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Biomedical subjects

S J Yaffe

Publications and source records attributed to S J Yaffe.

At least 37 records · Page 2Linked to original sources
PubMed1983

Delayed effects of drug exposure during pregnancy: reproductive function.

This article reviews the delayed effects of anticonvulsants (phenobarbital, phenytoin, and valproate) administered in utero upon the reproductive function in the offspring. Experimental data from the authors' laboratories are discussed in light of this context. Furthermore, comments are made emphasizing the gaps in our knowledge concerning the problem of drug exposure during pregnancy and the complex nature of drug effects upon the reproductive system.

Animals↗
PubMed1983

Influence of dietary carbohydrates (alpha-saccharides) on hepatic drug metabolism in male rats.

Young male rats (SD, CD strain) were fed semisynthetic isocaloric diets ad lib for different time periods (3,7,14, or 28 days); both carbohydrate (starch or sucrose) content and fat content were varied. High starch (HST) diet contained starch (73% of calories), corn oil (6%), and casein (21%); low starch (LST) diet contained 6, 73, and 21% of calories, respectively. In high sucrose (HS) or low sucrose (LS) diets, starch was replaced by sucrose. Rats fed LST and LS diets had decreased liver weight compared to those fed HST and HS diets, while liver microsomal protein content (mg/gm liver) was the same in all groups. Significant decreases in microsomal cytochrome P-450 from the basal level were observed in all diets over the period of experimental feeding. This decrease was more prominent with HST or HS diets compared to LST or LS dietary groups. HS diet feeding produced this decrease in cytochrome P-450 levels by 3 days; however, animals on HST diet required 7 days of feeding before they experienced a similar decrease in cytochrome P-450 levels. At 14 days, HST-fed animals had 52% lower liver microsomal cytochrome P-450 than did LST-fed animals. HS-fed animals had 36% lower cytochrome P-450 than LS-fed at 28 days. Similar results were observed for dietary effects on cytochrome b5. Aminopyrine demethylase activity decreased steadily on all diets. p-Nitrophenol glucuronidation was significantly increased in all dietary groups after 2 weeks of diet feeding. These results suggest that dietary carbohydrates and fat (particularly the relative quantities of carbohydrate and fat) may significantly influence the hepatic drug-metabolizing enzymes. It is speculated that these changes may occur due to alteration in the phospholipid composition of endoplasmic reticulum or by limiting the supply of cofactor(s) necessary for optimal mixed function oxidation and conjugation.

Aminopyrine N-Demethylase↗
PubMed1982

Effects of endotoxin upon rat hepatic microsomal drug metabolism in vivo and in vitro.

1. Bacterial endotoxin, a soluble lipopolysaccharide, has been studied to ascertain its effects in vivo and in vitro on the hepatic drug-metabolizing enzymes of adult male and female rats. 2. 24 h after a single 1 X 0 or 2 X 0 mg/kg i.p. dose of endotoxin, hexobarbital sleeping time was significantly increased in adult male rats. Significant inhibition of liver microsomal cytochrome P-450 occurred after 6 h and continued only until 24 h after endotoxin administration, while injection of inactivated endotoxin did not result in any significant decrease of hepatic mixed-function oxidase enzymes or cytochrome P-450. In contrast, rho-nitrophenol-UDP-glucuronyltransferase enzyme activity was unaffected by these levels of endotoxin. 3. Electron-microscopic examination of rat liver hepatocytes did not reveal any significant change in ultrastructure 24 h after a single i.p. dose of endotoxin. 4. Endotoxin failed to depress the phenobarbitone- or 3-methylcholanthrene-induced forms of cytochrome P-450 and the dependent mono-oxygenase enzymes. Simultaneous administration of phenobarbital and endotoxin resulted in 100% mortality of rats. Combination of 3-methylcholanthrene and endotoxin did not block the induction of cytochrome P-448 or dependent benzo[a]pyrene hydroxylase activity. 5. Addition of endotoxin in vitro resulted in significant inhibition of hepatic microsomal cytochrome P-450 and aminopyrine N-demethylase activity only on preincubation with an NADPH-generating system supplemented with EDTA.

Animals↗
PubMed1982

Phenobarbital-induced alterations in the sexual differentiation of the female rat: reversal by hydroxyurea and cycloheximide.

