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PubMed1987

Hepatic toxicity during chemotherapy for severe tuberculosis meningitis.

The possible development of hepatotoxic effects as a result of high dosages of isoniazid, rifampin, pyrazinamide, and ethionamide was assessed in 56 young children (median age, 22 months) treated for severe tuberculous meningitis (TBM). Only one of the 56 children became jaundiced, probably as result of hepatitis A infection. Of 33 children observed for at least eight weeks, only five (15%) had normal serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase levels throughout, but in only three patients were AST or ALT values greater than 200 U/L, and enzyme levels tended to normalize toward the end of the period. In this group of 33 children, those at stage III TBM had higher enzyme levels than did those at stage II. The remaining 23 children were observed for a mean period of only four weeks, and 18 (75%) had at least one abnormal liver function test result.

Alanine Transaminase↗
PubMed1999

Hepatic enzyme abnormalities in children on triple therapy for tuberculosis.

Standard chemotherapy for tuberculosis (TB) in children uses hepatotoxic drugs. Published data and guidelines on monitoring of liver function during TB treatment are often contradictory and not directly relevant to the pediatric population. We carefully monitored 43 children (age 6.6 years, 0.7-15.1 [median, range]; 49% male; 72% Caucasian) being treated for TB infection (n = 8) or disease (n = 35) with triple therapy, using pyrazinamide, rifampicin, and isoniazid in standard recommended doses. Children on other hepatotoxic drugs were excluded. Measurements of liver function tests (LFT) included aspartate transaminase (AST), alanine transaminase (ALT), and bilirubin, and they were checked before and a median of 5 times (1-23) during treatment. Only one child had mildly abnormal LFTs pretreatment. Thirteen children (n = 13, [30%]; age 7.6 years, 1.8-10.9; 54% male; 77% Caucasian) developed abnormal LFTs (> mean + 2 SD) and of these 10 had TB disease. Eight of the 13 had mildly elevated enzymes (< twice upper limit of normal) while in five, all with disease, the enzymes were more markedly raised. In the group with normal LFTs (n = 30, [70%]; age 6.6 years 0.7-15.1; 47% male; 70% Caucasian) 25 had disease (83%). Liver enzyme elevation occurred early (1.65 weeks, 0.6-16.6). Only two children had symptoms (one jaundice, one pruritus) with treatment being stopped temporarily only in the jaundiced child. Otherwise, LFTs normalized without interrupting treatment. We conclude that elevated liver enzymes are not uncommon in children receiving triple therapy for TB, generally occurring early in treatment. Symptoms are rare. Current British Thoracic Society and American Thoracic Society guidelines (that if LFTs are normal prior to treatment then further monitoring should only be performed if clinically indicated) seem adequate for children.

Adolescent↗
PubMedDate not supplied

Hypouricemia and hyperuricosuria as expressions of renal tubular damage in primary biliary cirrhosis.

Renal tubular damage, in particular, renal tubular acidosis is associated with primary biliary cirrhosis (PBC), but hypouricemia has not been described. We studied four patients with PBC whose serum uric acid levels were 1.4 to 1.8 mg per dl, and compared their renal and liver functions with those of 11 patients with PBC whose serum uric acid levels were normal. In the patients with PBC and hypouricemia, uric acid clearance (Cua) and the ratio of Cua and creatinine clearance (Cua/Ccr) were high enough to cause hypouricemia. Elevated Cua/Ccr was suppressed by administration of pyrazinamide, a blocker of tubular secretion of uric acid, but was not affected by probenecid; the effects of drugs on Cua/Ccr were similar to those reported in Wilson's disease. Elevation in Cua/Ccr was associated with increased serum bilirubin and urinary copper excretion. These observations indicate that hypouricemia and hyperuricosuria, which may be caused by defective postsecretory reabsorption of uric acid, are additional indicators of renal tubular damage in PBC.

Acidosis, Renal Tubular↗
PubMed2003

Follow-up of compliance with tuberculosis treatment in children: monitoring by urine tests.

