Isoniazid active

Pierattelli R, L Banci, NA Eady, J Bodiguel, JN Jones, PCE Moody, EL Raven, B Jamart-Gregoire, K A Brown (2004) Enzyme-catalyzed mechanism of isoniazide activation in Class I and Class III peroxidases. J Biol Chem 279 39000-39009. 

Timmins GS, S Master, F Rusnak, V Deretic (2004) Nitric oxide generated from isoniazid activation by KatG source of nitric oxide and activity against tunerculosis. Antimicrob Agents Chemother 48 3006-3009. 

Pierattelli R, Banci L, Eady NAJ, Bodiguel J, Jones JN, 38. Moody PCE, Raven EL, Jamart-Gregoire B, Brown KA. Enzyme-catalyzed mechanism of isoniazid activation in class 1 and 39. class 111 peroxidases. J. Biol. Chem. 2004 279(37) 39000-39009. 

Wei, C.J., Lei, B., Musser, J.M., and Tu, S.C. (2003) Isoniazid activation defects in recombinant Mycobacterium tuberculosis catalase-peroxidase (KatG) mutants evident in InhA inhibitor production. Antimicrob. Agents. Chemother. 47, 670-675. 

Over 250 analogues of the B vitamers have been reported (11,100). Nearly all have low vitamin B activity and some show antagonism. Among these are the 4-deshydroxy analogue, pyridoxine 4-ethers, and 4-amino-5-hydroxymeth5i-2-methyipyrimidine, a biosynthetic precursor to thiamine. StmcturaHy unrelated antagonists include dmgs such as isoniazid, cycloserine, and penicillamine, which are known to bind to pyridoxal enzyme active sites (4). 

Substitution of an amino group into the molecule affords an iigent with antibacterial activity. Although seldom used alone, l, ira- aminosalicylic acid (PAS, 7) has been employed as an adjunct Id streptomycin and isoniazid in treatment of tuberculosis. 

A/-acetyltransferase 2 Low activity in about 60% of Caucasian populations. High incidence of adverse events from the drug isoniazide in slow acetylators. 

Most aiititubercular drag s are bacteriostatic (slow or retard the growth of bacteria) against the M. tuberculosis bacillus. These dm usually act to inhibit bacterial cell wall synthesis, which slows the multiplication rate of the bacteria. Only isoniazid is bactericidal, with rifampin and streptomycin having some bactericidal activity. 

Aiititubercular drug s are used in combination with other aiititubercular dm to treat active tuberculosis. Isoniazid (INH) is the only aiititubercular drug used alone While isoniazid is used in combination with other drains for the treatment of primary tuberculosis, a primary use is in preventive therapy (prophylaxis) against tuberculosis. For example, when a diagnosis of tuberculosis is present, family members of the infected individual must be given prophylactic treatment with isoniazid for 6 months to 1 year. Display 12-1 identifies prophylactic uses for isoniazid. 

Stiepton dn was isolated by Waksman in 1944, and its activity against M tuberculosis ensured its use as a primaiy ding in the treatment of tuberculosis. Unfortunately, its ototoxicity and the rapid development of resistance have tended to modify its usefulness, and although it still remains a front-hne dmg against tuberculosis it is usually used in combination with isoniazid and p(4)-aminosalicyhc acid (section 11.5). Streptomycin also shows activity against other types of bacteria,... 

Pyrazinamide is a structural analogue of isoniazid and is converted to the active acid derivative intracellularly by a nicotinamidase. Pyrazinamide resistance has been linked to reduced levels of nicotinamidase but the genetic determinants of resistance have not been fully elucidated. 

With the exception of tranylcypromine (a phenylcycloalkylamine), the first MAOIs (e.g. iproniazid, isoniazid, phenelzine, isocarboxazid) were derivatives of hydrazine (originally used as a rocket fuel) (Fig. 20.2). All are irreversible inhibitors of the enzyme and restoration of MAO activity requires the synthesis of new enzyme. 

Vitamin K is a fat-soluble vitamin cofactor for the activation of factors II, VII, IX, and X in the liver. Almost all neonates are vitamin K-deficient at as a result of (1) insignificant transplacental vitamin K crossover, (2) lack of colonization of the colon by vitamin K-producing bacteria, and (3) inadequate dietary vitamin K intake (especially in breast-fed infants because human milk contains less vitamin K than infant formula or cow s milk). Vitamin K-deficiency bleeding (VKDB) refers to bleeding attributable to vitamin K deficiency within first 6 months of life. It occurs in three general time frames early (0-24 hours), classic (1-7 days), and late (2-12 weeks). Early onset occurs rarely and usually is associated with maternal ingestion of anticonvulsants, rifampin, isoniazid, and warfarin. Classic vitamin K-dependent bleeding usually results from the lack of prophylactic vitamin K administration in... 

Isoniazid is used for treating LTBI.2,6,12,28 Typically, isoniazid 300 mg daily (5-10 mg/kg of body weight) is given alone for 9 months. Lower doses usually are less effective.2,31 The treatment of LTBI reduces a person s lifetime risk of active TB from about 10% to about 1%20 (Table 72-2). Rifampin 600 mg... 

The prodrug isoniazid (34) targets M. tuberculosis InhA [3] after activation by a mycobacterial catalase-peroxidase by reacting irreversibly with the cofactor nicotinamide adenine dinucleotide (NAD). This covalent adduct... 

Direct InhA inhibitors have also been sought to avoid isoniazid resistance mediated by catalase-peroxidase mutation. Lipophilic analogs of triclosan such as 36 show a nanomolar K on the enzyme with an MIC of 1-2 pg/mL on isoniazid-resistant strains [56]. Structure-based optimization of two separate HTS leads afforded 37 and 38, both submicromolar inhibitors of InhA but devoid of any significant antibacterial activity [57,58],... 

The answer is b. (Hardmanr p 1158.) Isoniazid inhibits cell-wall synthesis in mycobacteria. Increasing vitamin B6 levels prevents complications associated with this inhibition, including peripheral neuritis, insomnia, restlessness, muscle twitching, urinary retention, convulsions, and psychosis, without affecting the antimycobacterial activity of INH. 

Hofstra AH, Li-Muller SM, Uetrecht JP. Metabolism of isoniazid by activated leukocytes. Possible role in drug-induced lupus. Drug Metab Dispos 1992 20(2) 205-210. 

The activity of rifampicin against mycobacteria has been intensively studied [430—432] both in vivo and in vitro, as has its activity in combination with other drugs such as isoniazid [433] and ethambutol [434]. 

Aminosalicylic acid is a bacteriostatic that inhibits most tuberculous mycobacteria, hi terms of tuberculostatic activity it is inferior to isoniazid and streptomycin. It is nephro-and hepatotoxic, and is rarely used. A synonym of this drug is apacizin. 

Drugs that may affect APAP include barbiturates, carbamazepine, hydantoins, isoniazid, rifampin, sulfinpyrazone, ethyl alcohol, and activated charcoal. 

Pharmacology Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels, isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. 

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