- Email: [email protected]
Metal antagonists
R.H.B. Meyboom and I.A. Jaffe
24 Penicillamine (SED-IO, 409; SEDA-8, 235; SEDA-9,223; SEDA-10,217; SEDA-11,211) General In a study of 162 children (54 receiving penicillamine), Brewer and co-workers were unable to demonstrate that, when given along with a non-steroidal anti-inflammatory drug, either penicillamine or hydroxychloroquine is superior to placebo in the treatment of juvenile rheumatoid arthritis (lCR); this is however in contradiction with earlier findings (2ca). In the light of the previously reported absence of taste disturbances in children (SED-10,414), it is noteworthy that in this study taste malfunction was again not reported. Kay has reported on the European League Against Rheumatism's study of adverse reactions to penicillamine (3c). The results of this very interesting study confirm the frequent occurrence of adverse reactions and the unparalleled variety of these reactions. Skin reactions, nephropathy, thrombocytopenia, myasthenia gravis and pemphigus were all observed. Similar experiences were reported by the Epidemiology Team of the French Rheumatology Society. Major causes for stopping penicillamine were (in decreasing order) lack of efficacy, proteinuria, skin rashes and hematologic reactions (4CR). Also, a Japanese series showed increasing loss of efficacy with longer duration of treatment (48 % after 5 years), wheras 52 % of the patients had adverse reactions (5c). In a recent report from the Multicentre Trial Group (U.K.), penicillamine was found to be ineffective in arresting radiographic deterioration of rheumatoid arthritis (6c; see also SEDA-10, 217). Sheikh and Kaplan have studied the effects of various antirheumatic drugs on the activities of the enzymes carboxypeptidase and angiotensinconverting enzyme (ACE) in human plasma. All drugs studied were marked inhibitors of ACE,
Side Effectsof DrugsAnnual 12 M.N.G. Dukes and L. Beeley,editors 9 ElsevierSciencePublishers B.V., 1988
Metal antagonists but only penicillamine had a demonstrable inhibition of carboxypeptidase (7c). The consequences of these findings with regard to the effects of penicillamine on patients need further study. Hendel and co-workers described markedly impaired absorption of peniciUamine in a patient with gastrointestinal involvement in systemic sclerosis (8c). In a Dutch series of 8 patients with Wilson disease, who had to stop penicillamine because of side effects, good control of the disease was achieved with oral zinc treatment (9~ Experimental use in 13 asymptomatic AIDS patients showed that penicillamine suppresses HTLVIII/LAV replication. Skin rashes (3 patients) and transient elevation of liver enzymes were the only associated events (10c).
Respiratory Alveolar hemorrhage as part of Goodpasture syndrome (in association with renal failure) is known to be a rare but serious complication of penicillamine (SEDA-8,236). Louie and co-workers have now described the first report of diffuse pulmonary hemorrhage without evidence of renal disease, developing after prolonged treatment with penicillamine for Wilson disease (1 lC). Nervous system Several further cases have been described of penicillamine-induced myasthenia gravis, underlining the similarity to idiopathic myasthenia gravis (12CR--17CR). The complete recovery of all clinical manifestations and of abnormal serological findings (e.g. antiacetylcholine-receptor antibodies) indicates that in these patients the disorder is a newly initiated autoimmune response rather than the enhancement of ongoing subclinical myasthenia. Moreover, patients with penicillamineinduced myasthenia have different HLA antigens from those with genuine myasthenia gravis (SEDA-8, 238; 14r). The article by Fried and Protheroe underlines the relevance of penicillamine-induced myasthenia for the anesthesist (SED-10, 415; 15CR). Another case was unusual in that myasthenia relapsed twice, first after rechallenge with penicillamine and later with chloroquine (16CR).