This study was designed to follow up patient compliance by detection of antituberculous drugs in urine during the course of treatment. It was conducted in the Outpatient Clinic of Pediatric Infectious Diseases, Sisli Etfal Hospital (Istanbul, Turkey). In total, 45 children with pulmonary tuberculosis participated. Patients were seen twice in the first month and once a month thereafter during the 6-month course of treatment. The second urine of the day was collected at each visit. Urine was tested for isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA). In the presence of these drugs or their metabolites, the addition of certain chemicals caused a color change in the urine. On day 15 of treatment, urine tested positive for INH in 82% of patients, for RIF in 67%, and for PZA in 73%. At the end of the second month, the ratio of adherence was 96, 89, and 96% for each drug, respectively. All patients were found to be adherent at months 5 and 6. We recommend detection of antituberculous drugs in urine to assess compliance to treatment. Once the defaulting patients were identified, adherence was improved by repeatedly providing patient education throughout the treatment.

Antitubercular Agents↗
PubMed2005

Protective effect of a 50% hydroalcoholic fruit extract of Emblica officinalis against anti-tuberculosis drugs induced liver toxicity.

The present report showed the hepatoprotective property of a 50% hydroalcoholic extract of the fruits of Emblica officinalis (fruit) (EO-50) against antituberculosis (anti-TB) drugs-induced hepatic injury. The biochemical manifestations of hepatotoxicity induced by rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA), either given alone or in combination were evaluated. In vitro studies were done on suspension cultures of rat hepatocytes while sub-acute studies were carried out in rats. The hepatoprotective activity of EO-50 was found to be due to its membrane stabilizing, antioxidative and CYP 2E1 inhibitory effects.

Animals↗
PubMed2001

Modulating effect of Liv.100, an ayurvedic formulation on antituberculosis drug-induced alterations in rat liver microsomes.

The influence of Liv.100 on the hepatotoxicity of antituberculosis drugs [isoniazid (INH), rifampicin (RMP) pyrazinamide (PZA)] was studied in male albino rats. INH, RMP, and PZA were proved to be the most hepatotoxic. Rats were treated with antituberculosis drugs daily for a period of 6 weeks by intragastric administration. The combined use of antituberculosis drugs elevated the levels of cytochrome P-450 and cytochrome-b5. A significant increase was observed in the levels of NADPH-cytochrome P-450 reductase and NADH-cytochrome-b5 reductases after antitubercular drug administration. During antitubercular drug treatment a significant decrease was also observed in the activity of glucose-6-phosphatase. The extent of NADPH-induced and ascorbic acid-induced lipid peroxides were marked in antitubercular drug treatment, when compared with normal control animals. Oral Liv.100 co-administration, for the same period, modulated the alterations in the xenobiotic metabolizing system and microsomal lipid peroxidation in experimental animals. The results are discussed with reference to drug metabolizing enzymes, lipid peroxidation and the hepatoprotective nature of Liv.100.

Animals↗
PubMed1997

beta-Galactosidase reporter system in mycobacteria and its application in rapid antimycobacterial drug screening.

Pathogenic mycobacteria are generally slow growing organisms and it takes several weeks to evaluate inhibitors of growth. Therefore, for rapid screening of the inhibitors of mycobacterial growth, a beta-galactosidase reporter system has been described which utilises a recombinant Mycobacterium smegmatis mc(2)155 expressing E. coli lacZ gene as the test organism. The assay is based on production of beta-galactosidase in presence of drugs during growth. A correlation between beta-galactosidase production and colony forming ability of mycobacteria was obtained. beta-galactosidase production was inhibited within 6 h by front line standard antimycobacterial drugs like streptomycin, rifampicin, isoniazid, ethambutol, pyrazinamide and ofloxacin at their reported MICs. The assay was performed on mycobacterial cells permeabilized with chloroform and sodium dodecyl sulfate.

Anti-Bacterial Agents↗
PubMed1980

Urate metabolism in a mongrel dog.

