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Drugs used in tuberculosis and leprosy
J. Elis
31
Drugs used in tuberculosis and leprosy
DRUGS USED IN TUBERCULOSIS Two excellent reviews of the clinical pharmacology of antitubercular drugs ( 1 4 ) and their adverse effects (2 R) have been published during the past year. Both papers analyze the frequency, severity, type, clinical manifestations and management of adverse reactiohs after a single as well as after combined administrations of antitubercular drugs in adults and/or in children. Isoniazid (INH) Hepatotoxicity This adverse reaction which is far from being rare and sometimes even ends fatally, still receives considerable attention. Alexander et al (3 4 ) have summarized present knowledge of INH-associated hepatitis. The disease resembles viral hepatitis biochemically and histologically as well as clinically. Its onset is usually overt during the first 3 months of INH administration. Acetylhydrazine, an INH metabolite, is presumed to be responsible for the liver lesion. The monitoring of serum transaminase levels at regular intervals is the best m e t h o d for detection (and hence for prevention) of liver damage. The incidence of the disease varies considerably, from less than 1% to more than 30%, depending on the patient population studied and the definition of hepatitis. On the average, when biochemical tests are routinely conducted, the hepatitis is estimated to develop in 18.4% of patients. Advancing age and regular and/or excessive alcohol consumption are the main risk factors. The majority of clinical studies lead to the conclusion that
Side Effects of Drugs Annual 8
M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1984 ISBN 0 444 90339 9 .80 per article per page (transactional system) .20 per article per page (licensing system)
~0
the risk of hepatotoxicity during INH treatment with or without rifampicin is not dependent on the acetylator status of the patient. The last of the above conclusions is indeed widely accepted, but it should be pointed out that a group of German authors (4 4 ) consider that slow acetylators treated with a combination of INH and rifampicin have a higher risk of hepatic injury. Interaction INH is a well-documented inhibitor of the metabolism of many drugs (e.g. alcohol, vitamin D, bishydroxycoumarin, levodopa and carbamazepine (5c). Recently, a further ease of inhibition has been reported. The blood level of phenytoin was significantly increased in a patient temporarily treated with a combination of INH and pyrazinamide. INH affects phenyrein metabolism through interference with phenytoin parahydroxylation which is the first and rate-limiting step in the detoxication and elimination of the drug. As a consequence, clinical signs o f phenytoin intoxication appeared in the patient (6c). Some observations have shown that INH may induce, not only inhibition, but also stimulation of drug metabolism. Thompson et al (7 c ) have described an interaction in which the effect of INH upon theophylline may represent a case of increased metabolism. Administration of an oral dose of 300 mg INH for 6 consecutive nights to their patient increased the mean theophyUine clearance by 16%. The authors presume that INH may have an inductive effect upon the P448 microsomal enzymatic system, which may be responsible for the theophylline metabolism. Mazze et al (8 c ) found that INH treatment significantly enhanced enflurane defluorination in about half of the surgical patients whom they studied. The authors assume that rapid acetylator phenotype is
J. Elis
288 the decisive factor for increased anesthetic defluorination.
