Alterações hematológicas, hemostáticas e bioquímicas induzidas pela clofazimina e claritromicina, em doses única e múltiplas, em ratos / Hematological, hemostatic and biochemical alterations induced by clofazimine and clarithromycin, in single and multiple doses, in rats

Claritromicina e clofazimina têm sido utilizadas no tratamento da hanseníase, tuberculose e infecções causadas pelo complexo Mycobacterium avium. Como os dados sobre a toxicidade de esquemas terapêuticos que incluem estes fármacos são escassos, este estudo teve como objetivo determinar os efeitos adversos destas terapias, por meio da avaliação dos parâmetros hematológicos, hemostáticos e bioquímicos. Os fármacos foram administrados em ratos machos Wistar, em monoterapia, em regime de doses única e múltipla. Claritromicina provocou aumento de leucócitos mono e polimorfonucleares. Ambos os fármacos inverteram a proporção entre células mono e polimorfonucleares e provocaram aumento do número de células polimorfonucleares e células em degeneração. Clofazimina e claritromicina prolongaram o tempo de protrombina e claritromicina também prolongou o tempo de tromboplastina parcial ativa. Claritromicina causou aumento de bilirrubinas total e direta e, ambos os fármacos, elevaram os níveis plasmáticos de gama-glutamiltransferase. Portanto, clofazimina e claritromicina induzem alterações hematológicas, hemostáticas e hepáticas.

Clarithromycin and clofazimine have been used to treat leprosy, tuberculosis and infections caused by the Mycobacterium avium complex. Since there is a scarcity of data on the toxicity of therapeutic regimens that include these drugs, this study had the aim of determining the adverse effects of these therapies, through evaluation of hematological, hemostatic and biochemical parameters. The drugs were administered to male Wistar rats, as monotherapy, in regimens of single and multiple doses. Clarithromycin caused increases in the numbers of mononuclear and polymorphonuclear leukocytes. Both of the drugs inverted the proportions between mononuclear and polymorphonuclear cells and increased the numbers of polymorphonuclear cells and degenerating cells. Clofazimine and clarithromycin prolonged the prothrombin time and clarithromycin also prolonged the activated partial thromboplastin time. Clarithromycin caused increases in total and direct bilirubin. Both of the drugs increased the plasma levels of gamma-glutamyltransferase. Therefore, clofazimine and clarithromycin induce hematological, hemostatic and hepatic changes.

Drug resistant-Mycobacterium leprae--results of mouse footpad studies from a laboratory in south India.

Out of 265 biopsies of leprosy patients received at the Experimental Pathology Laboratory of Schieffelin Leprosy Research and Training Centre from 1987 to 1997 for evaluating resistant strains of M. leprae, using the mouse footpad technique, 49 showed resistant strains of M leprae to varying concentrations of dapsone, rifampicin and clofazimine. 23 (47%) of these were from a control area. With 369 skin-smear positive multibacillary (MB) patients as the risk group (denominator), 23 (6.23%) were resistant to one or more drugs. 18 (4.88%) had dapsone resistance, 5 (1.36%) were resistant to rifampicin and 9 (2.44%) had resistance to low concentrations of clofazimine (0.0001%). Out of the 23 biopsies with drug resistance from the control area, primary dapsone resistance was seen in 7 (30%) biopsies and secondary dapsone resistance in 11 (48%). Primary rifampicin resistance was seen in 4 (17.4%) patients, secondary rifampicin resistance in 1 (4.35%) and primary clofazimine resistance in 7 (30%). 3 (13%) of the strains showed secondary clofazimine resistance. One biopsy had resistant strains to all the three drugs. In a control area where properly supervised effective multidrug therapy (MDT) was regularly administered over the years, the emergence of drug resistance is negligible. It may not be the case if the content, duration and regularity of the drug regimen were not satisfactory. Aware of the possible shortcomings in mass administration of MDT, it is emphasized that mouse footpad studies on drug resistance should be made available at least in endemic areas where the incidence of the disease has not changed despite good MDT coverage in order to monitor the emergence of drug resistance. Research into molecular biological identification of drug resistant-M.leprae should be intensified. These steps would help to institute timely measures to check the spread of any drug-resistant organisms in the community.

