Biomedical subjects
A H Neims
Publications and source records attributed to A H Neims.
Prolonged half-life of caffeine in healthy tem newborn infants.
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Behavioral and cognitive effects of caffeine in boys and adult males.
The behavioral and cognitive effects of single doses of caffeine (3 and 10 mg/kg) were studied using a double blind placebo-controlled crossover design. Subjects were 19 prepubertal boys and 20 college age men. In general, children tended to show more objective effects of caffeine than did adults, with increased motor activity, increased speech rate, and decreased reaction time. Adults generally reported side effects following caffeine while children did not, and side effects were more prominent for adults with low habitual caffeine intake. Autonomic measures of arousal were similarly affected for both age groups. Caffeine had some effects that differed from those of amphetamine, indicating distinctive actions of the two stimulants.
The disposition of caffeine during and after pregnancy.
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Relationship between the clearance of caffeine and its 7-N-demethylation in developing beagle puppies.
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Caffeine metabolism in the newborn.
The concentrations of caffeine and metabolites in urine have been examined as a function of age to explore the remarkably slow elimination of caffeine by human infants. Urine samples were obtained from 3 adults and 10 infants aged 8 days to 8 months during therapeutic treatment with caffeine. A high-performance liquid chromatographic (HPLC) procedure involving reversed-phase partition chromatography was developed to separate caffeine and 13 of its metabolites. During the first month of life, caffeine accounted for more than 85% of the identifiable products in urine. Caffeine remained the predominant component for the first 3 months, but its percentage decreased gradually to the adult value of less than 2% by the age of 7 to 9 months. This change reflected increasing metabolite production, not decreasing urinary caffeine concentration. The adult metabolite pattern of partially demethylated xanthines and urates was attained by 7 to 9 months. The data indicate that the 4-day plasma t1/2 of caffeine characteristic of the newborn depends in large part on slow urinary excretion of unchanged drug since there is little or no metabolism. Subsequent decrease in the t1/2 to about 4 hr by the age of 8 months correlates closely with the rise in metabolite production.
Pharmacokinetic profile of caffeine in the premature newborn infant with apnea.
The pharmacokinetic profile of caffeine was studied in 32 premature newborn infants with apnea: 12 following a single intravenous dose; 3 after a single oral dose; 7 during treatment with an initial empirical (high) maintenance dose schedule; and 10 during treatment with a revised (lower) dose schedule. Mean (+/- SE) AV d, t 1/2, ke1, and clearance following a single intravenous dose were 0.916 +/- 0.070 1/kg, 102.9 +/- 17.9 hours, 0.009 +/- 0.001/hours and 8.9 +/- 1.5 ml/kg/hour, respectively. Rapid absorption was noted with plasma concentrations of 6 to 10 mg/l achieved within 30 minutes to two hours following an oral dose of 10 mg/kg. Cpss of caffeine in infants given a high empirical dose (11.2 +/- 1.5 mg/kg/day) ranged from 22.5 to 84.2 mg/l (mean = 45.3) whereas a dose schedule based on kinetic data (2.5 mg/kg/day) yielded plasma concentrations ranging from 7.4 to 19.4 mg/l (mean = 13.7). We suggest a loading dose of 10 mg/kg intravenously or orally followed by a daily maintenance dose of 2.5 mg/kg/day administered as a single dose for the treatment and prevention of neonatal apnea.
Isoelectric focusing of glutathione S-transferases from rat liver and kidney.
