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Biomedical subjects

L J Fischer

Publications and source records attributed to L J Fischer.

At least 55 records · Page 3Linked to original sources
PubMed1983

Phenytoin and folic acid interaction: a preliminary report.

The effect of folic acid (1 mg/day orally) on phenytoin steady-state pharmacokinetics was studied in four male folate-deficient epileptic patients who were treated with only one anticonvulsant. Each patient served as his own control before and after starting folic acid replacement therapy. The Michaelis-Menten parameters, Vmax and Km, were calculated for each patient, and compliance with the single anticonvulsant drug (phenytoin) regimen was documented. Blood and urine samples were collected just before (day 1) and after 180 or 300 days of vitamin administration. Total and free phenytoin were measured in plasma; and phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin (DHD) were measured in 24-h urine. After the addition of folic acid, total phenytoin plasma concentration decreased 7.5-47.6% in three of the four patients, and the extent of this change correlated with Km (r2 = 0.99). Ratios of urinary metabolites to parent drug increased in those patients showing a decrease in plasma phenytoin caused by folic acid supplementation. This indicated that a folic acid-associated increase in phenytoin oxidative metabolism had occurred.

Adult↗
PubMed1983

Phenytoin and folic acid: individualized drug-drug interaction.

The effect of folic acid supplementation on the disposition of phenytoin and the resultant loss of seizure control in a male folate-deficient epileptic is reported. Due to the increase in tonic-clonic seizures after the initiation of folic acid (1 mg, orally) the sodium phenytoin dosage was increased by 130 mg until control was achieved. Because of these dosage changes, the Vmax and Km were calculated before and after initiation of the folic acid. The Vmax remained relatively the same, but the Km decreased after folate supplementation.

Drug Interactions↗
PubMed1982

Alloxan toxicity in isolated rat hepatocytes and protection by sugars.

Suspensions of isolated rat hepatocytes incubated in the presence of the diabetogenic agent alloxan exhibit time- and concentration-dependent damage. At concentrations of 3.5 mM and above, alloxan caused an increase in lactate dehydrogenase (LDH), glutamate-pyruvate transaminase (GPT) and intracellular potassium (K+) leakage, all of which are indices of plasma membrane damage, and decreased the intracellular reduced glutathione content (GSH) of the cells. Preincubation (10 min) in D-glucose (50 or 100 mM, but not 10 mM) partially protected the hepatocytes from LDH, GPT and K+ leakage and the decrease in GSH produced by alloxan (7 mM) during a 60-min incubation period. Other sugars (D-galactose, 2-deoxy-D-glucose, D-fructose, D-mannoheptulose and D-mannitol) were also found to protect hepatocytes against damage caused by alloxan. D-Fructose was found to be the most potent protective sugar. These results indicate that alloxan is not selectively toxic to the pancreatic beta-cell and that sugars can protect against alloxan-induced cytotoxicity in hepatocytes.

Alloxan↗
PubMed1981

Impaired insulin release after exposure of pancreatic islets to autooxidizing dihydroxyfumarate.

Autooxidizing dihydroxyfumarate (DHF) is a known generator of superoxide anions and by hydroxyl free radicals. Isolated rat pancreatic islets were exposed for 5 min to 0.4 mg/ml DHF in an oxygenated buffer solution. As a result of this exposure, the islets exhibited a 60% reduction in glucose-stimulated insulin release. The presence of superoxide dismutase, catalase, or diethylenetriaminepentaacetic acid, a metal chelator, during the exposure period protected the islets from the effects of autooxidizing DHF. This suggests that superoxide anions, hydrogen peroxide, and, ultimately, hydroxyl free radicals play a role in the insulin inhibitory effects caused by DHF exposure. Glucose (5 mg/ml), but not galactose, was also capable of protecting islets from DHF. The effects of DHF exposure on isolated islets appear to be similar to those previously reported for alloxan and lend support to the concept that hydroxyl free radicals generated during the oxidation of certain compounds can alter endocrine cell function.

Animals↗
PubMed1981

Levels of acetaminophen and its metabolites in mouse tissues after a toxic dose.

