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PubMed1998

Antiproliferative and cytotoxic effects of geldanamycin, cytochalasin E, suramin and thiacetazone in human prostate xenograft tumor histocultures.

PURPOSE: We have shown that the three human prostate xenograft tumors, i.e. the androgen-dependent CWR22 tumor, and the androgen-resistant CWR22R and CWR91 tumors, are comparable to patient tumors in their expression of prostate specific antigen, multidrug resistance p-glycoprotein, p53 and Bcl-2 and in their sensitivity to doxorubicin and paclitaxel. The present study used histocultures of these xenograft tumors to evaluate the antiproliferative and cytotoxic effects of several drugs (geldanamycin, cytochalasin E and thiacetazone), which have diverse action mechanisms and have shown activity against primary cultures of human prostate cancer cells. Suramin, a clinically active compound was included for comparison. Methods. The antiproliferative effect of 96 h drug treatment was measured by inhibition of DNA precursor incorporation, and the cytotoxic or cell kill effect was measured by in situ DNA end labeling of apoptotic and necrotic cells and by reduction of live cell density. RESULTS: The rank order of molar potency was geldanamycin > cytochalasin E > suramin > or = thiacetazone. Thiacetazone produced antiproliferation only in CWR22 tumor and had no cytotoxicity, whereas the other three drugs produced both antiproliferation and cytotoxicity in all three tumors. Geldanamycin, but not cytochalasin E and suramin, showed greater antiproliferation and cytotoxicity in tumor cells compared to normal stromal cells. The two androgen-resistant tumors were 4 to >40-fold less sensitive than the androgen-dependent tumor to drug-induced antiproliferation but were about equally or 4 to >20-fold more sensitive to drug-induced cytotoxicity. The ratios of drug concentrations that produced 50% antiproliferation to the concentrations that produced 50% cytotoxicity ranged from <0.04 to 0.3 in CWR22 tumor, but ranged from 0.3 to 2.7 in CWR22R and CWR91 tumors, indicating a shift from antiproliferation as the predominant drug effect in the androgen-dependent tumor to cytotoxicity in the androgen-resistant tumors. CONCLUSIONS: Our results indicate (a) differential drug effects in human prostate xenograft tumors with antiproliferation and cytotoxicity as the predominant drug effect in the androgen-dependent and androgen-resistant tumors, respectively, (b) that progression of tumors from androgen-dependent state to androgen-resistant state appears to be associated with a lower sensitivity to drug-induced antiproliferation and an equal or greater sensitivity to drug-induced cytotoxicity, and (c) that geldanamycin but not thiacetazone warrants further development.

Animals↗

PubMed1984

Combined and individual effects of isoniazid and thiacetazone on human lymphocyte chromosomes in vitro and in vivo.

Genetic effects of the drugs, isoniazid and thiacetazone used for antituberculosis chemotherapy were investigated on human lymphocyte chromosomes in vitro and in vivo. Therapeutic concentrations of these drugs did not induce chromosome aberrations in vitro both in combination and individually during any of the treatment period in 72 h lymphocyte cultures. At higher concentrations both the drugs were found to be cytotoxic. The frequency of chromosome damage was increased significantly in first-division metaphases of the patients, i.e. in vivo during treatment with isoniazid (300 mg) + thiacetazone (150 mg); this could be due to the synergistic action between the metabolites of the two drugs in the body or due to the metabolites of thiacetazone since isoniazid was found to be nonclastogenic in vivo. The frequency of sister chromatid exchanges was not increased in any of the patients except in one, who probably had a higher baseline level. These results suggest that chromosome aberrations and sister chromatid exchanges represent two different lesions. Chromosome damage induced by drugs could lead to congenital malformations, cancer, ageing and therefore contributes to the overall toxicology of the drugs and hazard to human genetic health. Hence drugs like isoniazid and thiacetazone which induce chromosome damage, should be used with caution.

Cell Division↗

PubMed2002

In vitro activity of thiacetazone on mycobacterial species belonging to the Mycobacterium tuberculosis complex.