(1) We have performed short-term turnover studies in a trained mongrel dog, and found remarkably linear turnover curves for both urate and its principle metabolic product, allantoin. (2) Infusions of Pyrazinamide, Probenecid, and Sodium Salicylate had no apparent effect on urate metabolism. (3) The "uricolytic index" for endogenous urate is consistenely lower than that of infused, isotopic urate. This finding suggests renal synthesis and direct excretion of unlabelled urate. (4) The renal clearance of labelled urate is higher than that of endogenous urate despite apparent renal synthesis. This finding suggests that urate may exist in more than one molecular form.

Allantoin↗
PubMed1984

A microelectrode for continuous monitoring of redox activity in isolated perfused tubule segments.

The design and application of a micro-plantinum electrode for continuous monitoring of reducing activity in the isolated tubule preparation is described. The electrodes response to H2O2 up to 0.1 mmol/l, to uric acid up to 0.3 mmol/l, ascorbic acid up to 1.0 mmol/l and cysteine up to 2.0 mmol/l is almost linear. The electrode is insensitive to extracellular ions, to changes of pH (5.5-8.0), CO2 (1-10%) and O2 (1-100%). The reading of the electrodes is almost doubled when the temperature is increased from 20-40 degrees C. When reducing substances are omitted from the perfusate for isolated perfused proximal tubules of the mouse, the reading is identical in perfusate and collected fluid, indicating that the tubular epithelium does not produce redox substances in sufficient amount to interfere with the electrode reading at flow rates approximately 10 nl/min. When the tubule is perfused with solutions containing 0.3 mmol/l uric acid, the uric acid concentration in the collected fluid is 0.16 +/- 0.01 mmol/l after a contact time of 1.36 +/- 0.1 S, revealing net uric acid reabsorption. Adding probenecid to the luminal perfusion fluid leads to a 37.5 +/- 1.0% increase of uric acid concentration in collected fluid, disclosing the inhibitory effect of probenecid on uric acid reabsorption. If 0.3 mmol/l uric acid is added to the bath, 0.017 +/- 0.002 mmol/l uric acid is detected in the luminal fluid. The entry of uric acid into the lumen is abolished by 10(-4) mol/l pyrazinamide.

Animals↗
PubMed1985

Hypouricemia and renal tubular acidosis in primary biliary cirrhosis.

A 51-year-old woman with primary biliary cirrhosis developed distal renal tubular acidosis and hypouricemia (1.4 mg per 100 ml) in the course of hepatic injury. Her renal clearance of uric acid reached 33.7 ml/min (mean +/- SD in five normal age-matched women: 9.2 +/- 3.1 ml/min). Pyrazinamide, an inhibitor of uric acid secretion, considerably reduced the uric acid clearance, while it was not enhanced by probenecid, a blocker of uric acid reabsorption. Thus, the hypouricemia may have been due to a defect of postsecretory reabsorption of uric acid in the renal tubules. The present case emphasizes the significance of hypouricemia and hyperuricosuria as indicators of renal tubular injury in primary biliary cirrhosis.

Acidosis, Renal Tubular↗
PubMed2003

[Septic loosening of a Wagner revision stem provoked by Mycobacterium tuberculosis].

Only a few cases of specific tuberculous infections of total hip arthroplasties have been published. We report the case of a 66-year-old male patient who received a cementless total hip arthroplasty due to osteoarthritis of the left hip in 1990. Four years later, revision arthroplasty with a Wagner revision stem was performed because of aseptic loosening. In 1995 revision of a loosened acetabular cup was necessary. In 1996 we saw the patient for the first time in our outpatient unit. He complained of increasing pain in the region of the left hip. X-rays showed loosening of the Wagner stem. Aspiration of the synovial fluid of the left hip revealed an infection with mycobacterium tuberculosis (radioimmunoassay). There were no signs of tuberculous infection in the patient's history. Treatment consisted of removal of the prosthesis followed by antituberculosis chemotherapy for 12 months with rifampicin, ethambutol, isoniazid, and pyrazinamide. In April 2001 revision of the left hip joint and implantation of a MRP titanium revision stem and reconstruction of the acetabulum with an acetabular reconstruction ring was done. Until today the patient exhibits no signs of recurrence of the tuberculous infection.

