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At least 19 recordsLinked to original sources
PubMed1961

Rate of inactivation of isoniazid in South Indian patients with pulmonary tuberculosis. 3. Serum concentrations of isoniazid produced by three regimens of isoniazid alone and one of isoniazid plus PAS.

A series of studies on the rate of inactivation of isoniazid in Indian patients with pulmonary tuberculosis in a 1-year comparison of four domiciliary chemotherapeutic regimens-three of isoniazid alone, either in moderate (HI-1 and HI-2 regimens) or in low (H regimen) dosage, and one of isoniazid in low dosage plus p-aminosalicylic acid (PAS) (PH regimen) -has recently been undertaken by the Tuberculosis Chemotherapy Centre, Madras. This paper-the third of the series-presents information on the length of time during which inhibitory concentrations of isoniazid (0.2 mug/ml or more) were maintained in the serum and on the estimated peak serum concentrations of isoniazid produced by the four regimens and relates these factors to the therapeutic effectiveness of the different regimens.THE RESULTS SUGGESTED THAT: (a) the therapeutic superiority of the PH regimen over the isoniazid-alone regimens was only in part due to the effect of PAS in enhancing the serum levels of isoniazid; (b) the therapeutic superiority of the HI-1 regimen (moderate dosage, given in one dose a day) over the HI-2 and H regimens (moderate and low dosage, respectively, given in two doses a day) was due to the higher peak serum concentration of isoniazid produced rather than to the period minimal inhibitory concentrations of isoniazid were maintained in the serum; and (c) there was a possibility that raising the peak serum concentration of isoniazid above a critical concentration of about 3 mug/ml had a greater therapeutic effect than similar proportional increases below this concentration. It also appeared that the slightly better therapeutic response observed in the slow inactivators of isoniazid than in the rapid inactivators was due to the higher peak serum concentrations of isoniazid produced; the enhanced therapeutic effect was approximately the same as would be expected from a 50% increase in isoniazid dosage.

Humans↗
PubMed1964

THE EMERGENCE OF ISONIAZID-RESISTANT CULTURES IN PATIENTS WITH PULMONARY TUBERCULOSIS DURING TREATMENT WITH ISONIAZID ALONE OR ISONIAZID PLUS PAS.

Previous reports from the Tuberculosis Chemotherapy Centre, Madras, have described a comparison of four regimens (three of isoniazid alone and one of isoniazid plus PAS) in the treatment of pulmonary tuberculosis and an investigation of the serum isoniazid levels in the patients concerned. The present report studies the emergence of isoniazid-resistant organisms in these patients during treatment. All patients with an unsatisfactory response to treatment yielded resistant cultures, showing that the isoniazid dosage was never too low to inhibit sensitive organisms. From the degree of resistance of the first resistant cultures and of the six-month cultures from the patients treated with isoniazid alone it was concluded that resistance emerged in two stages. In the first stage, very earlyin treatment, highly resistant mutant bacilli grew freely whatever the isoniazid dosage, but mutants of lower resistance were prevented from growing to an extent dependent on the peak isoniazid concentration in the serum. Consequently, when the isoniazid dosage was increased the proportion of patients with resistant organisms decreased, since fewer low-resistance strains were able to develop. In the second stage, organisms with relatively low resistance continued to multiply, though still partially inhibited by isoniazid, and became more resistant, particularly in slow inactivators. The first-stage events determined the results of treatment since, once resistance had emerged, its extent was unrelated to the patient's eventual progress. These findings emphasize the importance of early intensive chemotherapy and adjustment of the isoniazid dosage according to peak serum concentrations rather than concentrations measured three or six hours after the dose. Concomitant administration of PAS prevented emergence of isoniazid resistance in many patients and in others delayed its emergence and reduced its degree, possibly because growth in the second stage was slow.

Aminosalicylic Acid↗
PubMed1961

Response of patients infected with isoniazid-resistant tubercle bacilli to treatment with isoniazid plus PAS or isoniazid alone.