The effects of clofazimine, niclosamide & amphotericin B, on electron transport of Leishmania donovani promastigotes.

BACKGROUND & OBJECTIVES: The study was undertaken to explore the locus of interaction of clofazimine and niclosamide which showed substantial growth inhibition property in Leishmania donovani promastigotes. METHODS: The uptake of final electron acceptor oxygen and 2,6-dichlorophenolindophenol (DCPIP) reduction in the electron transport chain were measured by constant volume Warburg respirometer and monitoring absorbance at 600 nm, respectively. Irreversibility of O2 uptake inhibition by clofazimine and niclosamide was determined by dilution of cell suspension followed by centrifugation. RESULTS: Clofazimine and niclosamide showed their minimum inhibitory concentration (MIC) at 33 and 150 micrograms/ml, respectively. Oxygen uptake inhibition by clofazimine and niclosamide was not reversed by removal of the drug by centrifugation. Rotenone, a potent inhibitor of mammalian electron transport chain showed no inhibition on the electron transport chain of L. donovani promastigotes. Cyanide at 1 mM concentration showed partial inhibition in L. donovani promastigotes. Oxygen uptake and DCPIP reduction by L. donovani promastigotes were highly sensitive to sulphhydryl group inhibitors. Strong inhibition of oxygen uptake (80-100%) by L. donovani promastigotes was achieved by clofazimine, niclosamide and amphotericin B. Amphotericin B failed to inhibit DCPIP reduction by L. donovani promastigotes, whereas DCPIP reduction was inhibited by clofazimine and niclosamide, respectively. INTERPRETATION & CONCLUSION: DCPIP reduction was mediated by transplasma membrane electron transport as evidenced by its inhibition with membrane impermeable quinone 1,2-naphthoquinone-4-sulphonic acid (NQSA). Transplasma membrane electron transport requires b-cytochromes and sulphhydryl groups for its function and was inhibited by clofazimine and niclosamide.

Pioderma gangrenoso: a propósito de un caso controlado con bajas dosis de clofazimina / Pyoderma gangrenosum: report of a case controlled with low dose of clofazimine

Se presenta una paciente de 49 años con pioderma gangrenoso atendida en el Hospital Regional Ushuaia entre 1991 y 1996. Presentó lesiones que comenzaron como nódulos en miembros inferiores y evolucionaron a úlceras necróticas, mostrando distintos cuadros histopatológicos como expresión de una misma enfermedad, sin manifestaciones sistémicas. Fue tratada con clofazimina a bajas dosis con resultado favorable, sin efectos colaterales y sin concurrencia a la fecha

Drug resistance in leprosy: lessons from past and future perspective.

Some recent studies indicate that the problem of drug resistance in leprosy is very much there but the exact picture is not clear. In the emerging scenario with increasing number of new cases with low bacterial load, the conventional in-vivo and most of current in-vitro methods for determination of drug resistance may not help. It is pointed out that newer molecular approaches may be more useful and that it will be important to undertake studies to develop such tools.

Impregnaçäo sui generis conjuntivo-escleral por clofazimina em um paciente portador de hanseníase / Impregnation sui generis of the conjunctiva and sclera by clofazimine in a carrier Hansen's disease

Os autores apresentam o caso de um paciente de 40 anos de idade, portador de hanseníase forma virchoniana que recebeu, por via oral, durante 9 anos, clofazimina, numa dose total de 324 gramas. Apresentou intensa pigmentaçäo na conjuntiva e esclera por este medicamento. A biomicroscopia observavam-se com facilidade cristais policromáticos na conjuntiva e esclera de ombos os olhos. O estudo destes cristais também foi possível à microscopia óptica de fragmento da conjuntiva a fresco. O caso é discutido com os achados na literatura e os autores chamam a atençäo para os diagnóticos diferenciais

Effect of drug treatment on electroneurological measures of peripheral nerve function in leprosy patients.

