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Biomedical subjects

K G Tolman

Publications and source records attributed to K G Tolman.

At least 55 records · Page 3Linked to original sources
PubMed1985

Urinary kallikrein: assay validation and physiological variability.

Decreased urinary kallikrein (UK) output has been suggested as a preclinical indicator of essential hypertension. In preparation for UK studies in hypertension prone Utah kindreds, we assessed selected UK assay parameters and physiological variability. Precision for the colorimetric kallikrein assay was quite acceptable, coefficient of variation (CV) less than 5% within run and 14% day-to-day at a concentration of 9.5 TU/l. The mean recovery was 105% and assay results were correlated with results from the 3H-TAME esterase method, r = 0.990. Urine specimens were stable at room temperature for up to 4 days, frozen at -20 degrees C for 6 weeks, or frozen at -80 degrees C after Sephadex treatment for a year. UK output varied significantly throughout the day with excretion highest in the morning. Urine collections at 10.00, 12.00 and 14.00 had significantly (p less than 0.05) more UK than the overnight collection. Intra- and inter-individual variations were of the same magnitude, mean 20%. In children UK output increased with age until the adult levels were reached at age 15. Male and female values were similar. Smoking; consumption of alcohol, coffee, tea, cola of chocolate; and female hormone medications did not significantly influence the 12-hour UK output in the 1110 caucasian subjects.

Adolescent↗
PubMed1985

Methotrexate and the liver.

The findings of liver studies in 29 patients who were treated with low dose pulse methotrexate for rheumatoid arthritis (RA) are described. The biopsy specimens of 22 patients (76%) showed liver abnormalities, but cirrhosis did not develop in any patient. There were no statistically significant differences in age, duration of treatment, or cumulative dose between patients in whom abnormal liver histology developed and those in whom it did not. Our findings showed that isolated elevations of the aminotransferase enzymes or alkaline phosphatase levels did not predict liver disease, nor did the absence of elevation of these enzymes assure the absence of liver disease. Serial elevations of the aminotransferase and/or alkaline phosphatase enzyme levels and the development of hypoalbuminemia during treatment were specific indicators of the development of liver disease. In the patients studied, significant liver disease did not develop before 2 years of therapy or with a cumulative dose of methotrexate of less than 1500 mg.

Adult↗
PubMed1984

Toxicity of heparin in isolated rat hepatocytes.

The effect of heparin on isolated rat hepatocytes in monolayer culture was assessed to investigate the observed increase in serum aminotransferase activity in patients treated with heparin for thromboembolic disorders. Cells were treated with porcine intestinal mucosal heparin or beef lung heparin in concentrations ranging from 0.01 to 100 units/ml. Toxicity was evaluated based on cell damage or death measured by LDH release into the culture media as a fraction of total system LDH (LDH index). Toxicity appeared at concentrations between 1 and 10 units/ml (P less than 0.05). The uptake and binding of heparin by the hepatocyte were evaluated by addition of tritium-labeled heparin to the cultures. Sucrose gradient centrifugation with isolation of the liver plasma membranes (LPM) showed little membrane binding of heparin. The majority of intracellular heparin was located in the cytosol fraction. Heparin gains access to hepatocytes and causes a dose-related toxic effect resulting in cell damage and death. This investigation indicates that the increased serum aminotransferase concentrations seen with heparin treatment may be due to a direct hepatotoxic effect of heparin.

Animals↗
PubMed1984

Protection against sodium valproate injury in isolated hepatocytes by alpha-tocopherol and N,N'-diphenyl-p-phenylenediamine.

The possibility that lipid peroxidation is involved in valproic acid (VPA) hepatotoxicity was explored by testing the ability of the free-radical scavengers alpha-tocopherol (vitamin E) and N,N'-diphenyl-p-phenylenediamine (DPPD) to protect against VPA toxicity. Rat hepatocyte cultures were treated with toxic doses of VPA, in conjunction with varying doses of vitamin E and DPPD. Lactate dehydrogenase (LDH) release into the culture media was used to calculate an LDH index as a measure of toxicity. Vitamin E afforded increasing protection against VPA toxicity at concentrations of 1.0 to 4.0 microM but then leveled off and did not give complete protection at concentrations up to 8.0 microM. No protection was seen at less than 1.0 microM. DPPD showed increasing protection from 0.05 to 0.50 microM, with complete protection at the highest concentration. These data indicate that VPA toxicity can be prevented by simultaneous administration of free-radical scavengers and support the concept that VPA hepatotoxicity is due to lipid peroxidation.

Animals↗
PubMed1984

Anticonvulsant activity and neurotoxicity of piperonyl butoxide in mice.

Piperonyl butoxide, a microsomal monooxygenase inhibitor, administered intraperitoneally to mice exerts peak anti-maximal electroshock activity and peak neurotoxicity at 5 and 7h, respectively. The median neurotoxic dose is 1,690 mg/kg. In the maximal electroshock seizure test, the median effective dose (ED50) is 457 mg/kg and the protective index (PI) is 3.69. In the subcutaneous pentylenetetrazol test, the ED50 is 443 mg/kg and the PI is 3.81. Piperonyl butoxide prevents seizure spread and elevates seizure threshold. Its PI compares favorably with PIs of clinically useful anticonvulsants.

Animals↗
PubMed1984

Effects of SKF525A, phenobarbital, fasting, and carnitine on the anticonvulsant activity and neurotoxicity of valproate in mice.