The glutathione S-transferases that were purified to homogeneity from liver cytosol have overlapping but distinct substrate specificities and different isoelectric points. This report explores the possibility of using preparative electrofocusing to compare the composition of the transferases in liver and kidney cytosol. Hepatic cytosol from adult male Sprague-Dawley rats was resolved by isoelectric focusing on Sephadex columns into five peaks of transferase activity, each with characteristic substrate specificity. The first four peaks of transferase activity (in order of decreasing basicity) are identified as transferases AA, B, A and C respectively, on the basis of substrate specificity, but the fifth peak (pI6.6) does not correspond to a previously described transferase. Isoelectric focusing of renal cytosol resolves only three major peaks of transferase activity, each with narrow substrate specificity. In the kidney, peak 1 (pI9.0) has most of the activity toward 1-chloro-2,4-dinitrobenzene, peak 2 (pI8.5) toward p-nitrobenzyl chloride, and peak 3 (pI7.0) toward trans-4-phenylbut-3-en-2-one. Renal transferase peak 1 (pI9.0) appears to correspond to transferase B on the basis of pI, substrate specificity and antigenicity. Kidney transferase peaks 2 (pI8.5) and 3 (pI7.0) do not correspond to previously described glutathione S-transferases, although kidney transferase peak 3 is similar to the transferase peak 5 from focused hepatic cytosol. Transferases A and C were not found in kidney cytosol, and transferase AA was detected in only one out of six replicates. Thus it is important to recognize the contribution of individual transferases to total transferase activity in that each transferase may be regulated independently.
Effect of smoking on caffeine clearance.
The elimination of caffeine from saliva was compared in groups of healthy smokers (n = 13) and nonsmokers (n = 13). Mean caffeine t1/2 in smokers (3.5 hr) was shorter than that in the nonsmokers (6.0 hr). The body clearance of caffeine in the smokers (155 +/- 16 ml . kg-1 . hr-1) was greater than that in the nonsmokers (94 +/- 18 ml . kg-1 . hr-1) (p less than 0.05). No significant difference was noted in the apparent volume of distribution in smokers (720 +/- 67 ml . kg-1) and nonsmokers (610 +/- 80 ml . kg-1). These differences probably reflect the induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity in smokers. The increased clearance of caffeine by smokers may contribute to the higher consumption of coffee reported to occur in this group.
The effects of postnatal hyper- and hypothyroidism on the development of D-amino acid oxidase in rat cerebellum and brain stem.
Treatment of rats with propylthiouracil for the first 30 days of postnatal life drastically retards the ontogenesis of D-amino acid oxidase in the brain stem and cerebellum. There is a marked terminal deficit of D-AAO in both the brain stem (--64%) and cerebellum (--67%) at 94 days (adults) despite the near euthyroid status at this age. If initiated early enough, thyroxine replacement therapy reverses the effects of PTU on the development of D-AAO. Hyperthyroidism significantly accelerates the development of D-AAO in both brain stem and cerebellum. Nonetheless, animals treated with thyroxine the first month of life display a net deficit of cerebellar D-AAO content in adulthood. The results are discussed in terms of the localization of D-AAO in cell types especially sensitive to thyroid hormone: (1) a cell type which is among the last to derive from the external germinal zone in the developing cerebellum, and which in the adult is located adjacent to the Purkinje cell soma; and (2) mossy fiber neurons and cerebellar glomeruli.
Stimulation of caffeine metabolism in the rat by 3-methylcholanthrene.
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Induction of rat hepatic glutathione S-transferase B by phenobarbital and 3-methylcholanthrene.
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Alteration of ovine fetal respiratory-like activity by diazepam, caffeine, and doxapram.
The effects of diazepam, caffeine citrate, and doxapram on fetal respiratory-like activity (RLA) were studied in 10 chronic sheep preparations (90 to 130 days' gestation). We define fetal RLA as regular changes in fetal tracheal pressure occurring with a frequency of at least 1 Hz and an amplitude greater than -5 mm. Hg in the absence of fluctuations in amniotic cavity pressure. In all maternal (8) and fetal (7) intravenous infusions of diazepam (5 to 10 mg.), RLA ceased almost instantaneously. The duration of fetal apnea varied from 29 to 70 minutes with a mean of 57 minutes, and on occasion, a gasping pattern preceded recovery of RLA. Maternal and fetal plasma concentrations of diazepam indicated rapid bidirectional placental transfer. Intravenous infusion of doxapram (3 mg.) to the fetus immediately initiated a transient episode of RLA in 19 of 20 trials. Fetal infusion of caffeine citrate (10 to 20 mg.), especially via the carotid artery, was also associated with the rapid onset of a transient episode of fetal breathing. Saline control infusions were without effect. Fetal blood gases and pH were not altered by the administration of diazepam, caffeine citrate, or doxapram. It is suggested that each drug owes its action on RLA to an effect on fetal central nervous system. The influence of pharmacologic agents on the process and interpretation of fetal monitoring requires continued attention.