Metal antagonists Chapter 24 Endocrine, metabolic; mineral and fluid balance Weismann has reviewed the effect of chelating drugs, including penicillamine, on zinc metabolism (18 R). Interpretation of data may be difficult since penicillamine increases not only the excretion but also the absorption of zinc. As illustrated by the case study of Dastych and co-workers, a daily dose of 750 mg penicillamine is unlikely to cause zinc depletion in the presence of normal zinc intake (19c). Although this patient had a greatly increased excretion of copper, penicillamine did not influence the excretion of calcium, magnesium or iron. Camus and Kroeger have reviewed the pharmacological effects of penicillamine on collagen (SED- 10, 414; SEDA-11, 211 ; 20R), and Chamson and Frey have studied inhibition in vitro by penicillamine of collagen synthesis by fibroblasts (21c); their conclusions are similar to those presented earlier in this series. Hematological One further case has been described of thrombotic thrombocytopenic purpura (Moschcowitz syndrome), attributed to the use of penicillamine (only 250 mg/d) (SEDA-9,224; 22CR). A letter by the same authors in the Presse M~dicale of 31 May, 1986, apparently pertains to the same patient. Plasma exchange was not effective, but a lasting remission was achieved by treatment with corticosteroids and vincristine. The patient reported from the Netherlands with fatal aplastic anemia induced by penicillamine had sideroblastic changes. The findings indicated a stem cell injury (23CR). Hamilton and Williams demonstrated that in vitro development of both murine and human myeioid colonies from progenitor cells was markedly suppressed by d-penicillamine (or gold derivatives) in therapeutic concentrations (24c). These results, together with the earlier finding of inhibited megakaryopoiesis (SEDA-10,219), provide evidence that besides immunological processes - a pharmacological effect may be involved in the development of penicillamine-related bone marrow failure. Urinary system Penicillamine nephropathy with membranous glomerulitis as the characteristic lesion and nephrotic syndrome as the clinical manifestation - is a well-recognized entity (SED-10,412; 25R). Seherberich and coworkers have recently reviewed the occurrence of renal damage as part of rheumatoid arthritis, predominantly mesangioproliferative nephropathy (26CR). It may be difficult to distinguish
195 between rheumatic and drug-induced renal disease on the one hand, and also between penicillamine and NSAID-related renal damage on the other. This latter issue has also been adressed in a case-report by Feehally et al (27CR); in their patient acute tubulo-interstitial nephritis developed during the concomitant use of fenbufen and penicillamine. Although fenbufen was initially the suspected drug, a relapse on rechallenge with penicillamine showed that this drug was in fact the cause. In addition, another study described the spontaneous occurrence of membranous glomerulonephritis in rheumatic patients using neither penicillamine nor gold (28CR). Malaise and co-workers studied the titers of antigalactosyl antibodies in the serum of rheumatic patients (29CR). In this series high titers of antigalactosyl antibodies were strongly correlated with the prior development of proteinuria during penicillamine (and gold) therapy. Antigalactosyl antibodies may in the future be found to be useful for the monitoring of penicillamine nephropathy. Observations in 2 patients have underlined the fact that penicillamine-induced systemic lupus erythematosus (SLE) can be associated with diffuse crescentic glomerulonephritis and renal failure (SEDA-8, 237; SEDA-11, 213; 30CR). These 2 patients occurred in a series of only 52 patients treated for systemic sclerosis, giving a frequency of this complication of 4%. Skin and appendages A case-report on penicillamine-related cheilosis (31 c) is a reminder to the oral manifestations that can occur while using penicillamine (SED-10,411). Unfortunately, no details are given on the nature of the lesions in this patient. Two new case-reports describe penicillamine induced pemphigus (SED-10,413; SEDA-11,213; 32c, 33c). The predominance of penicillamine in iatrogenic pemphigus is illustrated in a review of the literature by Tholen (33R). Forty-two of 60 cases were associated with penicillamine, whereas in the remaining 18 patients 14 different drugs were involved. Kohn has commented upon the fatality rate of penicillamine-induced pemphigus, which appears to be in the range of 10 % (34R). Light and co-workers have described the collagen and elastin changes in pseudoxanthoma-elasticum-like lesions, induced by penicillamine (SEDA-I1,214; 35CR). A single report describes a further case of penicillamine-induced elastosis perforans serpiginosa (SED-10,413; 36CR). On histological exami-
