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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↗
PubMedDate not supplied

Population screening for isoniazid acetylator phenotype.

PURPOSE: To establish a useful method for acetylator phenotypification and therapeutic drug monitoring of patients receiving isoniazid. METHODS: Sixty patients with uncomplicated pulmonary tuberculosis were given a 5-mg/kg oral dose of isoniazid each. Plasma concentrations of isoniazid and its metabolite, acetyl-isoniazid, were determined by HPLC analyses at various post-dose times. From the isoniazid concentration and the concentration ratio of acetyl-isoniazid and isoniazid (metabolic ratio), phenotypification methods were assessed. RESULTS: The metabolic ratios at 3 h post-dose revealed a trimodal distribution; a fast, intermediate and slow acetylator phenotype group. The 2-h and 6-h data showed different bimodal combinations of these phenotype groups. The metabolic ratio phenotypification method could be simplified by using the HPLC data directly without converting it to absolute concentrations. CONCLUSIONS: A single-sample test based upon the plasma isoniazid concentration, combined with the metabolic ratio of acetyl-isoniazid and isoniazid, appears to be a reliable parameter for phenotype discrimination and for bioavailability testing.

Acetylation↗
PubMed2002

Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes.

OBJECTIVE: In order to evaluate the inhibitory effects of isoniazid on cytochrome P450 (CYP) mediated drug metabolism, the in vitro inhibitory potency and specificity as well as the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-, time- and concentration dependency of isoniazid as an inhibitor of the activity of the major human CYP isoforms were studied. METHODS: Using pooled human liver microsomes, the in vitro inhibitory effects of isoniazid on CYP1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2CI9 (S-mephenytoin 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation), CYP2E1 (chlorzoxazone 6-hydroxylation) and CYP3A4 (midazolam 1'-hydroxylation) activities were examined. RESULTS: After a 15-min preincubation without NADPH, isoniazid reversibly inhibited microsomal CYP2C19- and CYP3A4-mediated reactions with apparent Ki values of 36 microM and 73 microM, respectively. However, isoniazid had only weak inhibitory effects on the five other CYP-mediated reactions (Ki > 110 microM). After a 15-min preincubation with NADPH, isoniazid showed an increased inhibitory potency toward CYP1A2, CYP2A6, CYP2C19 and CYP3A4 activities (Ki = 56, 60, 10 and 36 microM, respectively). In addition, the inactivation of CYP1A2, CYP2A6, CYP2C19 and CYP3A4 by isoniazid was NADPH-, time- and concentration dependent, and was characterised by Kinact values of 0.11, 0.13, 0.09 and 0.08 min(-1), and K1 values of 285, 173, 112 and 228 microM, respectively. CONCLUSIONS: As the peak plasma concentrations of isoniazid are around 30-50 microM, isoniazid at clinically relevant concentrations reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 in human liver microsomes. Co-administration of isoniazid and drugs that are primarily metabolised by these CYP isoforms, particularly by CYP2C19 and CYP3A4, may result in significant drug interactions.

Antitubercular Agents↗
PubMed1993

Decreased acetylation of isoniazid in chronic renal failure.

Pharmacokinetic parameters of isoniazid obtained from 37 normal subjects were compared with parameters obtained from 14 patients with chronic renal failure. In the 29 normal rapid acetylators and eight normal slow acetylators, the mean plasma half-life values of isoniazid were 1.54 +/- 0.31 and 3.68 +/- 0.59 hours, respectively. The plasma half-life values of isoniazid in patients with chronic renal failure varied widely from 1.30 to 10.13 hours, but the values were significantly longer than those of normal subjects. Because isoniazid clearance is governed mainly by hepatic metabolism, such a significant prolongation of plasma half-life of isoniazid was unexpected; thus the pharmacokinetics of isoniazid were reevaluated in the same patients with chronic renal failure after the kidney transplantation. After successful kidney transplantation, the shortening of isoniazid half-life was pronounced and the nonrenal clearance was markedly increased. These findings indicate that decreased isoniazid clearance in chronic renal failure is caused in minor part by the decreased renal excretion of isoniazid and in major part by the depressed hepatic N-acetylation of isoniazid.

Acetylation↗
PubMed1996

Determination of the primary target for isoniazid in mycobacterial mycolic acid biosynthesis with Mycobacterium aurum A+.