The anticonvulsant potency of valproate (VPA), as measured by the maximal electroshock seizure model in mice, was improved by pretreatment with the microsomal inhibitor SKF525A and by fasting, but was reduced by chronic phenobarbital pretreatment. Carnitine did not significantly alter the anticonvulsant properties of VPA. These findings suggest that the efficacy of VPA can be improved by factors that alter its metabolic pattern.

Animals↗
PubMed1984

Upper gastrointestinal polyps in Gardner's syndrome.

Upper gastrointestinal polyps have been considered an uncommon finding in patients with Gardner's syndrome and familial polyposis coli. Investigators from Japan, however, have recently reported finding gastric and duodenal polyps in a high percentage of Japanese patients with these conditions. We endoscopically examined 11 affected members of the originally described Gardner's syndrome kindred to determine if upper gastrointestinal polyps also occurred in patients with Gardner's syndrome living in the United States. Six of the patients were found to have numerous small polyps of the gastric fundus and body. Polyp histology in 5 of the 6 patients was consistent with fundic gland hyperplasia. Biopsy specimens from the remaining patient demonstrated normal mucosa only. Another patient with no fundic polyps had a single antral polyp that was an adenoma. Eight patients exhibited small polyps of the duodenum. Biopsy specimens were obtained in 7 of the 8. All polyps biopsied were adenomas. The terminal ileum was examined by endoscopy in 9 of the 11 study patients. All 9 had ileal polyps, but the polyps were adenomas in 6 patients and lymphoid aggregates in 3 patients. The results indicate that upper gastrointestinal polyps are a common pleiotropic manifestation of the genetic defect responsible for Gardner's syndrome.

Adenoma↗
PubMed1983

The toxicity of metabolites of sodium valproate in cultured hepatocytes.

Sodium valproate is hepatotoxic in both humans and rat hepatocytes. The toxicity is dose related and frequently associated with simultaneous ingestion of drugs which induce the drug metabolizing system. For these reasons, metabolites of sodium valproate were tested for toxicity using rat hepatocyte cultures. The sodium salts of three metabolites, 2-propylpent-4-enoate, 4-hydroxyvalproate, and perhaps 5-hydroxyvalproate, were toxic in this system. In addition, 2-propylpent-4-enoate was toxic in a dose-related fashion. All are omega and omega-1 oxidation products in the microsome-mediated pathway of valproate metabolism.

Animals↗
PubMed1983

Effect of probenecid on the pharmacokinetics of cefmenoxime.

In this study, we were concerned with the effect of probenecid on the pharmacokinetics of 1,000 mg of cefmenoxime administered over a 30-min period by intravenous infusion. Each of a total of 10 subjects received cefmenoxime twice, once with and once without adjunctive probenecid. The data were fit by iterative nonlinear regression procedures to a two-compartment open pharmacokinetic model, with elimination from the central compartment. The mean calculated peak concentration, area under the curve from zero to infinity, and half-life without probenecid were 78.1 micrograms/ml, 77.2 micrograms . h/ml, and 1.14 h, respectively. When cefmenoxime was administered with probenecid, these values were 86.7 micrograms/ml, 158.2 micrograms . h/ml, and 1.78 h, respectively. Averages of about 55 and 46% of the administered doses were recovered in urine samples collected at 0 through 24 h for doses administered without and with probenecid, respectively. The mean corrected renal drug clearance was 159 and 66 ml/min without and with probenecid, respectively. Statistical significance (P less than 0.05) was demonstrated for the differences in beta half-life, (K/net), calculated peak concentration, area under the curve from 0 to infinity, and renal clearance, but not for K21, K12, volume of distribution, or alpha-phase distribution rate constant. The results of this study indicate that tubular secretion is the predominant mechanism of clearance for cefmenoxime and that probenecid alters the pharmacokinetics of the compound by competitively inhibiting its tubular secretion without affecting either the rate or the extent of its distribution.

Adult↗
PubMed1980

Ischemic colitis in a young adult due to inferior mesenteric vein thrombosis.

A thirty-two-year-old male presented with abdominal pain and rectal bleeding due to ischemic colitis. Inferior mesenteric vein thrombosis was documented angiographically. No predisposing factors for thrombosis were found. The natural course of the disease was documented with fiberoptic endoscopy. The pathological changes which account for the radiologic alterations were documented.

Adult↗
PubMed1980

Hepatotoxicity of sodium valproate and other anticonvulsants in rat hepatocyte cultures.

Valproic acid has recently been shown to be associated with liver disease in man. Rat hepatocyte cultures were used to test the hepatotoxicity of valproic acid and several other anticonvulsants. Dose-related hepatotoxicity was demonstrated for valproic acid at concentrations ranging from 10 to 320 micrograms/ml, therapeutic concentrations being 50-100 micrograms/ml. Hepatotoxicity could not be demonstrated for phenobarbital, phenytoin, primidone, and clonazepam. It is concluded that valproic acid is a dose-related hepatotoxin.

Animals↗
PubMed1978

Hepatotoxicity of salicylates in monolayer cell cultures.

The influence of graded doses of sodium salicylate on rat liver cells cultured in monolayers was assessed by measuring lactic dehydrogenase activity in a culture media after incubation. Morphological alterations were studied by electron microscopy. The influence of different albumin concentrations in the media on toxicity was also evaluated. Lactic dehydrogenase concentrations rose with increasing doses of salicylate up to 40 mg per dl. High concentrations of albumin were associated with reduced salicylate toxicity. These findings suggest that salicylate-induced hepatic injury is dose related and my be influenced by serum albumin levels

Albumins↗