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[Vesical uric acid lithiasis in a child with renal hypouricemia].

We report a 12-month-old boy with renal hypouricemia who presented with crying due to obstructing vesicourethral uric acid stones. Metabolic study revealed persistent acidic urine with normal blood pH, and hypouricemia (1.4-1.7 mg/dl) with an increased ratio of uric acid clearance to creatinine clearance (24-32 %). Pyrazinamide produced no response but the patient showed a positive response to benzbromarone. These findings were consistent with a presecretory defect. No other tubular dysfunctions, such as renal glycosuria, aminoaciduria or phosphaturia were found. The patient underwent surgical treatment and was subsequently treated with potassium citrate. After a 2-year follow-up, he remains asymptomatic, despite persistent hyperuricosuria. To our knowledge, this is the youngest reported case of renal hypouricemia and lithiasis.

Humans↗

[Orchiectomy for tuberculous epididymitis: a report of two cases with intractable to antituberculosis treatment].

This paper describes two cases with tuberculous epididymitis. The first case was a 69-year-old man who was admitted to our hospital because of ulceration or right scrotum. Physical examination revealed a hard, rounded, a little bigger than egg-sized mass in the right scrotum. The second case was a 40-year-old man who was admitted to our hospital because of cough, fever and body weight loss. He was treated for pulmonary tuberculosis with isoniazid, rifampicin, streptomycin and pyrazinamide. Six months after admission, he complained of a painless swelling of the right scrotum. Physical examination revealed a hard, rounded, more than egg-sized mass in the right scrotum. Right orchiectomy was performed in these two cases, and they were cured.

Adult↗

[A case of endobronchial tuberculosis associated with bronchial asthma treated with high doses of inhaled corticosteroid].

A 46-year-old woman had been treated with 1,600-2,000 micrograms/day of beclomethasone dipropionate (BDP) and oral theophylline on the basis of a diagnosis of bronchial asthma in 1993. Eosinophilic pneumonia was diagnosed in June 1999, and she was then treated with 40 mg/day of oral prednisolone (PSL), which was gradually tapered off, and then stopped in October 1999. She was referred to our hospital because acid-fast bacilli were found in the sputum on January 18, 2000. Her chest radiographs and CT scans showed partial atelectasis of the right upper lobe, and fiberoptic bronchoscopy revealed bronchial inflammatory changes and whitish mucosal nodular lesions in the walls of the lower trachea, the right main bronchus and the orifice of the right upper lobe bronchus. She was found to have endobronchial tuberculosis. Anti-tuberculosis treatment with isoniazid, rifampicin, streptomycin and pyrazinamide was started. Serum levels of interferon-gamma were markedly elevated on admission. Asthma symptoms improved for a period of one month after the beginning of anti-tuberculosis treatment, despite the termination of inhaled corticosteroid. However, as the tuberculosis improved, the frequency and severity of the asthma increased and so corticosteroid inhalation was started again. Four months after administration of the anti-tuberculosis drug, fiberoptic bronchoscopy revealed that the endobronchial lesions had improved without any stenosis or constrictive changes. It was speculated that high doses of inhaled corticosteroid may have the potential to cause endobronchial tuberculosis whilst, ironically, at the same time preventing bronchial stenosis by endobronchial tuberculosis. This is an interesting case in which the asthma symptoms first decreased during the acute phase of endobronchial tuberculosis and then increased again after the tuberculosis improved.

Administration, Inhalation↗

Pulmonary tuberculosis in Kumasi, Ghana: presentation, drug resistance, molecular epidemiology and outcome of treatment.

