This study investigated the ontogeny of contractile and relaxation responses in aortic and tail artery preparations from 3-, 7-, and 11-week-old male Sprague-Dawley rats. Contractile responses to norepinephrine, serotonin, KCl, electrical stimulation, and potassium-free physiological solution were significantly increased in vascular smooth muscle from 3-week-old rats when compared to 7- and 11-week-old rats. Endothelium-dependent acetylcholine-induced relaxation and beta-adrenoceptor mediated isoproterenol-induced relaxation were significantly attenuated with maturation. These data demonstrate that significant changes occur in aortic and tail artery smooth muscle responsiveness during the postweaning maturational period of the rat. The alterations may have significant implications with regard to cardiovascular and thermoregulatory function as well as the age of the animal when utilized as an experimental model for identifying pathogenic mechanisms involved in various disease states such as hypertension. As such, further studies are warranted to determine if similar ontogenic changes in vascular function occur at the level of the resistance vessel.
{"title":"Ontogeny of vascular smooth muscle responsiveness in the postweaning rat.","authors":"E E Soltis, P S Newman","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>This study investigated the ontogeny of contractile and relaxation responses in aortic and tail artery preparations from 3-, 7-, and 11-week-old male Sprague-Dawley rats. Contractile responses to norepinephrine, serotonin, KCl, electrical stimulation, and potassium-free physiological solution were significantly increased in vascular smooth muscle from 3-week-old rats when compared to 7- and 11-week-old rats. Endothelium-dependent acetylcholine-induced relaxation and beta-adrenoceptor mediated isoproterenol-induced relaxation were significantly attenuated with maturation. These data demonstrate that significant changes occur in aortic and tail artery smooth muscle responsiveness during the postweaning maturational period of the rat. The alterations may have significant implications with regard to cardiovascular and thermoregulatory function as well as the age of the animal when utilized as an experimental model for identifying pathogenic mechanisms involved in various disease states such as hypertension. As such, further studies are warranted to determine if similar ontogenic changes in vascular function occur at the level of the resistance vessel.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12653621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We examined the effect of the calcium channel blocker nimodipine on postischemic hypoperfusion in the newborn piglet brain. A severe pneumothorax (SP) was induced by injecting air into the right thorax until the mean arterial blood pressure fell to 25% of baseline and was maintained for 4 min. Blood flow was immediately reduced 70-90% from baseline in each brain region during SP. In untreated animals postischemic hypoperfusion existed at 60 min, following recovery from SP with regional brain blood flow reduced 20-30% from baseline. Nimodipine infusion after SP prevented postischemic hypoperfusion in all brain regions and increased blood flows by as much as 40% above baseline in midbrain and brainstem structures. Nimodipine infusion began after severe brain ischemia prevented postischemic hypoperfusion and enhanced brain blood flow in this model.
{"title":"Effects of nimodipine on brain blood flow following acute brain ischemia in the newborn piglet.","authors":"C S Easley, F S Wartman, A E Kopelman, T M Louis","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We examined the effect of the calcium channel blocker nimodipine on postischemic hypoperfusion in the newborn piglet brain. A severe pneumothorax (SP) was induced by injecting air into the right thorax until the mean arterial blood pressure fell to 25% of baseline and was maintained for 4 min. Blood flow was immediately reduced 70-90% from baseline in each brain region during SP. In untreated animals postischemic hypoperfusion existed at 60 min, following recovery from SP with regional brain blood flow reduced 20-30% from baseline. Nimodipine infusion after SP prevented postischemic hypoperfusion in all brain regions and increased blood flows by as much as 40% above baseline in midbrain and brainstem structures. Nimodipine infusion began after severe brain ischemia prevented postischemic hypoperfusion and enhanced brain blood flow in this model.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12653623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
(+)-[3H]PN 200-110 (a dihydropyridine calcium channel antagonist) binding sites were studied in ureters of 1-day (neonatal), 6-week (premature), 6-month (young) and 4.5- to 5-year (old) female rabbits. Specific binding of (+)-[3H]PN 200-110 to ureteral membrane particulates was saturable, reversible and of high affinity. The densities (Bmax) of (+)-[3H]PN 200-110 binding sites were 46.7 +/- 2.5, 22.6 +/- 2.0, 12.7 +/- 1.8 and 11.9 +/- 1.6 fmol/mg protein in 1-day, 6-week, 6-month and 4.5- to 5-year rabbit ureters, respectively. The affinity constants (KD) of the binding sites for (+)-[3H]PN 200-110 were similar in all groups. Calcium agonists and antagonists inhibited (+)-[3H]PN 200-110 binding to 1-day and 6-week rabbit ureters with the following rank order of Ki values: nitrendipine < nifedipine < BAY K 8644 < verapamil. There were no significant differences in Ki values between the neonatal and premature groups. The data demonstrate the presence of an age-related down-regulation of (+)-[3H]PN 200-110 binding sites in rabbit ureteral membrane particulates.