A high-performance liquid chromatographic method for analysis of acetaminophen and its conjugated metabolites in tissues was developed and used to determine tissue, plasma and urine levels of the drug and its glucuronic acid, sulfate, glutathione, cysteine mercapturic acid conjugates in mice given a 500 mg/kg oral dose of [14C]acetaminophen. Peak levels of unchanged drug occurred at 0.5 hr in plasma, liver and kidney. At the same time, only 30% of the radioactive dose could be recovered from the gastrointestinal tract, indicating rapid absorption of the drug. Peak concentrations of acetaminophen were high in all tissues (1500-2000 nmol/g) and declined with an apparent half-life of 1 hr. Tissue levels of drug conjugates reached a peak at 1 hr and were low relative to unchanged drug for the first 2 hr after the dose. The glucuronic acid and glutathione conjugates reached a similar peak in the liver (325 nmol/g). The glucuronide declined slowly over a 4-hr period, but the glutathione conjugate dropped rapidly between 1 and 2 hr, reflecting depletion of glutathione. Tissue/plasma ratios of metabolites indicated that the glutathione conjugate was concentrated in liver, whereas the cysteine conjugate was concentrated in kidney. Brain levels of unchanged acetaminophen were similar to levels found in other tissues, but conjugates were essentially excluded from the brain reflecting the influence of the blood brain barrier. The results show that certain drug conjugates reach relatively high levels in plasma, liver and kidney, but not brain, after a toxic dose of acetaminophen.

Acetaminophen↗
PubMed1980

Inhibition of alloxan action in isolated pancreatic islets by superoxide dismutase, catalase, and a metal chelator.

The possible participation of superoxide anions, hydrogen peroxide, and hydroxyl radicals in the action of alloxan was investigated using isolated rat pancreatic islets. Exposure of islets for 5 min to alloxan (0.15 or 0.2 mg/ml) inhibited subsequent glucose-stimulated insulin release. The presence of superoxide dismutase (1000 U/ml), catalase (50 microgram/ml), or a metal chelator diethylenetriaminepentacetic acid (1 mM) markedly attenuated this effect of alloxan. Use of these agents afforded complete protection from the lower concentration of alloxan and partial protection from the higher concentration of the toxic compound. Inactivation of the enzymes or addition of excess iron to the chelating agent before its use with alloxan eliminated the protective action of these agents. The results are consistent with the proposal that hydroxyl radicals, generated via reactions that involve superoxide anions, hydrogen peroxide, and iron, mediate the deleterious effect of alloxan in pancreatic islets.

Alloxan↗
PubMed1978

A selected ion monitoring method for glutethimide and six metabolites: application to blood and urine from humans intoxicated with glutethimide.

A method employing selected ion monitoring for the analysis of glutethimide and six of its metabolites has been developed. Hydroxylated metabolites analyzed as trifluoroacetates, included 4-hydroxyglutethimide, (1-hydroxyethyl)glutethimide and p-hydroxyglutethimide. The unchanged drug, 3-dehydroglutethimide, desethylglutethimide and the internal standard, [2H5]glutethimide, were chromatographed underivatized on OV-225. The assay was used to measure drug and metabolites in the plasma and urine of patients intoxicated with glutethimide. High levels (e.g. 20--35 microgram ml-1) of unconjugated 4-hydroxyglutethimide, an active metabolite, were found in all patients at a time when levels of unchanged drug were lower and declining. Other unconjugated and conjugated metabolites were found in relatively low concentrations in the plasma (i.e. less than 4 microgram ml-1). The major urinary metabolites were conjugates of 4-hydroxyglutethimide and (1-hydroxyethyl)glutethimide. The unchanged drug and other conjugated and unconjugated metabolites were found in lower amounts in the urine. Normal plasma half-lives of glutethimide and the relatively small amounts in urine of unchanged drug and unconjugated metabolites indicated that drug elimination was not markedly impaired in the intoxicated patients.

Adult↗
PubMed1978

High-performance liquid-chromatographic assay for chloramphenicol in biological fluids.

We describe a method for measuring chloramphenicol by high-performance liquid chromatography. The assay involves a single extraction of the biological sample with ether, evaporation of the extract, and chromatography of the residue, redissolved in methanol. A reversed-phase column with an eluting solvent of methanol/water (30/70 by vol) is used. Chloramphenicol is eluted from the column in about 4 min and is well separated from the internal standard (mephenesin), which is eluted at 5.5 min. Absorption of the effluent at 278 nm is monitored and measured. As little as 0.1 microgram of the antibiotic can be analyzed after its extraction from a 0.1-ml sample. The method is suitable for rapid and specific analysis for the drug in plasma, urine, cerebrospinal fluid, and other biological fluids.