This study from the Tuberculosis Chemotherapy Centre, Madras, compares patients infected with isoniazid-resistant tubercle bacilli ("R" patients) with those infected with isoniazid-sensitive tubercle bacilli ("S" patients) as regards, first, their pretreatment status and, secondly, their response to a year's chemotherapy, either with isoniazid plus p-aminosalicylic acid (PAS) or with isoniazid alone. With regard to the first comparison, there was, on admission to treatment, little difference between the R and S patients in terms of the extent of the radiographic lesion, the extent of cavitation or the bacterial content of the sputum, but there were major differences in the age and sex distributions, the R patients showing a greater preponderance of young males than the S patients. As to the second comparison, statistically significant differences in the bacteriological response to treatment of the S and the R patients were observed in both the isoniazid-plus-PAS and the isoniazid-alone series, the response of the S patients being much better than that of the R patients. When the response to treatment was assessed in terms of radiographic progress and weight changes, however, hardly any difference was observed between the progress of the S and the R patients. The reasons for the response in the R patients are discussed.

Bacillus↗
PubMedDate not supplied

Isoniazid preventive therapy in areas of high isoniazid resistance.

BACKGROUND: Previous decision analyses of isoniazid preventive therapy for low-risk tuberculin reactors aged 20 to 34 years have not accounted for the recently increased isoniazid resistance rate. Drug resistance trends could also affect the decision to use isoniazid preventive therapy for patients with recent conversion of tuberculin skin tests who are seronegative for human immunodeficiency virus. METHODS: A decision analysis was performed with a Markov simulation to assess the difference in life expectancy between those who receive isoniazid preventive therapy and those who do not. Probability estimates were determined from a review of the literature. RESULTS: For tuberculin reactors aged 20 to 34 years living in areas with 26% isoniazid resistance, isoniazid preventive therapy increases life expectancy by 2 days. Withholding isoniazid is clearly favored if the isoniazid hepatitis rate is 1.1% and the hepatitis fatality rate exceeds 2.8%. For recent tuberculin converters, isoniazid preventive therapy increases life expectancy by 14 to 17 days, depending on patient age. Withholding isoniazid from converters is favored only if the isoniazid resistance rate exceeds 90% to 98%, according to patient age. Two-way sensitivity analysis of isoniazid-associated hepatitis and hepatitis-related fatality rate did not affect the decision to use isoniazid for recent converters. CONCLUSIONS: For tuberculin reactors aged 20 to 34 years who are seronegative for human immunodeficiency virus and living in areas with high isoniazid resistance, there is minimal net benefit of isoniazid preventive therapy. The current recommendation to provide isoniazid preventive therapy to this patient population should be reexamined. For recent tuberculin converters aged 20 to 64 years who are seronegative for human immunodeficiency virus, isoniazid preventive therapy provides a small increase in life expectancy. Withholding isoniazid preventive therapy for human immunodeficiency virus-seronegative skin test converters at high risk for isoniazid-induced hepatitis may be considered; preventive therapy is advisable for all other recent converters.

Adult↗
PubMed1980

Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid.

The effect of prednisolone and rifampin, alone and in combination, on the biodisposition of isoniazid in slow and rapid inactivators of isoniazid was investigated. In one investigation, we made serial determinations of plasma isoniazid concentrations up to 8 h and of isoniazid and acetylisoniazid in excreted urine up to 8.5 h in patients receiving isoniazid alone on one occasion and isoniazid plus prednisolone or isoniazid plus rifampin on another. Prednisolone caused a significant decrease in the plasma isoniazid concentrations in both slow and rapid inactivators. It also enhanced the renal clearance of isoniazid in both slow and rapid inactivators and increased the rate of acetylation of isoniazid in slow inactivators only. Rifampin had no effect on the biodisposition of isoniazid in either slow or rapid inactivators. In a second investigation, one group of slow and rapid inactivators received isoniazid and rifampin, and a different group received prednisolone, in addition. Plasma isoniazid concentrations in slow inactivators receiving prednisolone were significantly lower than in those who received isoniazid and rifampin only. In rapid inactivators, plasma isoniazid concentrations were similar in the two groups of patients, suggesting that concomitant administration of rifampin had considerably modified the prednisolone effect on the biodisposition of isoniazid in these patients.

Acetylation↗
PubMed2000

Twelve months of isoniazid compared with four months of isoniazid and rifampin for persons with radiographic evidence of previous tuberculosis: an outcome and cost-effectiveness analysis.

