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Heavy metal antagonists
R. H. B. Meyboom
21
heavy metal antagonists
PENICILLAMINE General Enthusiasm about the efficacy o f penicillamine in rheumatoid arthritis has been overclouded by its adverse effects (1C R). Recent publications have confirmed the high incidence of adverse reactions (2, 3, 4, 5). Mery et aL observed that the concomitant use of zinc (5 mg daily) strongly decreased the therapeutic action o f peniciUamine, but did not prevent its adverse effects (6). Hill has given an extensive review of experience with 109 patients on penicillamine, and of the literature on the drug (2CR). From this study one can differentiate between those adverse reactions that usually develop early in the course of penicillamine treatment (gastrointestinal upset, loss of taste, diarrhoea, allergic rashes, thrombocytopenia) and other reactions that usually develop after the patient has been treated for more than six months (proteinuria, late itchy scaling, erythematous eruptions). The incidence of the early reactions in particular can be much reduced by employing monthly increments rather than fortnightly, and by using low doses (2; SED VIII, p. 531). In teractions There are no known interactions between penicillamine and anti-inflammatory or analgesic drugs (2; see also SED VIII, p. 530), with the possible exception of paracetamol (see 'Gastrointestinal' section). Immunological effects It has been noticed in two patients with rheumatoid arthritis as well as in patients with Wilson's disease that D-penicillamine can induce IgA deficiency, with IgA levels sometimes declining towards undetectable levels (8, 9, 10). In these cases the concentration of IgA in the saliva was also decreased. On immunofluorescence investigation, biopsy material from the small bowel mucosa showed a normal number of IgA-bearing plasmacytes. One of the patients with rheumatoid
arthritis is known to have experienced no ill-effects from the IgA deficiency within the three years after it was detected (10). One of the patients with Wilson's disease, on the other hand, had recurrent benign upper respiratory tract infections, which were reported not to have been present before the start of D-penicillamine therapy. However, normal IgA levels were found in the serum of eight patients with Wilson's disease who had been treated with D-penicillamine for a long time (9). It is not y e t clear whether penicillamine has immunosuppressive (11 - 14) or immunostimulating properties (15, 16). Kendall has suggested that in lymphocyte transformation testing L-cystine deficiency in the medium, caused by penicillamine, brings about depression of DNA-synthesis, thus masking the intrinsic enhancing effect of penicillamine on lymphocyte transformation (15). Skin and appendages Early skin reactions Allergic rashes are a frequent complication of penicillamine (SED VIII, p. 531; 2 CR, 3, 4) which, however, can often be overcome by reduction of the dose or temporary withdrawal of the drug. Since trace impurities may be implicated in allergic reactions, it has been suggested that, if a patient does not tolerate a particular brand of penicillamine, he may on resuming the treatnient benefit from a trial with a different pharmaceutical preparation (17). Tardive skin eruptions It is becoming increasingly clear that some drug-induced eruptions are associated with antibodies against the intercellular substance of the epidermis, although the appearance of the eruptions may be different from pemphigus (18). Although other drugs have been implicated (e.g. phenylbutazone, isoniazid, rifampicin) penicillamine is apparently the best known factor responsible for the induction of such antibodies. Many well-documented reports, not only from France, but also from Denmark, Switzerland and from the United Kingdom, have
216 confirmed that D-penicillamine can cause frank pemphigus ( 1 9 - 2 6 ) . Unlike idiopathic pemphigus, D-penicillamine-induced eruptions often present as pemphigus foliaceus. In pemphigus foliaceus the predominant lesions are crusts, erosive sloughs and scaly lesions. The lesions often appear on the trunk, scalp or face and may closely resemble seborrhoeic dermatitis. The main difference between pemphigus foliaceus and the bullous type of pemphigus is that in the former the intra-epidermal blisters are more superficially located. The crusts and sloughs represent ruptured bullae; the thin walls account for the fragility of the blisters. Although this disorder is often rapidly reversible after discontinuation of D-peniciUamine and may even improve after reduction of the dose, the symptoms are sometimes persistent and may require prolonged treatment with corticosteroids. In some patients D-penicillamine has been re-introduced without recurrence of the eruption (see also under Goodpasture's syndrome, below). In one patient with pemphigus of the skin and mucous membranes the conjunctivae were also involved. The eye lesions healed with conjunctival scarring and symblepharon formation (25). It has been suggested that the scaly, itching eruption which is the most common tardive skin reaction to penicillamine, is in fact often an unrecognized manifestation of this form of pemphigus foliaceus (2 cR, 19CR). Unlike idiopathic pemphigus foliaceus the penicillamine-induced type is extremely itchy. An interesting case has been reported of another tardive skin syndrome induced, at least partially, by penicillamine (27). In this patient after about 10 years of treatment with penicillamine (2 g daily) for Wilson's disease a skin abnormality had developed with yellowing, crinkling and wrinkling of the skin of her face and neck and with multiple soft white papules (1-2 mm in diameter) overlying the veins in both antecubital fossae (where many years earlier multiple venepunctures had been performed) and surrounding a surgical scar (the lesions coinciding with suture sites). The patient had never developed blisters or bruises secondary to skin trauma. Investigation of a biopsy specimen from the skin of the antecubital fossa showed focal degeneration and homogenization of the connective tissue. The degenera-' tion was characterized by a loss of the normal elastic and coUagenousarchitecture. There was replacement of the dermal fibrillar structures with clump-
R. H. B. Meyboom
ed and granular eosinophilic material. There was no evidence of cyst formation. Kirsch and Hukill have reported a further case of elastosis perforans serpiginosa induced by penicillamine (28Cr). The patient had been treated for years with 2 g of penicillamine daily for Wilson's disease; the eruption predominantly involved the skin of the neck, but the glans penis was also affected. Electron microscopical examination revealed distinct abnormalities of the elastin; these abnormalities, however, were different from those observed in idiopathic elastosis perforans. The authors suggest that penicillamine-induced elastosis perforans may be due to deficiency to one of the trace metals. The elastin abnormalities which are found in experimental copper deficiency, however, are not identical to those in elastosis perforans. R e n a l disorders
Again attention has been focussed upon immune-complex nephritis as a complication of peniciUamine (2, 2 9 - 3 3 ) . Bacon et al. observed persistent proteinuria in 14 patients (7.4%) out of a series of 189 treated with penicillamine; 11 had a clinical nephrotic syndrome, while three had only proteinuria (29). Both the nephrotic group and those with uncomplicated proteinuria showed evidence of the same immunopathological mechanism. Renal biopsies were performed at different intervals after the cessation of penicillamine therapy, revealing in some patients striking persistence of electron-dense deposits in the glomerular basement membrane. The authors conclude that the use of peniciUamine in rheumatoid arthritis may induce protracted renal changes. Hill observed proteinuria in 25 out of 109 patients (23%) (2). Characteristically, proteinuria is a late complication of penicillamine. The incidence of proteinuria rose from 2% during the first six months of treatment to 30% during the next six months, falling to 5% thereafter. In four (3.7%) of the 109 patients a nephrotic syndrome developed with proteinuria exceeding 10 g/24 hr; clinical and laboratory abnormalities persisted for 1 2 - 2 4 months. Hill advises a reduction in dose of 250 mg as soon as proteinuria occurs; proteinuria should be monitored thereafter fortnightly, on 24-hour urine samples. If proteinuria exceeds 2 g/24 hr penicillamine should be stopped forthwith. For Goodpasture's syndrome see p. 219.
