A K Hemanth Kumar

National Institute for Research in Tuberculosis, Chennai, Tamil Nādu, India

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Publications (21)49.44 Total impact

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    ABSTRACT: Background & objectives: Among patients with HIV-associated tuberculosis (TB), reduced plasma non-nucleoside reverse transcriptase inhibitors (NNRTI) concentrations during rifampicin (RMP) co-administration could lead to HIV treatment failure. This study was undertaken to examine the association between plasma nevirapine (NVP) and efavirenz (EFV) concentrations and virological outcomes in patients infected with HIV-1 and TB. Methods: This was a nested study undertaken in a clinical trial of patients with HIV-1 and TB, randomized to two different once-daily antiretroviral treatment (ART) regimens along with anti-TB treatment (ATT). Trough concentrations of plasma NVP and EFV were estimated at months 1 (during ATT and ART) and 6 months (ART only) by HPLC. Plasma HIV-1 RNA level >400 copies/ml or death within 6 months of ART were considered as unfavourable outcomes. Genotyping of CYP2B6 516G>T polymorphism was performed. Results: Twenty nine per cent of patients in NVP arm had an unfavourable outcome at 6 months compared to 9 per cent in EFV arm (P<0.08). The mean NVP and EFV levels estimated at 1 and 6 months did not significantly differ between favourable and unfavourable responders. Logistic regression analysis showed CYP2B6 516G>T polymorphism significantly associated with virologic outcome in patients receiving EFV-based regimen. Interpretation & conclusions: Trough plasma concentrations of NVP and EFV did not show any association with response to ART in patients on ATT and once-daily ART. CYP2B6 516G>T polymorphism was associated with virologic outcome among patients on EFV.
    The Indian Journal of Medical Research 12/2013; 138(6):955-61. · 2.06 Impact Factor
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    ABSTRACT: Rifabutin (RBT) is reported to be as effective as and to have less inducing effect on cytochrome P450 enzymes than rifampicin against tuberculosis (TB). The optimal dose of RBT during ritonavir (RTV) co-administration remains a matter of debate. To study the pharmacokinetics of 150 mg RBT thrice weekly during concomitant atazanavir/RTV administration in human immunodeficiency virus (HIV) infected TB patients. This observational study was conducted in 16 adult HIV-infected TB patients being treated for TB with an RBT-containing regimen and an antiretroviral therapy regimen with RTV; the dose of RBT was 150 mg thrice weekly. Serial blood draws were performed at pre-dosing and at 1, 2, 4, 6, 8, 12 and 24 h after the drug was administered. Plasma RBT was estimated using high-performance liquid chromatography. Peak RBT concentration was below the lower therapeutic limit (<0.3 μg/ml) in seven patients, while 10 patients had trough concentrations below the minimal inhibitory concentration against Mycobacterium tuberculosis (0.06 μg/ml), suggesting that the RBT dosage may be inadequate. Prospective studies in different settings are required to arrive at the proper therapeutic dose for RBT to be used during co-administration with RTV.
    The International Journal of Tuberculosis and Lung Disease 12/2013; 17(12):1564-8. · 2.76 Impact Factor
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    ABSTRACT: The currently recommended dosages of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol in children are extrapolated from adult pharmacokinetic studies, and have not been adequately evaluated in children. To describe the pharmacokinetics of RMP, INH and PZA given thrice weekly in children with tuberculosis (TB), and to relate pharmacokinetics to treatment outcomes. Eighty-four human immunodeficiency virus negative children with TB aged 1-12 years in Chennai and Madurai, India, were recruited. Phenotypic INH acetylator status was determined. Nutritional status was assessed using Z scores. During the intensive phase of anti-tuberculosis treatment, a complete pharmacokinetic study was performed after directly observed administration of drugs. At 2 and 6 months, drug levels were measured 2 h post-dose. Drug concentrations were measured using high performance liquid chromatography and pharmacokinetic variables were calculated. Multivariable regression analysis was performed to explore factors impacting drug levels and treatment outcomes. Children aged <3 years had significantly lower RMP, INH and PZA concentrations than older children, and 90% of all children had sub-therapeutic RMP Cmax (<8 μg/ml). Age, nutritional status and INH acetylator status influenced drug levels. Peak RMP and INH concentrations were important determinants of treatment outcome. Recommendations for anti-tuberculosis treatment in children should take these factors into consideration.
