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Side effects and toxicity in the combined regimen of thiacetazone and isoniazid in Morocco
58
TUIIF:RCLE SUPPLEMENT
Eight of the patients with generalized rashes had an accompanying stomatitis; a few of tl~em had haemorrhagic features: some of them complained of loss ot'hair and a number of them dcsquana,'~ted. including one who showed some features of cxlbliation. Of those whose rashes were not reported as generalized, two had stomatitis, two showed hacmorrhagic features: one complained of loss of hair and four were tbtlowed by desquamation. An attempt at desensitization was made in 60':'~; of the patients who developed rashes and was successful in 44 3;] (36 ?,~;at tlte tirst attempt). Hypersensitivity was confirmed in 33 ':~,; i/) nine patients there ~tls no confi/-matio/~ ot" the india.idual drug responsible as th.e hypersensitivity was established to tt~c combined tablet only: in seven patients tltiacetazone was confirmed as the offending drug and in two patients both thiacetazone and isoniazid were implit~ated.
ttaematoh~gical Side-<[l~cts In the PH se/-ies one patient developed a ncu~rol:~cnia ~'hich did t~o~ /'cquirc an intcr/-~ption of treatment but in the TH series 'hacmatologicat" side-effects were reported in ii '.',i (16 paticnt, l. One male patient developed agranulocytosis associated witll fc',cr. T:.'eatment was discontinued and his white cell count returned to normal after two weeks, Tt~rec p:tlicnts developed a leucopcnia bul one of them did not require any interruption of lreatment. ]'he remaining 12 patients were teported as h.aving anaemia only. Four of these were withdrawn from the treatment. I n four of tt~r remaining patients reported as having developed anaemia the treatment was iP,tcrrupted but rc'~ttmcd after an interval of two-tlaree weeks. A study of the haemoglobin levels reveals that in the PH series the mean level rose from i1.9 pretreatment to 13.3 at 12 months, but in the TH series it fell from II .9 pretrcatment to 11,5 at 1 2 months and as the patients withdrawn because of anaemia arc not included in th,e 12ttl month calculation, the fall is minimised. Conclusion
Although we had hoped to find a place tk)r this regimen we t]ow lY-el that we canno! recommend it in Hong Kong in view of its toxicity and relative therapeutic infcriority to PAS/ isoniazid (see the report by Horsfilll on page 30).
S I D E E F F E C T S A N D T O X I C I T Y IN "I:1-t1s C O M B I N E D THIACETAZONE
AND
ISONIAZID
REGI3,11~:N O F
IN 51OROCCO
By H, RADt,, A(_, {with F. J. M. BURZONI, " ' IF.J . CHWOU, C . L~:o, " NEt,t,l and F. H PaPILLO,X') fi'om the Service de Lutte Antituberculeuse du Maroc, ; tmlstere tie, la Santd Puhlilue, Rabat.
The combination of thiacetazone with isoniaS'_id in the treatment of tub,.rculosJs was introduced into Morocco in 1960 at the recommendation of Dr. Noel Rist. Later the tinancial supporters of the antituberculosis campaign persuaded the Ministry of Public Health in Morocco to devise a stud), including the combination of thiacetazone with isoniazid in a standardized pla~l of" treatment. In May 1963, the centres whict~ agreed to participate in this study were" Marrakech, Meknes. Rabat and Tangiers. The daily dose was 500 mg. o f isoniazid and I50 rag. thiacetazone in two combined tablets taken once daily t, nder the supervision of the hospital staff: The drug was supplied by t h e Central Pharmacy of the Ministry of Public Health" at the beginning, supplies came by Laboratoires Theraplix, but in 1964, p r o d u c t i o n of the tablets was carried out from bulk powder supplied by Messrs Smith & Nephew. The average duration of treatment ',,,,as 1l m o n t h s : this varied a little from centre to certtre.
