Preclinical pharmacokinetics of KBF611, a new antituberculosis agent in mice and rabbits, and comparison with thiacetazone.

Thiacetazone (TAZ), one of the oldest known antituberculosis drugs, causes severe skin reactions in patients co-infected with tuberculosis and human immunodeficiency virus (HIV). KBF611 is a new fluorinated thiacetazone analogue that has shown strong antituberculosis effects. In order to provide valuable information for subsequent preclinical development, pharmacokinetics of KBF611 and its analogue (TAZ) were studied and compared in two animal species (mice and rabbits) following intravenous and oral administration, and pharmacokinetic parameters were characterized. According to the calculated parameters, KBF611 showed a more favourable pharmacokinetics profile than TAZ in terms of half-life (0.89 h compared with 0.57 in mice, p < 0.05, and 2.71 compared with 0.98 in rabbits, p < 0.001) and volume of distribution (1.45 l kg(-1) compared with 0.86 l kg(-1) in mice, p < 0.05, and 1.01 l kg(-1) compared with 0.41 l kg(-1) in rabbits, p < 0.001) for tuberculosis therapy. In rabbits, the oral bioavailability of KBF611 was markedly lower than mice (39% compared with 82%), which may be attributed to a higher presystemic metabolism in rabbit liver. The results of in vivo studies on the metabolism of KBF611, supported by liquid chromatography-mass spectrometry (LC-MS) analysis, showed that the incorporation of a fluorine atom to the TAZ structure made the molecule susceptible to N-deacetylation, a pathway not seen in TAZ metabolism. In summary, KBF611 could be considered a suitable candidate for further preclinical and clinical evaluation.

Simultaneous determination of a new antituberculosis agent KBF-611 and its de-acetylated metabolite in mouse and rabbit plasma by HPLC.

KBF-611 is a new thiosemicarbazone derivative which has demonstrated significant antituberculosis effect. A sensitive and specific HPLC method was established and validated for the determination of KBF-611 and its deacetylated metabolite (KM) in mouse and rabbit plasma. Chromatographic separation was achieved on a Eurospher-100 C8 column using acetonitrile, methanol, phosphate buffer (pH 7) and TEA (25:5:70:0.1, v/v), as mobile phase at a flow rate of 1 mL/min. KBF-611, KM and internal standard (4-acetamido-3-chlorobenzaldehyde thiosemicarbazone) were detected at the wavelength of 323 nm. The calibration curves were linear within the concentration range from 0.02-5 microg/mL and 0.02-1 microg/mL for KBF-611 and KM respectively. The limit of detection and the limit of quantitation were 6 ng/mL and 20 ng/mL respectively for both KBF-611 and KM. The relative standard deviation for intra- and inter-day precision was less than 7.5%. Average recoveries were 70.8% and 75.0% for KBF-611 and KM respectively. The established HPLC method was validated to be a simple, rapid and reliable procedure and successfully applied to study the preclinical pharmacokinetics of KBF-611 and KM in mice and rabbits.

In vitro activity of thiacetazone on mycobacterial species belonging to the Mycobacterium tuberculosis complex.

Thiacetazone, despite frequent side-effects, may still be considered for the treatment of new tuberculosis cases when there is a shortage of drugs and for the management of multidrug-resistant tuberculosis. Fifty-four strains of M. tuberculosis complex were characterised based on the minimum inhibitory concentration (MIC) of thiacetazone and the growth pattern in the presence of different concentrations of the drug. The results showed that the MIC of thiacetazone to type II M. africanum strains was significantly higher than for other strains in the study (P < 0.01). Thiacetazone showed a paradoxical effect on 63% of strains where lower concentrations exhibited a better inhibiting activity than higher concentrations.

A report on home visiting practices conducted in remote districts of Nepal in an NGO-run tuberculosis control programme.