Thiacetazone, despite frequent side-effects, may still be considered for the treatment of new tuberculosis cases when there is a shortage of drugs and for the management of multidrug-resistant tuberculosis. Fifty-four strains of M. tuberculosis complex were characterised based on the minimum inhibitory concentration (MIC) of thiacetazone and the growth pattern in the presence of different concentrations of the drug. The results showed that the MIC of thiacetazone to type II M. africanum strains was significantly higher than for other strains in the study (P < 0.01). Thiacetazone showed a paradoxical effect on 63% of strains where lower concentrations exhibited a better inhibiting activity than higher concentrations.

Antitubercular Agents↗

PubMed1991

Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis.

The effects of the human immunodeficiency virus (HIV) on tuberculosis management was investigated in 227 patients initially treated with a regimen containing streptomycin, isoniazid, and thiacetazone (STH). 93 of these 227 were HIV-seropositive. 60 patients, of whom 18 were HIV-seropositive, received a regimen consisting of streptomycin, isoniazid, rifampicin, and pyrazinamide (SHRZ) in the initial phase, and thiacetazone and isoniazid (TH) in the continuation phase. Cutaneous hypersensitivity reactions occurred in 22 of 111 (20%) HIV-seropositive patients, and in 2 of 176 (1%) HIV-seronegative patients (RR = 18, 95% CI 4.4-76, p less than 10(-7]. During the first 8 weeks of treatment 18 reactions occurred among the 93 HIV-seropositive patients on STH, whereas no reaction occurred in 17 HIV-seropositive patients during the initial phase of SHRZ/TH (p = 0.04). None of the 18 HIV-seropositive patients with cutaneous reactions who were subsequently challenged with isoniazid reacted, nor did any of the 10 tested with streptomycin, but 6 of the 7 challenged with thiacetazone reacted. 3 patients (all HIV-positive and with toxic epidermal necrolysis) died as a result of the cutaneous reaction. These results have major implications for tuberculosis control programmes in Africa.

Adult↗

PubMed1980

Thiacetazone skin reaction in Papua New Guinea.

Thiacetazone is used as a first-line antituberculosis drug in most of the developing countries of the South Pacific. Skine reactions are considered the major side effects of this drug. In Papua New Guinea, 2.5% of Melanesian patients who received thiacetazone for the treatment of tuberculosis developed skin reactions. The reaction appears to be caused by hypersensitivity rather than by toxicity and has distinct clinical features. The therapeutic regimen for tuberculosis in the developing countries of the South Pacific is not likely to change in the near future. Recognition of this potentially fatal complication of thiacetazone is important in the mamnagement of patients with tuberculosis in countries where the drug is used.

Adolescent↗

PubMed2001

[Lyell syndrome in Senegal: responsibility of thiacetazone].

INTRODUCTION: Toxic epidermal necrolysis is a severe disease often leading to death or to mucosal, particularly ocular, after effects. The principle drugs responsible are antibacterial sulfonamides, anti-epileptics, non-steroid anti-inflammatories, allopurinol and chlormezanone. We report a series of 38 cases of toxic epidermal necrolysis, observed in Dakar, imputable to thiacetazone and lethal in 60 percent of cases. PATIENTS AND METHODS: Our study was retrospective. Diagnosis of toxic epidermal necrolysis was made in patients presenting more than 30 p. 100 of the epidermis of their total body surface stripped off, multi-orificial mucosal damage and epidermal necrosis revealed on histological examination. Drug imputability was established on classical criteria. Treatment was composed of reanimation and antibiotics. RESULTS: Among the 38 cases of toxic epidermal necrolysis counted, 24 were imputable to thiacetazone. All the patients presented typical clinical features, confirmed histologically. Evolution was lethal in 60 p. 100 of cases. The causes of death were frequently hypovolemic shock during the first week and septic shock during the second. The deceased were generally aged over 50, had more than 50 p. 100 of total epidermis stripped off, presented evolving tuberculosis at the time of the accident and HIV infection at the AIDS stage. After effects were vaginal synechia and 2 cases of blindness. COMMENTS: Our series is exceptional in that a) the drug responsible: thiacetazone, an economic tuberculostatic of minor efficacy, was systematically introduced after 2 months of intensive treatment with 4 major anti-tuberculosis agents; b) the 60 percent mortality rate, two-fold greater that that usually observed. Other than the known elements of poor prognosis in our patients, the treatment conditions of this dermatological emergency explain this high rate of mortality.

