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PubMed1983

Mutagenic activity of antileprosy drugs and their derivatives.

We tested the mutagenic activity of antileprosy drugs (clofazimine, ethionamide, prothionamide, prothionamide-S-oxide, rifampin, and dapsone and many of its derivatives) using the Ames Salmonella/microsome assay system. None of these, including N-acetylated and N-hydroxylated derivatives of dapsone, were found to be positive with or without metabolic activation of this test. However, the sulfoxide and sulfide analogs of dapsone were found to be mutagenic with metabolic activation. These two analogs could not be detected in pharmaceutical preparations of dapsone (less than 0.01%), nor could they be found (in either unconjugated or conjugated form) in urine from volunteers taking a single oral dose of 50 mg of dapsone or from patients receiving daily oral doses of 100 mg of dapsone. Also, urine concentrates from volunteers taking 50 mg of dapsone did not exhibit mutagenic activity in the Ames screen. These results indicate that patients receiving antileprosy therapy with clofazimine, dapsone, ethionamide, prothionamide, and/or rifampin are not being exposed to mutagenic (and thereby possible carcinogenic) drugs.

Clofazimine↗
PubMedDate not supplied

[Pharmaco-toxocologic study of the anti-tuberculosis preparation prothionimide].

Investigations of prothionamide effected on different animal species showed the drug to be of low toxicity. In relatively big doses it produced adynamia, hypothermy and a fall of arterial pressure. When employed in doses much higher (by 10-20 times) than therapeutic ones for humans prothionamide, when used repeatedly, may exercise a hepatotoxic action.

Animals↗
PubMed1988

Activity of ofloxacin against Mycobacterium leprae in the mouse.

Mice inoculated with 4800 Mycobacterium leprae in the left hind foot pad were treated from day 62 to day 150 after infection with 50 mg or 150 mg of ofloxacin per kg body weight, 150 mg pefloxacin per kg, or 50 mg prothionamide per kg. These drugs were administered by esophageal cannula 5 days weekly with dapsone (0.01 g per 100 g diet). Multiplication of M. leprae in the treated and in untreated control mice was assessed by monthly harvests. The treatment of mice with the smaller dosage ofloxacin, with pefloxacin, prothionamide, or dapsone uniformly resulted in a delay of multiplication of 4 months, compared to the multiplication of M. leprae in the untreated controls. The delay of multiplication (4 months) being 1 month longer than the duration of drug administration (3 months), all of the treatments may be considered as bacteriopausal or moderately bactericidal. In contast with these results, treatment of mice with 150 mg ofloxacin per kg resulted in no growth of the organisms whatever as late as 18 months after inoculation, strongly suggesting that, in that dosage, ofloxacin had killed all of the M. leprae. Such a profound killing activity has been observed only with rifampin. Although the pharmacokinetic characteristics of ofloxacin are different in man from those in the mouse, the daily dosage of 150 mg ofloxacin per kg body weight in the mouse is equivalent to 400 mg per day in man which is the usual therapeutic dosage; thus, the results obtained in the mouse may be extrapolated to man. Therefore, ofloxacin appears a very promising drug for the chemotherapy of leprosy.

Animals↗
PubMed1984

Comparative study of two regimens of combined chemotherapy of one year duration in multibacillary leprosy. Results after four and five years' follow-up.

Two therapeutic regimens of one-year duration were administered to two groups of 20 previously untreated multibacillary leprosy patients. Regimen A was rifampin 600 mg twice weekly, prothionamide 500 mg, and dapsone (DDS) 100 mg daily for six months, followed by 100 mg DDS daily for another six months. Regimen B was identical to Regimen A but without prothionamide. Follow-up was for 4 1/2 and 5 years in 15 and 14 patients, respectively. Clinical improvement was rapid, and the bacterial index (BI) of the patients diminished by one unit per year after stopping treatment. Five patients were skin-smear negative at 54 months. The BI in the nasal mucosa became negative after 48 months. There were many attacks of erythema nodosum leprosum between month 3 of treatment until 13 and 21 months. Up to now no relapses have been observed. These results have confidence limits of 20% and 23%, respectively. However, when the results of the two regimens are added, the confidence limit for six months' twice weekly rifampin together with DDS and followed by six months of DDS and 4 1/2 years follow-up is 12%.