Heavy metal antagonists B l o o d and bone marrow
Three further cases have been reported of aplastic anaemia, attributed to the use of D-penicillamine (34, 35, 36), which makes a total of six published cases (SED VIII, pp. 534, 535; SEDA-I, p. 191). Two of these patients died, one from septicaemia (this patient had previously been obliged to stop treatment with gold because of thrombocytopenia), the other from massive intrapulmonary bleeding. The third patient recovered; she had also used co-trimoxazole 3 months before, and a chloramphenicol-containing ointment f o r ' a n eye infection about one month before the development of the bone marrow hypoplasia. Both Hill (2) and White (37) have observed that thrombocytopenia is often rapidly reversible if D-penicillamine is discontinued. Hill noticed that, because the platelet count falls in about 75% of patients on penicillamine, it is often difficult to know when to discontinue the drug (2). She advises checking the platelets at weekly intervals when the count falls to between 100 x 109/1 and 70 x 109/1 and daily if the count falls below 70 x 10911. If any further fall occurs penicillamine should be stopped and frequent counts performed until the number of platelets exceeds 100 x 109/1. Hill observed the development of thrombocytopenia in eight (7.7%) out of 109 patients, necessitating withdrawal in four (2). In all cases the thrombocytopenia occurred within the first six months o f treatment (between the 10th and 20th weeks). The incidence of thrombocytopenia appeared to be related to the dose of penicillamine. The t h r o m b o c y t o penia was rapidly reversible in these four patients, the counts returning to normal within 7 - 1 0 days after penicillamine was stopped. It has been observed that the injection of large amounts of penicillamine into mice was associated with the development of a leukaemia-like condition (51). Gastrointestinal
According to Hill abnormalities of taste are the most common adverse effect of penicillamine; smell is not affected (2). Some patients describe the abnormality as a salty taste, other patients report that some foods 'do n o t taste right'. This usually affects sweet foods, and patients report that food tasted 'like cotton wool and blotting paper'. Complete loss of taste developed in four out
217 of 109 patients (2). The abnormalities of taste occur in the early weeks of treatment and are clearly related to the rate of introduction and the dose of penicillamine. Despite continuation of penicillamine, normal taste is restored in time (weeks or months). The use of penicillamine can be associated with nausea, vomiting, epigastric discomfort and diarrhoea (2). Camus et al. noticed gastric symptoms such as anorexia, nausea and vomiting in 27 (13.5%) out of 200 patients on D-penicillamine, leading to withdrawal in nine (3). Dippy observed gastric symptoms in 24 patients out of 70 (34.3%) (4). These authors made somewhat conflicting remarks as to the possible ulcerogenic properties of D-penicillamine. Dippy noticed that patients with previous gastric or duodenal ulcer were almost invariably troubled with gastric side effects, whereas Camus et al. did not notice the development of an ulcer in any of his patients and stressed that D-penicillamine was well tolerated by patients who had a previous or active peptic ulcer. In Dippy's study all patients were on anti-inflammatory analgesics as well; Camus et aL did not mention the possibility of the concomitant use of other drugs (see SED VIII, p. 535). Hill observed the development of an active peptic ulcer during treatment with penicillamine in two out of 109 patients (2). The incidence of gastrointestinal symptoms will be strongly reduced if low doses are used, and increments are made monthly instead of fortnightly (2, 3). Buccal ulcerations occurred in three out of 109 patients on penicillamine, leading to permanent discontinuation in two patients (2). The ulcers affected the tongue and/or the mucous membranes, and were painful, raised and clearly delineated; they took 3 4 weeks to heal after penicillamine had been stopped. A third case has been observed of pancreatitis occurring in a patient on treatment with penicillamine (L. Agerskov Andersen, personal communication). This patient, a 54-year-old woman, developed acute pancreatitis after 5 weeks of treatment with penicillamine for rheumatoid arthritis, in a maximum daily dose of 450 mg. She had never had a bout of pancreatitis before. Despite these observations, a causal relationship between the use of penicillamine and the occurrence of pancreatitis has not been established.
218 Digestive tract
The case is reported of a 13-year old girl who, after 20 weeks of treatment with Dpenicillamine (750 mg daily) and benorylate (6 g daily) for rheumatoid arthritis, developed toxic hepatitis (38). Both drugs were stopped and there was considerable improvement over the next two weeks. Benorylate is an ester of acetylsalicylic acid and paracetareel; 6 g benorylate is equivalent to 2.8 g paracetamol. D-penicillamine is largely excreted as L-cysteine-D-penicillamine disulphide. The authors suggest that, as cysteine is a precursor of glutathione, the excretion of D-penicillamine is perhaps linked with the exhaustion of hepatic cysteine, resulting in a decrease of glutathione below levels that are required for the detoxification o f paracetareel metabolites. The authors do not mention the salicylate levels in the serum of their patients; serum levels exceeding about 25 rag/100 ml are known to also be able to cause hepatitis (39). Neuromuscular system
A further two cases of polymyositis, apparently induced by D-penicillamine, have been reported; both patients recovered. In the first patient the disorder presented with palpitations and severe muscular weakness; she had no muscular aches (40). The polymyositis was associated with myocarditis, proteinuria and decreased serum levels of complement. In the second patient the polymyositis was associated with a facial rash with heliotrope discolouration around the eyes and peri-orbital oedema, presenting the characteristic picture of dermatomyositis (41). The patient had fever, some liver enlargement, tender back and thigh muscles, and proximal muscle weakness. S e i t z e t al. have reported a further 12 patients (all females) with symptoms of myasthenia gravis, attributed to the use of D-penicillamine for rheumatoid arthritis (42). The edrophonium test was positive in all. The disorder presented with ocular involvement leading to ptosis and double vision in nine patients, and remained confined to ocular s y m p t o m s in three. Speech, chewing and/or swallowing were frequently impaired. In some patients severe generalized myasthenia developed. The condition was reversible in most patients, although several cases required pyridostigmine treatment for
R. H. B. Me),boom
a long period and two patients required artificial respiration, one of them died. A second fatal case of myasthenia attributed to the use of penicillamine has been observed in France (43). This patient also had chronic atrophic thyroiditis and hypothyroidism, which was also thought to be induced by D-penicillamine. In the Netherlands, too, a patient has been observed with myasthenia gravis developing during treatment with penicillamine for rheumatoid arthritis (44). In this patient ptosis and impairment o f speaking and swallowing predominated. Six months after the discontinuation of penicillamine she still required pyridostigmine treatment. Apparently penicillamine-induced myasthenia is not associated with thymoma. Endocrine glands
A fatal case has been reported of myasthenia associated with hypothyroidism, developing in a patient on D-penicillamine for rheumatoid arthritis (43). Pathological examination of the thyroid gland revealed chronic non-specific atrophic thyroiditis with interstitial sclerosis and infiltration with lymphocytes and plasma ceils. The authors suggest that both conditions were, at least partially, induced by D-penicillamine. In addition Laitko et al. have listed enlargement of the thyroid gland amongst the side effects of peniciUamine (5). Foetal toxicity
The most recent opinion on the obscure subject o f the safety of D-peniciUamine in pregnancy is that it makes an important difference whether the drug is used for Wilson's disease or for other conditions (7, 45). It has been suggested that the apparent safety o f D-penicillamine in pregnancy in Wilson's disease could be explained on the basis that in Wilson's disease there is a high proportion of unbound copper, which is chelated by penicillamine, thus reducing the penicillamine level (7). This mechanism would not operate in a disorder such as rheumatoid arthritis. Further reports have in the meantime appeared on normal infants, born to women with Wilson's disease who had used penicillarnine in pregnancy (46, 47). There is, however, one newer report on an abnormal child, reminiscent of the case described by Mj~blner~d (SED VIII, p. 537; ref. 35), born to a mother who had received D-penicillamine for rheumatoid arthritis (7).