Rifampicin (RMP) Intravenous administration The parenteral form of RMP represents a therapeutic advance in the treatment of critically ill or comatose patients and also in patients with gastrointestinal or absorption problems. In a review presented by Kissling et al (9R), 237 tuberculous and non-tuberculous patients were treated with the usual daily dose of 4 5 0 - 6 0 0 mg of RMP. 80% of the patients in whom assessment of efficacy was possible showed favorable clinical results. A total of 31 unwanted effects were reported in 31 of 237 patients (13%). In 5 (2.1%) patients the treatment had to be stopped because of side effects. Thrombophlebitls occurred in 4.2% of patients, practically always in those treated for a period of more than 30 days. The results indicate that i.v. RMP is a useful and in some critically ill patients even a life-saving drug. Other effects Very good tolerance and efficacy of RMP in tuberculous as well as in non-tuberculous infections has been demonstrated in pediatric patients (10 C ). Miyachi et al (11 c) observed a case of severe hemolytic anemia and acute renal failure after re-administration of rifampicin. The authors recommend a direct antigiobin test using whole blood-drug mixture as a simple screening test. Liver dysfunction was reported by Japanese authors in 11.1% of patients treated with rifampicin containing regimens (14c), In the majority of cases liver dysfunction was already found in the early stage of chemotherapy while the elevation of serum transaminases was mild. Nigan et al (15 c ) reported on 2 patients treated with rifampicin who developed eosinophilia. Withdrawal of the drug led to a decrease of the eosinophil count, which increased again on administration of rifampicin. The induction of hepatic microsomal enzymes by rifampicin is believed to be the cause of vitamin K deficiency which has led to hemorrhagic disturbances in pregnant women and their newborns. It is proposed that vitamin K should be given prophylactically to all mothers and their offspring when the mother has received rifampicin
during pregnancy. It is recommended that blood coagulation studies should be repeated in both of them (17 c , 18c). It is well known that rifampicin and its metabolites may cause body fluids such as sweat, urine, feces, saliva and tears to turn orange. Liggett et al (16 e) observed a yellow tinge of the cerebrospinal fluid in 2 patients treated with the drug. Shortly after discontinuation of therapy the cerebrospinal fluid was clear and colourless. Elansary et al have observed an adrenal crisis precipitated by rifampicin (39c). Another 2 cases of rifampicin-prednisolone interaction have been described first in SEDA-4 (p. 216). The effectiveness of prednisolone was considerably reduced when the two drugs were used in combination. 7 patients were included in the study aimed at assessment of the effect of rifampicin on the pharmacokinetics of prednisolone. Overall, rifampicin increased the plasma clearance of prednisolone by 45% and reduced the amount of drug available to the tissues by 66% (19c). A further case (SEDA-6, 235) of a substantial decrease in the serum digitoxin level on addition of rifampicin to the therapeutic regimen has been observed (20 c). Within 3 weeks from the start of a continuous daily INH-rifampicin therapy, 2 patients developed acute renal failure (12 c, 13c). Renal biopsy demonstrated quite different pictures. In the f'trst case lesions characteristic of rapidly progressive glomemlonephritis with minor interstitial changes were found (12). The second patient's renal biopsy revealed acute interstitial nephritis, normal glornerular histology, effacement of glomerular epithelial cell foot processes and electron-dense deposits in the mesangial matrix and at subendothelial as well as in paramesangial sites (13).
Ethambutol To delineate the risk of ocular toxicity, Lal and Gupta (21 C) performed a clinical study in 680 ethambutol-treated patients. The dose of ethambutol was 25 mg/kg per day for 60 days followed by 15 mg/kg per day until 18 months from the start of theraPy. The study of 81 patients, of whom only 24 complained of any visual disturbance, revealed a definite change in the visual pattern in the form of a diminution of visual acuity and a change in the green color field of vision.
Drugs used in tuberculosis and leprosy Because the optic nerve' changes once produced are not reversible, except in mild and early cases, methods for the detection o f early signs of optic nerve damage have been searched for intensively. The method of visual evoked potentials seems to be a promising means of an early detection of subclinical optic nerve disease (22 c ) .
Pyrazinamide Combined therapy with INH, rifampicin and pyrazinamide was administered to 84 tuberculosis patients. All the patients who received pyrazinamide showed serum uric acid level increase which in 75 patients (90%) was twice as high as that found before treatment. Arthralgia was observed in 5 (14.3%) of 35 patients who received pyrazinamide daily for 2 months, and in 11 (22.4%) of 49 patients who received pyrazinamide daily for 6 months. Soon after discontinuation of the drug, the serum uric acid level returned to normal and the arthralgia disappeared (23c).
Thiacetazone Two cases of generalized hypertrichosis due to thiacetazone treatment have been reported. The mechanism of drug-induced hypertrichosis is unknown. This kind of side effect has not been reported after thiacetazone administration so far (24c).