Adolescent↗

PubMedDate not supplied

Cutaneous reactions to thiacetazone in Zambia--implications for tuberculosis treatment strategies.

Tuberculosis in patients infected with human immunodeficiency virus (HIV) is a growing threat to public health in Africa. Thiacetazone, one of the continent's most widely used antituberculous agents, may lead to severe cutaneous reactions in the HIV infected individual. We describe the impact of this reaction on the tuberculosis (TB) control programme of a district hospital in Zambia in 1990, and examine the cost implications of changing the standard treatment regime. We carried out a retrospective survey of records of all patients beginning TB treatment in 1990, together with HIV test results and the cost of all treatments given. From this we derived estimates of costs of different regimes which are and could be used in TB control in Zambia. Severe reactions occurred in 18.7% of all HIV seropositive patients receiving thiacetazone, fatally so in 1.2% (odds ratio 16.6). The greatest part of the cost of the current regime is that attributable to the inpatient stay; we estimated that 29.4% of patients would be unable to receive drugs as out-patients but, even allowing for this, rifampicin-based regimes given to outpatients where possible would not cost more than the current strategy. We conclude that ethical and economic considerations support a change to rifampicin-based regimes in areas of Africa where HIV seroprevalence is high.

AIDS-Related Opportunistic Infections↗

PubMed2003

Thiosemicarbazole (thiacetazone-like) compound with activity against Mycobacterium avium in mice.

In vitro screening of thiacetazone derivatives indicated that two derivatives, SRI-286 and SRI-224, inhibited a panel of 25 Mycobacterium avium complex (MAC) isolates at concentrations of 2 micro g/ml or lower. In mice, SRI-224 and thiacetazone had no significant activity against the MAC in livers and spleens, but treatment with SRI-286 resulted in significant reduction of bacterial loads in livers and spleens. A combination of SRI-286 and moxifloxacin was significantly more active than single drug regimens in liver and spleen.

Animals↗

PubMed2001

[Skin toxicity of thiacetazone (TB1) at a hospital service in Dakar].

From 1980 to 1997 we had observed 50 cases of cutaneous side effects of thiacetazone. There were 25 cases of Steven-Jonhson syndrome, 23 cases of Lyell syndrome, a case of erythrodermia and a case of lichenoid toxidermia. The mortality was 40% with 16 cases of Lyell syndrome and 4 cases of Steven Johnson syndrome. Thiacetazone is a minor tuberculostatic drug used widely in the national program against tuberculosis. Our results confirm the seriousness of cutaneous side effects due to this drug. So like in other neighboring countries, we suggest to avoid use of this drug in Senegal.

Adult↗

PubMed1989

Is thiacetazone necessary or useful in the intensive phase of anti-tuberculous chemotherapy?

A retrospective study of 596 case notes of 1195 patients notified for tuberculosis during a three year period, in one district, was conducted. Drug reactions occurred in 75 patients (12.6 percent) and required discontinuation of therapy in 59 (10 percent). In 69 patients the skin was involved. Thiacetazone was by far the commonest drug implicated: two patients died with the Stevens Johnson syndrome. This study suggests that in the all important first two months of anti-tuberculous chemotherapy, thiacetazone, a therapeutically unnecessary agent, should be omitted as its inclusion results in an unacceptably high rate of side effects.

Adult↗

PubMed1975

Comparative trial of thiacetazone with isoniazid and paraaminosalicyclic acid (PAS) with isoniazid in the treatment of pulmonary tuberculosis in Nigerians.