Chloramphenicol↗
PubMed1977

Role of the pituitary in cyproheptadine-induced pancreatic beta-cell toxicity.

Hypophysectomized rats given cyproheptadine (40 mg/kg) for 10 days exhibited a loss of pancreatic immunoreactive insulin and ultrastructural changes in the cytoplasm of beta-cells. Sham-operated animals given cyproheptadine showed identical changes in pancreatic beta-cells except that cytoplasmic involvement progressed to the formation of large vacuoles. The pituitary is not directly involved with the cyproheptadine-induced depletion of pancreatic insulin but plays a role in the formation of large cytoplasmic vacuoles.

Animals↗
PubMed1977

Isomeric specificity of diphenylmethylpiperidine in the production of rat pancreatic islet cell toxicity.

The relationship between chemical structure and the pancreotoxic potential of positional isomers of diphenylmethylpiperidine was investigated in rats. The chemical synthesis of these compounds and their N-methylated analogs is reported. Oral administration of 4-diphenylmethylpiperidine and its N-methylated derivative (130 and 260 micronmoles/kg) to rats for 14 days resulted in hyperglycemia, reduced pancreatic insulin content and the formation of large vacuoles in the cytoplasm of pancreatic islet cells. No effect on beta cell morphology or insulin content was observed after administration of 2- and 3-diphenylmethylpiperidine and their N-methylated analogs.

Animals↗
PubMed1977

Age-related differences in salicylamide and acetaminophen conjugation in man.

Following a concomitant oral dose of salicylamide and acetaminophen (5 mg/kg of each) the urinary excretion of glucuronide and sulfate conjugates of the drugs were followed in children (ages seven to ten years) and adults. No significant difference were observed between the two age groups in the half-lives for appearance of salicylamide conjugates in urine. Age-related changes in the metabolic pathways, however, were observed. The mean percentage of dose excreted as salicylamide sulfate was significantly higher in children (78%) than in adults (36%). In contrast, salicylamide glucuronide was the major excretory product in adults. Similar age-related differences were observed for acetaminophen conjugation. Pharmacokinetic analysis indicated that the deficiency in glucuronide conjugation of these drugs in children is accompanied by a higher rate of sulfate formation.

Acetaminophen↗
PubMed1977

Mechanism of protection from alloxan diabetes provided by n-butanol.

Pretreatment with n-butanol (10 mmol/kg i.p.) 30 minutes before alloxan (100 mg/kg) protects mice from the permanent hyperglycemic effects (measured at 72 hours) of the diabetogenic agent. This dose of n-butanol caused an elevation of serum glucose at 30 minutes, the time of alloxan administration. Since glucose administration can protect animals from alloxan, the possibility that alcohol-induced hyperglycemia protected mice from alloxan was investigated. Mannoheptulose, an antagonist of glucose action at the pancreatic beta-cell, when given 24 minutes after n-butanol and 6 minutes before alloxan, eliminated the alcohol-induced protection. Fasted mice did not exhibit n-butanol-induced hyperglycemia at 30 minutes and alloxan given at that time produced diabetes. No protection was observed in fed animals when n-butanol was given 5 minutes before alloxan. The high serum levels of butanol and normal serum glucose which were observed at 5 minutes after alcohol administration indicated that the lack of protection was not due to a lack of circulating alcohol but resulted from an absence of hyperglycemia. The results indicate that pretreatment with n-butanol protects mice from alloxan-induced diabetes by the indirect mechanism of producing hyperglycemia at the time of alloxan administration.

Animals↗
PubMed1976

Acetaminophen elimination kinetics in neonates, children, and adults.

The elimination of acetaminophen (APAP) following an oral dose of 10 mg/kg in newborn infants, children, and adults was compared. Urinary excretion of unchanged APAP, APAP-sulfate, and APAP-glucuronide was complete within 30 hr at all ages. Higher percentages of the dose were excreted in the urine as APAP-sulfate in neonates (0-2 days old) and children (3-9 yr old) than in 12-yr old children and adults. A pharmacokinetic analysis indicated that the higher rate of APAP-sulfate formation in younger age groups apparently compensated for a deficiency in glucuronide formation. No dramatic age-related differences in the overall elimination rate constant for APAP were observed despite the quantitative changes in the metabolic pathways during early childhood.

Acetaminophen↗