Short course regimens (SCR) Teo has published a review on the development of the drug therapy o f pulmonary tuberculosis during the last 30 years (27R), pointing out that present therapeutical trends are aimed at developing suitable and effective regimens of short duration (SCR), i.e. not longer than 6 to 9 months. The strategy of treatment is based on an effective combination o f 2, but mostly 3 or 4 bactericidal drugs, in order to kill both the quickly multiplying bacilli and the slowly growing strains known as persisters. Several large and carefully designed clinical studies have been carried out in East Africa, Hong Kong, Madras and Singapore. A t t e m p t s were made to solve gradually all related problems in order to find the most effective and least toxic therapeutic regimens. The studies are still in progress (25c), but to date the incidence of side effects in patients has been estimated to be 2 0 - 2 5 % ,
289 though the offending drugs had to be discontinued in only about 5% of cases. Adverse reactions usually comprise mild cutaneous, gastrointestinal and vestibular disturbances. Cases of severe exfoliative dermatitis are extremely rare. Hepatitis, usually described as abnormalities in liver function, has been found in about 1 - 2 % . In regimens containing pyrazinamide, the patients suffer more often from arthralgia, and their serum uric acid concentration may be increased. Adverse reactions are reported more frequently in regimens containing both streptomycin and pyrazinamide. Ethambutol regimens are usually associated with the lowest incidence of unwanted events. The usefulness of SCR has been corroborated by further clinical studies performed by research groups in Korea (28c), in the United States (26C), India (29 r and Argentina (30c). In other countries SCR are still under investigation (31 c). In a clinical study oral polyunsaturated phosphatidylcholine given in combination with RMP, INH and streptomycin, reduced the incidence of raised transaminase levels by approximately 50% as compared to a control group treated with antituberculous drugs only (32c). Polyunsaturated phosphatidylcholine is recommended for the prevextion of early gastrointestinal complications of antituberculous therapy. DRUGS USED IN LEPROSY P
.
.
~
Dapsone (4,4 -dmmmodlphenyl sulfone) (SED-9, 532; SEDA-7, 299, 313) Sinha e t - a l (33 C) reported a case of marked erythema of the labium majus with slight purulent discharge after a week of dapsone treatment. The symptoms disappeared within 10 days after drug withdrawal. Prolonged cyanosis associated with severe methemoglobinemia and delayed sulfhemoglobinemia has been described by Lambert et al (34 c ) in patients after a single massive (3 g) ingestion of dapsone. Serious and unexpected adverse reactions may develop even after a low dose of dapsone administered for other diseases than leprosy. A patient with chronic eczematous skin eruptions, treated with 150 mg o f dapsone daily, exhibited an infectious mononucleosis-like syndrome, accompanied by atypical cell displaying T-cen character-
J. Elis
290 istics with markedly increased spontaneous tritiated thymidine uptake (35c). Mild hemolytic anemia was found in a breast-fed infant and its mother who had continuously been taking 1 0 0 - 1 5 0 mg dapsone daily. Dapsone and its metabolite monacetyl dapsone were identified in the infant's serum (40c). Peripheral motor neuropathy due to excessive dapsone intake was described in a young man. The patient started with a dosage of 50 mg daily, increasing it himself to 400 mg and occasionally up to 800 rag. A t r o p h y o f various muscles appeared with reduced strength of dorsiflexion of the wrists and feet, but most reflexes remained normal. The condition improved significantly on reducing dapsone intake to a maximum of 300 mg per week. The patient was found to be a slow acetylator. In their report on the case Rosen and S6rn~is recommend that the acetylation capacity of patients be determined before starting longterm dapsone treatment (41c).
Clofazimine Ichthyosis, which is a frequent side effect after clofazimine administration in doses higher than 100 mg/day, may be substantially alleviated by local application of 25% urea in emollient lotion (36cr). Given in high doses over a long period, clofazimine may accumulate in the tissues and precipitate as a solid. Enteropathy may develop if crystals are stored in the lamina propria of the jejunal mucosa and in the mesenteric lymph nodes. After drug withdrawal, the drug precipitates slowly regress (37 C).