Heavy metal antagonists The mother was being treated with 900 mg penicillamine per day during most of the pregnancy. During the pregnancy placental insufficiency developed and the foetus was small for its age. A boy weighing 2.0 kg was delivered by Caesarean section at the end of the 37th week. Growth retardation was confirmed, the head circumference was 32 cm and crown-to-heel length 40 cm. The face was flattened, with a broad nasal bridge, the ears were lowset and the neck was short with loose folds of skin. Body skin too was unusually lax and wrinkled. Bilateral inguinal herniae were present. There were fixed flexion contractures of the hips and knees. The palms showed simian creases. Twelve hours after birth an acute abdomen developed, and a diagnosis of perforation of the bowel with meconium peritonitis was made. At laparotomy, however, no overt perforation was found; the child's condition remained poor and he died three days later. Routine histological examination showed no collagen abnormalities.
Influence on wound healing S u s p i c i o n has arisen t h a t p e n i c i l l a m i n e c o u l d i n t e r f e r e w i t h w o u n d healing ( S E D VIII). H o w e v e r , Hill c o u l d n o t d e t e c t impairm e n t o f w o u n d h e a l i n g a f t e r 23 surgical o p e r a t i o n s in 15 p a t i e n t s o n c o n t i n u e d t r e a t m e n t w i t h p e n i c i l l a m i n e (2).
Respiratory system R e c e n t l y in t h e N e t h e r l a n d s a p a t i e n t h a s b e e n o b s e r v e d w i t h a very severe e m p h y s e m a t o u s l u n g disorder, w h i c h was c o n s i d e r ed t o b e possibly r e l a t e d t o t h e use o f penicillamine, since n o o t h e r cause c o u l d b e detected (48). The patient, a 59-year-old woman (body weight 47 kg), with long-standing rheumatoid arthritis had been using 750 mg penicillamine daily for about 18 months. Other drugs used were indomethacin and a compound analgesic, containing phenazone and phenacetin. During treatment with penicillamine, with good results, the patient became progressively dyspnoeic, and finally developed extreme dyspnoea. On X-ray examination the lungs were somewhat radiolucent but otherwise normal. Howcver, blood gas analysis revealed severe oxygen undersaturation. Functional investigation of the lungs showed severe bronchial obstruction, most probably as a result of extreme emphysema. Diffusion was also deranged as one would anticipate with a severe emphysema. The patient had never
219 smoked, nor did she suffer from chronic bronchitis or asthma. The alpha~-antitrypsin level was normal (Pi-type M). A lung biopsy could not be taken because of the patient's poor condition. The prognosis for this patient is considered to be very unfavourable. Functional and X-ray investigation of the lungs at tile beginning of penicillamine treatment had been perfectly normal. T h e r e has b e e n s o m e s u s p i c i o n t h a t Dp e n i c i l l a m i n e m a y be i n v o l v e d in t h e development of fatal obliterative bronchiolitis (49). However, t h e e v i d e n c e is very weak a n d was n o t s u p p o r t e d b y an e x t e n s i v e survey b y t h e m a n u f a c t u r e r o f d a t a available to him on penicillamine (50). SEDA-1 (p. 191) r e f e r r e d t o t h e develo p m e n t o f G o o d p a s t u r e ' s s y n d r o m e in relat i o n to peniciUamine. M a r s d e n et aL a n d Hill h a v e since t h e n briefly r e p o r t e d t h e case hist o r y o f a p a t i e n t ( a p p a r e n t l y t h e same individual) w h o died f r o m Goodpasture's s y n d r o m e , 18 m o n t h s a f t e r p e n i c i l l a m i n e had been stopped because of thrombocytop e n i a (2, 19). Previously this p a t i e n t h a d suffered f r o m p e n i c i l l a m i n e - i n d u c e d p e m p h i gus. A l t h o u g h in this p a t i e n t G o o d p a s t u r e ' s syndrome may have been unrelated to penicillamine, t h e g r a n u l a r p a t t e r n o f i m m u n e f l u o r e s c e n c e in t h e renal b i o p s y was m o r e ak i n to a d r u g - i n d u c e d lesion t h a n to t h e linear p a t t e r n f o u n d w h e n t h e s y n d r o m e is idiopathic. DEFEROXAMINE (DESFERRIOXAMINE) A case has b e e n r e p o r t e d o f an a n a p h y l actic r e a c t i o n t o d e f e r o x a m i n e ( 5 2 c ) . Because t h e p a t i e n t h a d h a d a local skin react i o n t o an i n t r a m u s c u l a r i n j e c t i o n w i t h defe r o x a m i n e a series o f i n t r a d e r m a l desensit i z a t i o n i n j e c t i o n s was s t a r t e d . A b o u t 30 min u t e s a f t e r a skin dose o f 1.66 m g o f defere x a m i n e the p a t i e n t h a d a v i o l e n t a n a p h y l a c tic r e a c t i o n , c o n s i s t i n g of generalized itching, severe b a c k p a i n , l a r y n g o s p a s m , wheezing, cyanosis a n d t a c h y c a r d i a . T h e a u t h o r s c o n c l u d e t h a t d e f e r o x a m i n e or m i c r o b i a l i m p u r i t i e s p r o d u c e d b y Streptomyces pilosis m i g h t b e a p o t e n t allergen in c e r t a i n individuals.