The possible mechanism of action of phenobarbital in prenatal female rats has been studied using different inhibitors of protein/DNA/RNA synthesis. Administration of phenobarbital (40 mg/kg/day) subcutaneously from day 17 to day 20 of pregnancy resulted in a delay of the onset of puberty, disorders of estrous cycle, infertility, and high estrogen levels in the female offspring. Cycloheximide (60 microg/kg/day)--a protein synthesis inhibitor and hydroxyurea (160 mg/kg/day)--a DNA synthesis inhibitor when combined with phenobarbital, significantly reduced the incidence of reproductive dysfunctions listed above. Alpha-amanitin (15 microg/kg/day), an inhibitor of m-RNA synthesis, produced reproductive disorders in the female offspring when administered alone to pregnant rats and also failed to reverse the PB-induced reproductive alterations. Cycloheximide and hydroxyurea produced no effect upon reproductive function when administered alone. Cycloheximide administration resulted in low body weight at birth and delayed eye opening. These results suggest that prenatal administration of phenobarbital produces its effect via new protein synthesis and that cycloheximide and hydroxyurea protect the offspring from phenobarbital-induced toxic effects by inhibiting its biochemical action.

Animals↗
PubMed1982

The effect of obesity on apparent volume of distribution of theophylline.

An oral theophylline product was given to eight lean, normal subjects and eight obese subjects (four with asthma and four normals) in a single-dose study. The mean apparent volume of distribution (Vd) was 0.472 +/- 0.08 liters/kg for the lean group and 0.321 +/- 0.063 liters/kg for the obese group (P less than 0.001). When Vd wax expressed in liters, there was no difference between the two groups (lean:26.9 +/- 6.0 liters, obese: 28.5 +/- 6.3 liters). An inverse relationship existed between the ratio of total body weight to ideal body weight (TBW/IBW) and Vd expressed in liters/kg. One obese subject was studied before and after a weight loss of about 32 kg. The values of Vd in this subject were 32.1 and 34.9 liters, respectively. These data indicated that theophylline is not extensively distributed into adipose tissue and that loading-dose calculations should be based on ideal body weight. No difference in clearance of theophylline was seen between the two groups.

Adipose Tissue↗
PubMed1981

Comparative efficacy of aspirin and acetaminophen in the reduction of fever in children.

Antipyretics should be employed in the pediatric population whenever it is the clinical judgment of the attending physician that fever should be lowered. Aspirin and acetaminophen are equally effective as antipyretics. The efficacy and safety of these two most common antipyretic agents are examined, and various studies with these agents are critically reviewed. Since acetaminophen has a greater margin of safety at antipyretic dosages, it is preferred to aspirin when an anti-inflammatory effect is not required. The efficacy and safety of combination therapy with acetaminophen and aspirin in pediatric patients--or an alternative treatment regimen with both these drugs--warrant investigation.

Acetaminophen↗
PubMed1981

Reproductive dysfunction in female offspring after prenatal exposure to phenobarbital: critical period of action.

Phenobarbital (PB) (40 mg/kg/day) was administered to pregnant rats at 12 to 20, 14 to 20, and 17 to 20 days of gestation and female offspring were tested for the onset of puberty, estrous cycle pattern, and fertility. Another group of rats received PB (20 mg/kg/day) during the neonatal period (1 to 8 days). PB administration during both the pre- and postnatal periods resulted in a significant delay in the onset of puberty (control: 34.6 +/- 1.2 days, PB: 37.5 +/- 1.2 days), disorders of estrous cycle (control: normal cycles 91%, PB: normal cycles 40%), and infertility (control: 100% fertile PB: 50% fertile). Associated with these effects, we observed high levels of estrogen in plasma (control: 58.5 +/- 12.2 pg/ml, PB: 155.2 +/- 25.1 pg/ml) and increased estrogen receptors in the uterus (control: 0.136 +/- 0.026 pmole/mg protein, PB: 0.242 +/- 0.031 pmole/mg protein. This study shows that PB administration only during the period of neuroendocrine differentiation (17 to 20 days of pregnancy and 1 to 8 postnatal days) is capable of producing all of the adverse effects of PB, indicating that its action is upon neuroendocrine development.

Animals↗
PubMed1981

Postnatal development of mixed-function oxidation and conjugation in hemoglobin-free perfused rat liver.