Maloprim Maloprim is a combined drug (dapsone and pyrimethamine) used primarily for malarial prophylaxis. In a 23-year-old woman its administration caused agranulocytosis and red-cell hypoplasia which spontaneously remitted over a period of 4 weeks
(38c).
REFERENCES 1. Reed MD, Blumer L (1983) Clinical pharmacology of antitubercular drugs. Ped. Clin. North Am., 30, 177. 2. Gifting DJ (1982) Adverse effects ofantitubereulosis drugs. Current Therap., 23, 101. 3. Alexander MR, Louie SG, Guernsey BG (1982) Isoniazid-associated hepatitis. Clin. Pharm., 1, 148. 4. Munseh E, Eiehelbaum M, Wang JK et al (1982) Hepatotoxizit/it der tuberkulostatischen Kombination INH + RMP + EMB in Beziehung zum Arzneistoffwechsel der Leber. MedWelt Bd., 33, 23/911. 5. Fischer PR, Stanberry LR, Glasgow LA (1982) Carbamazepine-isoniazid interaction. Pediatrics, 69, 494. 6. Sandyk R (1982) Phenytoin toxicity induced by antituberculosis drugs. S. A fr. Med. J., 61,382. 7. Thompson JR, Burckart GJ, Self TH et al (1982) Isoniazid-induced alterations in theophyUine plmtmacokinetics. Current Therap. Res., 32, 92. 8. Mazze RI, Woodruff RE, Heerdt ME (1982) Isoniazid-induced enflurane defluorination in humans. Anesthesiology, 5 7, 5. 9. Kissling M, Bergamini N, Xilinas M (1982) Parenteral rifampicin in tuberculous and severe non-mycobacterial infections. Chemotherapy, 28, 229. 10. Bassetti D, Ciravegna B, Viscoli C (1982) Rifampicin's tolerance in paediatrics. Drugs Exp. Clin. Res., 8, 255.
11. Miyachi S, Kosuda T, Hisatomi T et al (1982) A case of severe hemolytic anemia and acute renal failure caused by RFP. Kekkaku, 57, 263. 12. Hirsch DJ, Bia FJ, Kashgarian M, Bia MJ (1983) Rapidly progressive glomerulonephritis during antitubereulous therapy. Am. Z Neph. roL, 3, 7. 13. Neugarten J, Gallo GR, Baldwin DS (1983) Rffampin-induced nephrotic syndrome and acute interstitial nephritis. Am. J. Nephrol., 3, 38. 14. Kutsukake F, Murakami T, Sasaki Y e t al (1982) Liver dysfunction induced by rffampicin. Kekkaku, 57, 257. 15. Pranesh Nigam, Goyal BM, Saxena HN (1981) Eosinophilia as a result of rifampicin therapy. J. Indian Med. Assoc., 77, 158. 16. Liggett SB, Berger JR, Hush J (1982) Cerebrospinal fluid xanthochromia with rffampin. Ann. Neurol., 12, 228. 17. Chottraqui JP, Bessaxd G, Favier M, Kolodle L, Rambaud P (1982) H6morragie par avitaminose K chez ia femme enceinte et le nouveau-n& Thdrapie, 37, 447. 18. Lissens J, Shih H, Verbist L et al (1983) Hemorragische ziekte bij boorling van een met rifampicine behandelde moeder. Tifdschr. Geneeskd., 39, 277. 19. McAllister WAC, Thompson PJ, AI-Habet SM, Rogers HJ (1983) Rifampicin reduces effectiveness and bioavailability of prednisolone. Br. Med. J., 286, 923. 20. Poor DM, Self TH, Davis HL (1983) Inter-
