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Biomedical subjects

G A Ellard

Publications and source records attributed to G A Ellard.

At least 73 records · Page 4Linked to original sources
PubMed1977

Acetylator phenotyping of tuberculosis patients using matrix isoniazid or sulphadimidine and its prognostic significance for treatment with several intermittent isoniazid-containing regimens.

1. The acetylator phenotype of over 600 pulmonary tuberculosis patients treated with intermittent isoniazid-containing regimens in two controlled clinical trials was determined using either sulphadimidine or a slow-release isoniazid formulation. 2. Both methods unequivocally classified over 99% of the patients as being either slow or rapid acetylators. 3. Rapid and slow acetylation did not differ in their ability of hydrolyse acetylisoniazid to isonicotonic acid plus monoacetylhydrazine, or to conjugate isonicotinic acid with glycine. 4. Rapid acetylators acetylated the monoacetylhydrazine liberated in vivo more rapidly than slow acetylators, demonstrating that this compound is also polymorphologically acetylated in man. 5. The acetylator phenotype of the patients was without prognostic significance when they were treated on a twice-weekly basis with isoniazid plus streptomycin plus pyraziniamide, or with isoniazid plus rifampicin. However, when patients were treated once every week for 12 months with isoniazid plus rifampicin, 5% of the rapid acetylators had an unsatisfactory response as contrasted to the complete success of the treatment in the slow acetylators.

Acetylation↗
PubMed1977

A sensitive urine-test method for monitoring the ingestion of isoniazid.

A method is described for monitoring the ingestion of isoniazid based on detecting its metabolites, isonicotinic acid, and isonicotinylglycine in the urine. The sensitivity of the method is high so that reliably positive results were obtained up to about 24 hours after the ingestion of 100 mg isoniazid. The method should facilitate monitoring the taking of isoniazid by tuberculosis patients and the use of isoniazid as a marker for assessing the regularity with which other drugs prescribed for self-administration are actually ingested.

Humans↗
PubMed1976

Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis.

Isoniazid is the most effective and widely used antituberculosis drug. The metabolism of isoniazid is noninducible and the primary metabolic route determining the rate at which isoniazid is eliminated from the body is acetylation. There are large diffrences between individuals in the rates at which isoniazid and certain other hydrazides and some sulfonamides are acetylated. The acetylation of isoniazid is inherited in a simple Mendelian fashion, individuals being either slow, heterozygous rapid, or homozygous rapid acetylators. Improved methods of discriminating between the different phenotypes have recently been described that are also more convenient to use. The proportion of slow acetylators among Japanese and Eskimos is about 10%; among Chinese about 20%; among Caucasians, Negroes, and South Indians about 60%. The results of a series of meticulously controlled clinical trials carried out in India, East Africa, Hong Kong, Singapore, Czechoslovakia, and Britain have shown the isoniazid acetylator status of tuberculosis patients treated with isoniazid-containing regimens is of no prognostic significance when treatment is given on daily basis. It may, however, be of significance when twice-weekly regimens are employed, especially in circumstances in which only a short period of initial daily chemotherapy is given, and where the companion drug employed during the twice-weekly continuation phase is relatively weak. The acetylator phenotype is, however, extremely important in once-weekly treatment, rapid acetylators always having fared considerably worse than slow acetylators on all the regimens evaluated so far. Experimental studies of the action of isoniazid against Mycobacterium tuberculosis in vitro and in vivo have enabled these findings to be understood.

Acetylation↗
PubMed1976

Observations on the reduction of the renal elimination of urate in man caused by the administration of pyrazinamide.

The urinary excretion of pyrazinamide, pyrazinoic acid, 5-hydroxypyrazinoic acid and uric acid were determined in a healthy subject after giving single or multiple doses of pyrazinamide or its metabolite pyrazinoic acid. The results obtained demonstrated that 5-hydroxypyrazinoic acid is a major metabolite of pyrazinoic acid in man and supported previous evidence indicating that the retention of uric acid caused by the administration of pyrazinamide is mediated by pyrazinoic acid. After giving 3 g pyrazinamide the urinary excretion of uric acid was maximally suppressed for 24 hours and partially reduced for a further 24 hours. Prolonged exposure to pyrazinoic acid resulted in a net reduction in the urinary excretion of uric acid. The findings suggested that the degree of uric acid retention in patients treated with pyrazinamide-containing regimens could be reduced by giving pyrazinamide intermittently.

Humans↗
PubMed1975

Determination of the acetylator phenotype using matrix isoniazid.

The development of a simple method for classifying subjects as slow or rapid acetylators is reported. The method is based on determining the ratio of acetylisoniazid to acid-labile isoniazid in the urine 23-24 hours after an oral dose of a slow-release isoniazid formulation. The results obtained when this method was applied to phenotype over 200 East African tuberculosis patients are described. It is suggested that the method would be particularly suitable for classifying tuberculosis out-patients.

Acetylation↗
PubMed1975

Reappraisal of the activity of morphazinamide against M. tuberculosis.

Morphazinamide was shown to have an in vitro activity similar to an equimolar concentration of pyrazinamide. This activity was not due, as had been previously assumed, to pyrazinamide formed by hydrolysis from morphazinamide, since it was demonstrated in slide cultures containing tubercle bacilli which were incubated with freshly prepared dilutions of morphazinamide in acid medium for several successive periods of only 1 hour, during which time little hydrolysis occurred. A new method was used for measuring morphazinamide and pyrazinamide separately in plasma. In man, the estimated in vitro antibacterial activity was similar after approximately equimolar oral doses of morphazinamide or pyrazinamide. However, it is uncertain whether the in vivo activity of morphazinamide is the same as its in vitro activity.

Animals↗
PubMed1975

The use of isoniazid as a marker to monitor the self-administration of medicaments.

1. Isoniazid was used as a marker to monitor the regularity of drug self-administration in a trial of chemoprophylaxis against natural influenza infection. Two hundred and sixty-two volunteers were treated for five weeks with a synthetic isoquinoline compound (U.K. 2371) or a matching placebo. 2. Five marker tablets containing isoniazid (150 mg) were incorporated into each regimen and their ingestion monitored by testing for acetylisoniazid in the urine. 3. Positive evidence of marker tablet consumption was obtained on 75% of the occasions on which urine samples were requested. The results obtained among the volunteers from each treatment group who returned urine specimens as requested (92%) indicated that they had swallowed at least 81% of their prescribed tablets. 4. The findings of the study suggest that when used in this way isoniazid is a very suitable compound for use on a few occasions for monitoring the self-administration of drugs in clinical trials.

Adolescent↗
PubMed1975

The penetration of dapsone, rifampicin, isoniazid and pyrazinamide into peripheral nerves.

1 Dapsone, rifampicin, isoniazid and pyrazinamide were shown to penetrate readily into the sciatic nerves of the dog and sheep. 2 These findings suggest that the continued persistence of viable drug-sensitive leprosy bacilli in the peripheral nerves of patients treated for long periods with either dapsone or rifampicin is not due to inadequate intraneural drug penetration.

Animals↗