R. H. B. Meyboom
220 REFERENCES 1. Van der Korst, J. K. (1976): Penicillamine op de terugtocht? Ned. T. Geneesk., 120, 431. 2. Hill, H. F. H. (1977): Treatment of rheumatoid arthritis with peniciUamine. Semin. Arthr. Rheum., 6, 361. 3. Camus, J.P., Crouzet, J., Prier, A. and Leca, A.P. (1976): Complications du traitement de la polyarthrite rhumatoi'de par la D-p6nicillamine.
Th~rapie, 31,385. 4. Dippy, J. E. (1977): Penicillamine in rheumatoid arthritis. A 2-year retrospective study in 70 patients. Brit. s clin. Pract., 31, 5. 5. Laitko, S., Hiige, H., Pr6hl, S., Hiige, W. and Ebert, H. (1976): H~/ufigkeit und Schwere yon Nebenwirkungen bei der Therapie der chronischrheumatischen Polyarthritis mit D-Penicillamin. Dtsch. Gesundh.-Wes., 31, 2084. 6. Mery, C., Delrieu, F., Ghozlan, R., Saporta, L., Simon, F., Amor, B., Menkes, C. J.: and Delbarre, F. (1976): Controlled trial of D-peniciUamine in rheumatoid arthritis. Dose effect and role of zinc. Scand. Z RheumatoL, 5, 241. 7. Solomon, L., Abrams, G., Dinner, M. and Berman, L. (1977): Neonatal abnormalities associated with D-penicillamine treatment during pregnancy. New Engl. J. Med., 296, 54. 8. Proesmans, W., Jaeken, J. and Eeckels, R. (1976): D-penicillamine induced IgA deficiency in Wilson's disease. Lancet, 2, 804. 9. Hjalmarson, O., Hanson, L.A. and Nilsson, L.A. (1977): IgA deficiency during D-penicillamine treatment. Brit. reed. Z, 1,549. 10. Stanworth, D. R., Johns, P., Williamson, N. et al. (1977): Drug-induced IgA deficiency in rheumatoid arthritis. Lancet, 1, 1001. 11. Roath, S. and Wills, R. (1974): Postgrad. med. s 50, 56. 12. Dewse, C. D. (1976): J. Pharm. Pharmacol., 28, 596. 13. Roath, S. (1:977): Letter to the editor. Lancet, 1, 1008. 14. Dewse, C.D. (1976): Letter to the editor. Lancet, 2, 683. 15. Kendall, P. A. (1976): Penicillamine. Pitfalls in interpreting in vitro studies. Lancet, 2, 862. 16. Huskisson, E. C.~, Scott, J., Ralme, H. W. et al. (1976): Immunostimulant therapy with levamisole for rheumatoid arthritis. Lancet, 1,393. 17. Deacon, S. P. and Masters, R. R. (1977): Allergic reactions to penicillamine. Brit. med. J., 1, 237. 18. Gange, R.W., Rhodes, E.L., Edwards, C. O. and PoweU, M. E. A. (1976): Pemphigus induced by rifampicin. Brit. J. Dermatol., 95,445. 19. Marsden, R. A., Ryan, T. J., Vanhegan, R. I. et al. (1976): Pemphigus foliaceus induced by penicillamine. Brit. med. J., 2, 1423. 20. Davies, M. G. and Holt, P. (1976): Pemphigus in a patient treated with penicittamine for generalized morphea. Arch. Derm., 112, 1306. 21. Tan, S. G. and Rowell, N. R. (1976): Pemphi-
gus-like syndrome induced by D-penicillamine.
Brit. Z DermatoL, 95, 99. 22. From, E. and Frederiksen, P. (1976): Pemphigus vulgaris following D-penicillamine. Dermatologica (Basel), 152, 358. 23. Kjeldstrup Kristensen J. and Wadskov, S. (1977): Penicillamine-induced pemphigus foliaceus. Acta dermatovener. (Stockh.), 57, 69. 24. Colliard, H. and Saurat, J. H. (1976): Pemphigus induit par la p6nicillamine. Rev. Stomatol., 77, 741. 25. Pegum, J.S. and Pembroke, A.C. (1977): Benign mucous membrane pemphigoid associated with penicillamine treatment. Brit med. J., 1, 1473. 26. Scherak, O., Kolarz, G. :and Holubar, K. (1977): Pemphigus erythematosus-like rash in a patient on penicillamine therapy. Brit. reed. J., 1, 838. 27. Greer, K.E., Askew, F.C. and Richardson, D.R. (1976): Skin lesions induced by penicillamine. Arch. Derm., 112, 1267. 28. Kirsch, N. arid Hukill, P. B. (1977): Elastosis perforans serpiginosa induced by penicillamine. Arch. Derm., 113, 630. 29. Bacon, P.A., Tribe, C.R., Mackenzie, J. C., Verrier Jones, J., Cumming, R. H., and Amer, B. (1976): Penicillamine nephropathy in rheumatoid arthritis. Quart. J. Med., 15, 661. 30. Brass, H., Genth, E., Hartl, P.W., Bauerdick, H., Buss, H., Lapp, H. and Heintz, R. (1976): Die D-Penizillamin Glomerulopathie. Med. Welt, 27, 2151. 31. Hampel, R., Meng, W. and KalweUis, G. (1976): Nephrotisches Syndrom nach Penizillamintherapie beim Morbus Wilson. Z. inn. Med.,
31,507. 32. Altrogge, G., Hofmann, K., Huth, F., Grabensee, B. and Schoppe, W. D. (1976): D-PeniciUamin und Glomerulonephritis. Med. Welt, 27, 2282. 33. Miiller, V., Krumhaar, 1., Schneider, W. and Ditscherlein, G. (1976): Penicillamin-bedingte Glomerulopathie bei Rheumatikern. Allerg. Immunol., 22, 291. 34. Bourke, B., Maini, R. N., Griffiths, I. D. and Scott, J. T. (1976): Fatal marrow aplasia in a patient on peniciUamine. Lancet, 2, 515. 35. McAllister, W. A.C. and Vale, J. A. (1976): Fatal marrow aplasia in patient on penicillamine. Lancet, 2, 631. 36. Barnet, A.J. and Whiteside, M.G. (1976): Marrow aplasia and penicillamine. Lancet, 2, 682. 37. White, A. G. (1976): Letter to the editor. Lancet, 2, 683. 38. Sacher, M. and Thaler, H. (1977): Toxic hepatitis after therapeutic doses of benorylate and penicillamine. Lancet, 1,481. 39. Editorial (1974): Aspirin-induced hepatic injury. Ann. intern. Med., 80, 103. 40. Cucher, B.G. and Goldman, A.L. (1976):
221
Heavy metal antagonists D-penicillamine induced polymyositis in rheumatoid arthritis. Ann. intern. Med., 85, 616. 41. Fernandes, L , $winson, D. R. and Hamilton, E. B.D. (1977): Dermatomyositis complicating penicillamine treatment. Ann. rheum. Dis., 36, 94. 42. Seitz, D., Hopf, H. C., Janzen, IL C.W. and Meyer, W. (1976): Penicillamin induzierte Myasthenie bei chronischer Polyarthritis. Dtsch. reed. Wschr., 101, 1153. 43. Delrieu, F., Menkes, C.J., Sainte-Croix, A., Babinet, P., Chesneau, A.M. and Delbarre, F. (1976): Myasth6nie et thyroidite auto-immune au cours du traitemefit de la polyarthrite rhumatoide par la D-penicillamine. Ann. M~d. interne, 127, 739. 44. Unpublished case reported to the Netherlands Centre for Monitoring of Adverse Reactions to Drugs, Ministry of Health, Leidsehendam, The Netherlands.
