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Biomedical subjects

K G Tolman

Publications and source records attributed to K G Tolman.

72 records · Page 4Linked to original sources

Plasma 1,25-dihydroxyvitamin D levels in patients receiving anticonvulsant drugs.

Recent evidence has linked altered plasma vitamin D metabolite levels to the reported occurrence of hypocalcemia and other metabolic abnormalities in patients receiving anticonvulsant drugs. We have measured plasma levels of 25-hydroxyvitamin D (25-(OH)D) and 1,25-dihydroxyvitamin D (1,25-(OH)2D) in institutionalized patients on diphenylhydantoin (Dilantin) and/or phenobarbital therapy. Values were compared with those obtained in institutionalized patients receiving no drugs and with normal ambulatory subjects. Although plasma 25-(OH)D levels were lower in the patients on drugs, a deficiency of 1,25-(OH)2D, the tissue active metabolite of vitamin D, was not present. These results indicate that in patients taking anticonvulsant drugs, the serum calcium, phosphorus, alkaline phosphatase and parathyroid hormone (PTH) abnormalities are not caused by a defective formation of 1,25-(OH)2D.

Adult↗

Chronic liver disease and acetaminophen.

A 59-year-old female patient with arthritis developed liver function abnormalities while taking therapeutic doses of acetaminophen. Liver biopsy showed evidence of acute and chronic liver damage. Rechallenge with acetaminophen induced abnormal liver functions almost immediately. The patient has been followed for 2 years since that challenge and remains asymptomatic. Biochemical tests of liver function have returned to normal.

Acetaminophen↗

Calcium balance in drug-induced osteomalacia: response to vitamin D.

The effect of oral vitamin D3 therapy on calcium balance was compared in 18 institutionalized subjects with drug-induced osteomalacia and in 18 similar subjects without osteomalacia. The subjects with osteomalacia were receiving standard doses of phenytoin and phenobarbital. Diagnosis of osteomalacia was based on low serum calcium and phosphorus, elevated alkaline phosphatase, and appropriate roentgenographic bone changes. The study group achieved positive calcium balance at approximately 975 IU of vitamin D3 per day, while the control group achieved positive calcium balance at approximately 380 IU of vitamin D3 per day. The difference is highly significant (p less than 0.001). These data support previous observations that the osteomalacia of patients receiving anticonvulsant drugs is related to the drugs and that these patients require supplemental doses of vitamin D.

Adolescent↗

Possible hepatotoxicity of Doxidan.

A patient with chronic constipation developed liver injury and leukopenia following the ingestion of Doxidan, a combination drug consisting of danthron and dioctyl calcium sulfosuccinate. Evidence is presented that dioctyl calcium sulfosuccinate may have potentiated the toxicity. The liver injury was associated with deposition of IgE in the Kupffer cells. The mechanism of toxicity remains unclear.

Adult↗

Rupture of a splenic artery aneurysm into the pancreatic duct.

A patient with hemorrhage into the pancreatic duct from a splenic artery aneurysm is presented. The angiographic, retrograde pancreatographic, and pathological findings are demonstrated. The diagnosis was established by demonstrating an enlarging aneurysm by serial angiograms. The location of the splenic artery aneurysm was confirmed by retrograde pancreatography before surgery. The distal pancreas containing the aneurysm was resected.

Aneurysm↗

Osteomalacia associated with anticonvulsant drug therapy in mentally retarded children.

A survey of 289 severely retarded inpatients at a school for retarded children in American Fork; Utah revealed 67 patients with osteomalacia as defined by hypocalcemia, hypophosphatemia, elevated serum alkaline phosphatase levels, and appropriate bone changes. Investigation of the variables which might influence bone mineralization revealed no differences in age, sex, physical activity, sunshine exposure, or dietary intake of vitamin D between the osteomalacia and nonosteomalacia groups. However, all of the patients with osteomalacia were receiving anticonvulsant medications, either phenobarbital, diphenylhydantoin, or both. Duration of anticonvulsant therapy was the most important contributing factor to the development of osteomalacia. Seventy-five percent of patients who had received anticonvulsants for more than ten years had osteomalacia. The single most costly medical problem at the school is the treatment of pathologic bone fractures due to demineralized bone.