Acetabulum↗
PubMed2002

Determination of antitubercular drugs by micellar electrokinetic capillary chromatography (MEKC).

A method for the determination of isoniazid (ISO), pyrazinamide (PYR) and rifampicin (RIF) in pharmaceutical products, by micellar electrokinetic capillary chromatography (MEKC) with ultraviolet detection is described. The influence of pH, concentration of surfactants, buffer and organic solvents, over the separation were studied as experimental variables. The optimal separation was carried out at 30 degrees C and 20 kV, using a 40 mM borate buffer and 100 mM sodium dodecylsulphate (SDS) adjusted to pH 8.5. Under these conditions, the analysis is accomplished in about 8 min. The method was applied to the determination of these compounds in different pharmaceuticals with good results when compared with a reference liquid chromatographic (LC) method.

Antitubercular Agents↗
PubMed2002

Tuberculous pericarditis in an infant evolving during triple chemotherapy.

UNLABELLED: A 36-month-old girl was treated for pulmonary tuberculosis (Mycobacterium tuberculosis) with isoniazid, rifampin and pyrazinamide. Four weeks after starting chemotherapy, she developed high fever and clinical signs of acute pericardial tamponade. Pericardial effusion was shown by echocardiography and subsequently removed by pericardiocentesis. M. tuberculosis was demonstrated in the pericardial fluid by microscopy, polymerase chain reaction and specific culture. After pericardial drainage, the actual therapy was extended to include streptomycin and prednisone. Follow-up examinations demonstrated complete recovery without signs of constrictive pericarditis. CONCLUSION: infants treated for tuberculosis should be followed closely in order to monitor not only side-effects of antituberculous drugs but also to detect early extrapulmonary spread that may occur even with adequate chemotherapy. Rapid intervention and treatment adjustment in infants with tuberculous pericarditis may prevent pericardial constriction and may lead to full recovery.

Antitubercular Agents↗
PubMed2006

A boy undergoing maintenance hemodialysis who developed mediastinal lymph node tuberculosis.

The incidence of tuberculosis (TBC) in patients undergoing maintenance hemodialysis is reported to be higher than that in the general population. We report an 8-year-old boy receiving such treatment for chronic renal failure who developed mediastinal lymph node TBC. He showed only intermittent fever, recurring every 2 weeks, with no other symptoms suggesting TBC. Although staining and culture of pharyngeal swab and gastric juice specimens failed to provide evidence of TBC, a lymph node biopsy specimen disclosed typical pathologic findings of tuberculoma, including caseating granulomas. Antituberculous therapy with isoniazid (INH), rifampicin, pyrazinamide, and ethambutol was given for 12 months, resulting in complete resolution of the TBC, with no subsequent recurrence. To our knowledge, mediastinal lymph node localization of TBC is relatively rare, in a patient on maintenance hemodialysis, especially in a child.

Child↗
PubMed1988

Substrate specificity of nicotinamide methyltransferase isolated from porcine liver.

Nicotinamide methyltransferase (EC 2.1.1.1) has been purified over 1300-fold from porcine liver. The enzyme is electrophoretically homogeneous, exhibiting a relative molecular mass of 27,000. In addition to acting on nicotinamide and close structural analogs such as thionicotinamide and 3-acetylpyridine, the enzyme actively accommodates poor analogs such as quinoline, isoquinoline, and 1,2,3,4-tetrahydroisoquinoline as methyl group acceptors. The enzyme may thus have the function of detoxicating numerous alkaloids in vivo. In some cases, the action of the enzyme might paradoxically increase the toxicities of substrates, but the hepatotoxic antibiotic pyrazinamide, which we considered as potentially such an enzyme-activated electrophile, did not function detectably as a substrate for the isolated enzyme.

Animals↗
PubMed1988

A retrospective comparison of two drug regimens RHE2/RH10 and RHZ2/RH10 in the treatment of tuberculous mediastinal lymphadenopathy.

