evidence of engraftment died shortly after transplantation and were excluded from further analysis. In four of the remaining 16 patients grafts were "rejected" three to eight weeks after transplant. A fifth patient who received a marrow graft from his identical twin showed a transient increase in marrow cellularity without clinical improvement. However, the second marrow transplantation in this patient using the same donor after conditioning with cyclophosphamide resulted in moderate clinical improvement. In four of the five patients developing graft "rejection" or failure there was an increase in marrow mast cells in pre- and post-transplant marrow samples. In contrast, only two of 11 patients with successful engraftment had an increase in mast cells. Although the pathophysiologic role of mast cells in marrow transplantation is unclear, the present study suggests a possible inverse correlation between the numbers of marrow mast cells and the likelihood of successful engraftment. Bone marrow samples in patients with graft versus host disease displayed a slight increase in the number of eosinophils, lymphocytes, and plasma cells. | [
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PMID:26636 | Mice bearing the ob/ob mutation have impaired immunity. | The obese mutant mouse C57BL/6J ob/ob showed impaired ability to reject skin grafts or react to a contact-sensitising agent in comparison with littermate controls (either +/ob or +/+). Ability of spleen cells from mice bearing the ob/ob mutation to produce a graft-versus-host reaction in C57BL/6J X DBA/2J F1 hybrid mice was not impaired. | Mice bearing the ob/ob mutation have impaired immunity. The obese mutant mouse C57BL/6J ob/ob showed impaired ability to reject skin grafts or react to a contact-sensitising agent in comparison with littermate controls (either +/ob or +/+). Ability of spleen cells from mice bearing the ob/ob mutation to produce a graft-versus-host reaction in C57BL/6J X DBA/2J F1 hybrid mice was not impaired. | [
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0.015311618335545063
] |
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