To establish the role of home visiting in an NGO-run tuberculosis control programme in Nepal, information was collected on home visits to a cohort of 205 smear-positive patients. Almost one third of new smear-positive cases were visited, either for treatment initiation (n = 33) or for retrieval following non-attendance (n = 29); thus 14% of patients required a home visit to ensure treatment completion. It is unlikely that the WHO-recommended target of 85% cure rate would be achieved without defaulter tracing, although a further study comparing home visiting against no visiting would be necessary to assess the contribution that this activity makes to improving treatment outcomes.

[Profile of the patients lost to treatment in the National Anti-Tuberculosis Program in Madagascar]. / Profil des malades perdus de vue en cours de traitment dans le Programme national de lutte contre la tuberculose à Madagascar.

A national anti-tuberculosis program has been in operation in Madagascar since 1991. Despite the significant efforts made in the management, education and surveillance of patients, the number of patients lost to treatment remains high (18.8%). Noncompliance with treatment is the principal cause of treatment failure and of the development of resistance to tuberculosis drugs. This study investigated the profile of the patients who discontinue treatment. The study population consisted of the patients withdrawing from a clinical trial carried out between August 1994 and September 1996. The aim of the trial was to compare several treatments in routine practice conditions in Madagascar. The treatments tested were streptomycin (S) or ethambutol (E) associated with isoniazid (H), rifampicin (R) or pyrazinamide (Z) for the first two months, followed by 6 months of treatment H and thiacetazone (T). The trial involved four public and three private diagnosis and treatment centers in Antananarivo, Fianarantsoa and Mahajanga. A total of 1, 023 patients were included in the trial and 192 (18.8%) withdrew during the eight-month treatment period. We tracked down 109 of these patients (56.8%) and 19 patients came back to the treatment center on their own initiative for a checkup. The rate of response to a recall letter sent by mail was low. The 106 patients interviewed mostly gave professional, financial or family reasons for discontinuing treatment. Many patients stopped the treatment as soon as they began to feel better. To reduce the number of patients discontinuing treatment, the National Anti-Tuberculosis Program should improve the education of patients and their families.

[The results of retreatment of pulmonary tuberculosis using a short 6-month protocol 1985-1991 in the pneumo-phthisiology department of the Point G hospital in Bamako]. / Résultats du retraitement de la tuberculose pulmonaire par un régime court de 6 mois de 1985-1991 dans le service de pneumo-phtisiologie de l'hôpital du point G à Bamako.

This study concerns 321 files of smear positive tuberculosis patients admitted in the pneumo-phtysiology service of Pt G Hospital for re-treatment from April 1985 to December 1991. The re-treatment pulmonary tuberculosis with positive spits represent 13.3% of pulmonary tuberculosis cases and 10.1% of the whole tuberculosis diseases. High rate with a ratio of 3 men for a woman was found among men. The same conclusion was reached by SAMAKE (7). Patients age raking from 20 to 49 were the most affected in a proportion of 75.7%. Evolutive relapses were the principal reasons for re-treatment (71.2%) and take place above all among patient treated with the 12 months conventional regime. The conclusion reached corroborates those of STYBLO (8). The regime was 3RHZES3/3R3H3E3. The maximum of negating has been reached during the 3rd month with 93.4% rate. It has been during these 3 last months consolidation phase that the highest drop out has been noticed (17.1%). This is certainly due to the better off felt by patients. At the end of treatment 76.3% of the patients have recovered against 1.5% failure rate and 5.3% drop out. Our treatment regime, though different from those advised by WHO and IUATLD, is an efficient one. However in the new programme of fighting against tuberculosis of Mali, it has been decided to replace our treatment with that of WHO and IUATLD.

Relapse after short-course chemotherapy of patients with sputum smear-positive pulmonary tuberculosis under routine conditions with additional information on side effects and contact tracing.

