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Biomedical subjects

J R Mitchell

Publications and source records attributed to J R Mitchell.

At least 217 records · Page 12Linked to original sources
PubMed1978

Hepatotoxicity and metabolism of iproniazid and isopropylhydrazine.

Iproniazid (1-isonicotinoyl-2-isopropylhydrazine), an antidepressant drug removed from clinical use because of hepatic injury, and isopropylhydrazine, a metabolite of iproniazid, were found to be potent hepatotoxins in rats. This animal model was used in studies in vivo and in vitro to define better the biochemical and chemical mechanism(s) by which iproniazid and isopropylhydrazine mediate hepatotoxicity. Phenobarbital, an inducer of a class of hepatic microsomal cytochrome P-450 enzymes, greatly potentiated the necrosis, whereas inhibitors of these microsomal enzymes such as cobalt chloride, piperonyl butoxide and alpha-naphthylisothiocyanate, prevented the necrosis. Bis-para-nitrophenyl phosphate, an inhibitor of esterase and amidase enzymes, prevented the necrosis caused by iproniazid but had no effect on the necrosis caused by isopropylhydrazine. Iproniazid and isopropylhydrazine labeled with tritium or carbon-14 in the isopropyl group were found to bind covalently to hepatic tissue macromolecules, and those pretreatments that increased hepatic necrosis significantly increased covalent binding, whereas those pretreatments which prevented necrosis significantly decreased covalent binding. Iproniazid labeled with tritium in the pyridine ring or carbon-14 in the carbonyl group did not bind significantly to hepatic tissue. Rats that were given iproniazid or isopropylhydrazine, labeled specifically with tritium and carbon-14 on the c-2 methine position of the isopropyl group, expired acetone and carbon dioxide labeled with carbon-14. More importantly, propane was expired and contained a ratio of 3H/14C that was identical to that in the administered iproniazid or isopropylhydrazine and also identical to the 3H/14C ratio of the metabolite that was covalently bound to hepatic tissue macromolecules. Experiments carried out with rat liver microsomes and isopropylhydrazine specifically labeled with deuterium, tritium and carbon-14 support the view that isopropylhydrazine is the metabolite of iproniazid that is oxidized by a microsomal P-450 enzyme to a species that alkylates tissue macromolecules. Some of the urinary metabolites excreted by rats that were administered hepatotoxic doses of iproniazid and isopropylhydrazine have been identified by cochromatography and isotope dilution with synthetic standards and by comparative mass spectra. Compounds excreted into the urine of rats dosed with iproniazid include iproniazid, iproniazid-1-oxide, isonicotinic acid, isonicotinoyl glycine, acetylisoniazid, isopropylhydrazine, 1-acetyl-2-isopropylhydrazine and acetone. Isopropylhydrazine, 1-acetyl-2-isopropylhydrazine, and acetone have been found in the urine of animals administered toxic doses of isopropylhydrazine.

Animals↗
PubMed1977

The influence of allopurinol and size of dose on the metabolism of phenylbutazone in patients with gout.

Administration of allopurinol 300 mg/day produced minimal changes in the disappearance of phenylbutazone in each of five subjects following single doses (6 mg/kg) in clinical range and caused some prolongation (21%, 52%) of drug half-lives in two of six subjects after single small doses (0.5 mg/kg); mean half-life was not significantly altered by allopurinol at either dose level (means of 52 versus 48 at 0.5 mg/kg and 68 versus 70 h at 6 mg/kg). Size of dose altered half-life when phenylbutazone was used alone; three subjects showed considerably longer half-lives at the higher dose (86 versus 47, 91 versus 41, 65 versus 38 h). Allopurinol caused a greater than 50% prolongation of half-lives in two of five subjects who received single 0.5 g doses of probenecid. These preliminary data do not indicate a need to change the dose of phenylbutazone when subjects are receiving allopurinol.

Adult↗
PubMed1977

Contribution of atenolol, bendrofluazide, and hydrallazine to management of severe hypertension.

The efficacy of various combinations of atenolol, bendrofluazide, and hydraliazine given twice daily was assessed in a double-blind trial on 39 patients with moderate to severe essential hypertension. Concurrent treatment with all three drugs proved most effective and produced a mean reduction in blood pressure of 43/31 mm Hg. In the dosage used, hydrallazine affected only the diastolic blood pressure, and when added to either bendrofluazide or bendrofluazide plus atenolol it produced a further mean reduction in pressure of 6 mm Hg. Once-daily treatment with atenolol and bendrofluazide was as effective in reducing blood pressure as the same combination given twice daily, and the hypotensive effect was still present at least 24 hours after the last dose of tablets. A combined tablet of atenolol and bendrofluazide taken once daily would be a simple regimen to follow and would provide almost as much hypotensive effect as a twice-daily regimen incorporating a modest dose of hydrallazine. The hypotensive effect of atenolol was equal to that of bendrofluazide on systolic pressure but significantly better than that of bendrofluazide on diastolic pressure. Atenolol reduced plasma renin and urate concentrations but increased plasma potassium levels. The biochemical effects of atenolol, therefore, may be an advantage over those of bendrofluazide when deciding on first-line treatment for essential hypertension.