To assist implementation of tuberculosis (TB) control measures, knowledge of the disease characteristics in a community is essential. This study in Kumasi, Ghana, correlates the clinical presentation, microbiology, molecular epidemiology and clinical outcome of thirty consecutively diagnosed patients with new smear-positive pulmonary TB. Several important factors that potentially promote disease transmission in the community were identified: patients had prolonged duration of productive cough prior to diagnosis (mean=4.1 months; SD=2.1); the disease was typically advanced at presentation and Ziehl-Neelson sputum smears indicated a high bacterial load (80% graded > AFB++); home accommodation was overcrowded with a mean of 3.3 other persons sleeping in the same room as the patients at night. IS6110 restriction fragment length polymorphism (RFLP) fingerprinting of 25 isolated (23 Mycobacterium tuberculosis and 2 Mycobacterium africanum) from epidemiologically unrelated cases identified 3 identical strains and 3 clusters containing 2, 4 and 8 isolates of > or =80% similarity, suggesting high rates of disease transmission. A high prevalence of primary resistance to isoniazid was found (6 out 26; 23%) but resistance to rifampicin, pyrazinamide, ethambutol, streptomycin and ciprofloxacin was not detected. Smear coversion at 2 months and final outcome of treatment with short courses chemotherapy were independent of isoniazid resistance, but the rate of treatment default was unacceptably high (37%). High rates of disease transmission, primary isoniazid resistance and treatment default all indicate poor TB control. The use of rifampicin-containing short-course chemotherapy in this community must be accompanied by adequate resources and infrastructure to ensure very stringent treatment supervision to improve case-holding and reduce the risk of multi-drug resistance.

Adult↗

[Treatment outcomes of multidrug-resistant tuberculosis--comparison between success and failure cases].

The thirty-two times of treatment in 27 patients with multidrug-resistant tuberculosis (MDR-TB) were analyzed retrospectively. In twenty-eight times of treatments cases had previous histories of antituberculosis chemotherapy. Drug sensitivity tests were performed by Microtiter method for isoniazid (INH), rifampicin (RFP), ethambutol, streptomycin, kanamycin, enviomycin, ethionamide, para-aminosalicylic acid and cycloserine. A drug is defined as 'active drug' when the drug was proved to be sensitive by the drug sensitivity tests or never used in the past or used for not more than 2 months in case of pyrazinamide (PZA) and less than one month for fluoroquinolones. Outcomes of treatments were grouped as follows; A: bacteriologically negative for more than 24 months, B: bacteriologically negative for more than 6 months but less than 24 months, C: bacteriologically relapsed after negative conversion, D: continuously bacilli positive for M. tuberculosis. Mean age of patients in each group were; 61.0 yrs for group A (n = 10), 61.0 yrs for group B (n = 7), 52.5 yrs for group C (n = 4), 57.9 yrs for group D (n = 11). All patients had cavitary disease and positive sputum smears for acid-fast bacilli. Mean numbers of 'active drugs' used per treatment in each group, were 3.6, 3.3, 2.5 and 1.8 respectively, while the mean number of resistant drug including INH and RFP were 2.8, 3.3, 2.5 and 3.7. The number of drugs, which was unable to use due to toxicity, were 0.20, 0.14, 0.50, and 0.73 per treatment respectively. All of 9 patients treated with four 'active drugs' were in group A or B and succeeded to achieve negative conversion. The duration of chemotherapy in group A was 13 to 44 months. Treatment had failed in 4 out of 11 patients treated with 3 'active drugs' and 11 out of 12 patients treated with less than 2 'active drugs'. Fluoroquinolones (ofloxacin, levofloxacin or sparfloxacin) were used in 7 out of 10 patients in group A and in 6 out of 9 patients treated with four-drug regimens while they were used only in 3 out of 11 patients in group D. Regimens with at least 4 sensitive drugs are mandatory for the successful treatment of MDR-TB and fluoroquinolones are needed in the majority of cases to ensure the four-drug regimen, because of frequent drug resistance or toxicity to other antituberculosis drugs.

Adult↗

[Pathologic review of 5,050 pulmonary tuberculosis cases].

OBJECTIVE: To summarize the pathomorphologic changes of pulmonary tuberculosis and the relationship between those changes and the combined chemotherapy regimens. METHODS: Observing the pathological changes in 5,050 cases with pulmonary tuberculosis, and the relationship between three different combined chemotherapy regimens HSP, HRS, HRZS and the pathological changes of pulmonary and bronchial tuberculosis. RESULTS: The rate of surgical excision of caseous cavities and fibrous-cavities declined markedly in cases treated by HRS and HRZS regimens (P < 0.01). Whereas, after treated by HSP, HRS and HRZS regimens, the rate of surgical excision of tuberculoma were 26.82% (897/3,345), 41.24% (464/1,125) and 47.8% (277/580) respectively which showed a rising tendency (P < 0.01). Open healing cavities were found in 42 patients. CONCLUSIONS: The effects of combined rifampicin and pyrazinamide chemotherapy caused the changing of pathologic types of pulmonary tuberculosis, that is: the increased proportion of tuberculoma and the decreased proportion of caseous and fibrous cavities. Tuberculoma ought to be taken into account in the classification of tuberculosis.