SETTING: The region of Leon/Chinandega in Western Nicaragua. OBJECTIVE: To assess the relapse rate after short course chemotherapy with thioacetazone in the continuation phase in patients with sputum smear-positive pulmonary tuberculosis. DESIGN: A cohort of 247 new sputum smear-positive patients with pulmonary tuberculosis, started on the national short-course treatment (2SRHZ/6TH) between October 1986 and April 1988 as part of the National Tuberculosis Programme, were followed up for 17-32 months after completion of treatment. Two thirds of the patients spent the first 2 months hospitalized, the rest received the whole treatment as out-patients. RESULTS: 204 (83%) completed treatment, seven failure cases were cured with retreatment, 24 defaulted, 10 were transferred out and two died. The patients who completed treatment continued to undergo smear examination for acid-fast bacilli every three months. Of the 204 patients who completed treatment, five died and 10 were lost to follow-up. The remaining 189 patients were followed up for a total of 388 person-years. Three relapses appeared (1.6%), one relapse during 129 person years of observation. Two of the relapse cases were hospitalized, and the third received the full treatment as an out-patient. In the 223 patients who first entered the study, contact tracing detected 24 new smear-positive and 43 smear-negative cases. Adverse reactions (jaundice) required suspension of treatment in one patient, but only temporarily. CONCLUSION: Short course chemotherapy with an ambulatory continuation phase with isoniazid and thioacetazone seems to have a low relapse rate under routine conditions and should continue to be used.

Randomised trial of thiacetazone and rifampicin-containing regimens for pulmonary tuberculosis in HIV-infected Ugandans. The Makerere University-Case Western University Research Collaboration.

Among HIV-positive patients who received treatment for active tuberculosis, thiacetazone has been associated with cutaneous hypersensitivity and recurrent tuberculosis. No controlled trials have investigated the safety and efficacy of thiacetazone-containing regimens compared with alternative regimens among patients with HIV. In a randomised clinical trial of 191 HIV-positive patients with active pulmonary tuberculosis, we examined the safety and short-term efficacy of isoniazid, rifampicin, and pyrazinamide for two months followed by isoniazid and rifampicin for seven months (RHZ) compared with streptomycin, thiacetazone, and isoniazid for two months followed by thiacetazone and isoniazid for ten months (STH). Between May, 1990, and September, 1991, 191 HIV-positive adult Ugandan patients with acid-fast bacilli sputum smear-positive pulmonary tuberculosis (93% confirmed by culture) received either STH or RHZ. Subjects had a standard evaluation that included Mantoux skin test, complete blood count with differential white blood cell count, and chest radiography. After starting therapy, subjects were followed-up over one year for three outcomes: complications of anti-tuberculosis therapy, early sterilisation of cultures, and survival. Of 191 eligible subjects, 90 received STH and 101 received RHZ. The overall one-year survival was similar for STH and RHZ (65% vs 72%), but when controlled for baseline differences in Mantoux reaction size and absolute lymphocyte count, the relative risk of death for STH compared with RHZ was 1.57 (95% CI 1.0-2.48). Overall, 12 adverse drug reactions occurred in the STH arm (18.2 reactions per 100 person years [PYO]) compared with one in the RHZ arm (1.6 reactions per 100 PYO) for a relative risk of 11.7 (95% CI 1.52-90.0). 10 cutaneous reactions occurred in the STH arm (15.2 events per 100 PYO) compared with one event in the RHZ arm (1.6 events per 100 PYO) for a relative risk of 9.7 (95% CI: 1.24, 75.8). A greater proportion of RHZ patients compared with STH patients had sterilised their sputum within two months (74% vs 37%, p < 0.001). In developing countries, rifampicin-containing regimens should be given, when possible, to HIV-positive patients to reduce drug toxicity and to prolong survival.

Thiacetazone--avoid like poison or use with care?

Recent 5 reports of severe cutaneous hypersensitivity reactions in patients infected with human immunodeficiency virus (HIV) and with tuberculosis treated with thiacetazone have prompted the World Health Organization to advise against the use of thiacetazone in patients known, or suspected, to be infected with HIV. Because the poorest countries will have great difficulty in replacing thiacetazone, the history, metabolism and possible mechanisms underlying the toxicity of this inexpensive, but problematic, drug are reviewed. Guidelines for National Tuberculosis Control Programme policies in response to thiacetazone toxicity are discussed, taking into account the differing levels of resources available to developing countries.

