Ethambutol was discovered in 1961. It possesses bacteriostatic action against Mycobacterium tuberculosis; however, the exact mechanism of its action is not known. It inhibits the diffusion of mycotic acid into cell membranes of Mycobacterium smegmatis, which also explains its selective toxicity. Ethambutol is active only against the mycobac-teria Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium scrofu-laceum. The sensitivity of other mycobacteria to ethambutol differs greatly. Practically, every other type of bacteria are resistant to it. Cases of primary resistance to ethambutol are isolated. Secondary resistance originates when the drug is used independently without simultaneous use of another effective antituberculosis drug, such as isoniazid and rifampin. The mechanism of resistance to this drug is not known. Synonyms of ethambu-tol are diambutol, chlorbutinol, tibistal, tubetol, and many others.
Pyrazinamide: Pyrazinamide, pyrazincarboxamide (34.1.11), is synthesized from quinox-aline (34.1.7) by reacting o-phenylendiamine with glyoxal. Oxidation of this compound with sodium permanganate gives pyrazin-2,3-dicarboxylic acid (34.1.8). Decarboxylation of the resulting product by heating gives pyrazin-2-carboxylic acid (34.1.9). Esterifying the resulting acid with methanol in the presence of hydrogen chloride and further reaction of this ester (34.1.10) with ammonia gives pyrazinamide [22-28].
Pyrazinamide was synthesized in 1952, and it is the nitrogen-analog of nicotinamide. It exhibits hepatotoxicity. Synonyms of this drug are dexambutol, miambutol, esnbutol, ebu-tol, and others.
Rifampicin: Rifampicin is 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-methyM-piperazinyl)-formamidoyl]-2,7-(epoxypentadeca-1,11-13-trienimino)-naphtho-[2,1-b] furane-1,11(2H)dion-21 acetate (32.7.8). It is a semisynthetic derivative of rifamicin B, which is synthesized by the actinomycete Streptomyces medit-eranei (Nocardia mediteranei), and was introduced into medical practice in 1968. Rifampicin is described in Chapter 32.
Rifampicin exhibits a bactericidal effect by inhibiting RNA synthesis. It inhibits DNA-dependent RNA polymerase by preventing the initial development of the chain, and not by destroying it. Rifampicin does not bind with RNA polymerase of mammalian cells, and does not have an effect on the corresponding RNA synthesis. It can inhibit mitochondrial RNA synthesis, although the concentrations required for this are several hundred times more than that necessary for RNA synthesis.
Rifampicin is highly active against Mycobacterium tuberculosis. Among atypical mycobacteria, it is active against Mycobacterium kansasii, Mycobacterium marinum, and most types of Mycobacterium scrofulaceum and Mycobacterium xenopi. Sensitivity of other mycobacteria varies. Rifampicin also exhibits activity against Mycobacterium leprae.
Besides mycobacteria, rifampicin also exhibits activity with respect to a large number of organisms. It is highly active with respect to Staphylococcus aureus and nonenterococcal forms of Streptococcus and Listeria monocytogenes. The Gram-negative bacteria that are very sensitive to rifampin are Neisseria meningitides, Haemophilus influenzae, and Legionella. Escherichia coli and Proteus mirabilis are resistant to it. Clostridium and Bacteroids forms of Anaerobic cocci frequently turn out to be sensitive to rifampin.
Rifampicin is the most effective drug for treating pulmonary and nonpulmonary forms of tuberculosis, including tuberculous meningitis. It should always be used in combination with other drugs. Synonyms of this drug are rifadin, rimactan, rifapiam, rimactazide and others.
Streptomycin: Streptomycin, ira«,y-2,4-diguanidino-3,5,6-trihydroxycyclohexyl-5-deoxy-2-0-(2-deoxy-2-methylamino-a-L-glucopyranosyl)-3-C-hydroxymethyl-/i-L-lyxo-pentofu-ranoside (32.4.1), is isolated from a cultural liquid of the vital activity of actinomycete Streptomyces griseus. It is described in Chapter 32.
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