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Biomedical subjects

A Rane

Publications and source records attributed to A Rane.

At least 271 records · Page 15Linked to original sources
PubMed1976

Loading and conventional dose therapy with phenytoin in children: kinetic profile of parent drug and main metabolite in plasma.

Epileptic children were given phenytoin (DPH) in loading (four doses of 4.4 to 6.3 mg/kg/dose given 8-hourly and then 6 mg/kg/day) or conventional (5 to 9 mg/kg/day) doses. Plasma levels of DPH and its main metabolite (p-OH-DPH) were measured by a mass fragmentographic technique. Plasma DPH levels of more than 10 mug/ml were achieved within 16 to 38 hr in the children given loading doses and within 5 days in the conventionally dosed children. No immediate side effects were noted, but within 8 to 10 days 9 of 13 children developed a generalized skin rash. Plasma p-OH-DPH (free or conjugated) paralleled DPH during the accumulation phase but not during DPH elimination. The ratio of metabolite to DPH in plasma showed both an interindividual variation and an inverse relation to the level of DPH. Identical twins in the study had a similar ratio and plasma level-time course profile. It is concluded that the loading dose regiment achieves an appropriate plasma level of DPH rapidly, that saturation kinetics are operative for p-OH-DPH formation, that the ratio of metabolite to DPH in plasma is an individual characteristic in children, and that further studies on the delayed toxicity are needed before the loading dose regimen can be recommended.

Adolescent↗
PubMed1976

Clinical pharmacokinetics in infants and children.

Wide variations in drug dose recommendations for children of the same or different ages reflect the inadequacy of data on pharmacokinetics and pharmacodynamics in children. Selected aspects of available literature on pharmacokinetics of drugs used in older infants and children has been reviewed with special attention to calculation of an age-appropriate dose. During the neonatal period and early infancy the elimination of many drugs that are excreted in the urine in unchanged form is restricted by the immaturity of glomerular filtration and renal tubular secretion. On the other hand, in late infancy and/or in childhood, a similar or greater rate of elimination from plasma than in adults has been observed for many drugs, notably digoxin, phenobarbitone, phenytoin, carbamazepine, ethosuximide, diazoxide, clindamycin and propoxyphene. Consistent with this, it has been shown that some drugs exhibit a lower plasma level/dose ratio in infancy and early childhood as compared with the adult. This is true for phenobarbitone, phenytoin and ethosuximide. Some age groups of children remain uninvestigated with regard to pharmacokinetics, even for the drugs reviewed. Therefore, pediatric therapy remains empirically based for many drugs.

Aging↗
PubMed1975

Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses.

Carbamazepine (Tegretol) was administered orally to four patients as a single dose, and one week later three times daily for 15-21 days. The plasma half-lives of the drug were shorter in all patients after multiple doses (20.9 +/- 5.0 hours) than after the initial single dose (35.6 +/- 15.3 hours). During the multiple dose the plasma concentrations of the metabolite carbamazepine-10,11-epoxide followed those of the parent drug. The steady-state plasma concentrations expected during multiple doses were calculated from the pharmacokinetic parameters obtained in the single dose studies. The calculated levels were higher (17.2+/-7.2 mug/ml) than the observed maximal concentrations (8.4+/-1.6 mug/ml on day 4), which were obtained 3-4 days after starting the multiple doses. The levels tended to decrease further during the experimental period. The results suggest that carbamazepine induces its own metabolism in man.

Carbamazepine↗
PubMed1975

Assay of the major (4-hydroxylated) metabolites of diphenylhydantoin in human urine.

A modified gas chromatographic procedure for the determination of unconjugated and conjugated 4-hydroxydiphenylhydantoin (4-OH-DPH) in urine has been developed. Unconjugated 4-OH-DPH is determined after selective extraction with toluene-ether (1:1). For the assay of conjugated 4-OH-DPH, the urine is pre-extracted with isoamylalcohol before acid hydrolysis to avoid interference by the dihydrodiol metabolite of DPH. The sensitivity of the method is 0.1 mug per ml. The method has been used to determine the urinary metabolites in two adult volunteers, during steady state plasma concentrations of DPH and in the elimination phase.

Adult↗
PubMed1975

Disposition of placentally transferred carbamazepine (Tegretol) in the newborn.

The plasma elimination of carbamazepine (Tegretol) was studied in five newborns who had got the drug transplacentally from their epileptic mothers. The half-lives ranged from 8.2-27.7 hours which is comparable or even shorter than those found in adults after a single oral dose, but in the same range as those found in adults after multiple oral doses. This suggests that the newborns' drug metabolizing capacity has been induced during fetal life.

Carbamazepine↗
PubMed1975

Properties of hydroxylase systems in the human fetal liver active on free and sulfoconjugated steroids.

The substrate specificity of the steroid sulfate-hydroxylating activity in microsomes from human fetal liver has been investigated. Twelve different C18, C19, C21, and C27 steroid sulfates and the corresponding free steroids were used as substrates. The introduction of a sulfate group on the steroid substrate was found to have two principal effects. (1) The hydrophilic sulfate group directs the steroid molecule so that it only interacts with the active site of cytochrome P-450 with its non-sulfurylated, hydrophobic end. (2) The sulfate group interacts with the enzyme surface resulting in exposure of a slightly different part of the hydrophobic end of the substrate to the active site of cytochrome P-450 than when the same end of the free steroid is exposed to the active site of the enzyme. As a consequence of these two effects of the sulfate group, the "steroid sulfate pathway" of steroid hydroxylations generally differs considerably from the "free steroid pathway," both from a qualitative and a quantitative aspect. This difference was found to be most pronounced with estrogens: whereas estradiol was not hydroxylated by human fetal liver microsomal preparations, estradiol 3-sulfate was both 15-alpha- and 16-alpha-hydroxylated. Thus, for certain steroids, sulfurylation is a prerequisite for further metabolism by microsomal hydroxylase systems. These results indicate the presence in human fetal liver microsomes of a multipotent, highly unspecific, hydrophobic "bulk" of cytochrome P-450. The existence of this hydroxylase system which efficiently hydroxylates steroid sulfates is probably of great physiological importance as a detoxifying mechansim in the human fetus.

Cytochrome P-450 Enzyme System↗
PubMed1974

Urinary excretion of diphenylhydantoin metabolites in newborn infants.

The plasma half-life of diphenylhydantoin newborn infants of epileptic mothers, treated with this drug, is in the same range as the plasma half-life in adults. The urinary excretion of diphenylydantoin and its main metabolites has been investigated in six newborn infants. The results show that the rapid plasma disappearance of diphenylhydantoin is due to rapid metabolism of the drug.

Chromatography, Gas↗