The development of D-amino acid oxidase in rat cerebellum.
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Hog cerebellar D-amino acid oxidase and its histochemical and immunofluorescent localization.
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Pharmacokinetic observations of phenytoin disposition in the newborn and young infant.
The pharmacokinetic profile of phenytoin (DPH) was studied in 30 infants aged 2 days to 96 weeks. The plasma DPH half-life during the first week of life in term infants was prolonged and very variable (20-7 +/- 11-6 h, mean +/-SD). Thereafter the plasma half-life was much shorter (7-6 +/- 3-5 h). In preterm infants the half-life was much longer (75-4 +/- 64-5 h) and more variable. The mean apparent volume of distribution was similar in these groups of infants: preterm newborn 0-80 +/- 0-22 l/kg, term infants during the first week of life 0-80 +/- 0-26 l/kg, and term infants greater than 2 weeks of age 0-73 +/- 0-18 l/kg. Predictions of steady-state plasma DPH concentrations, based on these kinetic parameters, were confirmed. Very low "trough" plasma DPH concentrations were observed after the 14th postnatal day in 19 infants receiving 8 mg/kg per 24 h orally. On the other hand, infants of less than one week of age receiving the same dose, especially if preterm, frequently showed drug accumulation to toxic plasma DPH concentrations. The impaired binding of DPH to newborn plasma protein was confirmed but "normal adult values" were approached by the age of 3 months. An intravenous loading dose of 8 mg/kg (sodium phenytoin) can be expected to generate a mean plasma DPH concentration of 10 mg/l (40 micronmol/l) in the newborn. Loading doses of up to 12 mg/kg were given without untoward effects. During the first week or so of life plasma Dph half-life is so variable that no fixed dosage regimen can be derived from the available data. Beyond the second week of life, however, a dose of 8 mg/kg per 24 h is probably inadequate for most infants.
The effect of birth on the maturation of hepatic cytochrome(s) P-450 mono-oxygenase and tyrosine aminotransferase activities in the guinea pig.
Mixed coat guinea pigs delivered by Cesarian section 5 days before term were compared to spontaneously delivered full-term animals with respect to the postnatal maturation of hepatic mono-oxygenase activity in vitro toward aniline and p-chloro-N-methylaniline. Tyrosine aminotransferase acitivity was studied in the same preparations as a positive control for birth-related phenomena. Mono-oxygenase activities toward both sustrates increased significantly in both premature and full-term animals during the first 3 postnatal days and approached adult values 72 h after birth. The maturation of tyrosine aminotransferase activity occured in a qualitatively similar fashion. The mechanism through which birth initiates the maturation of drug oxidative capacity is unresolved; the gestational age at which competence to respond to the event of birth is acquired, remains undefined.
A sex difference in hepatic glutathione S-transferase B and the effect of hypophysectomy.
The glutathione S-transferases are a group of proteins with overlapping substrate specificities and ligand-binding capacities. This report examines certain approaches to the measurement of transferase B (ligandin) in the rat liver. The ratio of catalytic activities toward 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene gives some indication of the relative proportions of the various transferases present in 100 000 g supernatants. The fraction of catalytic activity towards 1-chloro-2,4-dinitrobenzene, due to transferase B, was best measured by immunoprecipitation with anti-(transferase B). Male rat liver exhibited three times more activity towards 1,2-dichloro-4-nitrobenzene than female tissue; however, the activities towards 1-chloro-2,4-dinitrobenzene were almost identical. By assuming a specific activity of 11 mumol/min per mg, immunoprecipitable transferase B comprised 4.5 +/- 0.2% of total protein in the 100 000 g supernatant of female rat liver, and 70% of the transferase activity towards 1-chloro-2,4-dinitrobenzene. The amount of transferase B in the 100 000 g supernatant from male rat liver is significantly lower with respect to both fraction of total protein (3.3 +/- 0.2%) and overall transferase activity towards 1-chloro-2,4-dinitrobenzene (48%). Hypophysectomy eliminated this sex difference in the hepatic concentration of glutathione S-transferase B.