{"title":"Age-related changes in calcium antagonist receptors in rabbit ureter.","authors":"M Yoshida, J Latifpour, R M Weiss","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>(+)-[3H]PN 200-110 (a dihydropyridine calcium channel antagonist) binding sites were studied in ureters of 1-day (neonatal), 6-week (premature), 6-month (young) and 4.5- to 5-year (old) female rabbits. Specific binding of (+)-[3H]PN 200-110 to ureteral membrane particulates was saturable, reversible and of high affinity. The densities (Bmax) of (+)-[3H]PN 200-110 binding sites were 46.7 +/- 2.5, 22.6 +/- 2.0, 12.7 +/- 1.8 and 11.9 +/- 1.6 fmol/mg protein in 1-day, 6-week, 6-month and 4.5- to 5-year rabbit ureters, respectively. The affinity constants (KD) of the binding sites for (+)-[3H]PN 200-110 were similar in all groups. Calcium agonists and antagonists inhibited (+)-[3H]PN 200-110 binding to 1-day and 6-week rabbit ureters with the following rank order of Ki values: nitrendipine < nifedipine < BAY K 8644 < verapamil. There were no significant differences in Ki values between the neonatal and premature groups. The data demonstrate the presence of an age-related down-regulation of (+)-[3H]PN 200-110 binding sites in rabbit ureteral membrane particulates.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12654388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M Yazdani, F Fontenot, S B Gottschalk, Y Kanemaru, F Joseph, T Nakamoto
Pregnant rat dams were divided into four groups on the 3rd day of gestation. Group 1 dams were fed a 20% protein diet as controls. Dams of group 2 were fed a 20% protein diet supplemented with zinc (0.6 g ZnCl2/kg diet). Group 3 dams were fed a 20% protein diet supplemented with caffeine (2 mg/100 g body weight) and dams of group 4 were fed a 20% protein diet supplemented with both caffeine and zinc. Fetuses were surgically delivered on day 22, and brains were removed and analyzed for alkaline phosphatase activity, protein, zinc, cholesterol and DNA concentrations. Fetal brain caffeine levels, as well as maternal and fetal plasma caffeine levels, were determined in caffeine-supplemented groups. The body weight of group 4 and brain weights of groups 3 and 4 were higher than those of groups 1 and 2. Alkaline phosphatase activity of group 3 was less than that of group 1. The brain zinc concentration of group 2 was higher than in the other groups, but that of group 4 was less than that of group 1. The present study indicated that the supplementation of caffeine to the maternal diet decreased zinc levels in the fetal brain, and the addition of extra zinc to this diet did not return the zinc level to that of the control level as we had expected. In addition, the supplementation of caffeine and zinc together increased the body weights of the fetuses compared to the controls, but the addition of only one of these substances had no effect, suggesting that the combination of caffeine and zinc may have unique effects on fetal growth.
