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PubMed1998

[The adverse reactions of anti-tuberculosis drugs and its management].

This paper reviews adverse reactions to anti-tuberculous drugs. Hepatotoxicity occur with isoniazid, rifampicin, pyrazinamide and ethionamide. Risk factors include high age, malnutrition and high alcohol consumption. Liver function should be followed every two weeks to prevent serious hepatotoxicity. If this occurs drugs should be stopped until improvement of liver functions. Fulminant hepatitis has poorer prognosis in regimen with pyrazinamide than without. The Combination of pyrazinamide and ethionamide is frequently hepatotoxic and should be avoided. Gastric reactions occur frequently. Elderly persons are highly intolerant to rifampicin. Peripheral neuritis is reported with isoniazid, ethambutol and ethionamide, but effectively prevented with pyridoxine. Allergic reaction including fever or rash occur with many anti-tuberculosis drugs. If necessary desensitization to re-introduce the drugs. Ocular toxicity due to ethambutol occur infrequently with a dose of 15 mg/kg. Drug interactions are frequent in tuberculosis treatment. Rifampicin reduce serum the concentration of such drugs as Methadone, Corticosteroid, and Theophylline.

Aged↗
PubMed1998

[Chemotherapeutic agents under study].

The development of new drugs with strong antituberculous activity and fewer side effects which are not cross-resistant to conventional antituberculosis drugs is urgently desired now. The chemotherapeutic agents under study which are considered a candidate for a new antituberculosis drug are listed below. 1) Rifamycin derivatives: rifabutin, rifapentin, KRM-1648, FCE-22250, 22807, CGP-7040, 27557, 29035, 29861, P-DEA, SPA-S-565, R-76-1. 2) New quinolones: ofloxacin, ciprofloxacin, levofloxacin, sparfloxacin, gatifloxacin, CS-940, Du-6859a. 3) Phenazines: clofazimine, B746, B4101, B4154, B4157. 4) Pyrazinamide derivatives: N-hydroxy pyrazinamide, N-hydroxy pyrazinamide-4-oxide. 5) Nitroimidazole derivatives: metronidazole et al.

Anti-Infective Agents↗
PubMed1989

The activity of AA-193, a new uricosuric agent, in animals.

A new uricosuric agent, 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carbo xylic acid (AA-193), was compared with other uricosurics in the rat, mouse and cebus monkey. In rats, probenecid and tienilic acid increased the urate excretion, but benzbromarone did not have the uricosuric activity. Thus, the presecretory reabsorption of urate is probably dominant in rats. We found that in rats AA-193 was the most potent uricosuric tested. In mice, probenecid not only had so-called paradoxical actions but stimulated urinary urate wasting after administration of pyrazinamide. These data suggest that the renal transport system of urate in the mouse is similar to that in man. AA-193 as well as benzbromarone enhanced the urate excretion dose-dependently, but the effects were different in pyrazinamide suppression tests in mice. In cebus monkeys, the uricosuric and hypouricemic effects of AA-193 were more potent than those of probenecid and similar to those of tienilic acid, but less than those of benzbromarone. Benzbromarone had a considerable role in postsecretory reabsorption in the monkey. These results suggest that AA-193 is a new class of uricosuric agent that controls the renal reabsorption of filtered urate particularly.

Animals↗
PubMed1975

Influence of volume expansion, serum sodium, and fractional excretion of sodium on urate excretion.

The relative contributions of volume expansion and increased fractional excretion of sodium to the uricosuria of saline infusion were assessed in 19 subjects by volume expansion with rapid infusion of 21 of hypertonic saline (3%), isotonic saline (0.9%), or hypotonic saline (0.45%). Urate excretion increased 385 mug/min (P less than 0.01) with hypertonic, 145 mug/min (P less than 0.05) with isotonic saline, and 294 mug/min (P less than 0.001) with hyptonic saline. When 150 meq of sodium chloride was administered as appropriate volumes of hypertonic, isotonic of hypotonic saline, the magnitude or uricosuria was correlated with volume load (r = 0.66, P less than 0.002). fractional excretion of sodium correlated with infusion volumes for all studies taken together (r = 0.35, P greater than 0.1). The relationship between fractional excretion of sodium and fractional excretion of urate was entirely attributed to their correlation with infusion volume. Both post-pyrazinamide urate excretion and pyrazinamide suppressible urate excretion increased with volume expansion.

