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|Year : 1977 | Volume
| Issue : 4 | Page : 181-185
Acceptability of thioamides II. Prothionamide
Department of Tuberculosis and chest diseases, L.L.R.M. Medical College, Meerut-250102., India
D K Gupta
Department of Tuberculosis and chest diseases, L.L.R.M. Medical College, Meerut-250102.
Source of Support: None, Conflict of Interest: None
One hundred and fourteen patients with chronic advanced pulmonary tuberculosis were studied for 6 months to assess the acceptability of prothionamide at different dosage schedules and frequencies of intake of the drug. Gastrointestinal disturbances were most frequently encountered in patients of all the groups. Mild to severe toxic symptoms were recorded in 34.3 per cent, 44.7 per cent and 80 per cent patients receiving the drug in a daily dose of 500 mg, 750 mg and 1 gm respectively in groups A, B and C. At a dose of 500 mg per day, the incidence of toxicity was identical in the two sexes but beyond this dose it was slightly higher in females than in males. Age, chronicity o f illness and extent o f diseases did not have any influence on prothionamide acceptability. Toxic symptoms developed earlier in patients receiving higher doses of the drug.
Prothionamide in a dose of 500 mg per day was very well tolerated by 65.7 per cent of patients and a considerable number of them tolerated a dose of 750 mg per day.
|How to cite this article:|
Gupta D K. Acceptability of thioamides II. Prothionamide. J Postgrad Med 1977;23:181-5
| :: Introduction|| |
Prothionamide is an analogue of the parent substance 'Ethionamide' in which the ethyl group is replaced by a propyl molecule at alpha position. The therapeutic efficacy of the two drugs is almost equal but the former has been claimed to be a better tolerated and less toxic drug than its predecessor ethionamide. ,,,
This drug, prothionamide, was introduced in our country in 1971 . Hence, it was planned to assess the acceptability of this drug in Indian patients and to find out the maximum tolerated dose of the drug. Therapeutic value of the drug has not been considered.
| :: Material and Methods|| |
For this study, 120 patients with chronic advanced pulmonary tuberculosis resistant to primary line of drugs were selected and randomized into following groups:
Group-A: Patients receiving prothionamide 500 mg per day either in a single (Subgroup-A 1 -20 patients) or in two equally divided doses (SubgroupA 2 -25 patients).
Group-B: Patients receiving the drug 750 mg per day either in a single (Subgroup-B I -20 patients) or two divided doses (Subgroup-B 2 -20 patients).
Group-C: Patients receiving 1 gm of the drug either in a single (Subgroup-C 1 -15 patients) or two equally divided doses (Subgroup-C 2 -20 patients).
Prothionamide was given as sugar coated tablets of 250 mg each in combination with ethambutol 800 mg-1 gm once a day before breakfast plus Isoniazid 300 mg once a day. Isoniazid was given conventionally to all the patients.
The criteria for selection of patients, and method of assessment of acceptability of the drug was similar to that discribed earlier. , The patients were followed up for a period of six months.
| :: Bio-data of patients|| |
There were 79 (65.8%) males and 41 (34.2%) females between 20 to over 50 years of age, maximum number of them (83.3%) being in the age group of 20 to 40 years. 96 of 120 (80%/) patients were ill for 1 to 4 years and rest of the 20 per cent patients had chest complaints for over 4. years. 61 of 79 (77.2%) males and 35 of 41 (85.3%) females were suffering for 1 to 4 years. Majority of patients (78.3%) had far-advanced disease with bilateral involvement of lungs in 83 (69.1%). In rest of the patients, the disease was unilateral and moderately advanced.
During the period of study, 6 patients were withdrawn. Two patients each of groups A and B could not be followed up, and 2 patients of group-A could not afford the cost of drugs.
| :: Results|| |
Out of remaining 114 patients of this study, 70 (61.4%) patients complained of one or more, mild or severe toxic symptoms during the period of assessment. Gastrointestinal upsets were more frequently and more consistently encountered in patients of all the groups [Table 2] and [Table 3]. The incidence of toxicity increased with increase in the dose of prothionamide, more often when the drug was given in a single dose than in divided doses, and in females than in males. Age, chronicity of illness and extent of disease did not appear to affect prothionamide acceptability. Toxic symptoms appeared earlier in patients prescribed higher doses of prothionamide [Table 4].
| :: Discussion|| |
In my previous paper,  toxic manifestations due to ethionamide had been observed in 56.6 to 100 per cent patients depending upon different dosage schedules [Table 1]. In the present study, 70 of 114 (61.4%) patients exhibited toxic symptoms, gastrointestinal disturbances being most frequent. 14 of 41 (34.1%), 17 of 38 (42.1%) and 28 of 35 (80%) patients respectively receiving prothionamide in a dose of 500 mg, 750 mg and 1 gm per day in groups A, B and C developed gastrointestinal side-effects. Brouet et al  have reported gastrointestinal disturbances in 29 of 90 (33.3%) patients treated with prothionamide in a dose of 0.5 to 0.75 gm per day. In a follow up study of 4-9 months, Takahashi and Watabiki  observed gastrointestinal upsets in 15 of 30 (50%) patients treated with this drug in a dose of 500 mg per day. This is slightly higher as compared to the result of this study. British Tuberculosis Association's  report of 32 per cent gastric intolerance to 750 mg of drug given in two divided doses is comparable to that of group-B 2 , results. The figure of 80 per cent toxicity with 1 gm prothionamide in group-C of this study is much higher to that of Brouet et al 's 2 7 per cent and Chambatte et al's.  It has been reported that thioamides cause changes in gastric juice acidity towards achlorhydria which may be responsible for some of the gastrointestinal upsets. 