Stevens-Johnson syndrome and toxic epidermal necrolysis in Thailand.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are potentially life-threatening illnesses that have often been linked to drug exposure. METHODS: We looked retrospectively for all cases of SJS and TEN that were admitted to Siriraj Hospital between 1981 and 1990 to determine the drug etiology. RESULTS: Fifty-eight cases of SJS and 20 cases of TEN were identified. Eight patients initially had an SJS-like aspect, which subsequently evolved into TEN. A culpable drug was determined in 60 patients (77%). The mean time from first drug administration to onset of SJS or TEN was 6.8 +/- 6.5 days (range, 1 to 28 days). A longer incubation period was observed with thiacetazone (10.5 +/- 5.6 days), phenytoin (12 +/- 8.5 days), and carbamazepine (11.3 +/- 3.4 days). CONCLUSIONS: The culprit drugs included the following: antibiotics, 32 cases (penicillin, sulfonamides, tetracycline, erythromycin); anticonvulsants, nine (phenytoin, carbamazepine, barbiturates); antitubercular drugs, eight (thiacetazone); analgesics, four (acetylsalicylic acid, fenbufen); sulfonylurea, two; allopurinol, one; and others, four. The most frequent underlying diseases justifying the ingestion of one or more drugs in our patients were infections (52.7%), followed by pulmonary tuberculosis (10.8%), and by seizures (8.1%). The total mortality rate was 14%; 5% for SJS, and 40% for TEN. Mortality was not affected by the type of drug responsible.

Tuberculosis in children: treatment evaluation and results in a 5 year cohort of children with tuberculosis in Turiani Hospital, Tanzania.

Between January 1983 and January 1988, a total of 146 children started TB treatment in Turiani Hospital, Tanzania. During the treatment period 16 children died and another 16 have been transferred out. From the remaining 114, 84 could be traced and were visited at home. Out of this group, 85% were found to be in good clinical condition, and 1% was in bad shape. Death had occurred in 7% after finishing their treatment. Medical records of all children were analysed. Tuberculin sensitivity testing has been carried out in 53 children from the follow-up group. The indications for treatment and the results of the follow-up study are discussed.

PIP: Physicians began tuberculosis (TB) treatment on 146 children at Turiani Hospital in the Morogoro North district, Tanzania between January 1983-January 1988. 46% were 2 years old and 9% were 12 years old. Treatment consisted of daily doses of 20 mg/kg streptomycin and 15 mg/kg thiazina for the 8 week hospital stay followed by the same dose of thiazina for 10 months. Some cases also received rifampicin and pyrazinamide. They administered tubercullin sensitivity tests to 53 of the 84 children who could be traced and visited. Researchers followed the TB case to evaluate indications for and the results of TB treatment in children. The physicians began treatment in some case even though the cases did not exhibit clear symptoms of TB. 74% of the patients whose BCG status was recorded had earlier received a BCG vaccination. Research showed that BCG vaccination protects against 2 severe forms of TB, meningeal and milliary, both of which were not present in this population. At the end of 5 years, 7% (6) of the patients died and only 1% (1) was in poor condition. 85% of all follow up patients were in good condition and well nourished. Even most of the patients who ended treatment rather early after leaving the hospital (74%) were well. In fact, no significant difference in the condition between defaulters and patients who completed treatment existed. This showed that a shorter duration of treatment may be as effective as 10 months of treatment. Only 34% of tested children reacted to the tuberculin sensitivity test which could mean that physicians overtreated around 60% of the patients. 25% of the children who had a negative reaction had abcesses while none of those with a positive reaction had abcesses. In conclusion, physicians should administer a tuberculin sensitivity test at the end of the 8 weeks of treatment to prevent overtreatment.

Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis.