The target of the potent antituberculosis drug isoniazid was investigated in Mycobacterium aurum A+, against which isoniazid has an MIC (the minimum concentration required to give growth inhibition) of 0.3 microgram/ml. Mycolic acid biosynthesis, measured by the incorporation of label from [1-14C]acetate into mycolic acids, was inhibited differentially by isoniazid in cell-wall preparations of M. aurum A+. Thus at an isoniazid concentration of 1 microgram/ml, mycolic acid biosynthesis was inhibited by 80% but concomitant biosynthesis of non-hydroxylated fatty acids was inhibited by only 15%. Three lines of evidence identified 24:1 cis-5 elongase as the primary isoniazid target. First, 24:1 cis-5 did not restore isoniazid-inhibited mycolic acid biosynthetic activity in a crude cell-wall preparation, suggesting that the drug acts after the formation of the delta-5 double bond. Secondly, a 24:1 cis-5 elongase assay in which the product is mycolic acid is completely inhibited by isoniazid. Finally, the only intermediates that accumulate as a result of the addition of isoniazid are acids of 24 carbons. Both 24:0 and 24:1 are observed in a similar ratio whether or not isoniazid is present, even though concomitant mycolic acid biosynthesis is inhibited by isoniazid. These results are consistent with studies of the M. tuberculosis InhA protein by Dessen, Quemard, Blanchard, Jacobs and Sacchettini [(1995) Science 267, 1638-1641].

Acetyltransferases↗
PubMed1986

Emergency department management of children with acute isoniazid poisoning.

We suggest that the following therapeutic regimen be followed in cases of isoniazid poisoning in children. In cases of intractable seizure activity in a child which remains unexplained, consider isoniazid poisoning. Give pyridoxine as an intravenous bolus to all children in whom isoniazid toxicity is suspected, who exhibit seizure activity and are known to have been exposed to isoniazid, or who have a history of ingesting one gram or more of isoniazid. It should be given on a gram-for-gram basis, and the clinician need not await serum isoniazid levels before administering pyridoxine. It can be safely given at a rate of five grams per three minutes in a 50 ml volume. In fact, serum isoniazid determinations are not available in many emergency departments and have not been shown to correlate closely with symptomatology. When available, serum isoniazid levels at best are subject to variability owing to sampling procedures (serum protein must be removed within two hours of sampling). The result is that serum isoniazid levels play only a minor role in the emergency department management of isoniazid poisoning. To potentiate the antidotal effects of pyridoxine, diazepam (0.1 mg/kg) may be given intravenously, preferably at a second intravenous site. Because the lactic acidosis seen after seizures resolves spontaneously, and because metabolic alkalosis may result following excess lactate loading, administration of bicarbonate is usually not necessary, and may be harmful in some cases. After pyridoxine treatment, syrup of ipecac may be given to empty the stomach.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2005

Binding of the anti-tubercular drug isoniazid to the arylamine N-acetyltransferase protein from Mycobacterium smegmatis.

Isoniazid is a frontline drug used in the treatment of tuberculosis (TB). Isoniazid is a prodrug, requiring activation in the mycobacterial cell by the catalase/peroxidase activity of the katG gene product. TB kills two million people every year and the situation is getting worse due to the increase in prevalence of HIV/AIDS and emergence of multidrug-resistant strains of TB. Arylamine N-acetyltransferase (NAT) is a drug-metabolizing enzyme (E.C. 2.1.3.5). NAT can acetylate isoniazid, transferring an acetyl group from acetyl coenzyme A onto the terminal nitrogen of the drug, which in its N-acetylated form is therapeutically inactive. The bacterium responsible for TB, Mycobacterium tuberculosis, contains and expresses the gene encoding the NAT protein. Isoniazid binds to the NAT protein from Salmonella typhimurium and we report here the mode of binding of isoniazid in the NAT enzyme from Mycobacterium smegmatis, closely related to the M. tuberculosis and S. typhimurium NAT enzymes. The mode of binding of isoniazid to M. smegmatis NAT has been determined using data collected from two distinct crystal forms. We can say with confidence that the observed mode of binding of isoniazid is not an artifact of the crystallization conditions used. The NAT enzyme is active in mycobacterial cells and we propose that isoniazid binds to the NAT enzyme in these cells. NAT activity in M. tuberculosis is likely therefore to modulate the degree of activation of isoniazid by other enzymes within the mycobacterial cell. The structure of NAT with isoniazid bound will facilitate rational drug design for anti-tubercular therapy.

Antitubercular Agents↗
PubMed2002

Oxidative stress increases susceptibility of Mycobacterium tuberculosis to isoniazid.