Adolescent↗
PubMed1987

Drug interactions with urate excretion in man.

The effects of pyrazinamide and ampicillin on the uricosuric response to probenecid and benzbromarone were studied in six normal subjects. The amount of uric acid was calculated for the 24 h volume of urine and the urate and creatinine clearances were determined for each of three urinary collection periods in order to calculate the percentage Curate/Ccreatinine. Ampicillin alone caused a significant uricosuria in the 0-2 h (p less than 0.025) and 8-24 h (p less than 0.025) periods. Benzbromarone caused a significant reduction in all the parameters. These observations suggest that high concentrations ampicillin compete with uric acid for reabsorption, but that its delayed uricosuric action can be ascribed to the binding of this dipeptide to a charge-mediated receptor site on the brush border membrane of proximal tubular cells. It would also appear that benzbromarone is secreted by the pyrazinamide-sensitive mechanism for urate secretion as it can cause a paradoxical retention of urate, but leaves the other probenecid-sensitive secretory transport process unoccupied as indicated by the fact that it does not change the kinetics of ampicillin.

Adult↗
PubMed1986

Renal handling of uric acid in gout: impaired tubular transport of urate not dependent on serum urate levels.

Metabolic studies were conducted in 56 patients with primary gout and in ten normal subjects to assess differences in the tubular transport mechanisms of urate. Renal handling of uric acid was examined by means of pyrazinamide and probenecid tests at increased and pharmacologically reduced serum urate concentrations in both groups. Patients with gout showed similar serum urate levels and glomerular filtration rates than controls at both serum urate levels. Pyrazinamide decreased urinary uric acid excretion to less than 1.0% of the urate filtered load in both groups at increased and diminished serum urate concentrations. The maximum uricosuric response promoted by probenecid at high serum urate levels was (mean +/- SD) 3,707 +/- 443 micrograms/min/1.73 m2 in controls and 2,215 +/- 738 micrograms/min/1.73 m2 in patients with gout (P less than 0.01). Forty-four patients had a daily uric acid excretion rate below 700 mg/1.73 m2, and all of them showed a diminished uricosuric response to probenecid. When serum urate was reduced in normal subjects and 30 patients to a mean of 2.1 and 2.3 mg/dL, respectively, probenecid elicited a significantly lower urate excretion rate in gout (532 +/- 202 micrograms/min/1.73 m2) than in controls (922 +/- 136 micrograms/min/1.73 m2; P less than 0.01). Among these 30 patients examined in their basal state and at decreased serum urate levels, uric acid excretion following probenecid was normal in six and diminished in 24 in both situations. The difference between maximum uricosuria and basal urate excretion was not increased in gouty patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Ethanol as a xanthine dehydrogenase inhibitor.

In the present study, we investigated whether ethanol inhibits the activity of xanthine dehydrogenase. Ethanol and/or inosine were administered to normal subjects, and plasma concentration and urinary excretion of purine bases were measured together with blood concentrations of lactic acid and pyruvic acid. In addition, ethanol and pyrazinamide were administered to these subjects, and plasma concentration and urinary excretion of pyrazinamide and its major metabolites were measured. Increases in plasma concentration and urinary excretion of xanthine induced by a combination of ethanol and inosine were greater than the sums of increases induced separately by ethanol and inosine, although increases in plasma concentration and urinary excretion of uric acid induced by the combination of ethanol and inosine were not different from the sums of increases induced separately by ethanol and inosine. Ethanol increased the ratio of blood lactic acid to blood pyruvic acid and decreased plasma concentration and urinary excretion of 5-hydroxypyrazinamide and 5-hydroxypyrazinoic acid. These results suggest that ethanol inhibits xanthine dehydrogenase presumably by an ethanol-induced increase in the cytosolic concentration of NADH in the liver.