In perfused livers from normal developing rats, rates of p-nitroanisole O-demethylation, nearly undetectable at 8 days of age, increased progressively to a maximum of 5.1 mumol of p-nitrophenol formed per gram of liver wet weight per hour by 20 days of age. However, by 30 days of age, the rate of p-nitrophenol formation decreased to 2.8 mumol/g/h, in spite of a 300% increase in microsomal p-nitroanisole O-demethylase activity between 20 and 30 days of age. Conjugation of p-nitrophenol in perfused livers was minimal before 16 days of age. Subsequently, rates of conjugation of p-nitrophenol increase in parallel with the development of hepatic glycogen metabolism and uridine diphosphate-glucuronyltransferase activity. At all stages of development studied (8-30 days), phenobarbital treatment increased the liver weight, cytochrome P-450 content and and in vitro p-nitroanisole O-demethylase and glucuronyltransferase activities. In perfused livers from phenobarbital-treated pups, mixed-function oxidation and conjugation increased in parallel with the development of the microsomal enzymes. These data indicate that both the development of microsomal enzyme activity and the availability of required cofactors (e.g. NADPH) influence rates of mixed-function oxidation and conjugation in intact liver during development.

Animals↗
PubMed1981

Antimicrobial therapy and the neonate.

The newborn is particularly susceptible to bacterial infection because of its underdeveloped immune system. The newborn's inability to localize infection can also delay diagnosis by altering the manifestations of infection. Anti-microbial therapy is complicated, however, by the immaturity and rapid changes in metabolic and physiologic functions during the first weeks of life. Diminished renal function and activity of some hepatic enzymes alter the half-lives of various drugs, making extrapolation from adult dosage impossible. For some drugs there is also a difference in the rate of intramuscular absorption in the newborn as compared with adults and older children. Disease itself may also alter physiologic processes involved in metabolism, bioavailability, and absorption of a drug. This study presents pharmacokinetic data and dose information for penicillins, cephalosporins, aminoglycosides, and chloramphenicol in neonates and infants at different gestational and chronologic ages.

Absorption↗
PubMed1981

Serum protein binding of salicylate during pregnancy and the puerperium.

A detailed study of salicylate binding to human serum albumin was undertaken because of the widespread use of the drug, its deleterious effect on fetal development (in the laboratory animal) and its well-documented adverse effects on neonatal well-being. Serum was obtained from 82 patients during each trimester of pregnancy, labor, 4 days and 6 weeks post partum. Equilibrium dialysis at 4 degrees C was carried out utilizing therapeutic levels of C-labeled sodium salicylate. Scatchard plots were employed to translate the data into association constants (k') which characterized the binding affinity between salicylate and albumin. At the primary binding site, the mean k' values were: controls (nonpregnant females) 40, first trimester 32, second trimester 28, third trimester 26, labor 15.5, 4 days post partum 18.4, and 6 weeks post partum 37.6 X 10 M. These results demonstrate a decrease in the binding affinity between salicylate and serum albumin as pregnancy proceeds to the puerperium, at which time the binding affinity increases to near control values at 6 weeks post partum. The transplacental concentration of free (unbound) salicylate would be readily available for transplacental transport to exert an effect upon fetal receptors. The changes found may be attributable to competitive or allosteric binding of endogenous compounds such as hormones, characteristic of the normal physiology of pregnancy.

Blood Proteins↗
PubMed1980

Phenobarbital exposure in utero: alterations in female reproductive function in rats.

Phenobarbital administration to pregnant rats from day 12 to day 19 of gestation suppressed body weight gain and produced significant effects on reproductive function in their offspring. These effects included delays in the onset of puberty, disorders in the estrous cycle, and infertility. Moreover, the animals exposed to phenobarbital in utero showed altered concentrations of sex steroids, gonadotrophic hormones, and estrogen receptors. These findings suggest that phenobarbital treatment during prenatal development can produce permanent alterations in sexual maturation.

Animals↗
PubMed1980

The disposition of indomethacin in preterm babies.

Limited pharmacokinetic data are available concerning the disposition of indomethacin in preterm infants. Since oral absorption of the drug may be poor or incomplete, the current report provides pharmacokinetic data on 37 premature infants who received indomethacin intravenously. Each of these infants had a hemodynamically significant patent ductus arteriosus. Findings included variable serum indomethacin concentrations from four to 12 hours after a single dose of 0.2 mg/kg. Female preterm infants generally had lower serum drug values at 12 hours and beyond when compared to males. An extrauterine age dependence was found of serum indomethacin levels. Total body clearance, serum half lives and volumes of distribution also bore a direct relationship to extrauterine age. Thus, when indomethacin is administered shortly after birth, one may anticipate a longer duration of action after a single dose and a relatively greater risk of accumulation of the drug when more than one dose is required for treating a duct al patency.