SIDE E F F E C T S
IN MO.ROC, CO
59
Ttlere were 36 interruptions of treatment through toxicity, 23 as a result of" skin affections, i I urinary tract or haematological disturbances and there were two deaths. Ttle proportion of serious incidents was therefore 6 ~'.;; of patients treated, 2'.}i; of men and I ! "/,.oof women. Attention was quickly drawn to tile appearance of skin affections of tile erythrodermic type (kyell or Stevens-Johnson syndrome). The predominance of this type of incident in women (141)s compared with only 1 {";, in man) was rather disturbing but, in spite of many hypotheses no conclusion was reached concerning the cause. There was an above-average and disturbing number of incidents at Rabat. The centres could be classified in decreasing order as follows: Rabat, Tangiers, Meknes, Marrakech. The very good tolerance of the patmnt, . ", s at Marrakech should be noted. The blood disorders (in 18"/~ ,,,, which were noticed there, were in the majority of cases only minor; they never resulted in the interruption of treatment. Only I '!ii;had cutaneous reactions, compared with 14'.~.{;in Rabat. The two deaths were not followed by necropsies: ttley were however considered as accidents due to thiacetazone therapy in the absence of other causes. One of tile deaths was of a 40 year old woman weighing 45 kg. who died ti~llowing respiratory l:ailure after 54 days of treatment. The extent of tile lesions did not account For this death. The other was a 33 year old rnan weighing 42 kg. who, after 55 days of treatment, was affected by gastro-intestinal trouble Rfllowed by coma. Anaemia of "3 " ,~,,00,000 red cells per cubic mil[imeler with a haemoglobin of 70 ~ normal was observed at tlie start of treatment. In all the towns, the predominance of incidents in the female sex was so consistent as to require Special mention. Thus, in Marrakech, with tile lowest total incidence, there were no skin eruptions or urinary changes among 142 men, but two eruptions and three urinary abnormalities among 61 women. At Rabat, with the highest incidence, there was only one rash among 54 men and eigllt among 62 women. In all centres there was at higher incidence of eact~ category of side-effect among the women. Patients aged 45 and over showed fewer incidents than those below this age group: 37~ for patients over 44 ..'el ~ rs" old and 61,%,/,for tile 15 to 24 years age groups and 50 ~/,, for those between 25 9 and 44 years of age. Patients with low weight seemed to be the worst atTected, as were the female patients witilin the groups, 65 I"/i of those with side effects being in the range from 30 to 49 kg. and 35 ~ in the range from 50 to 69 kg. The numerous incidents, described above, cannot be termed 'major toxic manifestations'. In fact. only 6 {'4; interrupted treatment due to therapy intolerance. But the cost of treating some patients with theseside effects partly off-sets the economy of the combined therapy as a standard treatment for tuberculosis. Renal lesions investigated at Rabat by systematic determination of protein i n the urine of the patients under treatment and by repeating biopsies of the kidney, are still under study. The predominance of thiacetazone intolerance in w o m e n Ires not yet been explained although several suggestions have been put forward. Does tattooing: cause sensitivity to one of the chemical groups in thiacetazone? Does the traditiortal way of life of tile women produce increased sensitivity to various drugs? Is over-dosage one of the causes because of tlae Smaller average weight? From the results so far obtained it is impossible to draw any firm conclusion. A special study would be necessary to look into the allergic nature of the side effects and to examine the causes of uneven occurrence between the sexes and the centres. The ethical problems of the medical profession are increased b y e general r e c o m m e n d a t i o n to use a treatment which is unsuitable for certain categories
o f the population. If ttle conclusions of a new study taking place in Rabat, where toxicity is most prevalent, proves favourable by showing a lower incidence of intolerance and toxicity, modification in the attitude of the doctors who work in the field of tuberculosis in Morocco m a y be expected. The statistics were preparedwith the aid of'Mr. Abolfazli of the W.H.O. staff in Rabat.
TUIIF:RCLE SUPPLEMENT
Eight of the patients with generalized rashes had an accompanying stomatitis; a few of tl~em had haemorrhagic features: some of them complained of loss ot'hair and a number of them dcsquana,'~ted. including one who showed some features of cxlbliation. Of those whose rashes were not reported as generalized, two had stomatitis, two showed hacmorrhagic features: one complained of loss of hair and four were tbtlowed by desquamation. An attempt at desensitization was made in 60':'~; of the patients who developed rashes and was successful in 44 3;] (36 ?,~;at tlte tirst attempt). Hypersensitivity was confirmed in 33 ':~,; i/) nine patients there ~tls no confi/-matio/~ ot" the india.idual drug responsible as th.e hypersensitivity was established to tt~c combined tablet only: in seven patients tltiacetazone was confirmed as the offending drug and in two patients both thiacetazone and isoniazid were implit~ated.
ttaematoh~gical Side-<[l~cts In the PH se/-ies one patient developed a ncu~rol:~cnia ~'hich did t~o~ /'cquirc an intcr/-~ption of treatment but in the TH series 'hacmatologicat" side-effects were reported in ii '.',i (16 paticnt, l. One male patient developed agranulocytosis associated witll fc',cr. T:.'eatment was discontinued and his white cell count returned to normal after two weeks, Tt~rec p:tlicnts developed a leucopcnia bul one of them did not require any interruption of lreatment. ]'he remaining 12 patients were teported as h.aving anaemia only. Four of these were withdrawn from the treatment. I n four of tt~r remaining patients reported as having developed anaemia the treatment was iP,tcrrupted but rc'~ttmcd after an interval of two-tlaree weeks. A study of the haemoglobin levels reveals that in the PH series the mean level rose from i1.9 pretreatment to 13.3 at 12 months, but in the TH series it fell from II .9 pretrcatment to 11,5 at 1 2 months and as the patients withdrawn because of anaemia arc not included in th,e 12ttl month calculation, the fall is minimised. Conclusion
Although we had hoped to find a place tk)r this regimen we t]ow lY-el that we canno! recommend it in Hong Kong in view of its toxicity and relative therapeutic infcriority to PAS/ isoniazid (see the report by Horsfilll on page 30).
S I D E E F F E C T S A N D T O X I C I T Y IN "I:1-t1s C O M B I N E D THIACETAZONE
AND
ISONIAZID
REGI3,11~:N O F
IN 51OROCCO
By H, RADt,, A(_, {with F. J. M. BURZONI, " ' IF.J . CHWOU, C . L~:o, " NEt,t,l and F. H PaPILLO,X') fi'om the Service de Lutte Antituberculeuse du Maroc, ; tmlstere tie, la Santd Puhlilue, Rabat.