Acetates↗
PubMed1981

Clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis: the results up to 30 months.

In a study in Singapore, Chinese, Malay and Indian patients with pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampicin, and pyrazinamide followed by daily isoniazid, and rifampicin either with pyrazinamide (SHRZ/HRZ) or without it (SHRZ/HR), allocated at random. Both regimens were given for either 6 or 4 months by random allocation. All 330 patients with drug-sensitive tubercle bacilli pretreatment had a favourable bacteriological response during chemotherapy. After chemotherapy none of 78 SHRZ/HRZ patients and only 2 of 80 SHRZ/HR patients treated for 6 months relapsed bacteriologically, but 9 (11%) of 79 SHRZ/HRZ and 6 (8%) of 77 SHRZ/HR patients treated for 4 months relapsed. Of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs pretreatment, only 1 had an unfavourable response during chemotherapy; none of 9 patients treated for 6 months and 2 of 22 treated for 4 months relapsed bacteriologically after stopping chemotherapy.

Adolescent↗
PubMed1988

Comparison of a daily and three intermittent retreatment regimens for pulmonary tuberculosis administered under programme conditions.

One daily and 3 thrice weekly retreatment regimens given for 12 months under programme conditions were compared. The daily regimen was rifampicin and ethambutol (RE7). The three intermittent regimens also contained rifampicin and ethambutol: one of them, rifampicin and ethambutol throughout (RE3); the next one supplemented with pyrazinamide for the first 3 months (REZ3); the last one supplemented with prothionamide for the first 3 months (REPt3). The pyrazinamide containing regimen was subdivided into ordinary and high dose groups. The subjects for retreatment were those who have had, at least, more than 6 months of initial triple chemotherapy of isoniazid, PAS and streptomycin at the health centres, and failed to convert to bacteriologically negative status. Among 419 patients who were available for sensitivity tests before commencing retreatment, 393 (94.3%) were resistant to isoniazid. Six hundred and seventy-four patients (674) were allocated randomly to the regimens: 64 patients were excluded due to various pretreatment reasons and 109 did not complete 12 months of chemotherapy. There remain 501 patients who completed their retreatment. As assessed at 12 months, a bacteriologically favourable response was achieved in 68% of 135 RE7 patients, 62% of 129 RE3 patients, 74% of 132 REZ3 patients, and in 79% of 108 REPt3 patients. Adverse reactions were uncommon: 4% in RE7, 5% in RE3 and 9% in REZ3, but 32% in REPt3. Relapse rates during 2 years after termination of chemotherapy were 15% in RE7, 14% in RE3 and REZ3, and 26% in REPt3, as calculated by life table analysis.

Adolescent↗
PubMed1990

Five year results of a 3-month and two 5-month regimens for the treatment of sputum-positive pulmonary tuberculosis in south India.

A controlled study of three short-course regimens was undertaken in South Indian patients with newly diagnosed, sputum-positive pulmonary tuberculosis. The patients were allocated at random to one of three regimens: a) Rifampicin, streptomycin, isoniazid and pyrazinamide daily for 3 months (R3); b) the same regimen as above but followed by streptomycin, isoniazid and pyrazinamide twice-weekly for a further period of 2 months (R5); c) the same as R5 but without rifampicin (Z5). A bacteriological relapse requiring treatment occurred by 5 years in 16.8% of 113 R3, 5.2% of 97 R5, and 20.0% of 115 Z5 patients with organisms sensitive to streptomycin and isoniazid initially. The differences in the relapse rates between the R3 and R5 regimens and the R5 and Z5 regimens were statistically significant (p less than 0.01 for both). Considering patients with organisms initially resistant to streptomycin or isoniazid or both, 7 of 52 patients (4 R3, 2 R5, 1 Z5) had a bacteriological relapse requiring retreatment.