196 nation, lesional and non-lesional skin showed the same changes. Special emphasis was given to the finding that elastic fiber alterations were also found in an artery. (See above for more information on the effects of penicillamine on collagen and elastin). Dermatomyositis is discussed below (Musculoskeletal system). Mnsenloskeletal system Earlier reports have discussed the possibility of penicillamine-associated arthralgia and arthritis (SED-10,415). Butler and Tiliakos have now provided details of 3 patients who apparently had penicillamineinduced acute exacerbations of rheumatoid arthrit/s, with severe, disabling febrile, symmetric polysynovitis. There were normal complement levels and negative antinuclear antibodies, and the patients recovered upon discontinuation of penicillamine. As the authors point out, the symptoms were not part of a (drug-induced) SLE reaction; the pathogenesis has remained unclear (37CR). Until recently, polymyositis and dermatomyositis were considered to be very rare complications of penicillamine therapy. Recently, however, 9 further cases have been described (38CR-41r In a series from Japan of 329 patients receiving penicillamine (for rheumatoid arthritis), 4 patients with myositis were observed (38cs). This gives an incidence of 1.2%, which is in the same range as for pemphigus and myasthenia (SEDA-8, 236). In one of these patients the causal involvement of penicillamine was proven when readministration was followed by a relapse of polymyositis. In a study by Matsumura the causal role of penicillamine was supported by a positive lymphocyte stimulation test (39CR). Dysphagia and muscle weakness may be the first signs of polymyositis, which can occur at any time during treatment with penicillamine and with doses as low as 100 mg (38c). Masson and co-workers focussed attention on the concomitant existence of antinuclear antibodies in 90% of the cases ofpenicillamineinduced polymyositis (40 CR) and suggested that this finding may be helpful in distinguishing it from spontaneous polymyositis. The patient described by Car and co-workers had dermatomyositis, probably induced by penicillamine (41cR). Recovery on stopping penicillamine and the absence of a neoplastic condition during 2 years of follow-up, were here arguments in favor of a causal relationship with penicillamine.
Chapter 24 R.H.B. Meyboom and I.A. Jaffe Immune system and autoimmune reactions Petersen has studied the complex in vitro effects of pharmacological concentrations of penicillamine, with or without copper, on the function of human lymphocytes (42cR). The results indicate that there are different processes by which penicillamine suppresses lymphocyte responses. It is concluded that penicillamine may modify the manifestations of rheumatoid arthritis by inhibition of antigeninduced and polyclonal lymphocyte responses. Another interesting in vitro study concerned the effect of penieiUamine on the production of antiDNA antibodies by lymphocytes from SLE patients and controls (43c). Panayi and McKenzie Mills found that peniciUamine (as well as sodium aurothiomalate) depresses the autologous mixed lymphocyte reaction and propose that this may be the mechanism whereby this drug decreases rheumatoid factor production (44c). In patients with spontaneous SLE an association has been found between disease activity and the reticuloendothelial system Fc receptor function. Fields and co-workers found that in patients with drug-induced SLE, on the contrary, Fc-receptor-mediated immune clearance did not differ significantly from that in normal controls (45cR). This difference in immune clearance may be relevant to the understanding of differences between spontaneous and druginduced SLE. In only one of their series of 16 patients was penicillamine the offending drug; symptoms were thrombocytopenia and pleuritis. An interesting finding was that in this patient the clearance of immune complexes was markedly delayed compared with the other patients (t,/2 of 80 min compared with a mean of 52 min in these patients, and a normal range of 34-60 min). Unfortunately, this observation is not discussed by the authors. The issue of drug-induced autoimmune disease has been reviewed by Spears and Batchelor (45R), with special reference to penicillamine (and gold and hydralazine). Genetic factors The associations between HLA antigens and susceptibility to penicillamine side effects has been reviewed previously (SEDA-11, 211). Two new studies of comparatively small series of patients did not reveal any such associations (47or, 48cr). Second-generation effects Rosa has recently reviewed the teratogenicity of penicillamine and the occurrence of cutis laxa in prenatally
197
Metal antagonists Chapter 24 exposed children (SED-10, 416; 49R). One further case is on record of a healthy baby born to a woman who had been treated with 500 mg penicillamine daily (for Wilson disease) (50c).
Another case-report described bullous lichen planus in association with the use oftiopronine (56c).
Interactions When taken concomitantly with
OTHER METAL ANTAGONISTS
iron salts, the absorption of penicillamine is strongly imp aired (S EDA- 10). Ifan and Welling have shown that also AI 3 § and Mg 2§ containing antacids may lower the absorption of penicillamine by up to 45% (51CR). Apparently this effect is not due to a decrease of the pH in the stomach but to chelation of penicillamine with these metal ions.
