Developmental pharmacology and therapeutics最新文献

{"title":"Adrenal responsiveness in very-low-birth-weight infants treated with dexamethasone.","authors":"A Strauss,&nbsp;M Brakin,&nbsp;K Norris,&nbsp;H D Modanlou","doi":"10.1159/000457476","DOIUrl":"https://doi.org/10.1159/000457476","url":null,"abstract":"<p><p>This study was designed to investigate the effect of steroid administration in ill premature neonates. Twenty high-risk very-low-birth-weight (VLBW) infants [birth weight (BW) < or = 1,300 g] with a mean BW 948 +/- 220 g, gestational age (GA) 27 +/- 1.7 weeks underwent 1-hour ACTH (Cortrosyn) stimulation tests and determination of 17-hydroxyprogesterone (17OHP)/dehydroepiandrosterone sulfate (DHEAS) at 23.6 +/- 15.9 days poststeroid treatment for bronchopulmonary dysplasia (BPD)/airway obstruction. Metyrapone tests were also obtained in 18 infants. Baseline (nonsteroid-exposed) values for pre-/post-ACTH cortisol, 17OHP, DHEAS, and pre-/post-metyrapone compound S values were obtained in 5 infants. Eight of 18 (44%) infants had evidence of secondary (hypothalamic-pituitary) adrenal suppression based on abnormal metyrapone tests. No difference was found in BW, GA, time on O2 or AV, steroid dose/kg, or neonatal/postneonatal mortality between the suppressed and nonsuppressed groups. Two of 4 infants with borderline ACTH tests had subnormal compound S levels postmetyrapone. No relationship was found between steroid dose/kg and cortisol response post-ACTH. Additionally, corrected GA was not related to change in cortisol, 17OHP, and DHEAS pre-/post-ACTH. Two infants exhibited recovery of adrenal suppression documented by repeated metyrapone testing at 63 and 186 days poststeroid treatment. In conclusion, this study documents the apparent high incidence of secondary adrenal suppression in VLBW infants treated with dexamethasone. Clinical significance of these findings deserves further investigation.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":"19 2-3","pages":"147-54"},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457476","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12514421","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":"Benzoyl-CoA ligase activity in the liver and kidney cortex of weanling guinea pigs treated with various inducers: relationship with hippurate synthesis and carnitine levels.","authors":"A Ali,&nbsp;I A Qureshi","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Recent reports have indicated that guinea pig may be a better model for the study of benzoate conjugation in humans because of the presence of a salicylate-activating ligase. We gave intraperitoneal injections of sodium benzoate, sodium salicylate, sodium methylprednisolone and sodium phenobarbital for 4 consecutive days to groups of weanling guinea pigs before sacrifice. A measurement of benzoyl-CoA ligase activity and in vitro hippurate synthesis was done in liver and kidney cortex homogenates from each treated group at 21 days of age, as compared to an untreated (saline) 21-day control group. The results indicate that benzoyl-CoA ligase in guinea pigs is affected by phenobarbital (liver and kidney; p < 0.05-0.01) and methylprednisolone (liver; p < 0.01). Liver hippurate synthesis was also significantly induced by phenobarbital (p < 0.01). Both these treated groups also had reduced levels of free carnitine in plasma taken from 21-day-old guinea pigs as compared to the untreated control. Sodium benzoate did not have any effect on benzoyl-CoA ligase activity or on in vitro hippurate synthesis. However, sodium salicylate did show some effect on the induction of liver and kidney benzoyl-CoA ligase (not significant) and liver (p < 0.05) and kidney hippurate synthesis. It is important that studies on the guinea pig model be extended for application to children receiving therapy of benzoate and other aromatic acids like p-aminobenzoate or salicylate.