Adolescent↗
PubMed1991

Short-course chemotherapy for pulmonary tuberculosis under routine programme conditions: a comparison of regimens of 28 and 36 weeks duration in Algeria. Algerian Working Group/British Medical Research Council Cooperative Study.

Two chemotherapy regimens of 28 weeks (6M) and 36 weeks (8M) duration were compared in patients with previously untreated pulmonary tuberculosis in 30 health districts of Algeria. In the 6M regimen, patients received isoniazid plus rifampicin daily throughout with streptomycin and pyrazinamide in addition for the first 8 weeks. In the 8M regimen patients received isoniazid daily throughout plus rifampicin for the first 16 weeks and streptomycin and pyrazinamide as well for the first 8 weeks. The districts were allocated to apply either the 6M or the 8M regimen to all eligible patients. However, 22% of eligible patients were not admitted, the most common reason being oversight on the part of the personnel in the local health centres. A total of 2218 (977 6M, 1241 8M) patients was admitted and the results were assessed 2 years after the due date of completion of chemotherapy, irrespective of whether or not management had deviated from the study protocol. An appreciable proportion of patients (25% of 6M, 29% of 8M) could not be assessed because they failed to attend for follow-up or the collection of specimens was overlooked or because of difficulties in the transport of specimens to the reference laboratory in Algiers, and a further 5% and 4% of patients died. Of those who were assessable 7 (1%) of 731 6M and 15 (2%) of 875 8M were classified as having an unfavourable response during or after chemotherapy because they had one or more positive cultures. In addition 16 (2%) 6M and 18 (2%) 8M patients had received additional chemotherapy for failure, relapse or the development of non-pulmonary lesions but had achieved a favourable status. Of 1018 (488 6M, 530 8M) patients assessed who had fully sensitive strains pretreatment and completed treatment as planned, 97% in both series had a favourable status 2 years after their chemotherapy was due to be completed. In patients with initial strains resistant to isoniazid the results were less good in the 8M than the 6M series: none of the 19 6M compared with 5 of 26 in the 8M series having an unfavourable outcome suggesting that the duration of rifampicin may have been important in patients with initial isoniazid resistance. A slightly higher proportion of patients on the 8M regimen defaulted during chemotherapy (9.3% compared with 6.7% in the 6M regimen) but there was no difference between the regimens in other measures of compliance.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1993

Therapeutic monitoring of antituberculosis drugs by direct in-line extraction on a high-performance liquid chromatography system.

A direct in-line pre-column extraction technique in which guanidinium and ammonium sulfate are used, followed by column switching, was employed to analyze serum, plasma and cerebrospinal fluid samples of patients treated for tuberculous meningitis. Resolution of a wide range of polar to non-polar xenobiotics was obtained on a C8 silica column by using a linear gradient from a binary system consisting of solvent A (0.05 M KH2PO4) and solvent B (acetonitrile-isopropanol, 4:1, v/v). Apart from the antituberculosis drugs (isoniazid, pyrazinamide, ethionamide and rifampicin) the patients received up to sixteen different medicines for prevention of complications and the treatment of symptoms. Qualitative resolution of all the drugs was obtained by the chromatographic system. Quantitation of pyrazinamide and ethionamide was achieved with high precision and low inter-sample variation.

Antitubercular Agents↗
PubMed1993

Bacteriological investigations for short-course chemotherapy under the tuberculosis programme in two districts of India.

