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  IN THIS Article
 ::  Abstract
 ::  Introduction
 ::  Material and Methods
 ::  Bio-data of patients
 ::  Results
 ::  Discussion
 ::  Acknowledgement
 ::  References
 ::  Article Tables

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ARTICLE
Year : 1977  |  Volume : 23  |  Issue : 4  |  Page : 175-180

Acceptability of thioamides I. ethionamide


Department of Tuberculosis and Chest Diseases, L.L.R.M. Medical College, Meerut-250 102., India

Correspondence Address:
D K Gupta
Department of Tuberculosis and Chest Diseases, L.L.R.M. Medical College, Meerut-250 102.
India
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Source of Support: None, Conflict of Interest: None


PMID: 615264

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 :: Abstract 

Eighty four patients of chronic advanced pulmonary tuber­culosis were subjected to determine the acceptability of ethionamide at different dosage schedules and frequencies of intake of the drug over a period of 10 months. Mild to severe side-effects were observed in 56.6 per cent, 70 per cent and 100 per cent patients of groups A, B and C respectively receiving ethionamide in a dose of 500 mg, 750 mg and 1 gm per day. Gastro-intestinal disturbances were most frequently encountered. Toxic symptoms appeared earlier with higher doses of ethionamide. Patients taking the drug in a single dose had had higher incidence of toxicity than those who were prescribed in two divided doses. Pyrazinamide appeared to enhance ethionamide unacceptability. Age, chronicity of illness and extent of disease did not exhibit any influence on ethionamide acceptability.



How to cite this article:
Gupta D K. Acceptability of thioamides I. ethionamide. J Postgrad Med 1977;23:175-80

How to cite this URL:
Gupta D K. Acceptability of thioamides I. ethionamide. J Postgrad Med [serial online] 1977 [cited 2020 Feb 19];23:175-80. Available from: http://www.jpgmonline.com/text.asp?1977/23/4/175/42747



 :: Introduction Top


Soon after the discovery of Isoniazid in 1952, a number of pyridine derivatives were discovered bearing anfi-tuberculosis activity. E'hionamide is a thioamide of alpha-ethyl-isonicotinic acid which possesses potent anti-tuberculosis activity both in vivo and in vitro. However, limitations in clinical usefulness have been described mainly to its gastro-in­testinal intolerance and hepatotoxicity.

In the present study, an effort has been made to assess the acceptability of this drug in Indian patients at different dosage schedules and frequencies of intake. Therapeutic efficacy of the drug has not been considered.


 :: Material and Methods Top


For this study, 91 patients with chronic advanced pulmonary tuberculosis were selected at random. All the patients had clinical, bacteriological and radiological evidence of resistance to standard drugs with which they were treated previously. They were randomised into groups as follows:

Group-A: Patients receiving ethion­amide 500 mg per day either in a single (Subgroup-A l -­14 patients) or two equally divided doses (Subgroup­A 2 -20 patients).

Group-B: Patients receiving 750 mg of the drug in a single (Sub­ group-B 1 -14 patients) or two divided doses (Sub­group-B 2 -18 patients).

Group-C: Patients receiving ethion­amide 1 gm per day in a single (Subgroup-C 1 -10 pa­tients) or two equally divid­ed doses (Subgroup-C 2 -15 patients).

These patients were prescribed one of the following drug regimens:

Regimen-I: Ethionamide + Pyrazin­amide (PZA) 1 gm twice a day after meals + Ethambutol (ETH) 800 mg - 1 gm once a day before breakfast with or without Isoniazid 300 mg once a day.

Regimen-II: Ethionamide + Ethambutol + Isoniazid.

Regimen-III: Ethionamide + Pyrazin­amide + Cycloserine (CYC) 250 mg twice a, day.

Ethionamide was given as sugar coated tablets 250 mg each after proper meals the dose of which was adjusted accord­ing to group and subgroup. Ethambutol, pyrazinamide and Isoniazid were pre­scribed in the same dose as in Regimen-I.

The criteria for selection of the patients, and assessment of acceptability of ethion­amide in these patients was done ever a period of 9 to 10 months as described by Gupta et al. [6]


 :: Bio-data of patients Top


There were 66 males (72.5%) and 25 females (27.5% ) falling in the age range of 20 to over 50 years, maximum number of patients (90.1%) being in the age group of 20 to 40 years. 83 of 91 (91.2%) patients were suffering from the disease for a period of 1 to 4 years and only 8 pa­tients (8.8%) had complaints fog over 4 years. Bilateral involvement of lungs was seen in 57 (62.7%) patients and in the rest the disease was unilateral. 62 (68.1%) patients had far-advenced and 29 (31.9%), moderately advanced disease.