Adolescent↗

Widespread distribution of a single drug rifampicin formulation of inferior bioavailability in South Africa.

A pharmacokinetic study of rifampicin, isoniazid, pyrazinamide and ethambutol in 118 tuberculosis patients revealed low and variable concentrations of rifampicin after 2 months of treatment on standard daily doses. A group of 53 patients exposed to specific batches of formulations containing rifampicin alone showed particularly low and variable levels of the drug. The national drug regulatory authority subsequently withdrew the batches in question, as sufficient bioavailability data had not been submitted after what the manufacturer had considered to be a minor formulation change. The evidence supports initiatives to implement bioavailability testing of new formulations (and of established formulations subsequent to changes in the manufacturing process) prior to distribution. Concerns about the bioavailability of rifampicin-containing products, including those with adequate dissolution profiles, should not be confined to fixed-dose combination anti-tuberculosis drugs, but should also be applied to single drug formulations.

Adult↗

Risk factors for drug-resistant Mycobacterium tuberculosis in Saudi Arabia.

OBJECTIVE: To identify rates of primary and secondary drug-resistant Mycobacterium tuberculosis and their risk factors from a tertiary-care center in the Kingdom of Saudi Arabia. METHODS: Review of microbiological and clinical data of all patients with positive isolates of Mycobacterium tuberculosis between 1995 and 2000 at King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia. RESULTS: Susceptibility to antituberculosis agents was tested in 320 isolates from 320 patients. The median age was 50 years. Pulmonary tuberculosis was diagnosed in 106 (33%) patients, extrapulmonary in 183 (57%), and both in 31 (10%) patients. Two hundred forty-six isolates were sensitive to all 5 first line agents. Resistance to at least one of the first line agents was documented in 36 (11.3%) isolates. For the year 2000, resistance rates increased to 17.6%. Monoresistance was noted in 20 isolates (6.3%) and polyresistance in 16 isolates (5.0%) including 9 multidrug-resistant Mycobacterium tuberculosis isolates (2.8%). Resistance rates for antituberculosis agents are: Isoniazid, 9.1%; Rifampin, 2.8%; Ethambutol, 1.6%; Streptomycin, 5%; Pyrazinamide, 3.6%. Seventy-eight percent of the resistant isolates are considered primary resistance. History of antituberculosis therapy was the only risk factor associated with drug resistant Mycobacterium tuberculosis, odds ratio 19.9 (P< 0.00001). The mean age of patients with resistant isolates was 42 years compared to 49 years in patients with susceptible isolates (P= 0.047). CONCLUSION: In a population of mostly Saudi patients, primary and secondary drug-resistant Mycobacterium tuberculosis is relatively low but has increased lately. Previous history of antituberculosis chemotherapy and young age are risk factors identified.

Adolescent↗

Four-month chemotherapy in the treatment of smear-negative pulmonary tuberculosis: results at 30 to 60 months.

INTRODUCTION: Most patients with active pulmonary tuberculosis (PTB) are treated with a 6-month short course regimen. The purpose of the present study was to assess the efficacy of using 4 months of chemotherapy to treat patients with smear-negative PTB. METHODS: A total of 314 patients were randomised to a daily or combined (daily and intermittent) regimen as follows: (1) 2HRZ/2HR--2 months of isoniazid (H), rifampicin (R) and pyrazinamide (Z), followed by 2 months of H and R or (2) 2HRZ/2H3R3--2 months of HRZ as in regimen 1, followed by H and R given 3 times weekly for 2 months or 4 months if initial sputum specimens were culture positive. RESULTS: One hundred and fifty-eight patients were assigned to the daily regimen and 156 to the combined regimen. Of the 158 patients, 99 had negative cultures and 59 had positive cultures. There was no relapse among 96 culture-negative patients assessed at 30 months and 68 patients at 60 months. However, 6 patients had no radiological response while 1 was considered on review to have non-tuberculous disease. There was no relapse among 57 culture-positive patients assessed at 30 months and 41 at 60 months. In the combined regimen group, 102 had negative cultures and 54 had positive cultures. There was 1 relapse in the culture-negative group of 100 patients assessed at 30 months and 74 at 60 months. There was no radiological response in 5 patients. One patient in the culture-positive group failed therapy but there were no relapses during follow-up to 60 months. CONCLUSION: A 4-month daily or combined regimen appears to be highly effective in the treatment of non-immunocompromised patients with smear- and culture-negative PTB.