Tumor-inducing effects Speit and Haupter have found that penicillamine is mutagenic in vitro and advise that further in vivo studies are needed to evaluate the risk to patients treated with penicillamine (52c). Their test results suggest that the induction ofpenicillamine of sisterchromatid exchanges may be complex and not based on a single mechanism. Up to the present time, however, there have been no clinical indications for an excess incidence of neoplasia in penicillamine users. RELATED COMPOUNDS
Tiopronine (N- (2-mercaptopropionyi)glycine) (SEDA-11,215) Ferraccioli and co-workers have studied the HLA antigens in patients experiencing adverse reactions to tiopronine (16 patients) or aurothiosulfate compared with those without adverse reactions (53c). There was an obvious correlation between tiopronine-induced nephropathy (11 patients) and dermatitis (4 patients) and antigens B35 and Cw4; one other patient had thrombocytopenia. The same group presented details of 9 patients with proteinuria in a series of 80 patients on tiopronine (i.e. 11 ~ ) (54c). Biopsies in 6patients showed predominantly membranous glomerulonephritis (as is usually the case in penicillamine nephropathy), with minimal changes on light microscopy. Two patients also had mesangial changes. On immunofluorescence depositions of IgG with C3 or IgM were found in the glomerular walls. Five patients had become ANA-positive when the nephropathy started. Assessment of the HLA antigens showed predominance of B35 (in 6 of 7 patients) and Cw4. One case has been described of a lupus-like syndrome, apparently induced by tiopronine (55c).
I)eferoxamine (SED-IO, 416; SEDA-8, 239; SEDA-9, 224; SEDA-IO, 223; SEDA-11,215) In the light of the increasing interest in deferoxamine, it may be useful to remind the reader of the review on iron chelation, which was published some years ago by Peter (57R). Reference has been made to the experimental use of deferoxamine in malignant disorders, i.e. neuroblastoma and acute neonatal leukemia (58 c, 59c). Since hemoglobin-derived iron compounds are neurotoxic, Sadrzadeh and co-workers have suggested the use of deferoxamine in hemorrhagic injuries to the CNS, in an attempt to limit brain damage (60 r Praga and co-workers have successfully used deferoxamine in a patient with hemodialysis-related porphyria cutanea tarda (61c). Further reports confirm the ocular toxicity of deferoxamine. Bournerais and co-workers described a patient with severe and persistent visual loss and macular pigmentation, developing after a total dose of deferoxamine of 18 g, administered over a period of 9 weeks, for treatment ofhemodialysis aluminium storage (62 oR). Another study by Rahi and co-workers, presents the light- and electron-microscopic findings in this condition. The changes include loss of microvilli from the apical surface, patchy depigmentation, vacuolation of the cytoplasm, swelling and calcification of mitochondria, and thickening of Bruch's membrane (63c). Taylor et al found that abnormally prolonged visual evoked potential (VEP) latencies may be indicative of early deferoxamine toxicity and suggest the use of VEPs for the monitoring of patients receiving chronic deferoxamine therapy (64cR). Pall and co-workers suggested that the neuroophthalmic toxicity of deferoxamine may be the result of oxidative damage by decompartmentalized copper (65 c) and has drawn attention to the possible interaction between deferoxamine and phenothiazine derivatives (which also have chelating properties) (SEDA-10, 224; 66c). Further reports describe Yersinia enterocolitica sepsis, probably facilitated by the ironmobilizing effect of deferoxamine (67c, 68 c, 69cr). This complication has been reviewed previously (SEDA-11, 215). Since iron - as
198 mobilized by deferoxamine - may also be a growth-promoting factor for a number of fungi, deferoxamine may also be suspected of being a contributing factor to systemic mycosis. Fatal rhinocerebral mucormycosis has recently been described in 2 non-diabetic patients on chronic hemodialysis, receiving deferoxamine (70r These authors advise that dialysis patients on deferoxamine presenting with fever, sinusitis or
Chapter 24
R.H.B. Meyboom and I.A. Jaffe
neuroiogic symptoms should undergo evaluation for mucormycosis. Another indication that iron may in one way or another impair immuno-protection is the recent finding of an intracellular defect in microbicidal mechanisms of monocytes, associated with iron overload in patients with thalassemia major (71cr).