During the follow up period, 4 patients from group-A and 1 patient from group­B could not be followed after the 5th month of treatment. One patient of group­B failed to afford the cost of the drug after the 3rd month and 1 patient of group-C died within a fortnight of ad­mission.


 :: Results Top


Among the remaining 84 patients of this study, ethionamide side-effects were observed in 17 of 30 (56.6% ) and 21 of 30 (70%) patients in groups-A and B respectively, and none of the 24 patients in group-C could tolerate the drug [Table 1]. Toxic manifestations appeared in those patients who were adminis­tered ethionamide in higher doses [Table 2]. It was observed that the incidence of toxicity was enhanced with increase in the dose of ethionamide. Patients who were put on a drug regimen containing pyrazinamide had greater incidence of toxicity than those without it [Table 3]. Age, chronicity of illness and radiologi­cal extent of disease did not affect ethio­namide acceptability. Gastrointestinal disturbances were more frequently notic­ed. Jaundice occurred in 2 patients of group-A who were also taking pyrazina­mide [Table 4].


 :: Discussion Top


Ethionamide is associated with a num­ber of side-effects, such as gastrointesti­nal disturbances and hepatotoxicity, re­ported upto 100 percent. [1],[9],[13] In the present series, toxicity due to ethiona­mide was observed in 56.6 per cent, 70 per cent and 100 per cent of patients in groups A, B and C respectively. These differences are statistically significant at t = 5.9 (p < 0.001). Mild to severe gas­trointestinal disturbances were observed in 53.3 per cent, 66.6 per cent and 100 per cent patients in groups A, B and C respectively which is statistically signi­ficant at t = 5.7 (p < 0.00.1). All the patients in group-C necessitated either re­duction in the dose or withdrawal of the drug. In subgroup-A 1 , the incidence of toxicity was 55.5 per cent in males and 75 per cent in females. When the drug was given in divided doses (subgroup­A 2 ), the incidence fell to 50 per cent in males and 60 per cent in females. Simi­larly, in the subgroup-B 1 , the incidence was much higher (70% in males and 100% in females) but when the drug was prescribed in divided doses in the sub­group-B 2 , the toxicity was noticed only in 61 per cent of males and 75 per cent of females. A slightly higher incidence of eithionamide induced side-effects in females than in males have also been re­ported in literature. [4],[14] Toxic manifesta­tions developed earlier with higher doses of the drug. Gupta et al [5] have reported alterations in gastric juice acidity follow­ing oral administration of thiomides to­wards achlorhydria which may be res­ponsible for at least some of the gastro­intestinal disturbances.

Patients who were prescribed pyrazi­namide containing regimes exhibited higher incidence of toxicity than those without it. 12 out of 18 (66.6%) and 13 out of 16 (81.2%) patients in group A and B respectively, who were also taking pyrazinamide, developed toxic manifes­tations as compared to 5 out of 12 (41.6%) and 8 out of 14 (57.1%) patients without it in the two groups. Pyrazina­mide itself is known to cause gastrointes­tinal and hepatic disturbances.

Hepatic damage or insufficiency as manifested by clinical jaundice or ab­normal liver functions due to ethiona­mide have been reported by various authors. [2],[3],[7],[10] In this series, 2 patients of group-A developed clinical jaundice which was supposed to be due to ethio­namide. As we could not carry out estim­ations of serum transaminases, a correct figure of liver damage due to ethionamide could not be assessed.

Neuropsychotoxic reactions which manifested itself by headache, insomnia, sleepiness, depression, paraesthesia, ting­ling and numbness were observed in 4 out of 30 (30%), 8 out of 30 (26.6%) and 5 out of 24 (20.85) patients in groups A B and C respectively but none of then necessitated interruption of the therapy. Patients who took the drug for longer time were more prone to develop these side-effects. Result of this series are a little higher as compared to others [1],[8] because of the methods of assessment. Narang [11] has reported a case of acute psychotic reactions probably caused by ethionamide who committed suicide.

Like other reports, some minor side-­effects were also encountered in this study. Cutaneous lesions such as rashes, itching and pigmentation [1],[8] were noticed in 3 out of 30 (10% ) and 3 out of 30 (10%) patients of groups A and B res­pectively. Alopecia [1] and non-toxic goiter [12] have occasionally been reported. One patient receiving ethionamide 500 mg per day developed alopecia and an­other patient in subgroup A, developed ethionamide induced goitre.

