Of pyrazinamide

In many other cases, hydrolysis results in drug inactivation, as with the tuberculostatic agent pyrazinamide (4.69). In humans and rats, the metabolism of this compound involves deamidation to produce pyrazinoic acid (4.70). Ring oxidation is another major pathway, leading to 5-hydroxypyrazinamide (4.71), which, in turn, is hydrolyzed to 5-hydroxypyrazinoic acid (4.72). The rates of hydrolysis were found to determine the apparent half-life of pyrazinamide [42] [43]. 

C. Raynaud, M. A. Laneelle, R. H. Senaratne, P. Draper, G. Laneelle, M. Daffe, Mechanisms of Pyrazinamide Resistance in Mycobacteria Importance of Lack of Uptake in Addition to Lack of Pyrazinamidase Activity Microbiology 1999, 145, 1359-1367. 

Alternative dosing Alternatively, a twice weekly dosing regimen (50 to 70 mg/kg twice weekly based on lean body weight) has been developed to promote patient compliance on an outpatient basis. In studies evaluating the twice weekly regimen, doses of pyrazinamide in excess of 3 g twice weekly have been administered without an increased incidence of adverse reactions. 

Hepatotoxicity is the major concern in 15% of pyrazinamide recipients. It also can inhibit excretion of urates, resulting in hyperuricemia. Nearly all patients taking pyrazinamide develop hyperuricemia and possibly acute gouty arthritis. Other adverse effects include nausea, vomiting, anorexia, drug fever, and malaise. Pyrazinamide is not recommended for use during pregnancy. 

Fixed dose combination of pyrazinamide with other antitubercular drugs except combination of pyrazinamide with rifampicin and INH as per recommended daily dose given below ... 

Pyrazinamide is converted to pyrazinoic acid—the active form of the drug—by mycobacterial pyrazinamidase, which is encoded by pncA. The drug target and mechanism of action are unknown. Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA that impair conversion of pyrazinamide to its active form. 

Major adverse effects of pyrazinamide include hepatotoxicity (in 1-5% of patients), nausea, vomiting, drug fever, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy. Hyperuricemia may provoke acute gouty arthritis. 

Isoniazid (INH), rifampin, pyrazinamide, ethambutol, and streptomycin are the five first-line agents for treatment of tuberculosis (Table 47-1). Isoniazid and rifampin are the two most active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95-98% of cases of tuberculosis caused by susceptible strains. The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2 months allows the total duration of therapy to be reduced to 6 months without loss of efficacy (Table 47-2). In practice, therapy is initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin until susceptibility of the clinical isolate has been determined. Neither ethambutol nor streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if either drug is used), but they do provide additional coverage should the isolate prove to be resistant to isoniazid, rifampin, or both. Unfortunately, such resistance occurs in up to 10% of cases in the United States. Most patients with tuberculosis can be treated entirely as outpatients, with... 

The amides of pyrazine-2-carboxylic acids and -2,3-dicarboxylic acids undergo the Hofmann reaction. In the case of the conversion of pyrazinamide to aminopyrazine (Scheme 20), the intermediate sodium carbamate can be isolated.219 Pyrazinamides react with phosphoryl chloride to give the corresponding cyanopyra-... 

This process was undoubtedly developed for the manufacture of pyrazinamide (Zinamide, etc.),1696 a second-line drug for Mycobacterium tuberculosis infections, resistant to more effective and less toxic agents. Thus a mixture of 2-methyl-pyrazine (323), ammonia, oxygen, and steam is passed (at 400°C) over an alumina- or pumice-supported catalyst comprising one to three oxides of Ce, Cr, Mo, Mn, P, Sb, Ti, or (most importantly) V the main product (in up to 90% yield) is 2-pyrazinecarbonitrile (324), easily converted into 2-pyrazinecarboxamide... 

The first synthesis of phosphorylated analogues of pyrazinamides such as substituted pyrazines containing two phosphonate groups (2,5-position) (269) and pyrazines containing one phosphonate group (2-position) (270) has been elaborated. The synthesis is based on thermal ring opening of 2H-azirines (271) followed by dimerization of unstable nitrile ylide intermediates (272) (Scheme... 

Adverse effects include hyperuricaemia and arthralgia, which is relatively frequent with daily but less so with intermittent dosing and, unlike gout, affects both large and small joints. Pyrazinoic acid, the principal metabolite of pyrazinamide, inhibits renal tubular secretion of urate. Symptomatic treatment with an NSAID is usually sufficient and it is rarely necessary to discontinue pyrazinamide because of arthralgia. Hepatitis, which was particularly associated with high doses, is not a problem with modern short-course schedules. Sideroblastic anaemia and urticaria also occur. 

There is continuing concern about the hepatotoxicity of the combination of pyrazinamide with rifampicin for the treatment of latent pulmonary tuberculosis. Among 148 who... 

Pyrazinamide is distributed throughout the body. Peak plasma concentrations are reached 2 hours after oral administration. Excretion is primarily by glomerular filtration. Serum concentrations are generally 30-50 gg/ml with daily doses of 20-25 mg/kg. The maximum daily dose should not exceed 3 g, regardless of weight. At a pH of 5.5, the minimal inhibitory concentration of pyrazinamide for Mycobacterium tuberculosis is 20 pg/ml (1). 

The combination of pyrazinamide plus levofloxacin is first-line treatment for multidrug-resistant latent tuberculosis. In 17 Canadian patients there were important adverse reactions affecting the musculoskeletal and central nervous systems hyperuricemia, gastrointestinal effects, and dermatological effects were also common (3). This combination may be used with careful monitoring for adverse effects. 

Acute sjmptomatic hjrpertension consistently followed the administration of pyrazinamide to a 65-year-old woman with pulmonary tuberculosis (4). 

Liver damage is the most common adverse effect of pyrazinamide (6). It varies from asymptomatic alteration of hver function detectable only by laboratory tests, through a mild syndrome characterized by fever, anorexia, malaise, hver tenderness, hepatomegaly, and splenomegaly, to more serious reactions with clinical jaundice, and finally the rare form with progressive acute yellow atrophy and death. As most patients take a combined regimen of pjrazinamide with isoniazid and rifampicin, it is difficult to determine which of the three drugs causes the hepatotoxicity it could be due to a combined effect (7). As with isoniazid and rifampicin, hepatic function should initially be monitored every few weeks. 

In one case, erythema multiforme and urticaria occurred together after administration of pyrazinamide, and there were circulating immune complexes (9). 

Pretet S, Perdrizet S. La toxidte du pyrazinamide dans ies traitements antitubercuieux. [Toxicity of pyrazinamide in antituberculous treatments.] Rev Fr Mai Respir 1980 8(4) 307-30. 

Goldberg J, Moreno F, Barbara J. Acute hypertension as an adverse effect of pyrazinamide. JAMA 1997 277(17) 1356. 

Peloquin CA, Bulpitt AE, Jaresko GS, et al. Pharmacokinetics of pyrazinamide under fasting conditions, with food, and with antacids. Pharmacotherapy 1998 18 1205-1211. 

The target of pyrazinamide is the mycobacterial fatty acid synthase I gene involved in mycolic acid biosynthesis. Resistance develops rapidly if pyrazinamide is used alone. 

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