    The International Journal of Tuberculosis and Lung Disease 06/2013; 17(6):800-6. · 2.76 Impact Factor
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    ABSTRACT: Background & objectives : Moxifloxacin (MFX) is reported to have promising antimycobacterial activity, and has a potential to shorten tuberculosis (TB) treatment. We undertook this study to examine the influence of rifampicin (RMP) and isoniazid (INH) on the steady state pharmacokinetics of MFX individually in healthy individuals. Methods: A baseline pharmacokinetic study of MFX (400 mg once daily) was conducted in 36 healthy adults and repeated after one week of daily MFX with either RMP (450/600 mg) (n = 18) or INH (300 mg) (n = 18). Plasma MFX concentrations were determined by a validated HPLC method. Results: Plasma peak concentration and exposure of MFX was significantly lower and plasma clearance significantly higher when combined with RMP (P<0.001). The C max to MIC and AUC 0-12 to MIC ratios of MFX were significantly lower during concomitant RMP (P<0.001). INH had no significant effect on the pharmacokinetics of MFX. Interpretation & conclusions : Concomitant RMP administration caused a significant decrease in C max and AUC 0-12 of MFX, the mean decreases being 26 and 29 per cent, respectively. It is uncertain whether this decrease would affect the treatment efficacy of MFX. Prospective studies in TB patients are needed to correlate MFX pharmacokinetics with treatment outcomes.
    The Indian Journal of Medical Research 12/2012; 136(6):979-84. · 2.06 Impact Factor
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    ABSTRACT: A high performance liquid chromatographic method for determination of moxifloxacin in human saliva was developed. The method involved deproteinisation of the sample with perchloric acid and analysis of the supernatant using a reversed-phase C18 column (150 mm) and fluorescence detection at an excitation wavelength of 290 nm and an emission wavelength of 460 nm. The assay was specific for moxifloxacin and linear from 0.25 to 10.0 μg/ml. The relative standard deviation of intra- and inter-day assays was lower than 10%. The average recovery of moxifloxacin from saliva was 101%. Due to its simplicity, the assay can be used for pharmacokinetic studies of moxifloxacin.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 11/2011; 879(30):3663-7. · 2.78 Impact Factor
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    ABSTRACT: To determine factors affecting serum levels of Efavirenz and Nevirapine and analyze the effect of Rifampicin on Nevirapine drug levels. A cross-sectional study was conducted on 30 HIV infected children on Antiretroviral therapy (ART) with Nevirapine or Efavirenz. Patients on simultaneous Rifampicin and Nevirapine were given higher doses of Nevirapine with regular monitoring of liver function tests. Trough levels (before morning dose of Nevirapine) and levels after 2 hours of administration of Nevirapine and levels of Efavirenz were assessed using HPLC and were checked to see if they fall within the therapeutic range. Thirty patients (14 males) were enrolled in the study with 20 on Nevirapine and 10 (33.3%) on Efavirenz. Seven (23.3%) patients were simultaneously taking rifampicin. The mean Nevirapine dose given to the patients was 350.9±59.8 mg/m2/day (on simultaneous rifampicin) and 309.2±54.6 mg/m2/day (not on concurrent rifampicin). Thirteen (81.3%) of the 16 patients with trough Nevirapine had values in the normal range, 1 (6.3%) had low Nevirapine trough levels and 2 (12.5%) had high Nevirapine trough levels. Of the post 2 hours Nevirapine levels, 1 (5%) had low levels and 3 (15%) had high Nevirapine blood levels. Factors like age (P=0.4, P=0.4087), nourishment (P=0.2679, P=0.4132), ART combination (P=0.4199, P=0.4132), form of the drug (tablet/syrup) (P=0.1964, P=0.4696) or if it was being given as single or in a fixed dose combination (P=0.4179, P=0.4696) and even concurrent rifampicin administration (P=0.284, P=0.472) did not significantly affect the trough and post 2 hours Nevirapine values, respectively. All the five patients being given concurrent rifampicin had normal trough and post 2 hours levels of Nevirapine. The Efavirenz drug levels were 1.9±1.1 g/mL. Of the 10 patients on Efavirenz, 2 (20%) had high and 1 (10%) had low blood levels. Concurrent Rifampicin administration does not alter blood levels of Nevirapine; provided the dose of Nevirapine is increased by 20-30%. Formulation of drugs does not alter the blood levels provided drug administered is in the recommended dose.