Adolescent↗

[Primary resistance of Mycobacterium tuberculosis in 30 health institutions of El Salvador. A pilot study].

In view of the worldwide re-emergency of tuberculosis (TB) and the rise of pulmonary TB (TBP) resistant to the two main first line drugs, namely isoniazid (H) and rifampin (R), so called multidrug resistant TBP (MDR-TBP), it was considered necessary to carry out a national, non randomized, multicenter, prospective pilot survey to determine the rates of resistant Mycobacterium tuberculosis (MTB) in patients with no previous antituberculous treatment (primary resistance). A total of 30 health institutions were chosen (disseminated among the 14 districts of the country) with the most TBP cases reported in 1997, and asked to provide in a consecutive non random way, sputum samples from new smear positive TB patients starting the first working week of January until the last one of December 1998; these samples were processed for culture at the Tuberculosis Section of the Health Ministry Central Laboratory. Those that resulted positive for MTB underwent a test for resistance to the first line drugs used in this country (isoniazid, rifampin, pyrazinamide, ethambutol and streptomycin). A total of 348 MTB positive samples were collected. The rate of primary resistance to at least one drug was 3.3% and to H it was 0.3%, being these rates among the lowest in Latin America. For this reason further studies comprising the whole universe of new and already treated smear positive TB patients are to be performed in order to determine more accurately the primary resistance and acquired rates.

Antitubercular Agents↗

Detection of mycobacteria in patients with pulmonary tuberculosis undergoing chemotherapy using MGIT and egg-based solid medium culture systems.

SETTING: National Minami-Yokohama Hospital, Kanagawa, Japan. OBJECTIVE: To compare the performance of a liquid medium system using the Mycobacteria Growth Indicator Tube (MGIT) with that of the conventional Japanese culture system using egg-based Ogawa medium, equivalent to Lowenstein-Jensen medium, in cases with pulmonary tuberculosis on chemotherapy. DESIGN: A single-centre prospective case study of 61 hospitalised patients from 1 May to 31 July 1998 on a standard 6-month regimen of anti-tuberculosis chemotherapy including isoniazid, rifampin, streptomycin or ethambutol, and pyrazinamide. Sputum cultures using both culture systems were performed bi-weekly up to week 16 of treatment, and were further monitored by MGIT alone at the end of chemotherapy and every 6 months after the end of chemotherapy up to 2 years. RESULTS: The detection time by MGIT gradually became longer with the progression of chemotherapy. The recovery rate at weeks 2, 4, 6, 8, and 10 by MGIT were significantly higher (P < 0.05) than on the Ogawa slants. Although one case was microbiologically diagnosed as a relapse, using the more sensitive MGIT system did not increase the relapse rate. CONCLUSION: The gradual prolongation of detection time with the progression of treatment and an attainment of negativity of sputum culture at 4 months after chemotherapy could be a useful intermediate marker to monitor the efficacy of treatment for patients with pulmonary tuberculosis by the MGIT system. Further evaluation is necessary to establish the utility of MGIT in monitoring the treatment process.

Antitubercular Agents↗

[A case of multiple bone and joint tuberculosis which had been misdiagnosed as the rheumatoid arthritis and treated with prednisolone for eleven months].

A 34-year-old man had a multiple arthralgia for about eleven months. The swelling of his right wrist and foot had appeared in the dorsal side, and he had been misdiagnosed as the rheumatoid arthritis. He was treated with prednisolone in the dosages of 2.5 mg per day for one month, and 10 mg per day for ten months. When he admitted to our hospital, the bone X-ray examinations of the wrist and foot revealed the marked atrophy and destruction of the carpal and tarsal bones. The aspiration fluid from the swelling around his wrist and foot was positive for acid-fast bacilli on smear and Mycobacterium tuberculosis was found on culture. He was treated with isoniazid, rifampicin, ethambutol and pyrazinamide, however, these medication was not adequately effective to his complications of tuberculous arthritis. Curettage, irrigation and synovectomy of his right carpal and tarsal bone were performed in order to control his bone and joint infection. He recovered from his arthritis and tenosynovitis after these operations. The clinical practitioners should not omit tuberculosis from the differential diagnosis of persistent osteoarthralgia.

