Thiacetazone, tuberculosis

The antimicrobial activity of thiosemicarbazones against Mycobacterium tuberculosis in vitro was first reported by Domagk et al. [28] and later confirmed in vivo [29]. Screening revealed that only certain substituted be-nzaldehyde and heterocyclic thiosemicarbazones possess antitubercular activity [30-32]. The most widely used is p-acetamidobenzaldehyde thiosemicarbazone (trivial name = thiacetazone), 1. 

Since the causative organism of leprosy, one of the world s six major diseases, Mycobacterium leprae, is closely related to Mycobacterium tuberculosis, thio-semicarbazones have also been used as second-line drugs in the chemotherapy of leprosy [38]. The most widely used in leprosy treatment has been thiacetazone, and structure-activity relationships for it are similar to those observed for antitubercular thiosemicarbazones [39, 40]. 

Thiacetazone is active against many strains of M. tuberculosis. It is not marketed in the United States. However, because of its low cost, it is used as a first-line agent in East Africa, especially in combination with compounds such as isoniazid. The most common side effects of thiacetazone include GI intolerance and development of rashes. It causes significant ototoxicity, especially when coadministered with streptomycin. Life-threatening hypersensitivity reactions, such as hepatitis, transient marrow aplastic syndromes, neutropenia, and thrombocytopenia, have been reported. 

C. Pyrazinamide is known to cause hyperuricemia and precipitate gouty arthritis. Pyrazinamide-induced gouty arthritis does not respond to uricosuric therapy with probenecid but may respond to acetylsalicylic acid. Cycloserine (A) can cause headaches, confusion, tremors, and seizures, possibly secondary to low levels of magnesium in the cerebrospinal fluid cycloserine should be avoided in patients with epilepsy and mental depression. It is not associated with hyperuricemia. Thiacetazone (B) is an antibiotic that is rarely used in tuberculosis. The most common adverse reactions are general rashes and GI intolerance. Its use is not associated with hy-... 

Kuaban C, Bercion R, Koulla-Shiro S. HIV seroprevalence rate and incidence of adverse skin reactions in adults with pulmonary tuberculosis receiving thiacetazone free... 

Thiacetazone (thioacetazone, thiosemicarbazone) was greeted enthusiastically in 1946 as one of the first synthetic agents against tuberculosis. However, its use rapidly diminished with the increasing observation of untoward effects. It is currently rarely used and then only for economical reasons. Dosages should never exceed 200 mg/day. 

In a retrospective study, 38 cases of toxic epidermal necrolysis were observed in Dakar, and were attributed to thiacetazone in 24 cases 23 died, mainly because of hypovolemic shock during the first week and septic shock during the second (9). Those who died were generally aged over 50 years, had more than 50% skin involvement, and had evolving tuberculosis at the time of presentation or HIV infection. After-effects were vaginal synechia and two cases of blindness. 

Arguments have been advanced for the abandonment of thiacetazone as an antituberculosis drug (11,12), despite its cheapness, on the grounds that it often causes severe skin reactions, some rapidly fatal, in patients infected with HIV-1 (13). The WHO and lUATLD has recommended careful information and surveillance of possible adverse reactions, particularly cutaneous, in patients treated for tuberculosis in such countries and immediate replacement with ethambutol if there are any prodromal signs of toxicity. 

Anergy to tuberculin and lymphopenia have been associated with an increased risk of adverse reactions to thiacetazone. In a randomized study of rifampicin-and thiacetazone-containing regimens in HIV-positive adults with pulmonary tuberculosis, eight of 13 patients who developed adverse reactions were tubercuUn-aner-gic, compared with 12 of 77 patients who did not develop adverse reactions (13). An absolute lymphocyte count below 2.0 X 10 /1 was also associated with adverse reactions. 

Nunn P, Kibuga D, Gathua S, Brindle R, Imahngat A, Wasunna K, Lucas S, GUks C, Omwega M, Were J, McAdam K. Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet 1991 337(8742) 627-30. 

Okwera A, Johnson JL, Vjecha MJ, Wolski K, Whalen CC, Horn D, Huebner R, Mugerwa RD, Ellner JJ. Risk factors for adverse drug reactions during thiacetazone treatment of pulmonary tuberculosis in human immunodeficiency virus infected adults. Int J Tuberc Lung Dis 1997 l(5) 441-5. 

Co-operative study in East Africa by the East African and British Medical Research Councils (1974) A pilot study of two regimens of intermittent thiacetazone plus isoniazid in the treatment of pulmonary tuberculosis in East Africa. Tubercle, 55,211. 

Thiacetazone (150 mg) and isoniazid (300 mg), combined in one daily dose, is a much favoured contemporary treatment of tuberculosis. This combination has less toxicity to the patient than a higher dose of isoniazid alone, and staves off the drug resistance that so often develops when treatment depends on one single drug. One year s therapy seldom fails to cure, and six months usually suffice. Thiacetazone is also used a little in treating leprosy. A serious drawback is a tendency to cause agranulocytosis. 

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