在妊娠第3天将妊娠大鼠分为4组。1组饲喂蛋白质含量为20%的饲粮作为对照。2组饲喂蛋白质含量为20%的饲粮，并添加锌(0.6 g ZnCl2/kg饲粮)。第3组饲喂20%蛋白质饲粮中添加咖啡因(2 mg/100 g体重)，第4组饲喂20%蛋白质饲粮中同时添加咖啡因和锌。胎儿在第22天手术分娩，取下大脑，分析碱性磷酸酶活性、蛋白质、锌、胆固醇和DNA浓度。在咖啡因补充组中，测定了胎儿脑咖啡因水平，以及母体和胎儿血浆咖啡因水平。第4组的体质量和第3、4组的脑质量均高于第1、2组。3组的碱性磷酸酶活性低于1组。第2组脑锌浓度高于其他各组，第4组脑锌浓度低于第1组。本研究表明，在母体饮食中添加咖啡因会降低胎儿大脑中的锌含量，而在母体饮食中添加额外的锌并没有像我们预期的那样使锌水平恢复到对照组的水平。此外，与对照组相比，同时补充咖啡因和锌会增加胎儿的体重，但只添加其中一种物质没有效果，这表明咖啡因和锌的组合可能对胎儿生长有独特的影响。
{"title":"Relationship of prenatal caffeine exposure and zinc supplementation on fetal rat brain growth.","authors":"M Yazdani, F Fontenot, S B Gottschalk, Y Kanemaru, F Joseph, T Nakamoto","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Pregnant rat dams were divided into four groups on the 3rd day of gestation. Group 1 dams were fed a 20% protein diet as controls. Dams of group 2 were fed a 20% protein diet supplemented with zinc (0.6 g ZnCl2/kg diet). Group 3 dams were fed a 20% protein diet supplemented with caffeine (2 mg/100 g body weight) and dams of group 4 were fed a 20% protein diet supplemented with both caffeine and zinc. Fetuses were surgically delivered on day 22, and brains were removed and analyzed for alkaline phosphatase activity, protein, zinc, cholesterol and DNA concentrations. Fetal brain caffeine levels, as well as maternal and fetal plasma caffeine levels, were determined in caffeine-supplemented groups. The body weight of group 4 and brain weights of groups 3 and 4 were higher than those of groups 1 and 2. Alkaline phosphatase activity of group 3 was less than that of group 1. The brain zinc concentration of group 2 was higher than in the other groups, but that of group 4 was less than that of group 1. The present study indicated that the supplementation of caffeine to the maternal diet decreased zinc levels in the fetal brain, and the addition of extra zinc to this diet did not return the zinc level to that of the control level as we had expected. In addition, the supplementation of caffeine and zinc together increased the body weights of the fetuses compared to the controls, but the addition of only one of these substances had no effect, suggesting that the combination of caffeine and zinc may have unique effects on fetal growth.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12654389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We examined the effect of the alpha 1-adrenergic antagonist prazosin on blood pressure, left ventricular output and blood flow redistribution during normoxemia and mild hypoxemia in the chronically instrumented, unanesthetized newborn piglet employing the radiolabeled microsphere technique. Prior to prazosin, hypoxemia caused increases in aortic pressure and blood flows to the brain, myocardium and diaphragm, accomplished by small, statistically insignificant decreases in flows to the carcass and viscera without an increase in cardiac index. Prazosin treatment during normoxemia caused a fall in blood pressure and resulted in greater blood flows of left ventricular origin to the carcass, myocardium and lung. Hypoxemia after prazosin administration increased not only aortic pressure and blood flows to the brain, myocardium and diaphragm, but also, unlike the situation before drug treatment, cardiac index. Thus, in the newborn piglet, the maintenance of critical organ oxygen delivery during hypoxemia is not blocked by prazosin, but is accomplished by an increase in cardiac index rather than simply by redistribution of blood flow.
{"title":"Effect of prazosin on hypoxemia-induced blood flow redistribution in the newborn piglet.","authors":"R. Green, M. Lasker, F. Mcdonnell, I. Holzman","doi":"10.1159/000480595","DOIUrl":"https://doi.org/10.1159/000480595","url":null,"abstract":"We examined the effect of the alpha 1-adrenergic antagonist prazosin on blood pressure, left ventricular output and blood flow redistribution during normoxemia and mild hypoxemia in the chronically instrumented, unanesthetized newborn piglet employing the radiolabeled microsphere technique. Prior to prazosin, hypoxemia caused increases in aortic pressure and blood flows to the brain, myocardium and diaphragm, accomplished by small, statistically insignificant decreases in flows to the carcass and viscera without an increase in cardiac index. Prazosin treatment during normoxemia caused a fall in blood pressure and resulted in greater blood flows of left ventricular origin to the carcass, myocardium and lung. Hypoxemia after prazosin administration increased not only aortic pressure and blood flows to the brain, myocardium and diaphragm, but also, unlike the situation before drug treatment, cardiac index. Thus, in the newborn piglet, the maintenance of critical organ oxygen delivery during hypoxemia is not blocked by prazosin, but is accomplished by an increase in cardiac index rather than simply by redistribution of blood flow.","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81234264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In the rat heart, monoamine oxidase (MAO)-B activity was shown to predominate in 2- to 3-week-old animals, whereas MAO-A activity was reported to be very low in newborn rats and to increase considerably with age until it predominates. These results are in contrast with those found in the mouse heart, where an age-dependent increase in MAO-B activity with no changes in 5-hydroxytryptamine deaminating activity was found to occur. There is evidence that the adult values of MAO activity are reached early in development in rat kidney and liver. In the rat lung the adult values of MAO-A activity are reached by day 40, whereas MAO-B activity is still increasing by day 80. Important differences have been reported in the developmental pattern of the two forms of MAO in the rat and mouse brain, with a decrease in the MAO-A/MAO-B ratio during postnatal development. In the human brain, the ontogenetic development of MAO-A and MAO-B appears to parallel that observed in the rodent brain. It is worth noting that most of the available data have to be considered with reservation owing to many methodological problems. Further studies are clearly needed to get reliable information on the ontogenesis of MAO in mammalian tissues.