    Indian pediatrics 03/2011; 48(12):943-7. · 1.04 Impact Factor
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    ABSTRACT: Tuberculosis (TB) is among the top 10 causes of death among children worldwide. Recent reports suggest that the currently recommended dosages of first-line anti-TB drugs are not adequate in children, particularly younger children. The objective of this review was to synthesize available pharmacokinetic data of anti-TB drugs in children from different settings that would help determine optimal doses of anti-TB drugs, in order to provide evidence-based recommendations. A PubMed database was searched from 1970 to present using the terms rifampicin, isoniazid, pyrazinamide, ethambutol, pharmacokinetics, HIV, TB, nutrition and children. References from identified articles were also reviewed and abstract from recent meetings were included. Available pharmacokinetic data from different settings suggest that age, nutritional status, HIV infection and gene polymorphisms in drug metabolising enzymes could significantly influence the pharmacokinetics of first-line anti-TB drugs. However, most of the pharmacokinetic studies conducted so far in children have failed to associate drug concentrations with treatment outcomes. Hence, more studies to examine the relationship between drug pharmacokinetics and response to anti-TB treatment are required. Studies to examine the impact of nutritional status and HIV infection on the pharmacokinetics of anti-TB drugs in children are needed.
    The Indian Journal of Pediatrics 12/2010; 78(4):435-42. · 0.72 Impact Factor
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    ABSTRACT: Simple and reliable methods to estimate drugs in pharmaceutical products are needed. In most cases, antiretroviral drug estimations are performed using a HPLC method, requiring expensive equipment and trained technicians. A relatively simple and accurate method to estimate antiretroviral drugs in pharmaceutical preparations is by spectrophotometric method, which is cheap and simple to use as compared to HPLC. We undertook this study to standardise methods for estimation of nevirapine (NVP), lamivudine (3TC) and stavudine (d4T) in single tablets/capsules by HPLC and spectrophotometry and to compare the content of these drugs determined by both these methods. Twenty tablets/capsules of NVP, 3TC and d4T each were analysed for their drug content by HPLC and spectrophotometric methods. Suitably diluted drug solutions were run on HPLC fitted with a C18 column using UV detection at ambient temperature. The absorbance of the diluted drug solutions were read in a spectrophotometer at 300, 285 and 270 nm for NVP, 3TC and d4T respectively. Pure powders of the drugs were used to prepare calibration standards of known drug concentrations, which was set up with each assay. The inter-day variation (%) of standards for NVP, 3TC and d4T ranged from 2.5 to 6.7, 2.1 to 7.7 and 6.2 to 7.7, respectively by HPLC. The corresponding values by spectrophotometric method were 2.7 to 4.7, 4.2 to 7.2 and 3.8 to 6.0. The per cent variation between the HPLC and spectrophotometric methods ranged from 0.45 to 4.49 per cent, 0 to 4.98 per cent and 0.35 to 8.73 per cent for NVP, 3TC and d4T,respectively. The contents of NVP, 3TC and d4T in the tablets estimated by HPLC and spectrophotometric methods were similar, and the variation in the amount of these drugs estimated by HPLC and spectrophotometric methods was below 10 per cent. This suggests that the spectrophotometric method is as accurate as the HPLC method for estimation of NVP, 3TC and d4T in tablet/capsule. Hence laboratories that do not have HPLC equipment can also undertake these drug estimations using spectrophotometer.