45. Corboran, R. and Castles, W. J.B. (1977): Penicillamine therapy and teratogenesis. Brit.
med. J., 1,838. 46. Maracek, Z. and Gaff, M. (1976): Pregnancy in penicillamine-treated patients with Wilson's disease. New Engl. J. Med., 295, 841. 47. Walshe, J. M. (1977): Quart. J. Med., 181, 73. 48. Bakker, W. and De Rooy, J. A. R. M. (1977): Unpublished observations. 49. Brewerton, D. (1976): D-penicillamine. Brit. reed. J., 2, 1507. 50. Lyle, W. H. (1977): D-penicillamine and fatal obliterative bronchiolitis. Brit. rned. J., 1, 105. 51. Harris, G. (1976): Leukaemia-like appearances in mice given penicillamine. Lancet, 2, 1356. 52. Athanasion, A., Shepp, M.A. and Necheles, T. F. (1977): Anaphylactic reaction to deferoxamine. Lancet, 2, 616.
21
heavy metal antagonists
PENICILLAMINE General Enthusiasm about the efficacy o f penicillamine in rheumatoid arthritis has been overclouded by its adverse effects (1C R). Recent publications have confirmed the high incidence of adverse reactions (2, 3, 4, 5). Mery et aL observed that the concomitant use of zinc (5 mg daily) strongly decreased the therapeutic action o f peniciUamine, but did not prevent its adverse effects (6). Hill has given an extensive review of experience with 109 patients on penicillamine, and of the literature on the drug (2CR). From this study one can differentiate between those adverse reactions that usually develop early in the course of penicillamine treatment (gastrointestinal upset, loss of taste, diarrhoea, allergic rashes, thrombocytopenia) and other reactions that usually develop after the patient has been treated for more than six months (proteinuria, late itchy scaling, erythematous eruptions). The incidence of the early reactions in particular can be much reduced by employing monthly increments rather than fortnightly, and by using low doses (2; SED VIII, p. 531). In teractions There are no known interactions between penicillamine and anti-inflammatory or analgesic drugs (2; see also SED VIII, p. 530), with the possible exception of paracetamol (see 'Gastrointestinal' section). Immunological effects It has been noticed in two patients with rheumatoid arthritis as well as in patients with Wilson's disease that D-penicillamine can induce IgA deficiency, with IgA levels sometimes declining towards undetectable levels (8, 9, 10). In these cases the concentration of IgA in the saliva was also decreased. On immunofluorescence investigation, biopsy material from the small bowel mucosa showed a normal number of IgA-bearing plasmacytes. One of the patients with rheumatoid
arthritis is known to have experienced no ill-effects from the IgA deficiency within the three years after it was detected (10). One of the patients with Wilson's disease, on the other hand, had recurrent benign upper respiratory tract infections, which were reported not to have been present before the start of D-penicillamine therapy. However, normal IgA levels were found in the serum of eight patients with Wilson's disease who had been treated with D-penicillamine for a long time (9). It is not y e t clear whether penicillamine has immunosuppressive (11 - 14) or immunostimulating properties (15, 16). Kendall has suggested that in lymphocyte transformation testing L-cystine deficiency in the medium, caused by penicillamine, brings about depression of DNA-synthesis, thus masking the intrinsic enhancing effect of penicillamine on lymphocyte transformation (15). Skin and appendages Early skin reactions Allergic rashes are a frequent complication of penicillamine (SED VIII, p. 531; 2 CR, 3, 4) which, however, can often be overcome by reduction of the dose or temporary withdrawal of the drug. Since trace impurities may be implicated in allergic reactions, it has been suggested that, if a patient does not tolerate a particular brand of penicillamine, he may on resuming the treatnient benefit from a trial with a different pharmaceutical preparation (17). Tardive skin eruptions It is becoming increasingly clear that some drug-induced eruptions are associated with antibodies against the intercellular substance of the epidermis, although the appearance of the eruptions may be different from pemphigus (18). Although other drugs have been implicated (e.g. phenylbutazone, isoniazid, rifampicin) penicillamine is apparently the best known factor responsible for the induction of such antibodies. Many well-documented reports, not only from France, but also from Denmark, Switzerland and from the United Kingdom, have
216 confirmed that D-penicillamine can cause frank pemphigus ( 1 9 - 2 6 ) . Unlike idiopathic pemphigus, D-penicillamine-induced eruptions often present as pemphigus foliaceus. In pemphigus foliaceus the predominant lesions are crusts, erosive sloughs and scaly lesions. The lesions often appear on the trunk, scalp or face and may closely resemble seborrhoeic dermatitis. The main difference between pemphigus foliaceus and the bullous type of pemphigus is that in the former the intra-epidermal blisters are more superficially located. The crusts and sloughs represent ruptured bullae; the thin walls account for the fragility of the blisters. Although this disorder is often rapidly reversible after discontinuation of D-peniciUamine and may even improve after reduction of the dose, the symptoms are sometimes persistent and may require prolonged treatment with corticosteroids. In some patients D-penicillamine has been re-introduced without recurrence of the eruption (see also under Goodpasture's syndrome, below). In one patient with pemphigus of the skin and mucous membranes the conjunctivae were also involved. The eye lesions healed with conjunctival scarring and symblepharon formation (25). It has been suggested that the scaly, itching eruption which is the most common tardive skin reaction to penicillamine, is in fact often an unrecognized manifestation of this form of pemphigus foliaceus (2 cR, 19CR). Unlike idiopathic pemphigus foliaceus the penicillamine-induced type is extremely itchy. An interesting case has been reported of another tardive skin syndrome induced, at least partially, by penicillamine (27). In this patient after about 10 years of treatment with penicillamine (2 g daily) for Wilson's disease a skin abnormality had developed with yellowing, crinkling and wrinkling of the skin of her face and neck and with multiple soft white papules (1-2 mm in diameter) overlying the veins in both antecubital fossae (where many years earlier multiple venepunctures had been performed) and surrounding a surgical scar (the lesions coinciding with suture sites). The patient had never developed blisters or bruises secondary to skin trauma. Investigation of a biopsy specimen from the skin of the antecubital fossa showed focal degeneration and homogenization of the connective tissue. The degenera-' tion was characterized by a loss of the normal elastic and coUagenousarchitecture. There was replacement of the dermal fibrillar structures with clump-
R. H. B. Meyboom
ed and granular eosinophilic material. There was no evidence of cyst formation. Kirsch and Hukill have reported a further case of elastosis perforans serpiginosa induced by penicillamine (28Cr). The patient had been treated for years with 2 g of penicillamine daily for Wilson's disease; the eruption predominantly involved the skin of the neck, but the glans penis was also affected. Electron microscopical examination revealed distinct abnormalities of the elastin; these abnormalities, however, were different from those observed in idiopathic elastosis perforans. The authors suggest that penicillamine-induced elastosis perforans may be due to deficiency to one of the trace metals. The elastin abnormalities which are found in experimental copper deficiency, however, are not identical to those in elastosis perforans. R e n a l disorders
Again attention has been focussed upon immune-complex nephritis as a complication of peniciUamine (2, 2 9 - 3 3 ) . Bacon et al. observed persistent proteinuria in 14 patients (7.4%) out of a series of 189 treated with penicillamine; 11 had a clinical nephrotic syndrome, while three had only proteinuria (29). Both the nephrotic group and those with uncomplicated proteinuria showed evidence of the same immunopathological mechanism. Renal biopsies were performed at different intervals after the cessation of penicillamine therapy, revealing in some patients striking persistence of electron-dense deposits in the glomerular basement membrane. The authors conclude that the use of peniciUamine in rheumatoid arthritis may induce protracted renal changes. Hill observed proteinuria in 25 out of 109 patients (23%) (2). Characteristically, proteinuria is a late complication of penicillamine. The incidence of proteinuria rose from 2% during the first six months of treatment to 30% during the next six months, falling to 5% thereafter. In four (3.7%) of the 109 patients a nephrotic syndrome developed with proteinuria exceeding 10 g/24 hr; clinical and laboratory abnormalities persisted for 1 2 - 2 4 months. Hill advises a reduction in dose of 250 mg as soon as proteinuria occurs; proteinuria should be monitored thereafter fortnightly, on 24-hour urine samples. If proteinuria exceeds 2 g/24 hr penicillamine should be stopped forthwith. For Goodpasture's syndrome see p. 219.