Adolescent↗

Hepatotoxicity due to pemoline. Report of two cases.

Pemoline, a central nervous system stimulant, has been used extensively in Great Britain and Europe for a variety of conditions including memory failure and depression. In the 10 years that the drug has been used no report of hepatotoxicity has appeared. A prospective study of efficacy and safety of pemoline was started in the United States approximately 3 years ago. This report describes two patients who developed reversible liver abnormalities while receiving pemoline during the study and following rechallenge with the drug.

Aged↗

Accidental hypothermia.

Accidental hypothermia was studied in 11 patients, five of whom died. This condition occurs spontaneously, usually in a cold environment, and should be suspected in the comatose hypotensive patient. It is easily missed because regular clinical thermometers do not record extremely low body temperatures. It is distinguished from other forms of hypothermia by the very low body temperature and by the absence of recognized causes of hypothermia. Ten of the 11 patients were either alcoholic or diabetic. Intravascular thrombosis was the most common complication leading to death.

Accidents↗

The influence of phenobarbital on biotransformation of 25-hydroxycholecalciferol.

Altered vitamin D metabolism has been implicated as a cause of anticonvulsant-induced osteomalacia. Previous studies have demonstrated accelerated biotransformation of vitamin D3 to 25-hydroxycholecalciferol (25-OHD3). However, it is not known whether the 25-OHD3 is metabolized to 1,25-dihydroxycholecalciferol (1,25-(OH)2D3), the tissue-active metabolite of vitamin D3. This study using rats was undertaken to study the influence of phenobarbital on the biotransformation of 25-OHD3 to 1,25-(OH)2D3. The disappearance rate of 25-OHD3 was virtually the same in the pheno-barbital-treated group (re = 0.0615 pmole/min) and the control group (re - 0.0549 pmole/min). Similarly, the appearance rate of 1,25-(OH)2D3 was virtually the same in the treated group (ra = 0.0133 pmole/min) and the control group (ra = 0.0134 pmole/min). These data suggest that phenobarbital does not affect the biotransformation of 25-OHD3 to 1,25-(OH)2D3. The implication of this observation is that altered vitamin D metabolism does not account for phenobarbital-induced osteomalacia.

Animals↗

Absorption and biotransfomation of cholecalciferol in drug-induced osteomalacia.

The gastrointestinal absorption of vitamin D3 and its biotransformation to 25-hydroxycholecalciferol was studied in patients with drug-induced osteomalacia. The mean coefficient of absorption was virtually identical in the drug-treated group (82.8%) and the control (83.8%). The biotransformation of vitamin D3 to 25-hydroxycholecalciferol was significantly accelerated (P less than 0.03) in the drug-treated group compared to the control group. These data suggest that vitamin D absorption is not significantly altered but that biotransformation of vitamin D3 to 25-hydroxycholecalciferol is accelerated in drug-induced osteomalacia.

Adolescent↗

The effects of five potassium chloride preparations on the upper gastrointestinal mucosa in healthy subjects receiving glycopyrrolate.

The effects on the upper gastrointestinal tract of five different preparations of KCl were compared in 90 healthy subjects treated with glycopyrrolate. The KCl preparations studied were wax-matrix KCl, microencapsulated KCl, liquid KCl, experimental extended-release capsules, experimental extended-release tablets,and placebo. The subjects were endoscoped prior to and after seven days of dosing. Upper gastrointestinal mucosal pathology was seen with all of the potassium preparations as well as with placebo. No statistically significant differences between the various KCl groups or between KCl groups and placebo were seen. All of the lesions were superficial, except for one ulcer seen with the microencapsulated KCl. None of the subjects developed occult gastrointestinal bleeding. There were no differences in the incidence of abdominal symptoms.

Adolescent↗

Gastrointestinal radiology. A study of iopanoate metabolism and toxicity in isolated cell cultures.