A comparative trial of a combination of thiacetazone 150 mg with isoniazid 300 mg in a once daily dose and that paraaminosalicyclic acid 12 gm uith isoniazid 300 mg daily in divided doses was carried out on 72 specially selected patients with pulmonary tuberculosis over a period of 12 months. The result of the trial showed that patients treated with thiacetazone/isoniazid combination responded equally favourably to therapy as the patients treated with PAS/isoniazid combination. The result of sputum conversion was similar in both groups. Radiological changes after treatment showed a significant similarity in both groups. It was observed that the thiacetazone/isoniazid combination is no more toxic than the PAS/isoniazid combination. There was no case of blood dyscrasia during the trial. Of the 72 patients who started the trial, a total of 19 (26 per cent) patients defaulted before the end of the third month. However, the remaining 53 patients (74 per cent) completed the trial, and the final analysis was based on this number. It was concluded that thiacetazone (150 mg/day) was of similar efficacy when compared with PAS (12 gm/day) as a companion drug for isoniazid (300 mg/day) in producing sputum conversion, and radiological changes in Nigerian tuberculosis patients and is therefore to be preferred because of its relative cheapness and once-a-day administration.

Adolescent↗

PubMed1981

Multiple drug therapy--a comparative study with 2 tier and 3 tier combination of rifampicin, clofazimine, DDS, INAH and thiacetazone in lepromatous cases.

A comparative study with 2 tier and 3 tier combination of Rifampicin, Clofazimine, DDS, INAH and Thiacetazone was conducted on fifty lepromatous leprosy cases for varying periods. Assessment showed that 2 tier combination of clofazimine and DDS produced good results but the cost stood in the way; whereas 3 tier combination of DDS, thiacetazone and INAH also yielded good results with much less expenses to be incurred by the patients. Whether therapy with this 3 tier combination could be continued for a longer period with sustained improvement is yet to be assessed by further studies for a considerable period.

Adolescent↗

PubMed1994

Relapse rates in patients treated with dapsone monotherapy and combinations of dapsone and thiambutosine, thiacetazone, isoniazid and streptomycin in the pre-MDT era.

Relapse rates were studied in patients from northern Thailand who were started on dapsone monotherapy between 1949 and 1976. Included are a group of patients who, for various reasons, also received combinations of dapsone and thiambutosine, thiacetazone, isoniazid and streptomycin. The overall relapse rate in paucibacillary patients on dapsone monotherapy only was 2.7 per 1000 person-years at risk (PYR) (average observation period 13.9 years). In the multibacillary patients who received dapsone monotherapy only, the relapse rate was 10.5 per 1000 PYR (average observation period 12.4 years). In both groups it was found that 50% of the relapses occurred after the seventh year of follow up. The overall relapse rate in those patients whose treatment included thiambutosine, thiacetazone, isoniazid and/or streptomycin for at least 3 months was 17.9 per 1000 PYR (average observation period 11.9 years). The difference with the multibacillary patients treated with dapsone monotherapy only is not significant. It is concluded that alternative antileprosy drugs included in therapy regimens with dapsone in the pre-MDT era did not result in relapses occurring less often.

Dapsone↗

PubMed1978

Thiacetazone toxicity in the treatment of tuberculosis patients in Nigeria.

In a series of 1,212 tuberculosis patients treated on a regime of streptomycin/isoniazid/thiacetazone (S/INH/thiacetazone) over a period of 10 years in Nigeria there were 171 cases considered to have toxic reactions to thiacetazone (14%). 134 of these (11%) were sufficient to require a change of treatment. Giddiness and rashes were the commonest effects, the former occurring mainly in association with streptomycin, and considered to be largely due to potentiation of streptomycin toxicity by thiacetazone. The advantages of the S/INH/thiacetazone regime in Nigeria are considered to outweigh the disadvantages, so long as necessary precautions are taken to keep the effects of toxicity to a minimum.

Adolescent↗

PubMed1997

Risk factors for adverse drug reactions during thiacetazone treatment of pulmonary tuberculosis in human immunodeficiency virus infected adults.