Isoniazid taken daily for 12 mo and isoniazid and rifampin taken daily for 4 mo are both recommended options for patients with radiographic evidence of previous tuberculosis and positive tuberculin skin tests who have not had prior treatment. We compared the completion rates, number of adverse effects, and cost effectiveness of these two regimens. Patients were treated at the San Francisco Tuberculosis Clinic from 1993 through 1996. A Markov model was developed to assess impact on life expectancy and costs. One thousand twenty-two patients, with a mean age of 52 yr, and > 90% foreign born, were treated; 545 received isoniazid and 477 received isoniazid and rifampin. For isoniazid, 79.8% completed 12 mo of therapy and 4.9% had adverse effects versus 83.6% completion, 6.1% adverse effects for isoniazid and rifampin (p > 0.05 for all between-group comparisons). Both regimens increased life expectancy by 1.4-1.5 yr. Compared with isoniazid, isoniazid and rifampin produced net incremental savings of $135 per patient treated. In patients with radiographic evidence of prior tuberculosis who have not been previously treated, isoniazid for 12 mo and isoniazid and rifampin for 4 mo have similar rates of completion and adverse effects, and both increase life expectancy compared with no treatment. Isoniazid and rifampin for 4 mo is cost saving compared with isoniazid alone. This advantage was maintained even when compared with 9 mo of isoniazid, the new American Thoracic Society/Centers for Disease Control (ATS/CDC) recommendation for treatment with isoniazid alone.

Antitubercular Agents↗
PubMed1975

Studies of serial plasma Isoniazid concentrations with different doses of a slow-release preparation of Isoniazid.

The suitability of a slow-release matrix preparation of isoniazid for use in once-weekly chemotherapy has been investigated in South Indian patients. Serial plasma isoniazid concentrations were determined up to 6 hours following doses of 15, 30, 45 and 60 mg/kg body-weight in rapid inactivators and up to 10 hours following doses of 15, 30 and 45 mg/kg in slow inactivators. The isoniazid levels were sustained, and the peak concentrations (per unit dose) were considerably lower than with ordinary isoniazid. It was estimated that a matrix isoniazid dose of 35 mg/kg in slow inactivators and 50 mg/kg in rapid inactivators would produce a peak similar to that attained with a non-toxic dose or ordinary isoniazid 15 mg/kg in slow inactivators. A second investigation showed that matrix isoniazid 40 mg/kg in rapid inactivators produced a coverage (with 0.2 mug/ml) and exposure similar to those attained in slow inactivators with a highly effective dose of ordinary isoniazid 15 mg/kg, while 30 mg/kg gave substantially lower values. In both investigations, disproportionately large increases in plasma isoniazid concentrations were observed in rapid inactivators with an increase in the matrix isoniazid dose. In slow inactivators, both doses of matrix isoniazid, 30 and 40 mg/gk, resulted in coverage and exposure that were substantially higher than those obtained with ordinary isoniazid 15 mg/kg.

Clinical Trials as Topic↗
PubMed1998

Evidence for differential binding of isoniazid by Mycobacterium tuberculosis KatG and the isoniazid-resistant mutant KatG(S315T).

Isoniazid is a mainstay of antibiotic therapy for the treatment of tuberculosis, but its molecular mechanism of action is unclear. Previous investigators have hypothesized that isoniazid is a prodrug that requires in vivo activation by KatG, the catalase-peroxidase of Mycobacterium tuberculosis, and that resistance to isoniazid strongly correlates with deletions or point mutations in KatG. One such mutation, KatG(S315T), is found in approximately 50% of clinical isolates exhibiting isoniazid resistance. In this work, 1H nuclear magnetic resonance T1 relaxation measurements indicate that KatG and KatG(S315T) each bind isoniazid at a position approximately 12 A from the active site heme iron. Electron paramagnetic resonance spectroscopy revealed heterogeneous populations of high-spin ferric heme in both wild-type KatG and KatG(S315T) with the ratios of each species differing between the two enzymes. Small changes in the proportions of these high-spin species upon addition of isoniazid support the finding that isoniazid binds near the heme periphery of both enzymes. Titration of wild-type KatG with isoniazid resulted in the appearance of a "type I" substrate-induced difference spectrum analogous to those seen upon substrate binding to the cytochromes P450. The difference spectrum may result from an isoniazid-induced change in a portion of the KatG heme iron from 6- to 5-coordinate. Titration of KatG(S315T) with isoniazid failed to produce a measurable difference spectrum indicating an altered active site configuration. These results suggest that KatG(S315T) confers resistance to isoniazid through subtle changes in the isoniazid binding site.