Heavy metal antagonists B l o o d and bone marrow
Three further cases have been reported of aplastic anaemia, attributed to the use of D-penicillamine (34, 35, 36), which makes a total of six published cases (SED VIII, pp. 534, 535; SEDA-I, p. 191). Two of these patients died, one from septicaemia (this patient had previously been obliged to stop treatment with gold because of thrombocytopenia), the other from massive intrapulmonary bleeding. The third patient recovered; she had also used co-trimoxazole 3 months before, and a chloramphenicol-containing ointment f o r ' a n eye infection about one month before the development of the bone marrow hypoplasia. Both Hill (2) and White (37) have observed that thrombocytopenia is often rapidly reversible if D-penicillamine is discontinued. Hill noticed that, because the platelet count falls in about 75% of patients on penicillamine, it is often difficult to know when to discontinue the drug (2). She advises checking the platelets at weekly intervals when the count falls to between 100 x 109/1 and 70 x 109/1 and daily if the count falls below 70 x 10911. If any further fall occurs penicillamine should be stopped and frequent counts performed until the number of platelets exceeds 100 x 109/1. Hill observed the development of thrombocytopenia in eight (7.7%) out of 109 patients, necessitating withdrawal in four (2). In all cases the thrombocytopenia occurred within the first six months o f treatment (between the 10th and 20th weeks). The incidence of thrombocytopenia appeared to be related to the dose of penicillamine. The t h r o m b o c y t o penia was rapidly reversible in these four patients, the counts returning to normal within 7 - 1 0 days after penicillamine was stopped. It has been observed that the injection of large amounts of penicillamine into mice was associated with the development of a leukaemia-like condition (51). Gastrointestinal
According to Hill abnormalities of taste are the most common adverse effect of penicillamine; smell is not affected (2). Some patients describe the abnormality as a salty taste, other patients report that some foods 'do n o t taste right'. This usually affects sweet foods, and patients report that food tasted 'like cotton wool and blotting paper'. Complete loss of taste developed in four out
217 of 109 patients (2). The abnormalities of taste occur in the early weeks of treatment and are clearly related to the rate of introduction and the dose of penicillamine. Despite continuation of penicillamine, normal taste is restored in time (weeks or months). The use of penicillamine can be associated with nausea, vomiting, epigastric discomfort and diarrhoea (2). Camus et al. noticed gastric symptoms such as anorexia, nausea and vomiting in 27 (13.5%) out of 200 patients on D-penicillamine, leading to withdrawal in nine (3). Dippy observed gastric symptoms in 24 patients out of 70 (34.3%) (4). These authors made somewhat conflicting remarks as to the possible ulcerogenic properties of D-penicillamine. Dippy noticed that patients with previous gastric or duodenal ulcer were almost invariably troubled with gastric side effects, whereas Camus et al. did not notice the development of an ulcer in any of his patients and stressed that D-penicillamine was well tolerated by patients who had a previous or active peptic ulcer. In Dippy's study all patients were on anti-inflammatory analgesics as well; Camus et aL did not mention the possibility of the concomitant use of other drugs (see SED VIII, p. 535). Hill observed the development of an active peptic ulcer during treatment with penicillamine in two out of 109 patients (2). The incidence of gastrointestinal symptoms will be strongly reduced if low doses are used, and increments are made monthly instead of fortnightly (2, 3). Buccal ulcerations occurred in three out of 109 patients on penicillamine, leading to permanent discontinuation in two patients (2). The ulcers affected the tongue and/or the mucous membranes, and were painful, raised and clearly delineated; they took 3 4 weeks to heal after penicillamine had been stopped. A third case has been observed of pancreatitis occurring in a patient on treatment with penicillamine (L. Agerskov Andersen, personal communication). This patient, a 54-year-old woman, developed acute pancreatitis after 5 weeks of treatment with penicillamine for rheumatoid arthritis, in a maximum daily dose of 450 mg. She had never had a bout of pancreatitis before. Despite these observations, a causal relationship between the use of penicillamine and the occurrence of pancreatitis has not been established.