Isoniazid is a first-line antibiotic used in the treatment of infections caused by Mycobacterium tuberculosis. Isoniazid is a prodrug requiring oxidative activation by the catalase-peroxidase hemoprotein, KatG. Resistance to isoniazid can be obtained by point mutations in the katG gene, with one of the most common being a threonine-for-serine substitution at position 315 (S315T). The S315T mutation is found in more than 50% of isoniazid-resistant clinical isolates and results in an approximately 200-fold increase in the MIC of isoniazid compared to that for M. tuberculosis H37Rv. In the present study we investigated the hypothesis that superoxide plays a role in KatG-mediated isoniazid activation. Plumbagin and clofazimine, compounds capable of generating superoxide anion, resulted in a lower MIC of isoniazid for M. tuberculosis H37Rv and a strain carrying the S315T mutation. These agents did not cause as great of an increase in isoniazid susceptibility in the mutant strain when the susceptibilities were assessed by using the inhibitory concentration that causes a 50% decrease in growth. These results provide evidence that superoxide can play a role in isoniazid activation. Since clofazimine alone has antitubercular activity, the observation of synergism between clofazimine and isoniazid raises the interesting possibility of using both drugs in combination to treat M. tuberculosis infections.

Antitubercular Agents↗
PubMed1986

Active tuberculosis after isoniazid chemoprophylaxis of Southeast Asian refugees.

The outcome of isoniazid chemoprophylaxis for tuberculosis was assessed in refugees from Southeast Asia. From July 1979 through June 1982, 2,795 tuberculin-positive refugees were prescribed isoniazid chemoprophylaxis at the time of their resettlement in King County, Washington. Through December 1983, 19 cases of active tuberculosis had arisen in those refugees. The annual incidence varied between 2.04 and 2.86 cases per 1,000 receiving treatment during the 4 yr after initiation of chemoprophylaxis (cumulative incidence, 9.66 per 1,000). Seven of the cases of tuberculosis occurring after isoniazid chemoprophylaxis were pulmonary, 1 was pulmonary and extrapulmonary (lymphatic), and 11 were extrapulmonary alone (lymphatic, 6 cases; pleural, 4 cases; soft tissue, 1 case). Fifteen of the 19 cases were culture positive, among which 8 M. tuberculosis isolates were susceptible to isoniazid and 7 were resistant. A case-control analysis showed that poor compliance, defined as taking isoniazid for 3 months or less, was associated with a sixfold increase in risk for subsequent isoniazid-susceptible tuberculosis but with no increased risk for subsequent isoniazid-resistant disease. Thus, active tuberculosis continued to occur with a low but relatively constant incidence after prescription of isoniazid chemoprophylaxis to Southeast Asian refugees. In this setting, poor compliance with chemoprophylaxis predisposed to isoniazid-susceptible, but not to isoniazid-resistant tuberculosis. There is a need to improve the approach to prevention of tuberculosis in Southeast Asian refugees.

Adolescent↗
PubMedDate not supplied

Clinical pharmacokinetics of isoniazid.

The pharmacokinetics of isoniazid in man are described. Pronounced interindividual variation in circulating isoniazid concentration and clearance which occur after dosing with the drug are associated with hereditary differences in the acetylator status. The variations in rate of isoniazid inactivation and elimination in different (rapid and slow) acetylator phenotypes are primarily due to differences in the rate of acetylation of isoniazid by a genetically controlled polymorphic N-acetyltransferase in liver and small intestine. An appreciable 'first-pass' effect is observed following oral isoniazid administration, particularly in the rapid acetylator phenotype. Liver disease can cause a significant prolongation in the clearance of isoniazid; in the acutely ill patient, the prolongation correlates most closely with serum bilirubin elevation, although the degree of prolongation is less important than the intrinsic genetic difference between acetylator phenotypes. The effect of renal impairment on isoniazid excretion is relatively unimportant, even in slow acetylators. Methods for monitoring blood and urine concentrations of isoniazid and for acetylator phenotype determination which are convenient for the patient and clinician are available. Implications of phenotype differences in acetylator status for the optimal management of tuberculosis with isoniazid are considered. Attempts to devise new isoniazid formulations for this purpose are being evaluated.

Acetylation↗
PubMed1997

Monitored isoniazid prophylaxis for low-risk tuberculin reactors older than 35 years of age: a risk-benefit and cost-effectiveness analysis.