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":"18 1-2","pages":"55-64"},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12653622","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":"Salivary excretion of drugs in children: theoretical and practical issues in therapeutic drug monitoring.","authors":"R Gorodischer,&nbsp;G Koren","doi":"10.1159/000457481","DOIUrl":"https://doi.org/10.1159/000457481","url":null,"abstract":"<p><p>Studies suggest that saliva could be used instead of blood in the therapeutic monitoring of many drugs. This has distinct advantages in pediatrics and neonatology as saliva sampling is painless and spares blood. Stimulation of saliva secretion with a chemical stimulus (i.e. citric acid applied over the tongue) facilitates the study of younger patients. Secretory and reabsorptive processes which take place in the ductal system of the salivary glands, and the rate of flow of the secretion play major roles in the determination of the concentration of solutes in saliva. Drug passage into saliva follows the general principles of movement of drugs across biologic membranes. Only the unbound fraction of the drug in plasma is available for diffusion into saliva and a relationship exists between saliva pH and the saliva/plasma concentration ratio of many polar drugs (tolbutamide, propranolol, procainamide, etc.). However, deviations from the pH theory exist and the inter -and intra-individual variations in saliva/plasma concentration ratios of salicylate and procainamide cannot be explained solely on the basis of fluctuations of salivary pH; on the other hand, a useful relationship exists between plasma and saliva phenobarbital concentrations with no need to correct for saliva pH. The use of stimulated saliva has several advantages over resting saliva: a larger volume of the sample is obtained, the pH gradient between plasma and saliva is smaller, the variability in saliva/plasma concentration ratios of some drugs is narrowed, and less specimens are too viscous or discolored to allow drug analysis. Thorough rinsing of the mouth is required prior to saliva sampling as remnants of orally administered medicines may contaminate saliva specimens and give spuriously high values. Deviation from a simple but strict methodology accounts for some of the discrepancies found in the literature. Studies in children uniformly recommend saliva for therapeutic monitoring of phenytoin, carbamazepine and phenobarbital. Saliva sampling for therapeutic monitoring of ethosuximide, primidone and digoxin in infants and children, and of theophylline and caffeine in the neonate is promising, but little pediatric experience is available as yet. The value of saliva in therapeutic monitoring of theophylline in children is still controversial. Little of highly polar compounds such as aminoglycosides, and of polar highly protein bound drugs such as valproic acid is present in saliva. More data are still needed on the excretion of drugs in saliva in infants and in acutely ill children, and few data exist in the premature and full-term neonate.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":"19 4","pages":"161-77"},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1159/000457481","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12516760","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":"7-Ethoxycoumarin metabolism in hepatocytes from pre- and postpubescent male rats.","authors":"L. B. Roochvarg, R. Thurman, F. Kauffman","doi":"10.1159/000480601","DOIUrl":"https://doi.org/10.1159/000480601","url":null,"abstract":"Marked changes in rates of drug metabolism occur during adolescence; however, biochemical events underlying alterations in drug metabolism in whole hepatocytes during this period of development are not well established. Accordingly, metabolism of 7-ethoxycoumarin, a model substrate for mixed-function oxidation, was studied in hepatocytes isolated from prepubescent and postpubescent male rats. Rates of 7-ethoxycoumarin O-deethylation increased 2.4-fold from 65 to 154 pmol/10(6) cells/min in intact hepatocytes during the narrow period of adolescence. In contrast, microsomal 7-ethoxycoumarin O-deethylase was the same in preparations from the two groups of animals. 7-Hydroxycoumarin glucuronide production in hepatocytes increased 2-fold and sulfate formation increased 16-fold across puberty. The results indicate that increases in drug metabolism, particularly sulfate conjugation, are mediated by biochemical events in addition to increases in total amounts and specific activities of hepatic drug-metabolizing enzymes.","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":"10 1","pages":"81-8"},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81956371","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":"Expression and release of neuroregulators during development: monoamines and neuropeptides.","authors":"H. Lagercrantz, H. Holgert, J. Pequignot, M. Srinivasan","doi":"10.1159/000480612","DOIUrl":"https://doi.org/10.1159/000480612","url":null,"abstract":"The turnover of catecholamines (CA) was determined