值得注意的是，由于许多方法上的问题，对现有的大多数数据必须加以保留。
{"title":"Developmental aspects of the monoamine-degrading enzyme monoamine oxidase.","authors":"M. Strolin Benedetti, P. Dostert, K. Tipton","doi":"10.1159/000480622","DOIUrl":"https://doi.org/10.1159/000480622","url":null,"abstract":"In the rat heart, monoamine oxidase (MAO)-B activity was shown to predominate in 2- to 3-week-old animals, whereas MAO-A activity was reported to be very low in newborn rats and to increase considerably with age until it predominates. These results are in contrast with those found in the mouse heart, where an age-dependent increase in MAO-B activity with no changes in 5-hydroxytryptamine deaminating activity was found to occur. There is evidence that the adult values of MAO activity are reached early in development in rat kidney and liver. In the rat lung the adult values of MAO-A activity are reached by day 40, whereas MAO-B activity is still increasing by day 80. Important differences have been reported in the developmental pattern of the two forms of MAO in the rat and mouse brain, with a decrease in the MAO-A/MAO-B ratio during postnatal development. In the human brain, the ontogenetic development of MAO-A and MAO-B appears to parallel that observed in the rodent brain. It is worth noting that most of the available data have to be considered with reservation owing to many methodological problems. Further studies are clearly needed to get reliable information on the ontogenesis of MAO in mammalian tissues.","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85078911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Data obtained from neonates receiving zidovudine as part of a phase I study were used to estimate the population pharmacokinetic parameters of this drug and to determine the minimum number of data points necessary to provide accurate estimates of the kinetic parameters and their variability. Analysis was performed with 541 concentrations of zidovudine, obtained from 32 infants and with a variety of reduced data sets using NONMEM (nonlinear mixed effect model). The reduced data sets were derived by randomly reducing the number of sampling time points per dosing interval and/or by randomly reducing the number of available subjects. We determined that accurate estimates of pharmacokinetic parameters and their variability were obtained with the inclusion of all 32 patients using only two concentration-time points per dose interval, provided that one of the points was obtained during the first 2 h after administration of the drug. The parameters themselves were adequately estimated with only 24 subjects and two concentration-time points per dose interval. We suggest that NONMEM should be used in addition to the traditional pharmacokinetic analysis to obtain more precise information directly in the population of interest with a minimum of blood sampling from each patient. This is especially critical in infants whose blood volumes are limited.