Radiologists are familiar with certain toxic manifestations of biliary and urinary contrast media (ie, acute tubular necrosis in dehydrated patients with diabetes or multiple myeloma), and with the specific effects of contrast media on other diagnostic tests (ie, I uptake, PBI, etc). These have been studied because of their clinical and diagnostic impact upon patient management. It has become apparent that many subtle, though perhaps predictable, drug interactions occur. Some of these are of obvious clinical and therapeutic significance and have been studied and described in detail. The authors have tried to establish the effects of clinically used drugs on the contrast medium iopanoic acid. The fact that both drugs thus far studied - aspirin and cholestyramine - have profound laboratory effects on iopanoic acid suggests that some systematic approach to the study of the clinical pharmacology of contrast agents is desirable. Others have also observed effects of contrast media on various clinical and laboratory parameters, but most observations are isolated empirical observations, and our basic understanding of the mechanisms involved are crude at best. How might this problem be approached? Although in vivo pharmacokinetic studies in unanesthetized animals allow identification of possible drug-drug interactions in the absence of multiple clinical variables and let us do crossover studies with each animal acting as its own control, such studies are difficult, expensive, and do little to establish the mechanism of the interaction. The authors are currently approaching this problem with a more basic technique. In conjunction with colleagues in gastroenterology and pharmacy, they are studying iopanoate metabolism and aspirin-iopanoate interaction in isolated hepatocyte monolayer cultures. The preliminary data from these experiments will be presented, and the significance of these results and the potential usefulness of this model will be discussed.

Animals↗

Effect of glycine on valproate toxicity in rat hepatocytes.

The interaction between the amino acid glycine and valproate (VPA), an antiepileptic drug (AED) that occasionally causes hepatotoxicity, was studied in rat hepatocytes in monolayer culture. Valproate caused a dose-dependent increase in leakage of lactic acid dehydrogenase (LDH), and glycine prevented this toxic response. L-Carnitine, L-alanine, and L-cysteine did not protect hepatocytes from VPA. Glycine also partially antagonized inhibition of fatty acid beta-oxidation by VPA, as estimated by the generation of acid-soluble products from [14C]palmitic acid. These results are consistent with the hypothesis that glycine prevents VPA toxicity by removing acyl-CoA esters, which accumulate during VPA exposure and interfere with fatty acid beta-oxidation. Glycine, however, also antagonized the toxic effects of acetaminophen on hepatocytes, although at higher concentrations than required to protect hepatocytes from VPA. Because the mechanism of toxicity of acetaminophen probably is different from that of VPA, a nonspecific cytoprotective effect may contribute to glycine antagonism of valproate toxicity. Our results emphasize the importance of glycine in protecting hepatocytes from noxious insult in general as well as from VPA in particular.

Acetaminophen↗

Metabolism and disposition of clarithromycin in man.

The metabolic fate and pharmacokinetics of clarithromycin following a single 250- or 1200-mg oral dose of 14C-clarithromycin were studied in six healthy adult males. Peak plasma levels of clarithromycin averaged 0.6 microgram/ml after the low dose and 2.7 micrograms/ml after the high dose. The AUC of clarithromycin increased 13-fold, with the 4.8-fold increase in dose, while the plasma half-life increased from 4.4 hr to 11.3 hr. The major metabolite in plasma and urine was the microbiologically active 14-hydroxylated-R epimer of clarithromycin. After 5 days, a mean of 38% of the low dose (18% as clarithromycin) and 46% of the high dose (29% as clarithromycin) was recovered in the urine, with approximately one-third eliminated during the first 24 hr. The nature of the urinary and fecal metabolites revealed the involvement of three metabolic pathways, viz. 1) hydroxylation at the 14-position to form the R and S epimers, 2) N-demethylation, and 3) hydrolysis of the cladinose sugar. Secondary metabolism via these pathways was also evident. The overall recovery of metabolites, but not total radioactivity, decreased 42% after the high dose. The nonlinear pharmacokinetic behavior of clarithromycin and the decrease in metabolite production suggest that clarithromycin metabolism can be saturated at high doses.

Adult↗