REFERENCES 1. Brewer EJ, Giannini EH, Kuzmina N, Alekseev L (1986) Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis. N. Engl. J. Med.. 314, 1269. 2. Prieur AM, Piussan C, Manigne P e t al (1985) Evaluation of d-penicillamine in juvenile chronic arthritis. Arthritis Rheum., 28, 376. 3. Kay A (1986) European League Against Rheumatism study of adverse reactions to d-penicillamine. Br. J. Rheumatol., 25, 193. 4. Cartier H, Chevallier J, Ghoussoub K, Paolaggi JB (1986) Enqu~tes du Rrsean Epidemioiogique de la Soci6t6 Francaise de Rhumatologie (RESFR) sur Ia prescription de la d-penicillamine dans le traitement de la polyarthrite rhumatoide. Rev. Rhum., 53, 331. 5. Kutsuna T, Maeda K, Okamoto T (1986) Longterm results of d-penicillamine treatment in rheumatoid arthritis. Ryumachi, 26, 270. 6. Multicentre Trial Group (1986) A prospective five-year comparison of treatment which included penicillamine with that excluding penicillamine in early rheumatoid arthritis. Br. J. Rheumatol. , 25, 184. 7. Sheikh IA, Kaplan AP (1987) Assessment of kininases in rheumatic diseases and the effect of therapeutic agents. Arthritis Rheum., 30, 138. 8. Hendel L, Ammitzbo T, Kreuzig F et al (1986) Bioavailability of d-penicillamine in a patient with gastrointestinal progressive systemic sclerosis. Scand. J. RheumatoL, 15, 91. 9. Hoogenraad TU, Van Hattum J, Van den Hamer CJ (1987) Management of Wilson's disease with zinc sulphate: experience in a series of 27 patients. J. Neurol. Sci., 77, 137. 10. SchulofRS, Scheib RG, Parenti DM et al (1986) Treatment of HTLV-III/LAV-infected patients with peniciltamine. Arzneim.-Forsch., 36, 1531. 11. Louie S, Gamble CN, Cross CE (1986) Penicillamine associated pulmonary hemorrhage. J. RheumatoL, 13, 963. 12. Kuncle RW, Pestronk A, Drachman DB, Rechthand E (1986) The pathophysiology of penicillamineinduced myasthenia gravis. Ann. Neurol., 20, 740. 13. Kolarz G, Maida EM (1986) AzetylcholinRezeptorantik6rper unter D-Penieillamintherapie. Z. Rheumatol., 45, 118. 14. Carter H, Job-Deslandre C, Delrieu F e t a l (1986) Myasthrnie induite par la d-prnicillamine au
cours du traitement de la polyarthrite rhumatoide. Rev. Rhum., 53, 341. 15. Fried M J, Protheroe DT (1986) D-Penicillaminr induced myasthenia gravis: its relevance for the anaesthetist. Br. J. Anaesth., 58, 1191. 16. Hearn J, Tiliakos NA (1986) Myasthenia gravis caused by penicillamine and chloroqnine therapy for rheumatoid arthritis. South. Med. J., 79, 1185. 17. Huaux JP, Delreux V (1986) Myasth6nie induite par la d-p6nicillamine: /L propos de deux observations. Acta Neurol. Belg., 86, 297. 18. Weismann K (1986) Chelating drugs and zinc. Dan. Med. Bull., 33, 208. 19. Datsych M, Jezek P, Richtrova M (1986) Der Einfluss einer Penicillamintherapie auf die Konzentration von Zink, Kupfer, Eisen, Kalzium und Magnesium im Serum und anf deren Ausscheidung im Urin. Z. Gastroenterol., 24, 157. 20. Camus JP, Kroeger AC (1986) D-P6nicillamine et collag~ne. Ann. Biol. Clin., 44, 296. 21. Chamson A, Frey J (1985) Effects of d-penicillamine on collagen biosynthesis by fibroblast cell cultures. Clin. Exp. Pharmacol. Physiol., 12, 549. 22. Masson C, Dion L, Myhal D etal (1986) Purpura thrombotique thrombop6nique induit par la d-prnicillamine lors de la polyarthrite rhumatoYde. Sere. Hdp., 62, 3639. 23. Ramselaar ACP, Dekker AW, Huber-Bruning O, Bijtsma JWJ (1987) Acquired sideroblastic anaemia after aplastic anaemia caused by d-penicillamine therapy for rheumatoid arthritis. Ann. Rheum. Dis., 46, 156. 24. Hamilton JA, Williams N (1985) In vitro inhibition of myelopoiesis by gold salts and d-penicillamine. J. RheumatoL, 12, 892. 25. Hill GS (1986) Drug-associated glomerulopathies. Toxicol. Pathol., 14, 37. 26. Scherberich JE, Sniehotta KP, Miehlke K, Schoeppe W (1987) Nierenbeteiligang bei rheumatoider Arthritis. Nieren- u. Hochdrukkr., 16, s.69. 27. Feehally J, Wheeler DC, Mackay EH et al (1987) Recurrent acute renal failure with interstitial nephritis due to d-penicillamine. Renal Fail., 10, 55. 28. Honkanen E, Toernroth T, Petterson E, Skrifvars B (1987) Membranous glomerulonephritis in rheumatoid arthritis not related to gold or d-penicillamine therapy: a report of four cases and review of the literature. Clin. Nephrol., 27, 87.