in the adrenal medulla and brain of rat fetuses and pups. In general we found a considerable increase soon after birth. The expression of mRNA for CA-synthesizing enzymes was also considerably enhanced in the adrenals shortly after birth. Furthermore, we demonstrated increased expression of neuropeptides after birth, increased synthesis of mRNA encoding for neuropeptide Y in the adrenals 24 h after birth; and considerable activation of the substance P gene in a respiratory nuclei of rabbit pups which had been breathing for 2 h as compared with fetuses at term.","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":"2 1","pages":"136-8"},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84659195","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":"Nervous and immune systems as targets for developmental effects of benzodiazepines. A review of recent studies.","authors":"M. Schlumpf, R. Parmar, A. Schreiber, H. Ramseier, E. Bütikofer, Hugues Abriel, M. Barth, T. Rhyner, W. Lichtensteiger","doi":"10.1159/000480614","DOIUrl":"https://doi.org/10.1159/000480614","url":null,"abstract":"Prenatal exposure to benzodiazepines (BDZ) can cause behavioral dysfunctions both in humans and in experimental animals. In addition, prolonged impairment of cellular immune functions is found in rats after low dose BDZ exposure (e.g., diazepam 1.25 mg/kg/day) during part of fetal life [gestational days (GD) 14-20]. Analysis of diazepam and its metabolites in maternal and fetal tissues revealed that in this rat model the drug is no longer present at birth, which excludes direct effects of diazepam during the postnatal period. The main target of BDZ in brain, the GABAA receptor complex, is structurally and functionally heterogeneous. Besides alpha- and beta-subunits, gamma 2- or gamma 3-subunit should be coexpressed for a fully functional BDZ response. Signals of mRNAs encoding for alpha 1, beta 2 and gamma 2 are detected in fetal rat spinal cord and lower brainstem by GD 14 and reach telencephalic regions in later fetal life, reminiscent of BDZ receptor ontogeny. Regional subunit distribution differs from the adult brain, one interesting feature being a preponderance of gamma 2 mRNA throughout fetal life. Since subunit composition influences the sensitivity to BDZ, these data suggest that prenatal effects of BDZ depend upon regional subunit compositions present at different developmental stages. The delayed depression of cellular immune responses in prenatally BDZ-exposed rat offspring during the first 2 postnatal months is accompanied by various changes in immune cell biology. Binding characteristics of the peripheral (omega 3) type BDZ receptor are altered until adulthood (8 weeks). Membranes of spleen cell preparations containing mainly lymphocytes exhibit a decrease of affinity for the peripheral ligand [3H]PK11195, splenic macrophage preparations a decrease of maximal binding capacity. Various defects in cytokine production by macrophages and T lymphocytes were observed: Mitogen-stimulated release of macrophage-derived tumor necrosis factor-alpha (TNF-alpha) and of the T cell-derived interleukin-2 (IL-2) was drastically reduced at 2 and 4 weeks of life and recovered in young adulthood, exhibiting the same time course of depression as lymphocyte proliferation in response to immune stimuli. Interleukin-6 (IL-6) release remained diminished until adulthood. In female offspring, additional alterations were found in splenic noradrenaline turnover after immune stimulation. The mechanisms underlying the breakdown of the cytokine network in prenatally diazepam-exposed offspring, and the long-term consequences are as yet unknown.","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":"56 1","pages":"145-58"},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82839863","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":"Thrombocyte monoamine oxidase activity and behavior deviances in adolescence.","authors":"M. Cederblad, L. Oreland, E. Zachrisson","doi":"10.1159/000480621","DOIUrl":"https://doi.org/10.1159/000480621","url":null,"abstract":"The frequencies of patients with low thrombocyte monoamine oxidase (MAO) activity (defined as having an activity lower than 1 SD below the mean of a respective control group) were studied in 100 consecutive cases admitted to a clinic for child and youth psychiatry. 