To examine the bacteriological profile and the prevalence of drug resistance among patients attending the health facilities where the District Tuberculosis Programme (DTP) was in operation with short-course chemotherapy (SCC) regimens, sputum specimens were collected on admission and the end of treatment in North Arcot district and Pondicherry region. In North Arcot district, rifampicin, isoniazid and pyrazinamide were given twice weekly for the first 2 months followed by rifampicin and isoniazid twice a week for the next 4 months under fully supervised administration. In Pondicherry, rifampicin, isoniazid and pyrazinamide were given daily for the first 2 months followed by rifampicin and isoniazid twice weekly for the next 4 months. Of the patients who had received 80% or more of the drugs, 80% from North Arcot and 92% from Pondicherry were rendered culture-negative for Mycobacterium tuberculosis at the end of treatment. Even among patients with initially resistant bacilli, a high proportion had a favourable response. Before start of treatment, of the 2779 patients from North Arcot, 25% had resistance to one or more drugs including 2% with resistance to rifampicin. In Pondicherry, 13% of the patients had initial resistance to one or more drugs. Initial resistance to rifampicin was observed in 0.9%. None of the initially drug-sensitive patients had acquired resistance to rifampicin at the end of treatment.

Adolescent↗
PubMed2004

Rapid, automated, nonradiometric susceptibility testing of Mycobacterium tuberculosis complex to four first-line antituberculous drugs used in standard short-course chemotherapy.

The increasing prevalence of drug-resistant tuberculosis necessitates rapid and accurate susceptibility testing. The nonradiometric BACTEC Mycobacteria Growth Indicator Tube 960 (MGIT) system for susceptibility testing was evaluated on 222 clinical Mycobacterium tuberculosis complex isolates for isoniazid, rifampin, and ethambutol. Fifty-seven of the isolates were tested for pyrazinamide. Results were compared to those of radiometric BACTEC 460 system and discrepancies were resolved by the agar proportion method. We found an overall agreement of 99.0% for isoniazid, 99.5% for rifampin, 98.2% for ethambutol, and 100% for pyrazinamide. After resolution of discrepancies, MGIT yielded no false susceptibility for rifampin and isoniazid. Although turnaround times were comparable, MGIT provides an advantage as inoculation can be done on any weekday as the growth is monitored automatically. The automated MGIT system is a rapid and reliable alternative for susceptibility testing of M. tuberculosis complex to first-line drugs.

Antitubercular Agents↗
PubMed2005

Oral solid lipid nanoparticle-based antitubercular chemotherapy.

The present study was planned to evaluate the chemotherapeutic potential of oral solid lipid nanoparticles (SLNs) incorporating rifampicin, isoniazid and pyrazinamide against experimental tuberculosis. The SLNs were prepared by the "emulsion solvent diffusion" technique with an encapsulation efficiency of 51+/-5% for rifampicin, 45+/-4% for isoniazid and 41+/-4% for pyrazinamide. Following a single oral administration to mice, therapeutic drug concentrations were maintained in the plasma for 8 days and in the organs (lungs, liver and spleen) for 10 days whereas free drugs were cleared by 1-2 days. In M. tuberculosis H37Rv infected mice, no tubercle bacilli could be detected in the lungs/spleen after 5 oral doses of drug loaded SLNs administered at every 10th day whereas 46 daily doses of oral free drugs were required to obtain an equivalent therapeutic benefit. Thus, SLN based antitubercular drug therapy forms a sound basis for reducing dosing frequency and improving patient compliance for better management of tuberculosis.

Administration, Oral↗
PubMed2003

Evaluation of the recently reported USP gradient HPLC method for analysis of anti-tuberculosis drugs for its ability to resolve degradation products of rifampicin.

The recently notified USP gradient HPLC method for quantitative determination of rifampicin, isoniazid and pyrazinamide in fixed dose combination (FDC) formulations was evaluated to determine its ability to resolve major degradation products of rifampicin, viz. 3-formylrifamycin SV, rifampicin N-oxide, 25-desacetyl rifampicin, rifampicin quinone, and the newly reported isonicotinyl hydrazone, an interaction product of 3-formylrifamycin and isoniazid. The first observation was that the requirements of theoretical plates listed in the given method were met for rifampicin, but not for isoniazid and pyrazinamide, even on columns of different makes. The resolving power of the method was also dependent upon make of the column. On two of the three columns of the three tested, it was able to resolve most degradation products, except rifampicin N-oxide and 25-desacetylrifampicin, which were overlapping. The method was modified and an overall satisfactory resolution for all components was obtained by changing the buffer: organic modifier ratio of solution B in the gradient from 45:55 to 55:45 and decreasing the flow rate from 1.5 to 1.0 ml/min, keeping all other conditions constant.