Metal antagonists Chapter 24 29. Malaise MG, Davin JC, Mahieu PR, Franchimont P (1986) Elevated antigalactosyl antibody titers reflect renal injury atter gold or d-penicillamine in rheumatoid arthritis. Clin. Immunol. lmmunopathoL, 40, 356. 30. Ntoso KA, Tomaszewski JE, Jimenez SA, Neilson EG (1986) Penicillamine-induced rapidly progressive glomerulonephritis in patients with progressive systemic sclerosis: successful treatment of two patients and a review of the literature. Am. J. Kidney Dis., 8, 159. 31. Rajendran N, Koteeswaran A, Kala M (1985) Penicillamine-induced cheilosis. Indian J. Dermatol. Venereol. Leprol., 51, 50. 32. Komatsu H, Inatani M, Ikezawa Z (1986) Pemphigus following d-penicillamine. Skin Res., 28, 400. 33. Tholen S (1987) Arzneimittelbedingter Pemphigus. Z. Hautkr., 61,719. 34. Kohn SR (1986) Fatal penicillamine-induced pemphigus foliaceus-like dermatosis. Arch. DermatoL, 122, 17. 35. Light N, Meyrick Thomas RH, Stephens Aet al (1986) Collagen and elastin changes in d-penicillamine-induced pseudoxanthoma elasticum-like skin. Br. J. DermatoL, 114, 381. 36. Price RG, Prentice RS (1986) Penicillamineinduced elastosis perforans serpiginosa: tip of the iceberg? Am. J. Dermatopathol., 8, 314. 37. Butler D, Tiliakos NA (1986) Penicillamineinduced exacerbation of rheumatoid arthritis. South. Med. J., 79, 778. 38. Takahashi D, Ogita T, Okudaira H et al (1986) D-Penicillamine-induced polymyositis in patients with rheumatoid arthritis. Arthritis. Rheum., 29, 560. 39. Matsumura T, Yuhara T, Yamane K et al (1986) D-PeniciUamine-induced polymyositis occurring in patients with rheumatoid arthritis: a report of two cases and demonstration of a positive lymphocyte stimulation test to d-penicillamine. Henry Ford Hosp. Med. J., 34, 123. 40. Masson CJ, M6nard HA, Audran M et al (1986) Polymyosite induite par la d-p6nicillamine lors d'arthrite rhumatoide: ~tpropos de deux cas avec des anticorps anti-nucl6aires. Un. M~d. Can., 115, 855. 41. Car J, Lorette G, Jacob C (1987) Dermatomyosite induite par la d-p6nicillamine. Sere. H6p., 63, 399. 42. Petersen J (1987) Inhibition ofT cell-dependent antibody production by d-penicillamine. Allergy, 42, 37. 43. Mach PS, Brouilhet H, Amor B (1986) D-Penicillamine: a modulator of anti-DNA antibodies production. Clin. Exp. Immunol., 63, 414. 44. Panayi GS, McKenzie Mills M (1986) Secondline drug treatment in rheumatoid arthritis associated with depressed autologous mixed lymphocyte reaction. Rheumatol. Int., 6, 25. 45. Fields TR, Zarrabi MH, Gerardi EN et al (1986) Reticuloendothelial system Fc receptor function in the drug-induced lupus erythematosus syndrome. J. RheumatoL, 13, 726.