Drugs used in tuberculosis and leprosy action of rifampin and digitoxin. Arch. lntern. Med., 143, 599. 21. Lal BB, Gupta RL (1982) Visual pattern in ethambutol treated tubercular patients. 1rid. J. Tub., 29, 222. 22. Aiannikas C, Walsh JC (1982) The use of visual evoked responses in the detection of subclinical optic neuritis secondary to etharnbutol. Neurology, 32, Part. 2, PP214. 23. Ishiguro S (1982) Arthralgia and uricemia produced by pyrazinamide. Kekkaku, 57, 483. 24. Nalr LV, Sugathen P (1982) Thlacetazone induced hypertrichosis. Indian J. Dermatol. Venereol. Lepr., 48, 161. 25. Aquinas M (1982) Short-course chemotherapy. S. Aft. Med. J. Spec. Issue, 62, 12. 26. Spagnolo AV, Raven JM (1982) Nine-month chemotherapy for pulmonary tuberculosis. South Med. J., 75, 134. 27. "leo SK (1982) Tuberculosis chemotherapy a review of current treatment regimens. Singapore Med., 23, 55. 28. Myoung Hae Lee, Sung Koo Han, Young See Shim, Yong Chul Hart (1981) Clinical experience of short-course chemotherapy for pulmonary tuberculosis. Tuberculosis Respir. Dis., 28, 145. 29. Purohit SD, Sobhawat VS, Bhutra BL et al (1982) Short course chemotherapy with rifampicin. Indian Med. Gazette, 116, 321. 30. Gonzalez Montener LJ, Dambrosi A, Manassero M, Dambrosi Vilar y Maria L (1982) Adverse effects of antituberculosis drugs causing changes in treatment. Tubercle 63, 291. 31. Br~indli O, Hacki MA, Scheel A, Stiefel M
291 (1983) Die Chemotherapie der TuberkuloseCompliance, Nebenwirkungen und RezidivFAufigkeit. Schweiz. Med. Wschr., 113, 92. 32. Djurie-Mflosavlijevic O (1982) Impiego delle fosfatidilcolina polinsatura (EPL) per la prevenzione delle lesione epatiche in corse di terapia antitubercolare. Epat 28, 3. 33. Sinha MR (1982) Fixed genital drug eruption due to dapsone. Leprosy 54, 152. 34. Lambert M, Sonnet J, Mahieu P, Hassoun A (1982) Delayed sulfhemoglobinemia after acute dapsone intoxication. J. Toxicol..Clin. Toxicol., 19, 45. 35. Gan TE, Van I)r Weyden B (1982) Dapsoneinduced infectious mononucleosis-like syndrome. Med. J. Aust., 1, 350. 36. Caret CV (1982) Clofazimine-induced ich~ thyosis and its treatment. Cutis, 29, 341. 37. De Micoo C, Boutboul R, Devaux J e t al (1982) Ent~ropathie /t la clofazimine. Ann. Pathol., 2, 149. 38. Nicholls MD, Concannon AJ (1982) Moloprim-induced agranulocytosis and red-cell aplasla. Med. J. Aust., 2, 564. 39. Elansary EH, Earls JE (1983) Rffampicin and adrenal crisis. Br. Med. Z, 286, 186. 40. Sanders SW, Zone JJ, Foltz RI et al (1982) Hemolytic anemia induced by dapsone transmitted through breast milk. Ann. Int. Med., 96, 465. 41. Rosen J, S6rn~is R (1982) Peripheral motor neuropathy caused by excessive intake of dapsone (avlosulfon). Arch. Psychiatr. Nervenkr., 232, 63.
