A new class of antituberculosis agents.

Long-chain lipid envelopes are characteristic of mycobacteria such as those that cause tuberculosis and leprosy. Inhibition of fatty acid synthesis or elongation is a strategy demonstrated to be clinically effective against M. tuberculosis. A new class of compounds designed to inhibit the beta-ketoacyl synthase reaction of fatty acid synthesis has been developed. Of >30 compounds described, the most active were acetamides containing alkylsulfonyl substituents. Inhibitory activities were acutely sensitive to net charge, chain length, and degree of unsaturation. The most active compound 5 (alkyl = C(10)) contained a single methylene spacer between the sulfone and carboxamide and exhibited an MIC of 0.75-1.5 microg/mL, comparable to first-line antituberculosis drugs. These compounds are species-specific, exhibiting no significant activity against bacterial species other than M. tuberculosis and closely related strains. The synthesis, biological activity, and specificity of these compounds are described.

In vitro and in vivo activity of K-130, a dihydrofolate reductase inhibitor, against Mycobacterium leprae.

The antimicrobial effects of a new dihydrofolate reductase inhibitor, K-130 (2,4-diaminodiphenyl sulfone substituted 2,4-diamino-5-benzylpyrimidine), alone and in combination with dapsone (CAS 80-08-0) against both dapsone-sensitive and dapsone-resistant strains of Mycobacterium leprae were evaluated in vitro, in cell-free culture system, and in vivo, in mouse foot pads. The minimal inhibitory concentration of K-130 against dapsone-sensitive as well as dapsone resistant strains of M, leprae was 0.03 microgram/ml, and the activity was bactericidal in both cases. However, when combined with dapsone, K-130 exhibited synergism in case of dapsone-sensitive M. leprae, while in case of dapsone-resistant M. leprae, the effect was merely additive. Similar synergistic effects were also observed in the mouse foot pad system for both types of M. leprae strains.

Teoría metabólica de la lepra

Se presenta una concepción etiopatogénica y terapéutica de la Lepra, diferente de la clásica. Texto sencillo y denso, escrito por un leprólogo con "Curriculum Vitae" extenso y destacado. Interesante para quienes deseen conocer más sobre el mal de Hansen. La única objeción de peso que hemos encontrado es que no hay ningún estudio estadístico de casos y controles o ensayos clínicos experimentales (en el libro) que avale lo propuesto por el autor

In vitro effect of DDS on phytohaemagglutinin (PHA) induced linphocyte transformation

Estudou-se o efeito do DDS, sobre a transformaçao linfocitaria estimulada pela PHA, in vitro, utilisando-se concentraçoes variaveis de DDS. Os linfocitos foram doados por voluntarios, divididos em tres gupos, e o estudo foi desenvolvido em tres fases. Foram empregadas 4 concentraçoes diferentes de DDS para 10 a sexta de linfocitos em cultura de tecidos alem de 0,02 ml de PHA. Foi observada uma diminuiçao estatisticamente significativa (P<0,05) no percentual de formaçao de celulas blasticas induzida pela PHA com todas as concentraçoes de DDS, exceto com a concentraçao mais baixa (0,01 ug de DDS). Enquanto que a diminuiçao observada na primeira e na terceira fases mostrou-se dependente de dose de DDS, na segunda fase nao se encontrou correlaçao significativa entre a concentraçao de DDS e a depressao da blastogenese induzida pela PHA. Discute-se a significancia destas observaçoes.

Chromosomal aberrations in leucocyte metaphases of leprosy patients under dapsone therapy

Chromosome analyses were made on leukocyte metaphases of 18 leprosy patients who were ingesting daily doses of 50 mg or 100 mg of DDS and of 40 healthy individuals used for control. These analyses have shown that the proportion of numerical chromosomal aberrations in the leukocyte metaphases of the leprosy patients did not differ significantly from that observed in the cells of the controls. In contrast, the frequency of cells with chromatid or chromosome breaks and gaps was significantly increased in the leukocytesof leprosy patients. Multiple regression analysis applied to the data recorded has shown that the increase of breaks and gaps in the chromosomes of leprosy patients can not be attributed to age, years under sulfonetherapy or to concentration of DDS in blood.

Terapeutica da lepra e farmacogenetica / Leprosy therapy and pharmacogenetics

No presente trabalho foram analisadas algumas características farmacogenéticas que são polimorfismos genéticos humanos e que influenciam a ação da 4,4 - diaminodifenilsulfona (DDS), o medicamento mais amplamente empregado na terapêutica da lepra. Deu-se atenção especial aos polimorfismos da acetiltransferase, da desidrogenase de 6 - fosfato de glicose e da NADH redutase de metemoglobina. Além da revisão e análise crítica da literatura, foram apresentadas sugestões para novas investigações.

Effect of inhibitors on phenoloxidase of Mycobacterium leprae.

Previous results had shown that the human leprosy bacilli possess a phenoloxidase, which, when compared with the enzyme from mammalian and plant sources, seemed unique in the range of substrates utilized and in the nature of the products formed. The effect of several inhibitors on the enzyme in Mycobacterium leprae was tested. Compounds which bind copper were found to be more effective than substrate analogues. Diethyldithiocarbamate penetrated the bacillus and completely suppressed its phenolase activity. Diasone (a derivative of diaminodiphenylsulfone used in the treatment of leprosy) proved to be a potent inhibitor of phenoloxidase of mammalian and plant origin. However, it was less efficient in the case of M. leprae. A biochemical peculiarity of M. leprae was observed in its ability to metabolize mimosine and penicillamine. These compounds produced total inhibition of tyrosinase in melanoma extract and of mushroom tyrosinase. Nontoxic inhibitors of phenoloxidase in the leprosy bacilli may be of value in developing a rational approach to chemotherapy of the disease.