199 46. Spears CJ, Batchelor JR (1987) Drug-induced autoimmune disease. Adv. Nephrol., 16, 219. 47. Nuotio P, Nissil/l M, Ilonen J (1986) HLA-D antigens in rheumatoid arthritis and toxicity to gold and penicillamine. Scand. J. Rheumatol., 15, 255. 48. Gladman DD, Anhorn KA (1986) HLA and disease manifestations in rheumatoid arthritis - a Canadian experience. J. Rheumatol., 13, 274. 49. Rosa FW (1986) Teratogen update: penicillamine. Teratology, 33, 127. 50. Morimoto I, Ninomiya H, Komatsu K, Satho M (1986) Pregnancy and penicillamine treatment in a patient with Wilson's disease. Jpn. J. Med., 25, 59. 51. Ifan A, Welling PG (1986) Pharmacokinetics of oral 500-rag penicillamine: effect of antacids on absorption. Biopharm. Drug Disposit., 7, 401. 52. Speit G, Haupter S (1987) Cytogenetic effects of penicillamine. Mutat. Res., 190, 197. 53. Ferraccioli G, Peri F, Nervetti A e t al (1986) Toxicity due to remission inducing drugs in rheumatoid arthritis: association with HLA-B35 and Cw4 antigens. J. Rheumatol,, 13, 65. 54. Ferracciole GF, Peri F, Nervetti A e t al (1986) Tiopronine nephropathy: clinical, pathological, immunological and immunogenetic characteristics. Clin. Exp. Rheumatol., 4, 9. 55. Katayama I, Nishioka K (1986) Lupus like syndrome induced by 2-mercaptopropionylglycine. J. Dermatol. (Tokyo), 13, 151. 56. Hsiao L, Yoshinaga A, Ono T (1986) Druginduced bullous lichen planus in a patient with diabetes mellitus and liver disease. J. Am. Acad. Dermatol., 15, 103. 57. Peter HH (1983) Eisenchelierung, biologische Bedeutung und medizinische Anwendungen. Schweiz. Med. Wochenschr., 113, 1428. 58. Blatt J, Stitley S (1987) Antineuroblastoma activity ofdesferoxamine in human cell lines. Cancer Res., 47, 1749. 59. Estrov Z, Tawa A, Wang XH et al (1987) In vitro and in vivo effects of deferoxamine in neonatal acute leukemia. Blood, 69, 75. 60. Sadrzadeh SM, Anderson DK, Panter SS et al (1987) Hemoglobin potentiates central nervous system damage. J. Clin. Invest., 79, 662. 61. Praga M, Enriques de Salamanca R, Andres A et al (1987) Treatment of hemodialysis-related porphyria cutanea tarda with deferoxamine. N. Engl. J. Med., 316, 547. 62. Bournerais F, Monnier N, Duffer JL, R~veillaud RJ (1987) Toxicit~ oculaire s~v~re de la desferrioxamine chez l'h6modialys6. N~phrologie, 8, 27. 63. Rahi AH, Hungerford JL, Ahmed AI (1986) Ocular toxicity of desferrioxamine: light microscopic, histochemical and ultrastructural findings. Br. J. OphthalmoL, 70, 373. 64. Taylor MJ, Keenan NK, Gallant T et al (1987) Subclinical VEP abnormalities in patients on chronic deferoxamine therapy: longitudinal studies. Electroencephalogr. Clin. Neurophysiol., 68, 81. 65. Pall H, Blake DR, Good PA et al (1986) Copper chelation and the neuro-ophthalmic toxicity of desferrioxamine. Lancet, 2, 1279.
200 66. Pall HS, Williams AC, Blake DR (1986) Iron, akathisia and antipsychotic drugs. Lancet, 2, 1469. 67. Hughes RT, Keidan J, Janmohamed R, Leyland MJ (1987) Yersinia and iron. Lancet, 1,929. 68. Mofenson HC, Caraecio TR, Sharieff N (1987) Iron sepsis: Yersinia enterocolitica septicemia possibly caused by an overdose of iron. N. Engl. J. Med., 316, 1092. 69. Gallant TSVI, Freedman MH, Vellend H et al (1986) Yersinia sepsis in patients with iron overload
Chapter 24
R.H.B. Meyboom and I.A. Jaffe
treated with deferoxamine. N. Engl. J. Med., 314, 1643. 70. Veis JH, Contiguglia R, Klein M e t al (1987) Mucormycosis in deferoxamine-treated patients on dialysis. Ann. Intern. Med., 107, 258. 71. BaUart IJ, Estevez ME, Sen L et al (1986) Progressive dysfunction of monocytes associated with iron overload and age in patients with thalassemia major. Blood, 67, 105.