Adult↗

Analysis of quantitative relationship between viability determination in leprosy by MFP, ATP bioluminescence and gene amplification assay.

Two hundred twenty-one untreated, borderline lepromatous/lepromatous (BL/LL) leprosy patients have been investigated for viability by the mouse foot pad method (MFP), adenosine triphosphate (ATP) and polymerase chain reaction (PCR). The biopsies were collected at the beginning of and 12/24 months after treatment. The patient group was treated with a) immunotherapy (BCG/Mw) + MDT; b) MDT + pyrazinamide; c) control MDT; d) MDT + minocycline 100 mg once a month supervised + ofloxacin 400 mg once a month supervised. Biopsies were divided in three parts for use in the mouse foot pad, molecular and ATP investigations. In untreated and treated patients (at 12 and 24 months), there was a general agreement among all three techniques, and PCR and ATP showed higher positivity as compared to MFP. Further, there was good correlation among the viable biomass estimated by bacillary ATP levels, PCR assay and growth in mouse foot pads. The positivity was observed by MFP as well as PCR assay (18-kDa and 36-kDa) from all of the specimens when the ATP content was more than 3.6 pg/million. When the ATP content was below 3.5 pg/million, the positive takes in MFP decreased but the PCR positivity correlated with ATP bioluminescence up to 0.04 pg/million. When the ATP content was even lower, the uptake in the MFP was possibly a matter of chance, while PCR positivity was observed in 96% of the cases. For specimens with undetectable ATP, positivity was seen in 1% of the cases, showing the inability of ATP bioluminescence method to detect low background due to host ATP. PCR signals in some cases could be due to the higher sensitivity of the method or persistence of DNA after bacterial death in some cases. On the whole, the PCR methods even though targeting DNA have shown good correlations with biomass which confirm their usefulness in monitoring therapeutic responses in leprosy.

Adenosine Triphosphate↗

[HIV-tuberculosis coinfection].

Coinfection with the human immunodeficiency virus (HIV) and tuberculosis is a major public health problem throughout the world. In subsaharan Africa and Southeast Asia, as many as one third of all patients with tuberculosis also have HIV infection. These two infection interact on each other, worsening the prognosis and increasing mortality. The diagnosis of tuberculosis is sometimes difficult to establish since the clinical presentation may be incomplete, but must always be evoked and sought whenever there is the slightest doubt. These patients should be given conventional anti-tuberculosis treatment using three or four anti-tuberculosis drugs for a duration of 9 months. Overall outcome is favorable. Drug interactions between antiretroviral drugs and anti-tuberculosis drugs is a real problem, limiting the use of certain agents. The restored immunization achieved with HAART protocols involve "paradoxical" reactions which complicate patient adherence to therapy. It would be reasonable to treat tuberculosis first, then, in 6 weeks, introduce an adapted antiretroviral regimen. Prevention of tuberculosis for patients at risk should be based on rifampicin and pyrazinamid for 2 months.

Drug Resistance, Bacterial↗

[Treatment of tuberculosis infection].

Tuberculosis is a chronic bacterial infection caused by Mycobacterium tuberculosis. It continues as an important cause of morbidity and mortality worldwide, especially in impoverished countries and where human immunodeficiency virus infection is endemic. The modern treatment of tuberculosis is based on the administration of effective drugs. Regimens do not differ for pulmonary and extra-pulmonary tuberculosis. In order to prevent the emergence of drug-resistant organisms, which is present initially in very small numbers, at least two effective drugs are always required. Short-course therapy has been developed to mitigate the consequences of patient default. It is best considered as consisting of two phases. An initial 2-month intensive phase of daily therapy should include isoniazid, rifampin, ethambutol and pyrazinamide. A consolidation phase of daily therapy with isoniazid and rifampin should be continued for an additional 4 months, preferably more for special clinical circumstances. This standardized drug strategy is successful only if the resources conserved by shortening treatment are used to maintain patient compliance. Completely supervised regimens have been also developed with success. Defaults lead not only to treatment failure but also the emergence and transmission of drug-resistant organisms. Treatment of confirmed or suspected drug-resistant tuberculosis is difficult and should only be made on experts consultation. More difficult to use and/or less effective than first line drugs, second line drugs could be chosen and associated. However drug toxicities should be monitored, with greatest concern to hepatitis. Follow-up of patients must be organised until 2 years after the completion of therapy to detect relapses. Treatment includes prophylactic measures which are a major modality for decreasing the spread of infection.