OBJECTIVE: To investigate whether drug treatment improves the electroneurological measures of affected peripheral nerve function in leprosy patients. DESIGN: Clinical status of patients determined on the first visit by an investigator administered, pre-designed questionnaire, followed by measurement of motor conduction velocity (MCV) and distal latency (DL) of ulnar, median, common peroneal and posterior tibial nerves bilaterally in patients referred consecutively from the dermatology unit and leprosy clinic, Teaching Hospital, Galle. MCV and DL measurements were repeated after 6 to 12 months of treatment. SETTING: Department of Physiology, Faculty of Medicine, University of Ruhuna, Galle. SUBJECTS: 24 diagnosed leprosy patients; tuberculoid, lepromatous and borderline in clinical type. INTERVENTIONS: Based on clinical typing. Tuberculoid (paucibacillary) type rifampicin 600 mg monthly and dapsone 100 mg daily for six months. Lepromatous and borderline (multibacillary) type rifampicin 600 mg and clofazimine 300 mg monthly and dapsone 100 mg and clofazimine 50 mg daily for 24 months. RESULTS: DL in all 4 nerves and MCV in 3 nerves tested were significantly different (p > 0.001) to those for the normal population and remained so after 6 to 12 months of treatment. The DL in the ulnar nerve showed significant improvement (p < 0.05) after treatment. When analysed in each patient individually, before and after treatment, the MCV showed an improvement in 48 to 72% of patients and the DL in 41 to 59%, but differences were not significant. CONCLUSIONS: Electroneurological recovery (return to normal state) of the affected peripheral nerves of leprosy patients does not occur after 6 to 12 months of drug treatment. The significant (p < 0.05) improvement (becoming better) of ulnar nerve DL indicates that, if at all, electroneurologically detectable improvement of nerve function occurs in the early stages of nerve damage, and that it may take longer than one year after starting treatment.

In vitro and in vivo interactions of drugs used in multidrug therapy in leprosy.

Interactions of different drugs commonly used in multiple drug therapy were evaluated using both in vitro culture (cell-free as well as macrophage) system and mouse footpad. No additive effects were obtained in the in vitro system when dapsone was combined with either rifampicin or clofazimine, while a strong antagonism was observed when clofazimine was combined with rifampicin but not with rifabutin. In the mouse footpad system, a strong synergism was obtained when clofazimine was combined with either rifampicin or rifabutin, but significant antagonism was observed with the combination of clofazimine and dapsone.

A comparative study of the efficacy of WHO and IAL multidrug therapy regimens for leprosy--an in-vivo and in-vitro study.

In the absence of definite evidence on utility of intensive therapy with rifampicin in multibacillary leprosy cases, a laboratory based investigation was undertaken basically to compare the efficacy of WHO and IAL regimens. In each group 4 untreated BL-LL patients were included and their skin biopsies were subjected for viability test both in vitro and in vivo systems. A consistant fall in BI with good clinical improvement was observed in both the groups. However good viability was maintained till about third pulse dose in WHO group whereas under IAL group rapid fall in viability was observed after intensive phase. Viable bacilli were seen even after 12,15,18 and 24 doses in both groups. These findings question the need for additional 21 doses of rifampicin in IAL schedule. However such studies are to be repeated on larger samples.

L.D.H. isoenzymes sub-unit ratio in leprosy and the effect of clofazimine treatment on L.D.H. isoenzymes sub-unit.

The clinical material for our studies of serum total LDH activity and LDH isoenzymes in leprosy included 255 patients consisting of Tuberculoid (74), Lepromatous leprosy (116), and Lepromatous leprosy with lepra reaction (65). 20 patients with suspected DDS resistance and repeated attacks of lepra reactions were selected for Clofazimine studies. All leprosy patients exhibited higher total LDH activity as compared to normals. M/H ratio was significantly increased in patients of Lepromatous leprosy and correlated closely with the clinical severity and advancement of disease. Tuberculoid leprosy patients showed values close to normals. Hence M/H ratio could demarcate two polar types of leprosy i.e. Tuberculoid and Lepromatous leprosy. Clofazimine treatment over a period of one year in patients with suspected DDS resistance and repeated attacks of lepra reaction decreased total LDH activity and M/H ratio considerably. Fall in M/H ratio during Clofazimine treatment could be attributed to the clearance of 'M' subunits by the drug due to removal of blockade of R.E.S. system produced by lepra bacilli.