Amino Acid Substitution↗
PubMed1987

Increased urinary excretion of toxic hydrazino metabolites of isoniazid by slow acetylators. Effect of a slow-release preparation of isoniazid.

To test the hypothesis that slow acetylators, who may have a greater risk of developing isoniazid hepatitis than rapid acetylators, are exposed to more acetylhydrazine and hydrazine, two toxic metabolites of isoniazid, the urinary excretion of hydrazino metabolites of isoniazid was measured following the ingestion of 300 mg isoniazid. Slow acetylators (n = 7) excreted significantly more isoniazid (32.4 vs 9.2% dose), acetylhydrazine (3.1 vs 1.6% dose), and hydrazine (1.0 vs 0.4% dose) in 24 h than rapid acetylators (n = 5), whereas the excretion of acetylisoniazid and diacetylhydrazine was significantly lower. As the acetylation (i.e. detoxification) of acetylhydrazine is inhibited in the presence of high concentrations of isoniazid, a study was also made of the effect of a slow-release preparation that results in lower plasma concentrations of isoniazid on the production of hydrazino metabolites. The ratio of acetylisoniazid to isoniazid in urine was significantly increased in slow acetylators from 0.84 to 1.02 following administration of the slow release preparation, indicating increased acetylation of isoniazid. However, the excretion of diacetylhydrazine relative to the excretion of acetylhydrazine and hydrazine did not change. It is concluded that exposure to toxic metabolites of isoniazid is increased in slow acetylators. Detoxification of the toxic metabolites was not enhanced by a slow-release preparation of isoniazid.

Acetylation↗
PubMed1981

Should isoniazid be used in retreatment of tuberculosis despite acquired isoniazid resistance?

The use of high-dose isoniazid in retreatment regimens for tuberculosis, despite acquired isoniazid resistance, could possibly improve therapeutic results if all or part of the organisms were resistant to only low concentrations of that drug. Furthermore, organisms resistant to low concentrations of isoniazid have been shown, on occasion, to be resistant to 2 of the retreatment drugs, ethionamide and pyrazinamide, whereas higher degrees of isoniazid resistance are associated with susceptibility to these drugs. Use of high-dose isoniazid might improve results in retreatment with ethionamide and pyrazinamide by eliminating any organisms with low degrees of isoniazid resistance that have associated ethionamide and pyrazinamide resistance. Two clinical trials concerning this topic have been reported. A controlled retreatment trial with various combinations of ethionamide, cycloserine, and pyrazinamide with and without conventional "low" doses of isoniazid (300 mg per day) showed no benefit when isoniazid was added. However, a noncontrolled trial using ethionamide and pyrazinamide with and without high doses of isoniazid, 1 to 1.5 g per day, showed marked benefit with the added isoniazid. In view of these conflicting data, the use of high-dose isoniazid in retreatment regimens needs further study, which could probably be carried out in the developing countries.

Dose-Response Relationship, Drug↗
PubMed2000

Rifapentine and isoniazid in the continuation phase of a 6-month regimen. Interim report: no activity of isoniazid in the continuation phase.

SETTING: Clinical trial amongst 762 patients with newly diagnosed pulmonary tuberculosis in Hong Kong. After an initial 2 months of a four-drug intensive phase consisting of streptomycin, isoniazid, rifampicin and pyrazinamide (SHRZ), a random allocation in continuation to once-weekly rifapentine + isoniazid (HRp1), HRp1 given in 2 of every 3 weeks (HRp1.2/3), or to three times weekly isoniazid + rifampicin (HR3). OBJECTIVE: Interim report evaluating progress of study and the role of isoniazid in the continuation phase. METHODS: Kaplan-Meier analysis and response of patients related to susceptibility of pretreatment organisms to isoniazid and to rate of isoniazid acetylation determined by NAT2 genotyping. RESULTS: In the 30-month follow-up, rates for adverse treatment events (failure and relapse) were 4.2% in the HR3, 10.2% in the HRp1 and 11.2% in the HRp1.2/3 series (P = 0.02 for HR3 vs HRp1 and P = 0.01 for HR3 vs HRp1.2/3). Occurrence of adverse events was not related to initial susceptibility to isoniazid nor to the rate of acetylation of isoniazid. CONCLUSIONS: The two rifapentine regimens had similar final rates of adverse events which were unsatisfactory. Isoniazid had little or no activity in the continuation phase, indicating that no improvement of the continuation regimen is likely to be obtained by alteration of the isoniazid dosage.