41 boys and 26 girls (group I) had behavior disorders, attention deficit disorders and/or alcohol and hashish abuse according to DSM III R. 16 boys and 17 girls had other diagnoses (group II). None of the 2 male patient groups differed significantly from the controls. A significantly higher percentage of the girls in group I had low activity of platelet MAO than in the control group (p = 0.015), while the girls in group II did not differ from the controls. Acting out, antisocial behavior and abuse is less accepted in women than in men. Therefore, the girls in the present study might be either more psychiatrically disturbed or have more deviant personalities than the boys, which might explain why our hypothesis about a lower thrombocyte MAO activity in the adolescents with externalizing symptoms (group I) was verified only in the girls.","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":" 21","pages":"184-90"},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91414388","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":"Benzoyl-CoA ligase activity in the liver and kidney cortex of weanling guinea pigs treated with various inducers: relationship with hippurate synthesis and carnitine levels.","authors":"A. Ali, I. Qureshi","doi":"10.1159/000480598","DOIUrl":"https://doi.org/10.1159/000480598","url":null,"abstract":"Recent reports have indicated that guinea pig may be a better model for the study of benzoate conjugation in humans because of the presence of a salicylate-activating ligase. We gave intraperitoneal injections of sodium benzoate, sodium salicylate, sodium methylprednisolone and sodium phenobarbital for 4 consecutive days to groups of weanling guinea pigs before sacrifice. A measurement of benzoyl-CoA ligase activity and in vitro hippurate synthesis was done in liver and kidney cortex homogenates from each treated group at 21 days of age, as compared to an untreated (saline) 21-day control group. The results indicate that benzoyl-CoA ligase in guinea pigs is affected by phenobarbital (liver and kidney; p < 0.05-0.01) and methylprednisolone (liver; p < 0.01). Liver hippurate synthesis was also significantly induced by phenobarbital (p < 0.01). Both these treated groups also had reduced levels of free carnitine in plasma taken from 21-day-old guinea pigs as compared to the untreated control. Sodium benzoate did not have any effect on benzoyl-CoA ligase activity or on in vitro hippurate synthesis. However, sodium salicylate did show some effect on the induction of liver and kidney benzoyl-CoA ligase (not significant) and liver (p < 0.05) and kidney hippurate synthesis. It is important that studies on the guinea pig model be extended for application to children receiving therapy of benzoate and other aromatic acids like p-aminobenzoate or salicylate.","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":"124 1","pages":"55-64"},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76172552","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":"Potential of population pharmacokinetics to reduce the frequency of blood sampling required for estimating kinetic parameters in neonates.","authors":"L Collart,&nbsp;T F Blaschke,&nbsp;F Boucher,&nbsp;C G Prober","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":"18 1-2","pages":"71-80"},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12653624","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":"Effects of betamethasone and thyroid hormone on fetal rat lung maturation in vivo.","authors":"F R Moya,&nbsp;I Sanchez,&nbsp;D Baudy","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We studied the effect of maternal administration at various intervals of betamethasone, triiodothyronine (T3), or both, on fetal rat lung maturation. T3 alone did not enhance choline incorporation to phosphatidylcholine by 20-day fetal lung explants, or morphometric lung maturation. Betamethasone, and betamethasone plus T3, increased both of those parameters over control and T3 values. However, addition of T3 offered no advantage over administration of betamethasone alone. Significant enhancement of morphometric lung maturation was already present after only 24 h of exposure to beta-methasone, or to the combination of hormones. However, choline incorporation to phosphatidylcholine only increased significantly by 36 h of exposure to betamethasone with or without T3.</p>","PeriodicalId":11160,"journal":{"name":"Developmental pharmacology and therapeutics","volume":"18 1-2","pages":"14-9"},"PeriodicalIF":0.0,"publicationDate":"1992-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12654391","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}