Adolescent↗
PubMedDate not supplied

[Experimental study of 2d order tuberculostatic preparations in Mycobacterium bovis resistance to isoniazid or streptomycin (based on the data from a morphological study)].

A comparative study on the therapeutic value of the II line drugs (ethoxide, prothionamide, cycloserin) and bacteriostatics (ethambutol anf rifampicin), with their action upon experimental tuberculosis produced by streptomycin- or isoniazid-resistant mycobacteria of the bovine type, was carried out. This showed rifampicin and ethambutol to be mose effective. Ethoxide and prothionamide proved more efficient when acting upon isoniazid-resistant strains. Cycloserin turned out to be virtually inactive with regard to both streptomycin- and isoniazid-resistant mycobacteria.

Animals↗
PubMed2005

Multidrug-resistant tuberculosis in Russia: clinical characteristics, analysis of second-line drug resistance and development of standardized therapy.

The aim of the study presented here was to identify patients with multidrug resistant tuberculosis (MDRTB) in the Samara region of Russia and to analyze the susceptibility of their isolates to second-line drugs in order to develop an empirical, standard, second-line treatment regimen. Treatment of MDRTB can be individualized based on in vitro laboratory analysis or standardized. In the latter case there is still a need to ascertain local second-line drug-resistance patterns. Described here are the clinical characteristics of 251 MDRTB patients identified in the study and the second-line drug susceptibility of 69 MDRTB isolates obtained from them. Antimicrobial resistance to the following agents was detected in the isolates: rifabutin (88.2%), streptomycin (42.8%), amikacin (7.2%), doxycycline (7.4%), ciprofloxacin (4.3%), clofazimine (2.9%), cycloserine (7.4%), and prothionamide (1.5%). The results of the study indicate it is possible to develop a standard, effective, clinical treatment regimen using ethambutol, pyrazinamide, prothionamide, a fluoroquinolone and amikacin.

Anti-Bacterial Agents↗
PubMed1999

Serum pharmacokinetics of antimycobacterial drugs in patients with multidrug-resistant tuberculosis during therapy.

Serum samples of 13 patients with multidrug-resistant tuberculosis were taken 0, 1, 2, 4, 8 h after administration of antimycobacterial drugs for assay of levels in order to gain further insight into their basic pharmacokinetics. The drugs assessed were amikacin, kanamycin, ofloxacin, levofloxacin, para-aminosalicylic acid, prothionamide, cycloserine, pyrazinamide and ethambutol. Techniques used for assay were reversephase high-performance liquid chromatography, gas liquid chromatography and fluorescent polarization immunoassay. The results from 12 patients were evaluated. These provided new pharmacokinetic data on high-dose levofloxacin, cycloserine and prothionamide given once daily, and could be useful in guiding the scheduling of drugs. The data obtained might also lead to insights into the development of therapeutic drug monitoring in multidrug-resistant tuberculosis.

Adult↗
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↗
PubMed1986

[Tuberculostatics-induced systemic lupus erythematosus].

Clinical manifestations including rheumatoid changes, lymph node swelling, fever, butterfly rash, anaemia and leukopenia had developed gradually over a period of years in a 46-year-old female patient. Due to these findings systemic lupus erythematosus (SLE) was suspected. Further diagnostic procedures revealed concomitant pulmonary tuberculosis. In the course of the tuberculostatic therapy, there occurred six episodes of marked exacerbation of drug-induced SLE signs and symptoms including fever, myalgia, swelling of joints, butterfly rash and high titers of antinuclear antibodies. These exacerbations were induced by single-agent or combination therapy with ethambutol, pyrazinamide, streptomycin and/or prothionamide and resolved readily after discontinuation of the drug(s). With concomitant use of hydroxychloroquine sulfate, a combination therapy with rifampicin and cycloserine did not give rise to further complications although the autoantibodies persisted. This treatment regimen was given until clinical cure was achieved.

Antitubercular Agents↗
PubMed2007

Mechanism of thioamide drug action against tuberculosis and leprosy.

Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target-drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.

Antitubercular Agents↗