BACKGROUND: Isoniazid chemoprophylaxis effectively prevents the development of active infectious tuberculosis. Current guidelines recommend withholding this prophylaxis for low-risk tuberculin reactors older than 35 years of age because of the risk for fatal isoniazid-induced hepatitis. However, recent studies have shown that monitoring for hepatotoxicity can significantly reduce the risk for isoniazid-related death. OBJECTIVE: To evaluate the effectiveness and cost-effectiveness of monitored isoniazid prophylaxis for low-risk tuberculin reactors older than 35 years of age. DESIGN: A Markov model was used to compare the health and economic outcomes of prescribing or withholding a course of prophylaxis for low-risk reactors 35, 50, or 70 years of age. Subsequent analyses evaluated costs and benefits when the effect of transmission of Mycobacterium tuberculosis to contacts was included. MEASUREMENTS: Probability of survival at 1 year, number needed to treat, life expectancy, and cost per year of life gained for individual persons and total population. RESULTS: Isoniazid prophylaxis increased the probability of survival at 1 year and for all subsequent years. For 35-year old, 50-year-old, and 70-year-old tuberculin reactors, life expectancy increased by 4.9 days, 4.7 days, and 3.1 days, respectively, and costs per person decreased by $101, $69, and $11, respectively. When the effect of secondary transmission to contacts was included, the gains in life expectancy per person receiving prophylaxis were 10.0 days for 35-year-old reactors, 9.0 days for 50-year-old reactors, and 6.0 days for 70-year-old reactors. Costs per person for these cohorts decreased by $259, $203, and $100, respectively. The magnitude of the benefit of isoniazid prophylaxis is moderately sensitive to the effect of isoniazid on quality of life. The hypothetical provision of isoniazid prophylaxis for all low-risk reactors older than 35 years of age in the U.S. population could prevent 35,176 deaths and save $2.11 billion. CONCLUSIONS: Monitored isoniazid prophylaxis reduces mortality rates and health care costs for low-risk tuberculin reactors older than 35 years of age, although reductions for individual patients are small. For the U.S. population, however, the potential health benefits and economic savings resulting from wider use of monitored isoniazid prophylaxis are substantial. We should consider expanding current recommendations to include prophylaxis for tuberculin reactors of all ages with no contraindications.

Adult↗
PubMed2002

[Determination of isoniazid in blood and urine samples by reversed-phase high performance liquid chromatography].

For the purpose of more accurate and rapid analysis of isoniazid in body fluid samples, a reversed-phase high performance liquid chromatographic (HPLC) method was developed. Vanillin, being as a derivatizing reagent, was added to the plasma and urine samples when they were pretreated. Isoniazid and vanillin reacted to form isonicotinoyl hydrazone which was separated and detected. The pretreatment method of sample, the linear range, the precision, and the recovery of isoniazid were investigated by using human's plasma and urine spiked with standard isoniazid. The linear range was 0.2 mg/L- 12.0 mg/L (for plasma, r =0.999 6; for urine, r = 0.999 4). The detection limit was 0.2 mg/L. The intra-day and inter-day precisions of assay for isoniazid were 2.3% - 2.6% and 3.8% - 4.0% (n = 5) for plasma, 1.3% - 4.0% and 2.1% - 3.9% (n = 5) for urine respectively. The average recoveries of isoniazid were from 96.5% to 99.8% in plasma and from 96.3% to 99.4% in urine. The HPLC method has been used to investigate the concentration of isoniazid in the volunteer's plasma. The quantitative analysis of isoniazid in plasma was not interfered by impurities, the metabolites of isoniazid and the derivatizing reagent residue. This analytical method for isoniazid is sensitive, rapid and convenient. It is suitable for the analysis of toxics in forensic samples, the detection of drug concentration in clinical medicines and pharmacokinetic studies.

Antitubercular Agents↗
PubMed2001

Characterization of isoniazid-resistant strains of Mycobacterium tuberculosis on the basis of phenotypic properties and mutations in katG.