Bendroflumethiazide↗
PubMed1977

Intravenous urography in the management of acute retention.

A retrospective analysis of the frequency of requests for an intravenous urogram (I.V.P.) in men with acute retention of urine showed that this investigation was performed in 82%. In no instance, however, did the urographic findings influence the decision to operate or the type of operation performed. The introduction of a specialised urological service did not reduce the number of I.V.P.s requested because most referrals to the urologist were made after the I.V.P. Patients who had an I.V.P. waited on average 8 days from admission to operation compared with 3-5 days for those who did not. We conclude that no purpose is served by a routine I.V.P. in every male patient admitted to hospital with acute retention of urine.

Acute Disease↗
PubMed1977

Preventing venous thromboembolism in elderly patients with hip fractures: studies of low-dose heparin, dipyridamole, aspirin, and flurbiprofen.

Low-dose heparin, dipyridamole (alone and in combination with aspirin), and flurbiprofen were evaluated as potential prophylactic agents against deep venous thrombosis in elderly patients with hip fractures. None of the agents that modify platelet behaviour could reduct the frequency of isotopically diagnosed venous thrombosis. Low-dose heparin reduced the overall frequency of venous thrombosis and its extent as judged by the frequency of bilaterally abnormal scans, but this reduction did not achieve statistical significance.

Age Factors↗
PubMed1977

Evaluation of 125I-fibrinogen test for venous thrombosis in patients with hip fractures: comparison between isotope scanning and necropsy findings.

The results of 125I-fibrinogen leg scanning during life were compared with the findings at a detailed post-mortem dissection of the leg veins in 31 patients with hip fractures who died during the period of isotope scanning or within seven days of the last scan. Thigh scanning on the side of the hip fracture proved valueless, and criteria for the confident isotopic diagnosis of venous thrombosis in the uninjured thigh could not be determined. In the lower leg a difference in uptake of 20% or more that persisted for 24 hours between adjacent positions on one leg or between corresponding positions on the two legs was consistently associated with the presence of venous thrombosis at necropsy.

Autopsy↗
PubMed1977

Molecular basis for several drug-induced nephropathies.

A recent clinical advance has been the discovery that many drug-induced hepatic diseases result from the metabolic activation of chemically stable drugs to potent alkylating agents by the liver. In addition to the liver, however, the kidney also contains active enzyme systems capable of metabolically activating drugs and other chemicals. For this reason a systematic investigation of the possible role of metabolic activation in the pathogenesis of several drug-induced renal diseases has been undertaken. These laboratory results are reviewed in the light of the clinical spectrum of the renal injuries, and possible therapeutic implications of these new findings are briefly discussed. The potential use of these models of nephrotoxicity to probe a variety of physiologic and pathophysiologic mechanisms of renal function are noted.

Acetaminophen↗
PubMed1977

Aortic size and aortic calcification. A necropsy Study.

Measurements of aortic length and circumference in 336 post-mortem specimens confirm earlier, neglected observations on the progressive increase in aortic size which occurs with advancing years. The increase is not related to atherosclerosis , or to hypertension and seems to be part of a true ageing process. The value of measurement of aortic size in body age determination merits exploration by forensic pathologists. Aortic calcification is found in raised and complicated atherosclerotic plaques and its prevalence and severity closely follows the accepted pattern of plaque severity, occurring earlier and more severely in men, in the abdominal aorta and in patients with overt vascular disease in other territories such as patients with cardiac infarcts. No association was found between the amount of calcification and the presence of hypertension, diabetes or neoplasia.

Adolescent↗
PubMed1977

Pilot studies on recombinant cold-adapted live type A and B influenza virus vaccines.

Recombinant live attenuated type A and B influenza virus vaccines derived from standardized cold-adapted parent strains were given singly and in combination to volunteers. The vaccine viruses were well tolerated, functioned as good antigens, and failed to spread to intimate household contacts. Thirty-nine isolates that were recovered after a single passage in humans appeared genetically stable. The results of histopathologic studies in ferrets encourage development of an animal model for attenuation of the virus.

Animals↗
PubMed1977

Toxicity-related changes in benzene metabolism in vivo.

1. The influence of microsomal enzyme inducers and inhibitors on the metabolism of [U-14C]benzene in the rat was examined. 2. Pre-treatment of animals with the inhibitors piperonyl butoxide and cobaltous chloride tended to reduce the urinary excretion of metabolites in 24 h but increase the overall urinary excretion. Piperonyl butoxide tended to increase expired benzene. 3. Pre-treatment of animals with the inducer phenobarbital tended to increase urinary excretion of metabolites but decrease expired benzene, as did pre-treatment with benzene itself. 4. All pre-treatments appeared to increase the excretion of phenolic glucuronides, particularly benzene pre-treatment. Phenobarbital and benzene pre-treatment tended to increase phenylmercapturic acid excretion and benzene pre-treatment markedly increased excretion of quinol. 5. The results are discussed in relation to the effect of microsomal enzyme inhibitors and inducers on benzene-induced bone marrow toxicity.

Acetylcysteine↗