Antitubercular Agents↗

[Epidemiology of resistance to antituberculosis drugs in Mycobacterium tuberculosis complex strains isolated from adenopathies in Djibouti. Prospective study carried out in 1999].

Tuberculosis is a major cause of death in the Republic of Djibouti. Tuberculous lymphadenitis represents about 25% of the clinical forms of tuberculosis in this country. Between January 1999 and April 1999, 196 lymph node specimens were consecutively collected from 153 patients living in Djibouti. Testing of susceptibility to the major anti-tuberculosis drugs was performed by the proportion method. Growth of Mycobacterium tuberculosis complex strains was obtained from specimens of 85 patients including 9 with prior treatment. Strains were identified as Mycobacterium tuberculosis in 78 cases, Mycobacterium canetti in 3, Mycobacterium africanum in 3, and Mycobacterium bovis in 1. Prevalence of HIV infection was 15%. Assessment of primary resistance demonstrated that the overall resistance rate, i.e., resistance to 1 or more drugs, was 18 (21.2%). Results showed resistance to isoniazid (H) in 6 cases (7.1%), rifampicin (R) in 3 (3.5%), ethambutol (E) in 1 (1.2%), streptomycin (S) in 13 (15.3%) and pyrazinamide (Z) in 1 (1.2%). Multidrug resistance (MDR) was found in 2 cases (2.4%). Assessment of acquired resistance demonstrated resistance to H in 4 cases (44%), R in 2 (22%), S in 2 (22%), E in 0, Z in 0 and MDR in 1 (11%). These findings were not significantly different from data obtained from sputum samples analysed between 1997 and 2000 or from those described in a study conducted in 1985.

Antitubercular Agents↗

European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.7.2. Late infections. Tuberculosis.

GUIDELINES: A. Tuberculosis (TB) is not rare after renal transplantation, and can be life-threatening. Treatment of active TB in renal transplant recipients should be the same as in the general population, i.e. 2 months of quadruple therapy combining rifampin, isoniazid, ethambutol and pyrazinamide, followed by a 4-months double therapy with isoniazid and rifampin. The drug ethambutol should not be used initially if the rate of resistance to isoniazid is less than 4% in the community. B. As rifampin will reduce the plasma concentration of calcineurin antagonists and rapamycin, the blood levels of these agents must be monitored closely. Rifabutin may be used as an alternative to rifampin, as this drug is a less potent inducer of the microsomal P450 enzymes. C. Renal transplant candidates and renal transplant recipients should be screened for latent TB infection. Patients considered to have latent TB infection are defined as: (i) those who display a 5 mm (renal transplant recipients) or a 10 mm (dialysis patients) induration after tuberculin skin testing; (ii) those with chest X-ray images suggestive of past TB infection; (iii) those with a history of past TB infection that was not treated adequately; and (iv) those who have been in close contact with infectious patients. The preferred treatment of latent TB infection is isoniazid 300 mg/day for 9 months.

Humans↗

[Use of the plant hepatoprotector Galstena tuberculostatics-induced hepatic lesions: experimental and clinical study].

The efficiency of the use of the natural drug Galstena (Richard Bittner GmbH) was experimentally and clinically studied on a model of damage induced by toxic doses of tuberculostatics (rifampicin, isoniazid, pyrazinamide) in laboratory rats and in patients with different forms of pulmonary tuberculosis and with hepatitis caused by specific antituberculous drug therapy, who were treated at the Clinic of Phthiziology. Galstena was found to have marked hepatoprotective properties and to be able to prevent renal and pancreatic disorders. The drug also showed an antioxidative activity. The use of Galstena in patients with pulmonary tuberculosis substantially reduced the magnitude of clinical and laboratory signs of drug-induced hepatic damage.

Adult↗