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Biomedical subjects

J R Mitchell

Publications and source records attributed to J R Mitchell.

At least 253 records · Page 14Linked to original sources
PubMed1976

Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis.

The clinical spectrum of isoniazid-induced liver injury seems to be clinically, biochemically, and histologically indistinguishable from viral hepatitis, except that the injury occurs primarily in persons older than 35 years. A possible relation between susceptibility of patients to isoniazid liver injury and rapid metabolism (acetylation) of the drug has been found. Examination of isoniazid metabolites showed that patients with rapid acetylator phenotype hydrolyze much more isoniazid to isonicotinic acid and the free hydrazine moiety than do slow acetylators. The hydrazine moiety liberated from isoniazid is primarily acetylhydrazine, and studies in animals show this metabolite to be converted to a potent acylating agent that produces liver necrosis. It seems likely that formation of chemically reactive metabolites is also the biochemical event initiating isoniazid liver injury in man. Recognition of the seriousness of isoniazid hepatic injury, not readily accepted at first, has led to revisions in the uses of isoniazid prophylaxis.

Acetylation↗
PubMed1976

Metabolic activation of furosemide to a chemically reactive, hepatotoxic metabolite.

The possibility that furosemide-induced hepatic necrosis results from the formation of a chemically reactive hepatotoxic metabolite has been examined. Hepatotoxic doses of 3H-furosemide or 14C-furosemide were administered to normal mice and to mice pretreated with piperonyl butoxide, cobalt chloride, alpha-naphthylisothiocyanate or phenobarbital. Mice were killed at various time intervals and tissues were examined for necrosis, for free furosemide concentrations and for covalently bound metabolites of furosemide. Little furosemide was covalently bound to muscle, whereas the amount of covalently bound material in liver usually paralleled the severity of live necrosis after alteration by the pretreatments. The severity of hepatic necrosis failed to correlate with furosemide concentrations in liver or plasma. Furosemide was shown to be metabolically activated to an arylating intermediate by a cytochrome P-450 mixed function oxidase in hepatic microsomes. Additional experiments demonstrated that the furan ring of furosemide was the portion activated.

Alanine Transaminase↗
PubMed1975

Relative contributions of history-taking, physical examination, and laboratory investigation to diagnosis and management of medical outpatients.

To evaluate the relative importance of the medical history, the physical examination, and laboratory investigations in the diagnosis and management of medical outpatients some physicians recorded their diagnosis and a prediction of the method of managementafter reading the patient's referral letter, again after taking the history, and againafter performing the physical examination. These diagnoses and predictions were compared with the diagnosis and method of management which had been adopted two months after the patient's initial attendance. A diagnosis that agreed with the one finally accepted was made after reading the referral letter and taking the history in 66 out of 80 new patients; the physical examination was useful in only seven patients, and the laboratory investigations in a further seven. In only one of six patients in whom the physician was unable to make any diagnosis after taking the history and examining the patient did laboratory investigations lead to a positive diagnosis.

Clinical Laboratory Techniques↗
PubMed1975

Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydranize metabolites.

Approximately 10% to 20% of isoniazid recipients manifest biochemical evidence of liver injury. A smaller number of patients develop clinically overt hepatitis. Isoniazid is metabolized in man at extremely variable rates, and the rate is under genetic control. Two separate clinical studies have noted a possible relation between susceptibility of patients to isoniazid liver injury and rapid metabolism (acetylation) of the drug. For this reason, 21 patients who had recovered from probable isoniazid hepatitis and 5 patients who previously had manifested biochemical evidence of mild isoniazid liver injury were genetically phenotyped as rapid or slow isoniazid acetylators by the sulfamethazine method. The rapid phenotype was found in 86% of patients with probable hepatitis and in 60% of the possible ones, whereas the expected frequency was 45%. Eximination of isoniazid metabolites revealed that rapid acetylators hydrolze much more isoniazid to isonic otinic hydrazine moiety than do slow acetylators. The hydrazine moiety liberated from isoniazed is primarily acetylhydrazine, and studies in animals show this metabolite to be converted to a potent acylating agent that produces liver necrosis. We suggest that release of the hepatotoxic hydrazino moiety of isoniazid in man is responsible for isoniazid liver injury.

Acetylation↗
PubMed1975

Acetylation rates and monthly liver function tests during one year of isoniazid preventive therapy.

A blind, prospective evaluation of the incidence and course of isoniazid-associated liver injury was made in 358 hospitalized men. The men were psychiatric patients during one year of tuberculosis preventive therapy. Blood samples were obtained at monthly intervals from the patients, the majority of whom were taking isoniazid. When the data were analyzed at the end of the year, a strikingly increased incidence of abnormal serum transaminase (SGOT) and bilirubin values was found among the isoniazid recipients. However, most subjects demonstrating biochemical evidence of hepatic injury recovered completely while continuing to take isoniazid and did not progress to clinically overt hepatitis. The mechanism underlying this adaptation to isoniazid injury is unknown. No serum antibodies against isoniazid could be demonstrated, and no correlation was found between the presence of antinuclear antibodies or elevated isoniazid plasma concentrations and the occurrence of hepatic injury. These data support the view that hepatotoxic metabolities of isoniazid may be responsible for the liver injury.

Acetylation↗
PubMed1975

Isoniazid-associated hepatitis in 114 patients.

Analysis of the overt hepatic disease that developed in 114 patients while taking isoniazid for chemoprophylaxis of tuberculosis showed it to be mainly hepatocellular. The severity of the hepatic injury was manifested by the 13 fatalities (12.3%) and by the histological demonstration of submassive necrosis in 9 and massive necrosis in 4 patients. The 20 other patients from whom hepatic tissue was available for study included 16 with moderately severe acute hepatocellular injury (4 had a mixed hepatocellular-cholestatic pattern), and 4 with chronic hepatic diseases (1 had cirrhosis). Clinical manifestations of hepatic disease prior to the onset of jaundice included vague digestive complaints in 55% of the group and "viral' disease-like complaints in 35%, some with and some without gastrointestinal symptoms. Jaundice was the presenting complaint in 10% of patients. Fever and rash were reported in very few patients (less than 4%) and eosinophilia of modest degree was noted in approximately 10%. Hepatic injury was recognized during the 1st month of isoniazid administration in 15% and during the 2nd month in an additional 31%. In the remaining 54% of patients, the drug had been administered for periods of 2 to 11 months before hepatic injury was noted. Analyses of variables suggested that hepatic injury which presented after 2 months, especially with bilirubin levels that exceeded 20 mg per 100 ml, was more likely to have a fatal outcome than disease that presented during the first 2 months even with higher bilirubin levels. The case fatality rate was significantly higher in black females than in black males or in whites of either sex. The observations of the present study offer no support for the view that isoniazid-induced hepatic disease results from hypersensitivity to the drug. Other data that support the view that hepatotoxic metabolites of isoniazid may be responsible for the injury are considered.

Age Factors↗