{"title":"Potential of population pharmacokinetics to reduce the frequency of blood sampling required for estimating kinetic parameters in neonates.","authors":"L. Collart, T. Blaschke, F. Boucher, C. Prober","doi":"10.1159/000480600","DOIUrl":"https://doi.org/10.1159/000480600","url":null,"abstract":"Data obtained from neonates receiving zidovudine as part of a phase I study were used to estimate the population pharmacokinetic parameters of this drug and to determine the minimum number of data points necessary to provide accurate estimates of the kinetic parameters and their variability. Analysis was performed with 541 concentrations of zidovudine, obtained from 32 infants and with a variety of reduced data sets using NONMEM (nonlinear mixed effect model). The reduced data sets were derived by randomly reducing the number of sampling time points per dosing interval and/or by randomly reducing the number of available subjects. We determined that accurate estimates of pharmacokinetic parameters and their variability were obtained with the inclusion of all 32 patients using only two concentration-time points per dose interval, provided that one of the points was obtained during the first 2 h after administration of the drug. The parameters themselves were adequately estimated with only 24 subjects and two concentration-time points per dose interval. We suggest that NONMEM should be used in addition to the traditional pharmacokinetic analysis to obtain more precise information directly in the population of interest with a minimum of blood sampling from each patient. This is especially critical in infants whose blood volumes are limited.","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84240095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Repeated exposure to drugs acting as direct or indirect stimulants of central dopamine transmission results in sensitization to their behavioural stimulant properties (behavioural sensitization). Priming provides a simple model of behavioural sensitization particularly suitable for studies of its neural and molecular mechanisms. The results obtained to date indicate that priming results in an increased responsiveness of postsynaptic dopamine receptor mechanisms in the caudate nucleus, possibly due to an increased affinity of the D-1 receptor for its agonist.
{"title":"Priming as a model of behavioural sensitization.","authors":"G. Di Chiara, M. Morelli, P. Barone, F. Pontieri","doi":"10.1159/000480624","DOIUrl":"https://doi.org/10.1159/000480624","url":null,"abstract":"Repeated exposure to drugs acting as direct or indirect stimulants of central dopamine transmission results in sensitization to their behavioural stimulant properties (behavioural sensitization). Priming provides a simple model of behavioural sensitization particularly suitable for studies of its neural and molecular mechanisms. The results obtained to date indicate that priming results in an increased responsiveness of postsynaptic dopamine receptor mechanisms in the caudate nucleus, possibly due to an increased affinity of the D-1 receptor for its agonist.","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74546099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The majority of synthetic drugs with chiral centers are administered as racemates. Thus chemically, and to an even greater extent biologically, a racemic drug is not a single compound, but a 50:50 mixture of two enantiomeric drugs. No generalization can be made concerning whether and to what extent the activity, in either qualitative or quantitative terms, differs between enantiomers. It is not unusual for the enantiomers of a drug to have a high degree of enantioselectivity for one action but no enantioselectivity for another action. For instance S-propranolol is at least two orders of magnitude more potent than R-propranolol with regard to beta-adrenoceptor antagonism. However, the two enantiomers are equipotent with regard to their membrane stabilizing effect. It is often overlooked that enantioselectivity in the activity of enantiomers as determined in vitro cannot be extrapolated to the in vivo situation since enantioselective drug disposition can lead to an enantiomer ratio in vivo which differs substantially from that in the dosage form administered. Enantioselectivity in drug disposition seems to be the rule rather than the exception and, depending on whether the active or less active enantiomer is preferentially affected, there may be amplification or attenuation of in vivo as compared to the in vitro drug potency.
{"title":"Enantiomers: implications and complications in developmental pharmacology.","authors":"M. Eichelbaum","doi":"10.1159/000480610","DOIUrl":"https://doi.org/10.1159/000480610","url":null,"abstract":"The majority of synthetic drugs with chiral centers are administered as racemates. Thus chemically, and to an even greater extent biologically, a racemic drug is not a single compound, but a 50:50 mixture of two enantiomeric drugs. No generalization can be made concerning whether and to what extent the activity, in either qualitative or quantitative terms, differs between enantiomers. It is not unusual for the enantiomers of a drug to have a high degree of enantioselectivity for one action but no enantioselectivity for another action. For instance S-propranolol is at least two orders of magnitude more potent than R-propranolol with regard to beta-adrenoceptor antagonism. However, the two enantiomers are equipotent with regard to their membrane stabilizing effect. It is often overlooked that enantioselectivity in the activity of enantiomers as determined in vitro cannot be extrapolated to the in vivo situation since enantioselective drug disposition can lead to an enantiomer ratio in vivo which differs substantially from that in the dosage form administered. Enantioselectivity in drug disposition seems to be the rule rather than the exception and, depending on whether the active or less active enantiomer is preferentially affected, there may be amplification or attenuation of in vivo as compared to the in vitro drug potency.","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83008225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Treatment of growth failure in renal disease with recombinant human growth hormone: 2 years' experience.","authors":"B Tönshoff, O Mehls","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12480985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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