A retrospective radiographic comparison of two regimens, RHE2/RH10 (n = 32) and RHZ2/RH10 (n = 37), used in the treatment of tuberculous mediastinal lymphadenopathy is reported. The two groups did not differ in age, pretreatment or post-treatment values. The rate of improvement in serial radiographs was compared between the two groups, each patient acting as his own control. There was no difference in the incidence of initial gland enlargement at 1 month, but at 2 months RHZ2/RH10 had less enlargement (0.05 greater than P greater than 0.01). The rate of improvement was faster in the RHZ2/RH10 group from 2-7 months' treatment, being significantly better than RHE2/RH10 at 2 (P = 0.003), 5 (0.01 greater than P) and 7 months (0.02 greater than P). Pyrazinamide (25-40 mg/kg) appears to be superior to ethambutol 15 mg/kg for the initial 2 months of treatment of tuberculous mediastinal lymphadenopathy. The findings may be applicable to peripheral tuberculous lymphadenopathy.

Adolescent↗
PubMed1975

A controlled trial of daily and intermittent rifampicin plus ethambutol in the retreatment of patients with pulmonary tuberculosis: results up to 30 months.

In a controlled clinical trial in Hong Kong, 575 Chinese adults with smear-positive isoniazid-resistant pulmonary tuberculosis, who had previously been treated with first-line chemotherapy, were allocated at random to regimens of rifampicin plus ethambutol daily (ER7), twice-weekly (ER2), once-weekly (ER1), or daily for 2 months and then once-weekly (ER7ER1), or to a standard retreatment regimen of daily ethionamide plus pyrazinamide plus cycloserine (EtZC). The ER7 patients were allocated to 12 or 18 months of chemotherapy, and the remainder to 18 months. As assessed at 18 months, a favourable response was achieved in 87 per cent of 91 ER7 patients, 79 per cent of 84 ER2, 81 per cent of 53 ER1, 87 per cent of 62 ER7ER1, and in 88 per cent of 68 EtZC patients (93 per cent of 59 EtZC patients if those with ethionamide-resistant strains pretreatment are excluded). As assessed at 18 and 30 months the ER7 regime was as effective as the control EtZC regimen, and 18 months of chemotherapy on the ER7 regimen conferred no benefit over 12 months. No patient on either regimen relapsed after 18 months. Adverse reactions were uncommon on the daily rifampicin regimen but relatively common on the intermittent and control regimens. The commonest reaction to the intermittent regimens was the 'flu' syndrome, which was associated with the presence of circulating rifampicin-dependent antibodies (P less than 0-001).

Antibody Formation↗
PubMed1986

Three chemotherapy studies of tuberculous meningitis in children.

Chemotherapy studies were undertaken in 180 patients with tuberculous meningitis. They were treated for 12 months with 1 of 3 regimens: the first consisted of streptomycin, isoniazid and rifampicin daily for the first 2 months, followed by ethambutol plus isoniazid for 10 months; in the second, pyrazinamide was added for the first 2 months, and in the third, rifampicin was reduced to twice weekly in the first 2 months. Steroids were prescribed for all the patients in the initial weeks of treatment. Approximately 50% of the patients were aged less than 3 years. On admission, 13% of the patients were classified as stage I, 77% as stage II and 9% as stage III. Cerebrospinal fluid (CSF) culture results were available for all the 180 patients and M. tuberculosis was isolated in 59 (33%). CSF smear results for acid fast bacilli were available only for the 103 patients admitted to the second and the third studies, and of these in 60 (58%) the CSF was positive either by smear or culture. The response to therapy was similar in the 3 studies. Despite administration of rifampicin for 2 months, the mortality was high. In all, 27% of the patients died of tuberculous meningitis, 39% had neurological sequelae and 34% recovered completely. There was a strong association between the stage on admission and the mortality rate, the deaths being highest in stage III. In the first study, when isoniazid was prescribed daily in a dosage of 20 mg/kg, 39% of the patients developed jaundice; however, when the dosage was reduced to 12 mg/kg, the incidence fell to 16%. In the third study, where rifampicin was administered twice a week, the incidence of jaundice was much lower (5%).

Antitubercular Agents↗