Antibiotics, Antitubercular↗
PubMed1995

A controlled clinical trial of short-course chemotherapy for tuberculoma of the brain.

OBJECTIVE: The efficacy of a short-course regimen in the treatment of brain tuberculoma and computerised tomography (CT) scan appearance before, during and after antituberculosis treatment was studied in a controlled clinical trial. DESIGN: Patients aged over 5 years with tuberculoma of the brain diagnosed by CT scan were randomly allocated to one of the following 2 regimens: Regimen 1: rifampicin, isoniazid and pyrazinamide daily for an initial 3 months followed by rifampicin and isoniazid twice-weekly for 6 months. Regimen 2: rifampicin, isoniazid and pyrazinamide thrice-weekly for an initial 3 months followed by rifampicin and isoniazid twice-weekly for 6 months. The patients were followed intensively for 2 years from the start of treatment. RESULTS: Of the 108 patients analysed (regimen 1: 56, regimen 2: 52), at the end of treatment clinical status was normal in 91% in regimen 1 and 88% in regimen 2. Of the 91 patients with scan assessments, CT scan lesions disappeared at 24 months in 77% of 47 patients in regimen 1 and 80% of 44 in regimen 2, and in both groups 88% of the patients were clinically normal. None had relapses requiring treatment. CONCLUSIONS: Short-course regimens of 9 months' duration are effective in the treatment of tuberculoma of the brain; clinical recovery was faster than scan clearance.

Adolescent↗
PubMed1996

Liver injury during antituberculosis treatment: an 11-year study.

SETTING: Bispebjerg Hospital, Department of Pulmonary Medicine, tuberculosis referral center for the Municipality of Copenhagen. OBJECTIVE: To evaluate routine procedure for the management of liver injury during antituberculosis treatment. DESIGN: From 1983-1993, 765 patients for whom we could trace 752 files (98%) were treated at our ward with standard Danish treatment for tuberculosis. From 1983-1986 they received a three-drug (9-month) regimen and from 1986-1993 a four-drug (6-month) regimen consisting of isoniazid, rifampicin, ethambutol + pyrazinamide. Data from a retrospective chart review. RESULTS: An increase in aspartate aminotransferase (AST) of more than twice the upper limit of normal (ULN) was recorded in 127 patients (16%). 66 had elevated AST before treatment; most of these were men with a daily alcohol consumption in excess of 60 g. In the remaining 61 patients (8%) AST increased during antituberculosis treatment. 30 of these patients were excessive alcohol consumers, and seven had alcoholic liver cirrhosis. Despite an increase in AST of median 6 x ULN (range 2-25 x ULN), it was possible to continue treatment in 31 (15 excessive alcohol consumers) or reintroduce it fully in 14 (12 excessive alcohol consumers). Only 16 patients (2%), including 11 women with no daily alcohol consumption, needed a modified regimen. These patients were older (P < 0.05), seven were jaundiced, and one had alcoholic liver cirrhosis. Hepatotoxicity was confirmed by challenge with pyrazinamide (n = 7), isoniazid (n = 6) and combined isoniazid/rifampicin (n = 1). No deaths were caused by hepatotoxicity. CONCLUSION: In spite of an increase in AST levels to approximately 6 x ULN during antituberculosis treatment, the drugs can be continued or reintroduced in full in most cases. Risk factors of hepatotoxicity included old age, female sex and extensive tuberculosis, and not alcohol consumption. Overall, hepatotoxicity during antituberculosis treatment can be monitored and managed easily.

Adolescent↗