31
Drugs used in tuberculosis and leprosy
DRUGS USED IN TUBERCULOSIS Two excellent reviews of the clinical pharmacology of antitubercular drugs ( 1 4 ) and their adverse effects (2 R) have been published during the past year. Both papers analyze the frequency, severity, type, clinical manifestations and management of adverse reactiohs after a single as well as after combined administrations of antitubercular drugs in adults and/or in children. Isoniazid (INH) Hepatotoxicity This adverse reaction which is far from being rare and sometimes even ends fatally, still receives considerable attention. Alexander et al (3 4 ) have summarized present knowledge of INH-associated hepatitis. The disease resembles viral hepatitis biochemically and histologically as well as clinically. Its onset is usually overt during the first 3 months of INH administration. Acetylhydrazine, an INH metabolite, is presumed to be responsible for the liver lesion. The monitoring of serum transaminase levels at regular intervals is the best m e t h o d for detection (and hence for prevention) of liver damage. The incidence of the disease varies considerably, from less than 1% to more than 30%, depending on the patient population studied and the definition of hepatitis. On the average, when biochemical tests are routinely conducted, the hepatitis is estimated to develop in 18.4% of patients. Advancing age and regular and/or excessive alcohol consumption are the main risk factors. The majority of clinical studies lead to the conclusion that
Side Effects of Drugs Annual 8
M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1984 ISBN 0 444 90339 9 .80 per article per page (transactional system) .20 per article per page (licensing system)
~0
the risk of hepatotoxicity during INH treatment with or without rifampicin is not dependent on the acetylator status of the patient. The last of the above conclusions is indeed widely accepted, but it should be pointed out that a group of German authors (4 4 ) consider that slow acetylators treated with a combination of INH and rifampicin have a higher risk of hepatic injury. Interaction INH is a well-documented inhibitor of the metabolism of many drugs (e.g. alcohol, vitamin D, bishydroxycoumarin, levodopa and carbamazepine (5c). Recently, a further ease of inhibition has been reported. The blood level of phenytoin was significantly increased in a patient temporarily treated with a combination of INH and pyrazinamide. INH affects phenyrein metabolism through interference with phenytoin parahydroxylation which is the first and rate-limiting step in the detoxication and elimination of the drug. As a consequence, clinical signs o f phenytoin intoxication appeared in the patient (6c). Some observations have shown that INH may induce, not only inhibition, but also stimulation of drug metabolism. Thompson et al (7 c ) have described an interaction in which the effect of INH upon theophylline may represent a case of increased metabolism. Administration of an oral dose of 300 mg INH for 6 consecutive nights to their patient increased the mean theophyUine clearance by 16%. The authors presume that INH may have an inductive effect upon the P448 microsomal enzymatic system, which may be responsible for the theophylline metabolism. Mazze et al (8 c ) found that INH treatment significantly enhanced enflurane defluorination in about half of the surgical patients whom they studied. The authors assume that rapid acetylator phenotype is
J. Elis
288 the decisive factor for increased anesthetic defluorination.
Rifampicin (RMP) Intravenous administration The parenteral form of RMP represents a therapeutic advance in the treatment of critically ill or comatose patients and also in patients with gastrointestinal or absorption problems. In a review presented by Kissling et al (9R), 237 tuberculous and non-tuberculous patients were treated with the usual daily dose of 4 5 0 - 6 0 0 mg of RMP. 80% of the patients in whom assessment of efficacy was possible showed favorable clinical results. A total of 31 unwanted effects were reported in 31 of 237 patients (13%). In 5 (2.1%) patients the treatment had to be stopped because of side effects. Thrombophlebitls occurred in 4.2% of patients, practically always in those treated for a period of more than 30 days. The results indicate that i.v. RMP is a useful and in some critically ill patients even a life-saving drug. Other effects Very good tolerance and efficacy of RMP in tuberculous as well as in non-tuberculous infections has been