Forty isoniazid-resistant Mycobacterium tuberculosis isolates were characterized on the basis of phenotypic properties (i.e., catalase activity, MIC of isoniazid, and growth pattern in the presence of 7 different concentrations of isoniazid) and alterations in the katG gene (codons 315 and 463). Three different growth patterns could be distinguished: concentration-dependent inhibition of growth was observed in 29 strains, similar growth at all concentrations was seen in 7 strains, and enhanced growth at low concentrations of isoniazid was evident in 4 strains. The MIC of isoniazid was < or = microg/ml for 29 of 40 strains. Mutation at codon 315 of the katG was detected in 28 of 40 strains. However, only one of the seven strains for which the MIC of isoniazid was > or = 16 microg/ml had mutation at this codon. Five of these seven strains for which the MIC was > or = 16 microg/ml had no catalase activity. The results indicate that the MIC of isoniazid for a majority of strains is below the level achievable in serum. Therefore, isoniazid may be beneficial for the treatment of some cases of multidrug-resistant tuberculosis. Determination of catalase activity aids in the detection of isolates for which MICs are high and could, in conjunction with molecular methods, provide rapid detection of most isoniazid-resistant strains.

Antitubercular Agents↗
PubMed1993

Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection.

Tuberculosis occurring with human immunodeficiency virus (HIV) infection is a serious and growing public health problem. We have carried out a randomised clinical trial of a 12-month course of isoniazid plus vitamin B6 versus vitamin B6 alone in Port-au-Prince, Haiti, to assess the efficacy of isoniazid in preventing active tuberculosis in symptom-free HIV-infected individuals. The effect of prophylaxis on the development of HIV disease, AIDS, and death was also investigated. 118 subjects were assigned treatment with isoniazid plus B6 (n = 58) or B6 alone (n = 60) between 1986 and 1989. The treatment groups were similar at study entry in demographic, clinical, and immunological characteristics. Interim analysis in 1990 revealed no significant difference in tuberculosis outcome measures. Follow-up was continued until 1992, at which time significant protection by isoniazid against the development of tuberculosis was apparent, both for the whole study population and for subjects positive for purified protein derivative of tuberculin (PPD). The incidence of tuberculosis was lower in isoniazid recipients than in patients who received B6 alone (2.2 vs 7.5 per 100 person-years). The relative risk of tuberculosis was 3.4 (95% CI 1.1-10.6) for B6 alone versus isoniazid plus B6 (p < 0.05). Isoniazid also delayed progression to HIV disease and AIDS and death. Thus isoniazid effectively decreases the incidence of tuberculosis and delays the onset of HIV-related disease in symptom-free HIV-seropositive individuals. Isoniazid prophylaxis should be considered for HIV-seropositive, PPD-positive subjects, and may also be appropriate for PPD-negative patients in areas where tuberculosis is highly endemic.

AIDS-Related Opportunistic Infections↗
PubMed2006

Flow-injection chemiluminescence sensor for determination of isoniazid in urine sample based on molecularly imprinted polymer.

In this paper, molecularly imprinted polymer (MIP) of isoniazid is synthesized through thermal radical copolymerization of metharylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) in the presence of isoniazid template molecules. A novel flow injection chemiluminescence sensor for isoniazid determination is developed by packing the isoniazid-MIP into the flow cell as recognition elements. Isoniazid could be selectively adsorbed by the MIPs and the adsorbed isoniazid was sensed by its great enhancing effect on the weak CL reaction between luminol and periodate which were mixed in the flow cell. The enhanced CL intensity is linear in the range 2x10(-9) to 2x10(-7) g/mL and the detection limit is 7x10(-10) g/mL (3sigma) isoniazid with a relative standard deviation 2.8% (n=9) for 8x10(-8) g/mL. The sensor is reversible and reusable. It has a great improvement in sensitivity and selectivity for CL analysis. As a result, the sensor has been successfully applied to determination of isoniazid in human urine. At the same time, the binding characteristic of the polymer to isoniazid was evaluated by batch method and the dynamic method, respectively.

Flow Injection Analysis↗
PubMed1976

Bactericidal activity in vitro and in the guinea-pig of isoniazid, rifampicin and ethambutol.

Serial viable counts on Mycobacterium tuberculosis exposed in vitro to isoniazid, rifampicin and ethambutol in Tween-albumin liquid medium showed no bactericidal synergism between isoniazid and rifampicin and no influence of ethambutol on the bactericidal activity of isoniazid or isoniazid plus rifampicin. Guinea-pigs with moderately advanced experimental tuberculosis were treated fro 11 weeks with either (1) ethambutol, (2) isoniazid, (3) isoniazid plus ethambutol, (4) isoniazid plus rifampicin, (5) isonaiazid plus rifampic in plus ethambutol, or (6) no chemotherapy. The amount of tuberculous disease was scored and the spleen cultured in groups killed at intervals from 0--7 1/2 months after the end of chemotherapy. The regimens containing rifampicin were no more bactericidal during treatment than the corresponding regimens without rifampicin, but the onset of relapse after chemotherapy was delayed for at least 2 months following the rifampicin-containing regimens. Ethambutol alone did not protect guinea-pigs, nor did it influence the response to isoniazid or to isoniazid plus rifampicin. It was concluded that rifampicin may act selectively on a small proportion of the bacterial population and that it may be unnecessary to prescribe it for long periods in short course chemotherapy in man. Ethambutol does not appear likely to contribute to the sterilizing activity of short course regimens though it may prevent the emergence of drug resistance.