Age Factors↗
PubMed1980

Gram-negative endotoxin administration decreases hepatic drug-metabolizing enzymes during development in rats.

The frequency of gram-negative infections and endotoxemia in the perinatal period prompted an investigation of the effects of endotoxin (Escherichia coli 026B6) on hepatic drug metabolism. Gravid female rats given injections IP with different dosages of lipopolysaccharide during late pregnancy resulted in significant depression of the liver microsomal cytochrome P-450 dependent monooxygenase activities. The acute administration of endotoxin to mothers (1.4 mg/kg on seventh day after parturition) significantly decreased the hepatic activity of aminopyrine demethylase and contents of cytochrome P-450 of suckling neonates and mothers. However, chronic administration of endotoxin (0.2 mg/kg/day for 7 days) to lactating mothers did not alter neonatal enzyme activities. When neonates themselves were given injections of endotoxin (1.0 mg/kg) at 7, 16, and 27 days of age, a significant reduction in levels of mixed function oxidase enzymes was observed. These observations suggest that the ability of mothers and neonates to metabolize drugs is significantly decreased upon exposure to endotoxin, and this demands careful evaluation of drug disposition studies in gram-negative sepsis.

Age Factors↗
PubMed1980

Disposition of salicylazosulfapyridine (Azulfidine) and metabolites in human breast milk.

A nursing mother with ulcerative colitis was treated with salicylazosulfapyridine (SASP, Azulfidine). Multiple milk samples were collected over a 2-month period. Maternal plasma, saliva, urine and nursing infant's urine were collected. All fluids were analyzed for SASP and its metabolites. Milk did not contain SASP or its 5-amino salicylate component. Sulfapyridine (SP) and its metabolites were present in milk; the SP level was fairly constant at 3--6 micrograms/ml. The milk/saliva ratio for SP was 0.81; the milk/plasma ratio for SP was 0.60 and 0.63. Assuming an average milk concentration of 5 micrograms/ml of SP, the estimated 24-hour secretion (800 cm3 milk) would be approximately 4 mg or 0.3% of maternal dose of SP in the form of SASP. The levels of SP and metabolites determined in random urine samples from the infant were 3--4 micrograms/ml or a 24-hour excretion of 1.2--1.6 mg (30--40% of the total dose in milk). This exposure did not seem hazardous to this infant.

Adult↗
PubMed1980

Disposition of acetaminophen in milk, saliva, and plasma of lactating women.

Acetaminophen (APAP) is a widely used analgesic and antipyretic, but its disposition in human milk has not yet been reported. Twelve nursing mothers (nursing two to 22 months) were given a single 650-mg peroral dose of APAP. Simultaneous saliva and milk samples were collected at zero, 1/4, 1/2, 3/4, 1, 2, 3, 5, 8, 12, and 24 hours after maternal dosing. In two mothers, plasma samples were also obtained at several points during the first six hours. Single voided urine samples were collected from the infants three to five hours after maternal dosing (two hours after nursing at peak maternal milk levels). All samples were assayed for APAP by high pressure liquid chromatography (HPCL) using a mobile phase of 0.05 M Na acetate pH 4.0-acetonitrile (93:10) with n-butyryl-p-aminophenol as the internal standard. APAP appeared in saliva and milk in the 1/4-hour samples; peak level (10-15 micrograms/ml) were achieved by one to two hours. Saliva/milk ratios during the elimination phase ranged from 0.7 to 1.1, with most values between 0.8 and 0.9. In two patients studied, saliva/plasma ratios were 0.9 to 1.0. Elimination phase t 1/2 (calculated from beta) ranged from 1.35 to 3.50 (x = 2.28 +/- SD 0.69) hours for milk, and from 1.72 to 3.30 (x = 2.48 +/- 0.56) hours for saliva. There was close agreement between saliva t 1/2 and milk t 1/2 for each patient. Assuming each infant ingested 90 ml milk at 3, 6, and 9 hours after maternal ingestion of APAP, the amount of APAP available for ingestion ranged from 0.28 to 1.51 mg (x = 0.88 +/- 0.31) or from 0.04% to 0.23% (x = 0.14 +/- 0.04) of maternal dose. Neither APAP nor metabolite was detected in nursing infants' urine. Maternal APAP ingestion in usual analgesic doses does not appear to present a risk to the nursing infant.

Acetaminophen↗