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.

Intermittent chemotherapy of experimental leprosy in mice.

In this study we assess the degree of prolonged bacteriostasis of Mycobacterium leprae after temporary exposure to ehtionamide or thiacetazone, and relate this to their efficacy when administered intermittently to mice with experimental leprosy infections. The results show that temporary exposure of M. leprae to either of these drugs results in a prolonged bacteriostatic effect, but that efficacy is rapidly lost as the interval between doses is increased. Using the mouse foot pad system, growth of M. leprae is not inhibited by thiacetazone when the frequency of administration is less than three times weekly. When ethionamide is administered once weekly, growth of M. leprae is inhibited but bactericidal activity is lost. When ethionamide is administered in combination with continuous dapsone therapy, either continuously or three times weekly, the bactericidal activity of the drug combination is greater than when either drug is administered alone. However, when ethionamide is administered once weekly in combination with continuous dapsone treatment, the bactericidal effect is identical to that when dapsone is given alone: that is, ethionamide makes no contribution to the combination.

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.

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.

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.

[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.

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.

[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.

Evaluation of multiple regimens in leprosy.

Assessment of bacteraemia has been made at weekly intervals in 36 lepromatous leprosy patients who were put on different antileprosy drug under four regimens, viz., DDS alone, DDS in combination with rifampicin (DDS + RIF), clofazimine (DDS + CLF) and thiacetazone (DDS + TCT). In general, with the continuation of treatment the bacillary load in the blood decreased considerably while bacteriological index (BI) of the skin remained constant during the study. No significant difference was noted in M. leprae clearance from blood between the groups treated with DDS alone and groups treated in combination with CLF and TCT. However, DDS + RIF treatment was most efficient in clearing acid-fast bacilli (AFB) from blood as compared to those noted with other drug regimens.