Tuberculostatic drugs

The metabolic fate of isoniazid and iproniazid, two isonicotinoylhydra-zides, has been extensively studied, and it has been shown that metabolic hydrolysis represents an important step in their toxification. Isoniazid (4.269) is employed as a first-line tuberculostatic drug, but prolonged therapy is associated in 1 -2% of patients with significant hepatotoxicity. Isoniazid can be metabolized by either of two primary pathways, hydrolysis and direct -acetylation. Isonicotinic acid (4.271), the product of hydrolysis, can be formed either di-... 

Iproniazid (4.272) was originally synthesized as a tuberculostatic drug but was found to be an antidepressant due to its inhibitory effect on monoamine oxidase. However, this compound had to be withdrawn from clinical use due to a high incidence of hepatotoxicity. The metabolism and the mechanism of toxification of iproniazid were found to be comparable to those of... 

It is tuberculostatic drug effective against many atypical mycobacteria also. It acts mainly against rapidly multiplying organisms in the cavities walls. 

Blood urate concentrations can be increased because of reduced excretion of uric acid in patients taking ethambutol (390). This is probably enhanced by combined treatment with isoniazid and pyridoxine. Special attention should be paid when tuberculostatic drug combinations include pyrazinamide. However, severe untoward clinical effects are rare, except in patients with gout or renal insufficiency (391,392). 

The classical model of drug metabolism by acetylation is the tuberculostatic drug isoniacide (isonicotinic acid hy-drazide). The metabolism of isoniazide has two interesting aspects Firstly, non-enzymatic hydrolysis of the acetyl metabolite releases acetylhydrazine, which in turn is toxic. This, then, is an example of detrimental drug metabolism (Figure 2.30a, b). 

The prompt recognition of risk factors for severe complications, namely traumatic catheterization or concurrent cystitis, that increase BCG absorption, and treatment of early adverse effects, is expected to reduce the incidence of severe adverse effects. Severe local and systemic adverse effects can be successfully treated with tuberculostatic drugs for up to 6 months (14). 

Severe local and systemic adverse effects of BCG treatment can be treated successfully with tuberculostatic drugs, to most of which BCG is very susceptible, for up to 6 months (32). The effects of isoniazid on the incidence and severity of adverse effects of intravesical BCG therapy have been analysed in patients who received BCG with (n = 289) and without (n = 190) isoniazid (33). The authors concluded that prophylactic oral administration of isoniazid (300 mg/day with every BCG instillation) caused no reduction in any adverse effect of BCG. In contrast, transient liver function disturbances occurred slightly more often when isoniazid was used. The polymerase chain reaction has been used to monitor BCG in the blood after intravesical BCG instillation (22 patients) as well as after antituberculosis therapy (34). The early and fast diagnosis of BCG in the blood was considered to be potentially valuable in initiating specific early treatment of BCG complications. 

Bagchi, M.C., Maiti, B.C., Mills, D. and Basak, S.G. (2004b) Usefulness of graphical invariants in quantitative structure-activity correlations of tuberculostatic drugs of the isonicotinic add hydrazide type./. Mol. Model, 10, 102-111. 

Isoniazid, one of the most active of the tuberculostatic drugs, was discovered because it had been shown that nicotinamide exerted some tuberculostatic action (J). A deliberate search for more effective but related chemicals revealed that many pyridine derivatives, including congeners of isonicotinic acid, also were active. Further, it was known that the thiosemicarbazones could inhibit the growth of M. tuberculosis. An attempt to synthesize the thiosemicarbazone of isonicotinaldehyde provided, as the first intermediate compound, isonicotinylhydrazine, or isoniazid. 

Cycloserine is an antibiotic (antimycobacterial drug) duly obtained from S. orchidaceus. It is a chemical analogue of D-alanine. It belongs to the second-line tuberculostatic drug, and it also acts as an inhibitor of cell-wall synthesis. It is readily absorbed via the oral administration, and subsequently gets distributed amongst different body tissues and the cerebrospinal fluids (CSF). It is found to be excreted mostly unaltered in urine via glomerular filtration. 

Isoniazid (isonicotinoylhydrazine, inH) (26 R = 4-C5H5N) is a commonly used tuberculostatic drug with an activity increased by the presence of Cu ions. The structure of the mono chelate formed with Cu Cl2 shows the compound to coordinate through the O and N atoms. This same coordination mode is present in an Mn chelate. A report of the preparation and properties of several 1 1 and 2 1 complexes formed with inH and Mn , Fe , Co , Ni , Cu and Zn" has appeared recently. Bridged polymeric structures were concluded for compounds of general form [M(inH)2X2] (X = Cl or Br), but N deprotonation resulted in the more common N—O bidentate behaviour in the compounds [Cu"(in)Cl]H20 and tCu (in)Br]. 

Alpha-picoline (2-picoline 2-methylpryridine) is used for the production of 2-vinylpyridine, which, when copolymerized with butadiene and styrene, produces a product that can be used as a latex adhesive which is used in the manufacture of car tires. Other uses are in the preparation of 2-beta-methoxyethyl-pyridine (known as promintic, an anthelmintic for cattle) and in the synthesis of a 2-picoline quaternary compound (amprolium), which is used against coccidiosis in young poultry. Beta-picoline (3-picoline 3-methylpryridine) can be oxidized to nicotinic acid, which, with the amide form (nicotinamide), belongs to the vitamin B complex both products are widely used to fortify human and animal diets. Gama-picoline (4-picoline 4-methylpyridine) is an intermediate in the manufecture of isonicotinic acid hydra-zide (isoniazide), which is a tuberculostatic drug. 2,6-Lutidine (2,6-dimethylpyridine) can be converted to dipicolinic add, which is used as a stabilizer for hydrogen peroxide and peracetic acid. 

Therefore, in order to obtain the carboxylic acid as the final product, it was proposed to transform the amide using an amidase. The reactions can proceed in a single reactor or in two reactors connected in series. The utility of this method was exemplified by the hydrolysis of 4-cyanopyridine into isonicotinic acid [56], an intermediate in the synthesis of the tuberculostatic drug isoniazid. Nitrilases from Aspergillus niger or Fusarium solani and an amidase from R. erythropolis were chosen for this process, as they exhibited compatible substrate specificities. If the cascade reactions were carried out in two separate reactors, a crude extract from R. erythropolis A4 cells could serve as the amidase source. In a one-pot reaction, the NHase present in this extract would compete with the nitrilase and increase... 

Recently we attempted to prepare monosize PLA particles in micron size range as carriers for potential colloidal drug delivery formulations. We prepared PLA particles in a wide size range of 1-50 im by a conventional solvent evaporation method and its modified form. A tuberculostatic drug (i.e., rifampicin) was loaded in these particles. Here, the preparation procedure, the results of drug loading and release experiments of PLA are briefly presented. Details of these studies can be found elsewhere (90,91). 

This paper describes the formation of reactive intermediates from acetylhydrazine and isopropylhydrazine, hepatotoxic metabolites of the tuberculostatic drug, isoniazid, and the antidepressant drug. 

Trost has utilized the same class of chiral ligands for the conversion of butadiene oxide (54) into a number of useful chiral building blocks, such as 57 (Scheme 14.11) [67, 68]. In the course of reaction optimization studies, naphthyl-substituted ligand 56 proved optimal and led to the formation of 57 in 96% ee (>99% ee after recrystallization). A powerful illustration of the synthetic utility of such optically active building blocks involved the synthesis of several medicinally important agents, including the tuberculostatic drug ethambutol (58) [68]. 

---