218 Digestive tract
The case is reported of a 13-year old girl who, after 20 weeks of treatment with Dpenicillamine (750 mg daily) and benorylate (6 g daily) for rheumatoid arthritis, developed toxic hepatitis (38). Both drugs were stopped and there was considerable improvement over the next two weeks. Benorylate is an ester of acetylsalicylic acid and paracetareel; 6 g benorylate is equivalent to 2.8 g paracetamol. D-penicillamine is largely excreted as L-cysteine-D-penicillamine disulphide. The authors suggest that, as cysteine is a precursor of glutathione, the excretion of D-penicillamine is perhaps linked with the exhaustion of hepatic cysteine, resulting in a decrease of glutathione below levels that are required for the detoxification o f paracetareel metabolites. The authors do not mention the salicylate levels in the serum of their patients; serum levels exceeding about 25 rag/100 ml are known to also be able to cause hepatitis (39). Neuromuscular system
A further two cases of polymyositis, apparently induced by D-penicillamine, have been reported; both patients recovered. In the first patient the disorder presented with palpitations and severe muscular weakness; she had no muscular aches (40). The polymyositis was associated with myocarditis, proteinuria and decreased serum levels of complement. In the second patient the polymyositis was associated with a facial rash with heliotrope discolouration around the eyes and peri-orbital oedema, presenting the characteristic picture of dermatomyositis (41). The patient had fever, some liver enlargement, tender back and thigh muscles, and proximal muscle weakness. S e i t z e t al. have reported a further 12 patients (all females) with symptoms of myasthenia gravis, attributed to the use of D-penicillamine for rheumatoid arthritis (42). The edrophonium test was positive in all. The disorder presented with ocular involvement leading to ptosis and double vision in nine patients, and remained confined to ocular s y m p t o m s in three. Speech, chewing and/or swallowing were frequently impaired. In some patients severe generalized myasthenia developed. The condition was reversible in most patients, although several cases required pyridostigmine treatment for
R. H. B. Me),boom
a long period and two patients required artificial respiration, one of them died. A second fatal case of myasthenia attributed to the use of penicillamine has been observed in France (43). This patient also had chronic atrophic thyroiditis and hypothyroidism, which was also thought to be induced by D-penicillamine. In the Netherlands, too, a patient has been observed with myasthenia gravis developing during treatment with penicillamine for rheumatoid arthritis (44). In this patient ptosis and impairment o f speaking and swallowing predominated. Six months after the discontinuation of penicillamine she still required pyridostigmine treatment. Apparently penicillamine-induced myasthenia is not associated with thymoma. Endocrine glands
A fatal case has been reported of myasthenia associated with hypothyroidism, developing in a patient on D-penicillamine for rheumatoid arthritis (43). Pathological examination of the thyroid gland revealed chronic non-specific atrophic thyroiditis with interstitial sclerosis and infiltration with lymphocytes and plasma ceils. The authors suggest that both conditions were, at least partially, induced by D-penicillamine. In addition Laitko et al. have listed enlargement of the thyroid gland amongst the side effects of peniciUamine (5). Foetal toxicity
The most recent opinion on the obscure subject o f the safety of D-peniciUamine in pregnancy is that it makes an important difference whether the drug is used for Wilson's disease or for other conditions (7, 45). It has been suggested that the apparent safety o f D-penicillamine in pregnancy in Wilson's disease could be explained on the basis that in Wilson's disease there is a high proportion of unbound copper, which is chelated by penicillamine, thus reducing the penicillamine level (7). This mechanism would not operate in a disorder such as rheumatoid arthritis. Further reports have in the meantime appeared on normal infants, born to women with Wilson's disease who had used penicillarnine in pregnancy (46, 47). There is, however, one newer report on an abnormal child, reminiscent of the case described by Mj~blner~d (SED VIII, p. 537; ref. 35), born to a mother who had received D-penicillamine for rheumatoid arthritis (7).
Heavy metal antagonists The mother was being treated with 900 mg penicillamine per day during most of the pregnancy. During the pregnancy placental insufficiency developed and the foetus was small for its age. A boy weighing 2.0 kg was delivered by Caesarean section at the end of the 37th week. Growth retardation was confirmed, the head circumference was 32 cm and crown-to-heel length 40 cm. The face was flattened, with a broad nasal bridge, the ears were lowset and the neck was short with loose folds of skin. Body skin too was unusually lax and wrinkled. Bilateral inguinal herniae were present. There were fixed flexion contractures of the hips and knees. The palms showed simian creases. Twelve hours after birth an acute abdomen developed, and a diagnosis of perforation of the bowel with meconium peritonitis was made. At laparotomy, however, no overt perforation was found; the child's condition remained poor and he died three days later. Routine histological examination showed no collagen abnormalities.
Influence on wound healing S u s p i c i o n has arisen t h a t p e n i c i l l a m i n e c o u l d i n t e r f e r e w i t h w o u n d healing ( S E D VIII). H o w e v e r , Hill c o u l d n o t d e t e c t impairm e n t o f w o u n d h e a l i n g a f t e r 23 surgical o p e r a t i o n s in 15 p a t i e n t s o n c o n t i n u e d t r e a t m e n t w i t h p e n i c i l l a m i n e (2).
Respiratory system R e c e n t l y in t h e N e t h e r l a n d s a p a t i e n t h a s b e e n o b s e r v e d w i t h a very severe e m p h y s e m a t o u s l u n g disorder, w h i c h was c o n s i d e r ed t o b e possibly r e l a t e d t o t h e use o f penicillamine, since n o o t h e r cause c o u l d b e detected (48). The patient, a 59-year-old woman (body weight 47 kg), with long-standing rheumatoid arthritis had been using 750 mg penicillamine daily for about 18 months. Other drugs used were indomethacin and a compound analgesic, containing phenazone and phenacetin. During treatment with penicillamine, with good results, the patient became progressively dyspnoeic, and finally developed extreme dyspnoea. On X-ray examination the lungs were somewhat radiolucent but otherwise normal. Howcver, blood gas analysis revealed severe oxygen undersaturation. Functional investigation of the lungs showed severe bronchial obstruction, most probably as a result of extreme emphysema. Diffusion was also deranged as one would anticipate with a severe emphysema. The patient had never
219 smoked, nor did she suffer from chronic bronchitis or asthma. The alpha~-antitrypsin level was normal (Pi-type M). A lung biopsy could not be taken because of the patient's poor condition. The prognosis for this patient is considered to be very unfavourable. Functional and X-ray investigation of the lungs at tile beginning of penicillamine treatment had been perfectly normal. T h e r e has b e e n s o m e s u s p i c i o n t h a t Dp e n i c i l l a m i n e m a y be i n v o l v e d in t h e development of fatal obliterative bronchiolitis (49). However, t h e e v i d e n c e is very weak a n d was n o t s u p p o r t e d b y an e x t e n s i v e survey b y t h e m a n u f a c t u r e r o f d a t a available to him on penicillamine (50). SEDA-1 (p. 191) r e f e r r e d t o t h e develo p m e n t o f G o o d p a s t u r e ' s s y n d r o m e in relat i o n to peniciUamine. M a r s d e n et aL a n d Hill h a v e since t h e n briefly r e p o r t e d t h e case hist o r y o f a p a t i e n t ( a p p a r e n t l y t h e same individual) w h o died f r o m Goodpasture's s y n d r o m e , 18 m o n t h s a f t e r p e n i c i l l a m i n e had been stopped because of thrombocytop e n i a (2, 19). Previously this p a t i e n t h a d suffered f r o m p e n i c i l l a m i n e - i n d u c e d p e m p h i gus. A l t h o u g h in this p a t i e n t G o o d p a s t u r e ' s syndrome may have been unrelated to penicillamine, t h e g r a n u l a r p a t t e r n o f i m m u n e f l u o r e s c e n c e in t h e renal b i o p s y was m o r e ak i n to a d r u g - i n d u c e d lesion t h a n to t h e linear p a t t e r n f o u n d w h e n t h e s y n d r o m e is idiopathic. DEFEROXAMINE (DESFERRIOXAMINE) A case has b e e n r e p o r t e d o f an a n a p h y l actic r e a c t i o n t o d e f e r o x a m i n e ( 5 2 c ) . Because t h e p a t i e n t h a d h a d a local skin react i o n t o an i n t r a m u s c u l a r i n j e c t i o n w i t h defe r o x a m i n e a series o f i n t r a d e r m a l desensit i z a t i o n i n j e c t i o n s was s t a r t e d . A b o u t 30 min u t e s a f t e r a skin dose o f 1.66 m g o f defere x a m i n e the p a t i e n t h a d a v i o l e n t a n a p h y l a c tic r e a c t i o n , c o n s i s t i n g of generalized itching, severe b a c k p a i n , l a r y n g o s p a s m , wheezing, cyanosis a n d t a c h y c a r d i a . T h e a u t h o r s c o n c l u d e t h a t d e f e r o x a m i n e or m i c r o b i a l i m p u r i t i e s p r o d u c e d b y Streptomyces pilosis m i g h t b e a p o t e n t allergen in c e r t a i n individuals.