The effects of the human immunodeficiency virus (HIV) on tuberculosis management was investigated in 227 patients initially treated with a regimen containing streptomycin, isoniazid, and thiacetazone (STH). 93 of these 227 were HIV-seropositive. 60 patients, of whom 18 were HIV-seropositive, received a regimen consisting of streptomycin, isoniazid, rifampicin, and pyrazinamide (SHRZ) in the initial phase, and thiacetazone and isoniazid (TH) in the continuation phase. Cutaneous hypersensitivity reactions occurred in 22 of 111 (20%) HIV-seropositive patients, and in 2 of 176 (1%) HIV-seronegative patients (RR = 18, 95% CI 4.4-76, p less than 10(-7]. During the first 8 weeks of treatment 18 reactions occurred among the 93 HIV-seropositive patients on STH, whereas no reaction occurred in 17 HIV-seropositive patients during the initial phase of SHRZ/TH (p = 0.04). None of the 18 HIV-seropositive patients with cutaneous reactions who were subsequently challenged with isoniazid reacted, nor did any of the 10 tested with streptomycin, but 6 of the 7 challenged with thiacetazone reacted. 3 patients (all HIV-positive and with toxic epidermal necrolysis) died as a result of the cutaneous reaction. These results have major implications for tuberculosis control programmes in Africa.

Comparative efficacy of drug regimens in skin tuberculosis.

Three antituberculous drug regimens have been employed to study the therapeutic response in 90 patients with any one of the commonly encountered paucibacillary forms of skin tuberculosis, namely lupus vulgaris, tuberculosis verrucosa cutis and scrofuloderma. The first two regimens contained rifampicin, isoniazid and either pyrazinamide or thiacetazone, and the third regimen had rifampicin and isoniazid only. The disease was clinically defined as localized when confined to one area and widespread when the lesions were disseminated. The observations revealed that the response of lupus vulgaris and tuberculosis verrucosa cutis was alike in all the three regimens, with the localized lesions subsiding completely after 4 months of therapy and the more extensive forms taking 5 months. Patients with scrofuloderma responded similarly to both the triple drug regimens. The discharge, sinuses and ulcers cleared in 6 months but the lymph nodes took longer to regress, up to 7 months in localized and 9 months in more widespread scrofuloderma. To obtain the same results with rifampicin and isoniazid, all patients with widespread scrofuloderma and one-third of those with localized forms had to be treated for 10 and 9 months, respectively. No serious drug side-effects, apart from giddiness with rifampicin and acneiform eruptions with thiacetazone, were encountered. No instances of relapse were noted in the 50% of patients who were followed-up for 3 1/2 years after therapy. Single-drug therapy with isoniazid for lupus vulgaris, as given in the past, is to be discouraged as it may promote the emergence of drug-resistant bacilli in those with an undetected focus of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Problems of tuberculosis treatment in Thailand.

Problems of tuberculosis treatment in Thailand are an obstacle in the national tuberculosis control programme. Reasons concerning the problems on the health provider side being the most important are the budget and the health personnel attitude and behavior, convenience of service, distance of service, health provider-consumer social relation, social support and health service quality. On the health consumer side are patient attitude and behavior and patient economy. The most important understanding to the problems is the socio-economic status of the nation and health providers are responsible for the problems.

Pyrazinamide as a part of combination therapy for BL and LL patients--a preliminary report.

Pyrazinamide in a dose of 1500 mg was given to 63 borderline lepromatous (BL) and lepromatous (LL) leprosy patients on different drug regimens for the initial 2 months of therapy. Fifty-one BL and LL patients were put on the same drug regimens without pyrazinamide. There was a rapid and good clinical improvement in the patients in both of the groups. At the end of 2 years, the patients who received pyrazinamide had a morphological index (MI) of zero as compared to those patients who did not receive pyrazinamide, some of whom still had solidly staining bacilli. One out of 20 (5%) scrotal (smooth muscle) biopsies of the patients who received pyrazinamide had growth in the mouse foot pad as compared to 9 out of 38 (23.7%) smooth muscle biopsies of the patients who did not receive pyrazinamide. At the end of 5 years, the patients who received pyrazinamide had slightly better results compared with the non-pyrazinamide group. Pyrazinamide appears to have some effect against persisters in multibacillary leprosy. A well-controlled, randomized trial with longer duration of pyrazinamide therapy in a larger group of patients needs to be carried out to unequivocally determine the exact role of pyrazinamide in leprosy.