The combination of thiacetazone with isoniaS'_id in the treatment of tub,.rculosJs was introduced into Morocco in 1960 at the recommendation of Dr. Noel Rist. Later the tinancial supporters of the antituberculosis campaign persuaded the Ministry of Public Health in Morocco to devise a stud), including the combination of thiacetazone with isoniazid in a standardized pla~l of" treatment. In May 1963, the centres whict~ agreed to participate in this study were" Marrakech, Meknes. Rabat and Tangiers. The daily dose was 500 mg. o f isoniazid and I50 rag. thiacetazone in two combined tablets taken once daily t, nder the supervision of the hospital staff: The drug was supplied by t h e Central Pharmacy of the Ministry of Public Health" at the beginning, supplies came by Laboratoires Theraplix, but in 1964, p r o d u c t i o n of the tablets was carried out from bulk powder supplied by Messrs Smith & Nephew. The average duration of treatment ',,,,as 1l m o n t h s : this varied a little from centre to certtre.
SIDE E F F E C T S
IN MO.ROC, CO
59
Ttlere were 36 interruptions of treatment through toxicity, 23 as a result of" skin affections, i I urinary tract or haematological disturbances and there were two deaths. Ttle proportion of serious incidents was therefore 6 ~'.;; of patients treated, 2'.}i; of men and I ! "/,.oof women. Attention was quickly drawn to tile appearance of skin affections of tile erythrodermic type (kyell or Stevens-Johnson syndrome). The predominance of this type of incident in women (141)s compared with only 1 {";, in man) was rather disturbing but, in spite of many hypotheses no conclusion was reached concerning the cause. There was an above-average and disturbing number of incidents at Rabat. The centres could be classified in decreasing order as follows: Rabat, Tangiers, Meknes, Marrakech. The very good tolerance of the patmnt, . ", s at Marrakech should be noted. The blood disorders (in 18"/~ ,,,, which were noticed there, were in the majority of cases only minor; they never resulted in the interruption of treatment. Only I '!ii;had cutaneous reactions, compared with 14'.~.{;in Rabat. The two deaths were not followed by necropsies: ttley were however considered as accidents due to thiacetazone therapy in the absence of other causes. One of tile deaths was of a 40 year old woman weighing 45 kg. who died ti~llowing respiratory l:ailure after 54 days of treatment. The extent of tile lesions did not account For this death. The other was a 33 year old rnan weighing 42 kg. who, after 55 days of treatment, was affected by gastro-intestinal trouble Rfllowed by coma. Anaemia of "3 " ,~,,00,000 red cells per cubic mil[imeler with a haemoglobin of 70 ~ normal was observed at tlie start of treatment. In all the towns, the predominance of incidents in the female sex was so consistent as to require Special mention. Thus, in Marrakech, with tile lowest total incidence, there were no skin eruptions or urinary changes among 142 men, but two eruptions and three urinary abnormalities among 61 women. At Rabat, with the highest incidence, there was only one rash among 54 men and eigllt among 62 women. In all centres there was at higher incidence of eact~ category of side-effect among the women. Patients aged 45 and over showed fewer incidents than those below this age group: 37~ for patients over 44 ..'el ~ rs" old and 61,%,/,for tile 15 to 24 years age groups and 50 ~/,, for those between 25 9 and 44 years of age. Patients with low weight seemed to be the worst atTected, as were the female patients witilin the groups, 65 I"/i of those with side effects being in the range from 30 to 49 kg. and 35 ~ in the range from 50 to 69 kg. The numerous incidents, described above, cannot be termed 'major toxic manifestations'. In fact. only 6 {'4; interrupted treatment due to therapy intolerance. But the cost of treating some patients with theseside effects partly off-sets the economy of the combined therapy as a standard treatment for tuberculosis. Renal lesions investigated at Rabat by systematic determination of protein i n the urine of the patients under treatment and by repeating biopsies of the kidney, are still under study. The predominance of thiacetazone intolerance in w o m e n Ires not yet been explained although several suggestions have been put forward. Does tattooing: cause sensitivity to one of the chemical groups in thiacetazone? Does the traditiortal way of life of tile women produce increased sensitivity to various drugs? Is over-dosage one of the causes because of tlae Smaller average weight? From the results so far obtained it is impossible to draw any firm conclusion. A special study would be necessary to look into the allergic nature of the side effects and to examine the causes of uneven occurrence between the sexes and the centres. The ethical problems of the medical profession are increased b y e general r e c o m m e n d a t i o n to use a treatment which is unsuitable for certain categories
o f the population. If ttle conclusions of a new study taking place in Rabat, where toxicity is most prevalent, proves favourable by showing a lower incidence of intolerance and toxicity, modification in the attitude of the doctors who work in the field of tuberculosis in Morocco m a y be expected. The statistics were preparedwith the aid of'Mr. Abolfazli of the W.H.O. staff in Rabat.