SETTING: Prospective randomised clinical trial comparing the safety and efficacy of rifampicin- and thiacetazone-containing regimens in human immunodeficiency virus (HIV)-infected adults with pulmonary tuberculosis (TB) at the National Tuberculosis Treatment Centre, Kampala, Uganda. OBJECTIVE: To assess demographic, clinical and laboratory risk factors associated with toxicity during treatment with streptomycin, thiacetazone and isoniazid (STH) of HIV-1 infected adults with pulmonary TB. DESIGN: Nested case-control study of all subjects randomized to the STH treatment arm. Baseline demographic, clinical, microbiological, hematological and radiographic characteristics were compared between subjects who developed and those who did not develop adverse drug reactions (ADR). RESULTS: Of the 90 subjects randomized to STH, 13 developed ADR yielding an incidence rate of 19.6 events per 100 person years of observation (PYO). Eleven of the 13 ADR were cutaneous hypersensitivity reactions, including one fatal case of Stevens-Johnson syndrome. Eight of 13 patients who developed ADR were tuberculin anergic, compared to 12 of 77 patients who did not develop ADR (P < 0.001). An absolute lymphocyte count below 2000 cells/mm3 was also associated with ADR (P = 0.02). CONCLUSION: Initial anergy to tuberculin and lymphocytopenia, markers of advanced HIV infection and immunosuppression, were associated with increased risk for adverse drug reactions during STH chemotherapy.

AIDS-Related Opportunistic Infections↗

PubMedDate not supplied

[Cutaneous reactions to thiacetazone (TB1) (author's transl)].

Twelve cases of cutaneous reactions to TB1 (Thiacetazone associated with isoniazid) occurring on tuberculous black patients are reported: 8 of them are severe reactions (one Lyell's syndrome with fatal outcome). The different patterns of cutaneous side effects of Thiacetazone are reviewed.

Adult↗

PubMed1983

Cytogenetic effects of chemotherapy with three combinations of anti-tubercular drugs involving isoniazid, thiacetazone, para-aminosalicylic acid and streptomycin on human lymphocytes: chromosome aberrations, sister chromatid exchanges and mitotic index.

Cytogenetic effects of three combinations of anti-tubercular drugs were evaluated on human lymphocytes in vivo and were compared with controls of two types: (1) newly diagnosed tuberculosis patients before starting therapy and (2) individuals from the general population. The drugs used were: isoniazid (INH), thiacetazone (TAZ), para-aminosalicylic acid (PAS), and streptomycin (SM). These drugs were tested in the following combinations: (a) INH + TAZ + SM, (b) INH + PAS + SM, (c) INH + SM. The frequency of chromosome aberrations was significantly increased in patients treated with both the triple drug combinations, i.e., with INH + TAZ + SM and INH + PAS + SM, whereas patients treated with INH + SM did not exhibit an increase in the frequency of chromosome aberrations as compared to the controls. Although both the triple drug combinations were clastogenic, none of the three drug combinations tested induced an increase in the frequency of sister chromatid exchanges (SCEs). In other words, the mechanisms leading to SCEs and chromosome aberrations may be different. SM appeared to depress the mitotic index in patients treated with INH + SM and INH + PAS + SM, though it was found to possess a mild anti-clastogenic effect. INH + TAZ + SM, on the other hand, enhanced the mitotic index. This enhanced mitotic index was probably due to the presence of TAZ.

Aminosalicylic Acid↗

PubMed1990

Thiacetazone: in vitro activity against Mycobacterium avium and M. tuberculosis.

Bacteriostatic and bactericidal activity of thiacetazone was determined for 68 M. avium clinical isolates and 14 wild drug-susceptible M. tuberculosis strains. The drug had equally low bactericidal activity against both mycobacterial species. The inhibitory activity against most of the M. avium strains was greater than it was against M. tuberculosis. The broth determined MICs for 65 of 68 M. avium strains were between 0.02 and 0.15 micrograms/ml, while the MICs for M. tuberculosis ranged from 0.08 to 1.2 micrograms/ml.

Dose-Response Relationship, Drug↗