demonstrated in pediatric patients (10 C ). Miyachi et al (11 c) observed a case of severe hemolytic anemia and acute renal failure after re-administration of rifampicin. The authors recommend a direct antigiobin test using whole blood-drug mixture as a simple screening test. Liver dysfunction was reported by Japanese authors in 11.1% of patients treated with rifampicin containing regimens (14c), In the majority of cases liver dysfunction was already found in the early stage of chemotherapy while the elevation of serum transaminases was mild. Nigan et al (15 c ) reported on 2 patients treated with rifampicin who developed eosinophilia. Withdrawal of the drug led to a decrease of the eosinophil count, which increased again on administration of rifampicin. The induction of hepatic microsomal enzymes by rifampicin is believed to be the cause of vitamin K deficiency which has led to hemorrhagic disturbances in pregnant women and their newborns. It is proposed that vitamin K should be given prophylactically to all mothers and their offspring when the mother has received rifampicin
during pregnancy. It is recommended that blood coagulation studies should be repeated in both of them (17 c , 18c). It is well known that rifampicin and its metabolites may cause body fluids such as sweat, urine, feces, saliva and tears to turn orange. Liggett et al (16 e) observed a yellow tinge of the cerebrospinal fluid in 2 patients treated with the drug. Shortly after discontinuation of therapy the cerebrospinal fluid was clear and colourless. Elansary et al have observed an adrenal crisis precipitated by rifampicin (39c). Another 2 cases of rifampicin-prednisolone interaction have been described first in SEDA-4 (p. 216). The effectiveness of prednisolone was considerably reduced when the two drugs were used in combination. 7 patients were included in the study aimed at assessment of the effect of rifampicin on the pharmacokinetics of prednisolone. Overall, rifampicin increased the plasma clearance of prednisolone by 45% and reduced the amount of drug available to the tissues by 66% (19c). A further case (SEDA-6, 235) of a substantial decrease in the serum digitoxin level on addition of rifampicin to the therapeutic regimen has been observed (20 c). Within 3 weeks from the start of a continuous daily INH-rifampicin therapy, 2 patients developed acute renal failure (12 c, 13c). Renal biopsy demonstrated quite different pictures. In the f'trst case lesions characteristic of rapidly progressive glomemlonephritis with minor interstitial changes were found (12). The second patient's renal biopsy revealed acute interstitial nephritis, normal glornerular histology, effacement of glomerular epithelial cell foot processes and electron-dense deposits in the mesangial matrix and at subendothelial as well as in paramesangial sites (13).
Ethambutol To delineate the risk of ocular toxicity, Lal and Gupta (21 C) performed a clinical study in 680 ethambutol-treated patients. The dose of ethambutol was 25 mg/kg per day for 60 days followed by 15 mg/kg per day until 18 months from the start of theraPy. The study of 81 patients, of whom only 24 complained of any visual disturbance, revealed a definite change in the visual pattern in the form of a diminution of visual acuity and a change in the green color field of vision.
Drugs used in tuberculosis and leprosy Because the optic nerve' changes once produced are not reversible, except in mild and early cases, methods for the detection o f early signs of optic nerve damage have been searched for intensively. The method of visual evoked potentials seems to be a promising means of an early detection of subclinical optic nerve disease (22 c ) .
Pyrazinamide Combined therapy with INH, rifampicin and pyrazinamide was administered to 84 tuberculosis patients. All the patients who received pyrazinamide showed serum uric acid level increase which in 75 patients (90%) was twice as high as that found before treatment. Arthralgia was observed in 5 (14.3%) of 35 patients who received pyrazinamide daily for 2 months, and in 11 (22.4%) of 49 patients who received pyrazinamide daily for 6 months. Soon after discontinuation of the drug, the serum uric acid level returned to normal and the arthralgia disappeared (23c).
Thiacetazone Two cases of generalized hypertrichosis due to thiacetazone treatment have been reported. The mechanism of drug-induced hypertrichosis is unknown. This kind of side effect has not been reported after thiacetazone administration so far (24c).