    The Indian Journal of Medical Research 10/2010; 132:390-4. · 2.06 Impact Factor
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    ABSTRACT: We measured plasma concentration of efavirenz (EFV) in 16 HIV-infected Indian children receiving antiretroviral treatment at Government ART centres. The mean 12 hour concentration was 2.39 ug/mL (range: 0.72- 7.82 ug/mL). The majority of children treated with generic EFV at currently recommended doses had blood levels within the therapeutic range.
    Indian pediatrics 10/2010; 47(10):890-1. · 1.04 Impact Factor
  • Indian pediatrics 01/2010; 47(10). · 1.04 Impact Factor
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    ABSTRACT: Aims: To study single dose pharmacokinetics of lamivudine (3TC) in healthy subjects. Methods: Twelve healthy subjects were administered 3TC (150 mg) followed by timed blood and urine collections up to 24 hours. Pharmacokinetic variables and percent dose of 3TC in urine were calculated. Results: Plasma exposure and percent dose of 3TC in urine were highly correlated (p < 0.001; r = 0.96). 3TC concentration at 24 hours was undetectable in all study subjects. Conclusions: Timed urine measurements could be used to study bioavailabilty of 3TC. Plasma 3TC measurements could be used to monitor adherence among HIV-infected patients on antiretroviral treatment.
    01/2010;
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    ABSTRACT: Antiretroviral drug concentrations are important determinants of clinical response to a drug accounting for both toxicity and efficacy. Several factors such as age, ethnicity, body weight and patients' immune status may influence antiretroviral drug concentrations. The aim of the study was to determine the influence of immunological status, sex and body mass index on the steady state pharmacokinetics of lamivudine (3TC) and stavudine (d4T) in HIV-infected adults, who were undergoing treatment with generic fixed dose combinations (FDC) of these drugs in India. Twenty seven HIV-1 infected patients receiving antiretroviral treatment (ART) for at least two weeks at the Government ART clinic at Tambaram, Chennai, took part in the study. Serial blood samples were collected predosing and at different time points after drug administration. Plasma 3TC and d4T levels were estimated by HPLC. The patients' immune status, sex or body mass index had no impact on the pharmacokinetics of 3TC. In the case of d4T, peak concentration was significantly lower in patients with CD4 cell counts < 200 cells/microl than those with > or = 200 cells/ microl (P < 0.05), but were within the therapeutic range. The mean CD4 cell counts increased from 101 cells/microl at initiation of ART to 366 cells/microl at 12 months of treatment. Blood levels of 3TC and d4T drugs that are part of generic FDCs commonly used by HIV-infected individuals in India were within the therapeutic range and not influenced by nutritional or immune status. There was a significant improvement in CD4 cell counts over 12 months of treatment. Indian generic FDCs manufactured and used widely in the developing world provide effective concentrations of antiretroviral drugs.