In conclusion, ethionamide in a dose of 500 mg per day was tolerated by only 43.4 per cent of patients and increase in the dose beyond this was associated with higher incidence of toxic manifestations. None of the patients in this study could tolerate the drug in a dose of 1 gm per day. However, because of small number of patients distributed in various sub­groups, a large series trial is required.


 :: Acknowledgement Top


I am thankful to Mr. S. K. Bajpai, Lecturer in Statistics and Demography Department of Obstetrics and Gynaeco­logy, Medical College, Meerut for statis­tical analysis.

 
 :: References Top

1.British Tuberculosis Association: A com­parison of the toxicity of Prothionamide and Ethionamide; A Report of the Re­search Committee, Tubercle, 49: 125-135, 1968.  Back to cited text no. 1    
2.Clark, G. B. M. and O'Hea, A. J.: Chro­nic pulmonary tuberculosis-Treatment with ethionamide combined with cyclo­serine or oxytetracycline. Brit. Med. J., 1: €36-638, 1561.  Back to cited text no. 2    
3.Edge, J. R. and Weber. J. C. P.: Ethiona­mide (TH-1314) and Viomycin in the treatment cf resistant pulmonary tuber­culosis. Tubercle, 41: 424-429. 1930.  Back to cited text no. 3    
4.Fox, W., Robinson. D. K.. Ta 1, R., Mit­chison, D. A., Kend, P. W. and Macfad­yen, D. N.: A study of acute intolerance to ethionamide including a comparison with prothionamide and of the influence of a vitamin B-complex additive in pro­phylaxis. Tubercle. 50: 125-143. 1.969.  Back to cited text no. 4    
5.Gupta, D. K., Agarwal, M C. and Mital. 0. P.: Effects of Ethionamide (TH-1314) and Prothionamide (TH-1321) on gastric juice acidity. Indian J. Chest Dis., 16: 163-170. 1974.  Back to cited text no. 5    
6.Gupta. D. K.. Mital, O. P., Agarwal, M. C., Karsal. H. M. and Nath, S.: A comparison. of therapeutic efficacy and toxicity of Ethionamide and Prothiona­mide in Indian patients. J. lnd. Med. Asso., 68: 25 2 9. 1977.  Back to cited text no. 6    
7.Lees, A. W.: Jaundice due to Ethiona­mide. Brit. J. Dis. Chest, 57: 158-121. 1963.  Back to cited text no. 7    
8.Madakoro, K. and Oizumi, K : Compa­rison of anti-tuberculosis activity and side-effects of Prothionamide (TH,1321) and Ethionamide (TH-1314). Japanese J. Chest Dis., 29: 133-140, 1970.  Back to cited text no. 8    
9.Mital, O. P., Agarwal, M. C. and Singh. S. K.: Drug therapy cf resistant cases of Pulmonary tuberculosis, Paper read at XXth Tuberculosis and Chest Diseases Workers Conference. Ahmedabad, 1965, p. 171.  Back to cited text no. 9    
10.Moulding, T. S. and Goldstein, S.: Hepa­totoxicity due to Ethionamide. Amer. Rev. Resp. Dis., 86: 252-2555. 1962.  Back to cited text no. 10    
11.Narang, R. K.: Acute psychotic reactions probably caused by Ethionamide, Tuber­cle, 53: 137-138, 1972.  Back to cited text no. 11    
12.12 . Schiess, J . M . , Allison, R . F . , Inglis. R. M.. White. E. F. and Topperman, S.: The use of Ethionamide in ccmb:ned drug regimens in the retreatment of Isoniazid resistant pulmonary tuberculosis. Amer. Rev. Resp. Dis., 91: 728-737, 1965.  Back to cited text no. 12    
13.Takahashi, K. and Watabiki, S.: Side­effects of Prothionamide (T'H-1321) and Etihioramide (TH-1314). Japanese J. Chess. Dis., 29: 153-160. 1.970.  Back to cited text no. 13    
14.Verbist, L., Prignot, J., Cosemas, J. and Gyselen. A.: Tolerance to Ethionamide and P.A.S. in the original treatment of tuberculosis patients. Scand. J. Rasp. Dis.. 47: 225-235, 1966.  Back to cited text no. 14    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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