Animals↗
PubMedDate not supplied

Managing antituberculosis drug therapy by therapeutic drug monitoring of rifampicin and isoniazid.

BACKGROUND: Current therapeutic regimens with rifampicin and isoniazid have proven successful in treating tuberculosis, however, toxicity, therapeutic failure, relapse and multiple drug resistance are serious concerns. Optimizing drug dose using therapeutic drug monitoring (TDM) may be a better approach than administering therapy as a standard dose. AIMS: To establish and evaluate a TDM service to optimize rifampicin and isoniazid therapy. METHODS: A TDM service for rifampicin and isoniazid was established in November 1998. Drug concentration data were collected, with relevant information to interpret the results. The reason for the request, information on concomitant drug administration and a questionnaire to assess clinical response to the drug results were also obtained. RESULTS: Ninety patient episodes were accepted for study. The rifampicin plasma concentrations showed significant scatter, with 46% of the rifampicin concentrations below the normal range and 2% above the normal range. Similarly, 48% of isoniazid concentrations were below the lower target of the normal range and 29% were above the upper normal limit. There was a greater proportion of isoniazid concentrations above the normal range in female patients. CONCLUSION: Significant pharmacokinetic variability was observed for rifampicin and isoniazid in the patient population studied. Further, a substantial number of plasma concentrations fell outside the suggested normal range for both drugs. Isoniazid plasma concentrations were significantly higher in female patients compared with male patients. Despite these abnormal results, the dose of rifampicin and isoniazid was altered in only 17% of patients, however, many patients received follow-up education because of the drug result. The service was considered valuable by 83% of respondents to the questionnaire. While TDM of rifampicin and isoniazid is a valuable tool to optimize the dose of these drugs in some patients, there is an urgent need for concentration-effect studies and possibly education on the principles and practice of TDM for these drugs.

Adolescent↗
PubMed1997

Effects of isoniazid on the proliferation and cytokine production of bladder cancer cells in vitro induced by bacille Calmette-Guérin.

OBJECTIVE: To determine the effects of isoniazid (isonicotinic acid hydrazide), used to reduce the serious side-effects of immunotherapy of superficial bladder cancer with bacille Calmette-Guérin (BCG), on the proliferation and constitutive BCG-induced synthesis of interleukins 6 (IL6) and 8 (IL8) in human bladder cancer cells cultured in vitro. MATERIALS AND METHODS: Three poorly differentiated human cell lines, T24, TCC-SUP and BT-B, were used to study the effect of isoniazid on cell proliferation. Cells were inoculated in tissue culture plates and various concentrations of isoniazid added to the medium. Cell density was then monitored for up to 6 days using a colorimetric assay. To determine the effects of isoniazid on constitutive and BCG-induced cytokine synthesis, cells were cultured in medium containing no additions, BCG, isoniazid or BCG with isoniazid, at various concentrations. Samples of medium were collected regularly for 6 h and the cytokine content (IL6 and IL8) determined using enzyme-linked immunosorbent assays. RESULTS: Continuous incubation of proliferating T24, TCC-SUP and BT-B cells with isoniazid at concentrations of 0-100 micrograms/mL did not affect the rate of proliferation. Unlike TCC-SUP and BT-B cells, T24 cells released more IL6 and IL8 during incubation with BCG. At 6 h after the addition of BCG, the cumulative mean (SD) IL6 and IL8 production of T24 cells was 2.6 (0.1) and 2.3 (0.4) ng per 3 x 10(5) cells, compared with a constitutive level of 0.1 (0.0) and 1.3 (0.2) ng, respectively. There was no significant effect of isoniazid (1-100 micrograms/mL) on either the constitutive or BCG-induced synthesis of IL6 and IL8 in T24 cells. CONCLUSION: Assuming an essential role of (tumour) epithelial cells in the local immune response induced by BCG, these in vitro results suggest that the administration of isoniazid does not interfere with this part of the mechanisms by which BCG operates.

Antitubercular Agents↗