    The Indian Journal of Medical Research 10/2009; 130(4):451-7. · 2.06 Impact Factor
  • A K Hemanth Kumar, Geetha Ramachandran
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    ABSTRACT: A high performance liquid chromatographic method for determination of moxifloxacin in human plasma was developed. The method involved deproteinisation of the sample with perchloric acid and analysis of the supernatant using a reversed-phase C(18) column (150 mm) and fluorescence detection at an excitation wavelength of 290 nm and an emission wavelength of 460 nm. The assay was specific for moxifloxacin and linear from 0.125 to 10.0 microg/ml. The relative standard deviation of intra- and inter-day assays was lower than 10%. The average recovery of moxifloxacin from plasma was 101%. Due to its simplicity, the assay can be used for pharmacokinetic studies of moxifloxacin.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 05/2009; 877(11-12):1205-8. · 2.78 Impact Factor
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    ABSTRACT: The dose of efavirenz during concomitant rifampin (RMP) administration is a matter of debate. We studied the influence of RMP coadministration on the steady-state pharmacokinetics of efavirenz in human immunodeficiency virus type 1 (HIV-1)-infected patients in South India. Fifty-seven HIV-tuberculosis (TB)-coinfected and 15 HIV-1-infected patients receiving combination antiretroviral therapy (CART) with an efavirenz (600 mg once daily)-containing regimen were recruited. HIV-TB-coinfected patients were receiving treatment with RMP-containing regimens. A complete pharmacokinetic study was conducted with 19 HIV-TB patients on two occasions (with and without RMP). Trough concentrations of efavirenz were measured in the remaining 38 patients during RMP coadministration. The 15 HIV-infected patients underwent complete pharmacokinetic sampling on one occasion. Plasma efavirenz was estimated by high-performance liquid chromatography, and genotyping of CYP2B6 G516T polymorphism was performed by sequencing. Peak and trough concentrations and exposure to efavirenz were significantly higher in TT than in GT and GG genotype patients (P < 0.001). Although RMP coadministration decreased the peak and trough concentrations and exposure to efavirenz by 17.8, 20.4, and 18.6%, respectively, the differences were not statistically significant. The trough concentration of efavirenz was subtherapeutic (less than 1.0 microg/ml) in 6 (8%) of 72 patients. In this South Indian population of HIV-infected patients, CYP2B6 G516T polymorphism but not RMP coadministration significantly influenced the pharmacokinetics of efavirenz; patients with the TT genotype had very high blood levels of efavirenz. While a small proportion of patients had subtherapeutic efavirenz levels, the clinical implications are uncertain, as all had good immunological responses to CART.
    Antimicrobial Agents and Chemotherapy 01/2009; 53(3):863-8. · 4.57 Impact Factor
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    ABSTRACT: AIDS and its associated gastrointestinal complications may impair the absorption of anti-tuberculosis (TB) drugs. Impaired absorption of anti-TB drugs could lead to low drug exposure, which might contribute to acquired drug resistance and reduced effectiveness of anti-TB treatment. The aim of this study was to obtain information on the status of absorption of rifampicin (RMP) and isoniazid (INH) in asymptomatic HIV- positive individuals, who are less immunocompromised. The D-xylose absorption test was also carried out to assess the absorptive capacity of intestive. The absorption of RMP, INH and D-xylose was studied in 15 asymptomatic HIV-positive individuals with CD4 cell counts>350 cells/mm3 and 16 healthy volunteers, after oral administration of single doses of RMP (450 mg), INH (300 mg) and D-xylose (5 g). Urine was collected up to 8 h after drug administration. Percentage dose of the drugs and their metabolites and D-xylose excreted in urine were calculated. A significant reduction in the urinary excretion of INH and D-xylose in HIV-positive persons compared to healthy volunteers was observed. The per cent dose of RMP and its metabolite, desacetyl RMP was also lower in HIV-positive persons compared to healthy volunteers, but this difference was not statistically significant. Decreased urinary excretion of D-xylose and INH are suggestive of intestinal malabsorption in HIV-positive individuals. HIV infection could cause malabsorption of anti-TB drugs even at an early stage of the disease. The clinical implications of these findings need to be confirmed in larger studies.
    The Indian Journal of Medical Research 06/2007; 125(6):763-6. · 2.06 Impact Factor
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    ABSTRACT: A simple and rapid high performance liquid chromatographic method for determination of efavirenz in human plasma was developed. The method involved extraction of sample with ethyl acetate and analysis using a reversed-phase C(18) column (150 mm) with UV detection. The assay was linear from 0.0625 to 10.0 microg/ml. The method was specific for efavirenz estimation and the drug was stable in plasma up to one month at -20 degrees C. The average recovery of efavirenz from plasma was 101%. Due to its simplicity, the assay can be used for pharmacokinetic studies and therapeutic drug monitoring of efavirenz.