R. H. B. Meyboom
220 REFERENCES 1. Van der Korst, J. K. (1976): Penicillamine op de terugtocht? Ned. T. Geneesk., 120, 431. 2. Hill, H. F. H. (1977): Treatment of rheumatoid arthritis with peniciUamine. Semin. Arthr. Rheum., 6, 361. 3. Camus, J.P., Crouzet, J., Prier, A. and Leca, A.P. (1976): Complications du traitement de la polyarthrite rhumatoi'de par la D-p6nicillamine.
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Brit. Z DermatoL, 95, 99. 22. From, E. and Frederiksen, P. (1976): Pemphigus vulgaris following D-penicillamine. Dermatologica (Basel), 152, 358. 23. Kjeldstrup Kristensen J. and Wadskov, S. (1977): Penicillamine-induced pemphigus foliaceus. Acta dermatovener. (Stockh.), 57, 69. 24. Colliard, H. and Saurat, J. H. (1976): Pemphigus induit par la p6nicillamine. Rev. Stomatol., 77, 741. 25. Pegum, J.S. and Pembroke, A.C. (1977): Benign mucous membrane pemphigoid associated with penicillamine treatment. Brit med. J., 1, 1473. 26. Scherak, O., Kolarz, G. :and Holubar, K. (1977): Pemphigus erythematosus-like rash in a patient on penicillamine therapy. Brit. reed. J., 1, 838. 27. Greer, K.E., Askew, F.C. and Richardson, D.R. (1976): Skin lesions induced by penicillamine. Arch. Derm., 112, 1267. 28. Kirsch, N. arid Hukill, P. B. (1977): Elastosis perforans serpiginosa induced by penicillamine. Arch. Derm., 113, 630. 29. Bacon, P.A., Tribe, C.R., Mackenzie, J. C., Verrier Jones, J., Cumming, R. H., and Amer, B. (1976): Penicillamine nephropathy in rheumatoid arthritis. Quart. J. Med., 15, 661. 30. Brass, H., Genth, E., Hartl, P.W., Bauerdick, H., Buss, H., Lapp, H. and Heintz, R. (1976): Die D-Penizillamin Glomerulopathie. Med. Welt, 27, 2151. 31. Hampel, R., Meng, W. and KalweUis, G. (1976): Nephrotisches Syndrom nach Penizillamintherapie beim Morbus Wilson. Z. inn. Med.,
31,507. 32. Altrogge, G., Hofmann, K., Huth, F., Grabensee, B. and Schoppe, W. D. (1976): D-PeniciUamin und Glomerulonephritis. Med. Welt, 27, 2282. 33. Miiller, V., Krumhaar, 1., Schneider, W. and Ditscherlein, G. (1976): Penicillamin-bedingte Glomerulopathie bei Rheumatikern. Allerg. Immunol., 22, 291. 34. Bourke, B., Maini, R. N., Griffiths, I. D. and Scott, J. T. (1976): Fatal marrow aplasia in a patient on peniciUamine. Lancet, 2, 515. 35. McAllister, W. A.C. and Vale, J. A. (1976): Fatal marrow aplasia in patient on penicillamine. Lancet, 2, 631. 36. Barnet, A.J. and Whiteside, M.G. (1976): Marrow aplasia and penicillamine. Lancet, 2, 682. 37. White, A. G. (1976): Letter to the editor. Lancet, 2, 683. 38. Sacher, M. and Thaler, H. (1977): Toxic hepatitis after therapeutic doses of benorylate and penicillamine. Lancet, 1,481. 39. Editorial (1974): Aspirin-induced hepatic injury. Ann. intern. Med., 80, 103. 40. Cucher, B.G. and Goldman, A.L. (1976):
221
Heavy metal antagonists D-penicillamine induced polymyositis in rheumatoid arthritis. Ann. intern. Med., 85, 616. 41. Fernandes, L , $winson, D. R. and Hamilton, E. B.D. (1977): Dermatomyositis complicating penicillamine treatment. Ann. rheum. Dis., 36, 94. 42. Seitz, D., Hopf, H. C., Janzen, IL C.W. and Meyer, W. (1976): Penicillamin induzierte Myasthenie bei chronischer Polyarthritis. Dtsch. reed. Wschr., 101, 1153. 43. Delrieu, F., Menkes, C.J., Sainte-Croix, A., Babinet, P., Chesneau, A.M. and Delbarre, F. (1976): Myasth6nie et thyroidite auto-immune au cours du traitemefit de la polyarthrite rhumatoide par la D-penicillamine. Ann. M~d. interne, 127, 739. 44. Unpublished case reported to the Netherlands Centre for Monitoring of Adverse Reactions to Drugs, Ministry of Health, Leidsehendam, The Netherlands.
45. Corboran, R. and Castles, W. J.B. (1977): Penicillamine therapy and teratogenesis. Brit.
med. J., 1,838. 46. Maracek, Z. and Gaff, M. (1976): Pregnancy in penicillamine-treated patients with Wilson's disease. New Engl. J. Med., 295, 841. 47. Walshe, J. M. (1977): Quart. J. Med., 181, 73. 48. Bakker, W. and De Rooy, J. A. R. M. (1977): Unpublished observations. 49. Brewerton, D. (1976): D-penicillamine. Brit. reed. J., 2, 1507. 50. Lyle, W. H. (1977): D-penicillamine and fatal obliterative bronchiolitis. Brit. rned. J., 1, 105. 51. Harris, G. (1976): Leukaemia-like appearances in mice given penicillamine. Lancet, 2, 1356. 52. Athanasion, A., Shepp, M.A. and Necheles, T. F. (1977): Anaphylactic reaction to deferoxamine. Lancet, 2, 616.