In the present study, neuropsychotoxic reactions were observed infrequently in 2 of 41 (4.8%), 6 of 38 (15.8%) and 9 of 35 (25% ) patients in groups A, B and C respectively. Such manifestations have also been reported. , Similarly, cutaneous lesions due to prothionamide may also occur. , but they are not frequent. Such lesions were observed in 2.44 per cent, 5.2 per cent and 11.4 per cent patients of this study in the three groups A, B and C. It is believed that isoniazid and thioamides (ethionamide) cause cutaneous lesions and psychic disturbances in tuberculosis patients probably due to multiple B-complex deficiencies. ,
However, it is difficult to compare the results of this study with those of other workers because of differences in the type of patients, treatment regimen, method of assessment and racial variations. But females exhibited slightly higher incidence of toxicity than males.  It is also interesting to note that toxicity tended to rise in those who were prescribed prothionamide in a single and high dose than in divided and smaller doses. Age, chronicity and extent of disease did not seem to influence the drug acceptability. Other side-effects of prothionamide such as hepatotoxicity, arthralgia, alopecia, hypoglycemia etc. which are reported in literature, were not encountered in the present study.
| :: References|| |
|1.||British Tuberculosis Association: 'A comparison of the Toxicity of Prothionamide and Ethionamide.' Tubercle. 49: 125-135, 1968. |
|2.||Brouet, G., Chevallier, J. and Nevot, P.' 'Etude preliminaire du (1321-TH) thioamide de l'acide alpha-propyl-isonicotinique clans la tuberculose pulmonaire commune de 1'homme.' Revue de Tuberculose et de Pneumologie. 29: 1187, 162 (Eng. Abst.). |
|3.||Brouet. G., Chevallier, J., Meenus-Bi,h. L. and Nevot, P.: 'Etude clinique cony plementaire du thioamide de 1'acide alpha-propyl-isonicotinique (1321-TH) . Revue de Tubcrculose et de Pneumologie. 29: 133. 1965 (Eng. Abst). |
|4.||Chambatte, C., Kermarec, J., Haguenauer. G., Page, G. and Bach. J. F.' 'Essais clinique du thioamide de 1'acid? alpha-propyl-ieonkkotinique (1321-TH) dans la traitement de la tuberculose humaine. Tolerance toxicite vicerale comparees a celles du 1314-TH (A propos de 21 cas traites pendents deux mois et de 70 cas traites pendents trois mois).' Revue de Tuberculose et de Pneumologie: 29: 33, 1965 (Eng. Abst.) . |
|5.||Co-operative Study Unit on Chemotherapy of Tuberculosis of the National Sanatoria in Japan: `Comparison of the clinical usefulness of Ethionamide and Prothionamide in initial treatment: Tenth series of controlled trials.' Tubercle, 49: 281-2b0, 1968. |
|6.||De Voogd. A. and, Finietz, H. K.: 'Le traitement de la primoirfection par l'association INH-Ethionamide a doses elevees. Impression d'ensemble apre_ deux annees d'experience.' Revue de Tuberculose et de Pneumologie, 26: 340, 1962 (Eng. Abst.). |
|7.||Fox. W., Robinson, D. K., Tall. R., Mitchison, D. A., Kend. P. W. and Macfadyen, D. N.: 'A study cf acute intolerance to ethionamide including a comparison to prothionamide and of the influence of a vitamin B-complex additive in prophylaxis.' Tubercle, 50: 125-143, 1969. |
|8.||Gupta, D. K.: 'Acceptability of thioamide. I. Ethionamide.' J. Postgrad. Med., 23: 175-180, 1977. |
|9.||Gupta, D. K., Agarwal. M. C. and Mital. 0. P.: 'Effects of Ethionamide (TH-1314) and Prothionamide (TH.1321) on gastric juice acidity.' Ind. J. Chest Diseases, 16: 163-170, 1974. |
|10.||Gupta, D. K., Mital. O. P.. Agarwal. M. C., Kansal, H. M. and Nath, S.: 'A comparison of Therapeutic Efficacy and Toxicity of Ethionamide and Prothicnamide in Indian patients.' J. Ind. Med. Assoc.. 68: 25-29. 1977. |
|11.||Molina, C.: 'Les carences vitaminique B chez les tuberculeux pulmonaires traites parles medications antibacillaires.' Semaine des Hospitaux de Paris, 39: 24, 1963 (Eng. Abst.). |
|12.||Takahashi, K. and Watabiki, S.: 'Sideeffects of Prothionamide (1321-TH) and Ethionamide (1314-TH). Japanese J. Chest Diseases, 29: 153-160, 1970. |
[Table 1], [Table 2], [Table 3], [Table 4]