    Journal of Chromatography B 06/2006; 835(1-2):131-5. · 2.49 Impact Factor
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    ABSTRACT: Incomplete adherence is a major contributor to failure of antiretroviral therapy. Although the available methods to monitor adherence to therapy have proved to be predictive of outcomes, the results are variable. We assessed the feasibility of detecting nevirapine (NVP) in spot urine samples to monitor patient adherence to antiretroviral treatment and to study the urinary excretion of NVP in healthy volunteers after oral administration of a single dose of NVP (200 mg). Spot urine samples were collected from 50 HIV-infected patients (36 on treatment regimen containing NVP and 14 on drugs other than NVP) and tested for NVP by HPLC in a blinded manner. Sixteen healthy volunteers (9 males and 7 females) were administered a single oral dose of 200 mg NVP and spot urine samples were collected on day '0' before drug administration, and thereafter every 24 h up to 9 days and tested for NVP. All the urine samples collected from patients undergoing treatment with NVP-containing regimens at different time points after drug administration tested positive for NVP. Thirteen out of 14 samples from patients not on NVP yielded a negative result. The drug was detected in the urine of healthy volunteers up to 9 days. The urinary excretion of NVP was prolonged in females than in males. In view of its long half-life, NVP gets excreted in urine for a long period of time. Hence, testing spot urine samples for NVP may not be a useful measure to monitor patient adherence to treatment.
    The Indian Journal of Medical Research 05/2006; 123(4):565-8. · 2.06 Impact Factor
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    ABSTRACT: Patients with advanced HIV disease may exhibit malabsorption of anti-tuberculosis (TB) drugs. We evaluated the effect of isoniazid (INH) acetylator status on the bioavailability of INH in HIV-infected patients with and without tuberculosis, based on urinary excretion of the drug. Estimation of INH in urine collected up to 8 hours after oral administration of 300 mg INH were undertaken in 23 TB, 40 HIV and 26 HIV-TB patients. Determination of acetylator status of all these patients was also carried by differential estimations of INH and acetyl INH in urine collected between 5 and 6 hours after oral administration of 300 mg INH. Both slow and rapid acetylators in HIV and HIV-TB groups had significantly lower concentration of INH in urine compared to TB patients. The percent decrease in urinary excretion of INH was significantly higher in rapid than in slow acetylators, when compared to the corresponding TB patients. Acetylator status has an impact on the bioavailability of INH. Malabsorption in patients with advanced HIV disease may lead to decreased bioavailability of INH, particularly in rapid acetylators. Urinary estimation of INH provides reliable information on the bioavailability of the drug.
    SAARC J TB L DIS & HIV/AIDS. 01/2005; II(2):9-12.
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    ABSTRACT: We evaluated the effects of human immunodeficiency virus (HIV) disease on pharmacokinetics of antituberculosis medications by measuring concentrations of isoniazid and rifampin in blood and of pyrazinamide and ethambutol in urine. Peak concentration and exposure were reduced for rifampin, and rapid acetylators of isoniazid had lower drug levels. HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs.
    Antimicrobial Agents and Chemotherapy 12/2004; 48(11):4473-5. · 4.57 Impact Factor
  • A K Hemanth Kumar, Prema Gurumurthy
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    ABSTRACT: Disposition of uric acid upon administration of ofloxacin (O) alone and in combination with other anti-tuberculosis drugs, rifampicin (R), isoniazid (H) and pyrazinamide (Z) was studied. Twelve male healthy volunteers were investigated on four different occasions with the four drugs alone or in combinations. A partially balanced incomplete block design was adopted and the subjects were randomly allocated to each group. Uric acid concentration in urine samples excreted over 0-8 hr, were determined after coding the samples. There was significant decrease in the group receiving Z when compared to other groups. Though there was a decrease in uric acid excretion in the group receiving O, it was not statistically significant. Rifampicin and H seem to increase the uric acid excretion. The incidence of arthralgia was mainly due to Z and not due to either O or other drugs in the treatment of pulmonary tuberculosis.
    Indian journal of experimental biology 04/2004; 42(3):323-5. · 1.20 Impact Factor