Acetylation↗
PubMed1987

Acetylation of acetylhydrazine, the toxic metabolite of isoniazid, in humans. Inhibition by concomitant administration of isoniazid.

The effect of isoniazid and its metabolites on the disposition of acetylhydrazine, a toxic metabolite formed from isoniazid, was studied in humans. Acetylhydrazine was administered i.v. with and without prior ingestion of 300 mg of isoniazid. In the studies with isoniazid, 15N2-acetylhydrazine was administered in order to distinguish exogenous acetylhydrazine from the unlabeled acetylhydrazine formed from isoniazid. In each subject (two fast and three slow acetylators) the rate of elimination of acetylhydrazine was similar to the rate of elimination of isoniazid suggesting that the two compounds are subject to the same acetylation polymorphism. In the presence of isoniazid the rate of elimination of acetylhydrazine was consistently lower than in the absence of isoniazid, and the urinary excretion of diacetylhydrazine and the ratio of diacetyl/acetylhydrazine in urine decreased. The data indicate that therapeutic concentrations of isoniazid and its metabolites inhibit the acetylation of acetylhydrazine in humans. The inhibition of this detoxification pathway could contribute to the hepatotoxicity of isoniazid.

Acetylation↗
PubMed1966

Isoniazid plus thioacetazone compared with two regimens of isoniazid plus PAS in the domiciliary treatment of pulmonary tuberculosis in South Indian patients.

Previous reports from the Tuberculosis Chemotherapy Centre, Madras, have established that ambulatory treatment of pulmonary tuberculosis with a standard daily regimen of isoniazid plus PAS for one year yields satisfactory results. However, this regimen may be unsuitable for large-scale use in many developing countries, because PAS is expensive, bulky and unpleasant to take, and has poor keeping qualities, especially in tropical countries. It might be possible to overcome these disadvantages, by substituting for the PAS a drug which is equally effective but less expensive and more acceptable, or by reducing the daily dosage of PAS and the period for which it is prescribed.This paper presents the results over a 12-month period of a controlled comparison of (a) the standard regimen of isoniazid (average 4.5 mg/kg body-weight) plus sodium PAS (average 0.22 g/kg), daily in two divided doses; (b) a regimen of isoniazid (average 6.9 mg/kg) plus thioacetazone (average 3.4 mg/kg), daily in one dose; and (c) a 2-phase regimen of isoniazid (average 5.5 mg/kg) plus sodium PAS (average 0.17 g/kg), daily in one dose for 6 months, followed by isoniazid alone (average 6.8 mg/kg), daily in one dose for the second 6 months. The regimen of isoniazid plus thioacetazone was found to be therapeutically as effective as the standard regimen of isoniazid plus PAS; however, it was associated with a higher incidence of minor side-effects, and three cases of exfoliative dermatitis. The 2-phase regimen of isoniazid plus PAS followed by isoniazid alone was less effective.These findings are encouraging for the large-scale use in developing countries of the relatively inexpensive regimen of isoniazid plus thioacetazone; however, any such step should be preceded by carefully planned studies to investigate, under local conditions, the toxicity and the efficacy of the regimen.

Aminosalicylic Acids↗
PubMed1986

Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin.

The effect of daily administration of rifampin on the direct conversion of isoniazid to isonicotinic acid and hydrazine by isoniazid hydrolase was investigated in 6 slow and 8 rapid acetylators of isoniazid. The proportion of isoniazid metabolized through this direct pathway during the first 6 h was estimated from the ratio of total isonicotinic acid formed to acetylisoniazid in urine after administration of isoniazid or acetylisoniazid. In slow acetylators, this proportion was approximately 3% when isoniazid alone was administered and approximately 6% during the maximal phase of induction caused by the daily administration of rifampin in addition to isoniazid (p less than 0.001); in rapid acetylators, the proportions were considerably less (less than 1 and 2.5%, respectively), suggesting that isoniazid hydrolase was induced by rifampin. The increased formation of hydrazine, a known hepatotoxic agent in animals, could explain the substantially higher frequency of the occurrence of hepatitis in slow than in rapid acetylators among tuberculous patients treated with daily rifampin and isoniazid.

Acetylation↗