Short course regimens (SCR) Teo has published a review on the development of the drug therapy o f pulmonary tuberculosis during the last 30 years (27R), pointing out that present therapeutical trends are aimed at developing suitable and effective regimens of short duration (SCR), i.e. not longer than 6 to 9 months. The strategy of treatment is based on an effective combination o f 2, but mostly 3 or 4 bactericidal drugs, in order to kill both the quickly multiplying bacilli and the slowly growing strains known as persisters. Several large and carefully designed clinical studies have been carried out in East Africa, Hong Kong, Madras and Singapore. A t t e m p t s were made to solve gradually all related problems in order to find the most effective and least toxic therapeutic regimens. The studies are still in progress (25c), but to date the incidence of side effects in patients has been estimated to be 2 0 - 2 5 % ,
289 though the offending drugs had to be discontinued in only about 5% of cases. Adverse reactions usually comprise mild cutaneous, gastrointestinal and vestibular disturbances. Cases of severe exfoliative dermatitis are extremely rare. Hepatitis, usually described as abnormalities in liver function, has been found in about 1 - 2 % . In regimens containing pyrazinamide, the patients suffer more often from arthralgia, and their serum uric acid concentration may be increased. Adverse reactions are reported more frequently in regimens containing both streptomycin and pyrazinamide. Ethambutol regimens are usually associated with the lowest incidence of unwanted events. The usefulness of SCR has been corroborated by further clinical studies performed by research groups in Korea (28c), in the United States (26C), India (29 r and Argentina (30c). In other countries SCR are still under investigation (31 c). In a clinical study oral polyunsaturated phosphatidylcholine given in combination with RMP, INH and streptomycin, reduced the incidence of raised transaminase levels by approximately 50% as compared to a control group treated with antituberculous drugs only (32c). Polyunsaturated phosphatidylcholine is recommended for the prevextion of early gastrointestinal complications of antituberculous therapy. DRUGS USED IN LEPROSY P
.
.
~
Dapsone (4,4 -dmmmodlphenyl sulfone) (SED-9, 532; SEDA-7, 299, 313) Sinha e t - a l (33 C) reported a case of marked erythema of the labium majus with slight purulent discharge after a week of dapsone treatment. The symptoms disappeared within 10 days after drug withdrawal. Prolonged cyanosis associated with severe methemoglobinemia and delayed sulfhemoglobinemia has been described by Lambert et al (34 c ) in patients after a single massive (3 g) ingestion of dapsone. Serious and unexpected adverse reactions may develop even after a low dose of dapsone administered for other diseases than leprosy. A patient with chronic eczematous skin eruptions, treated with 150 mg o f dapsone daily, exhibited an infectious mononucleosis-like syndrome, accompanied by atypical cell displaying T-cen character-
J. Elis
290 istics with markedly increased spontaneous tritiated thymidine uptake (35c). Mild hemolytic anemia was found in a breast-fed infant and its mother who had continuously been taking 1 0 0 - 1 5 0 mg dapsone daily. Dapsone and its metabolite monacetyl dapsone were identified in the infant's serum (40c). Peripheral motor neuropathy due to excessive dapsone intake was described in a young man. The patient started with a dosage of 50 mg daily, increasing it himself to 400 mg and occasionally up to 800 rag. A t r o p h y o f various muscles appeared with reduced strength of dorsiflexion of the wrists and feet, but most reflexes remained normal. The condition improved significantly on reducing dapsone intake to a maximum of 300 mg per week. The patient was found to be a slow acetylator. In their report on the case Rosen and S6rn~is recommend that the acetylation capacity of patients be determined before starting longterm dapsone treatment (41c).
Clofazimine Ichthyosis, which is a frequent side effect after clofazimine administration in doses higher than 100 mg/day, may be substantially alleviated by local application of 25% urea in emollient lotion (36cr). Given in high doses over a long period, clofazimine may accumulate in the tissues and precipitate as a solid. Enteropathy may develop if crystals are stored in the lamina propria of the jejunal mucosa and in the mesenteric lymph nodes. After drug withdrawal, the drug precipitates slowly regress (37 C).
Maloprim Maloprim is a combined drug (dapsone and pyrimethamine) used primarily for malarial prophylaxis. In a 23-year-old woman its administration caused agranulocytosis and red-cell hypoplasia which spontaneously remitted over a period of 4 weeks
(38c).
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