24 Penicillamine (SED-IO, 409; SEDA-8, 235; SEDA-9,223; SEDA-10,217; SEDA-11,211) General In a study of 162 children (54 receiving penicillamine), Brewer and co-workers were unable to demonstrate that, when given along with a non-steroidal anti-inflammatory drug, either penicillamine or hydroxychloroquine is superior to placebo in the treatment of juvenile rheumatoid arthritis (lCR); this is however in contradiction with earlier findings (2ca). In the light of the previously reported absence of taste disturbances in children (SED-10,414), it is noteworthy that in this study taste malfunction was again not reported. Kay has reported on the European League Against Rheumatism's study of adverse reactions to penicillamine (3c). The results of this very interesting study confirm the frequent occurrence of adverse reactions and the unparalleled variety of these reactions. Skin reactions, nephropathy, thrombocytopenia, myasthenia gravis and pemphigus were all observed. Similar experiences were reported by the Epidemiology Team of the French Rheumatology Society. Major causes for stopping penicillamine were (in decreasing order) lack of efficacy, proteinuria, skin rashes and hematologic reactions (4CR). Also, a Japanese series showed increasing loss of efficacy with longer duration of treatment (48 % after 5 years), wheras 52 % of the patients had adverse reactions (5c). In a recent report from the Multicentre Trial Group (U.K.), penicillamine was found to be ineffective in arresting radiographic deterioration of rheumatoid arthritis (6c; see also SEDA-10, 217). Sheikh and Kaplan have studied the effects of various antirheumatic drugs on the activities of the enzymes carboxypeptidase and angiotensinconverting enzyme (ACE) in human plasma. All drugs studied were marked inhibitors of ACE,
Side Effectsof DrugsAnnual 12 M.N.G. Dukes and L. Beeley,editors 9 ElsevierSciencePublishers B.V., 1988
Metal antagonists but only penicillamine had a demonstrable inhibition of carboxypeptidase (7c). The consequences of these findings with regard to the effects of penicillamine on patients need further study. Hendel and co-workers described markedly impaired absorption of peniciUamine in a patient with gastrointestinal involvement in systemic sclerosis (8c). In a Dutch series of 8 patients with Wilson disease, who had to stop penicillamine because of side effects, good control of the disease was achieved with oral zinc treatment (9~ Experimental use in 13 asymptomatic AIDS patients showed that penicillamine suppresses HTLVIII/LAV replication. Skin rashes (3 patients) and transient elevation of liver enzymes were the only associated events (10c).
Respiratory Alveolar hemorrhage as part of Goodpasture syndrome (in association with renal failure) is known to be a rare but serious complication of penicillamine (SEDA-8,236). Louie and co-workers have now described the first report of diffuse pulmonary hemorrhage without evidence of renal disease, developing after prolonged treatment with penicillamine for Wilson disease (1 lC). Nervous system Several further cases have been described of penicillamine-induced myasthenia gravis, underlining the similarity to idiopathic myasthenia gravis (12CR--17CR). The complete recovery of all clinical manifestations and of abnormal serological findings (e.g. antiacetylcholine-receptor antibodies) indicates that in these patients the disorder is a newly initiated autoimmune response rather than the enhancement of ongoing subclinical myasthenia. Moreover, patients with penicillamineinduced myasthenia have different HLA antigens from those with genuine myasthenia gravis (SEDA-8, 238; 14r). The article by Fried and Protheroe underlines the relevance of penicillamine-induced myasthenia for the anesthesist (SED-10, 415; 15CR). Another case was unusual in that myasthenia relapsed twice, first after rechallenge with penicillamine and later with chloroquine (16CR).
Metal antagonists Chapter 24 Endocrine, metabolic; mineral and fluid balance Weismann has reviewed the effect of chelating drugs, including penicillamine, on zinc metabolism (18 R). Interpretation of data may be difficult since penicillamine increases not only the excretion but also the absorption of zinc. As illustrated by the case study of Dastych and co-workers, a daily dose of 750 mg penicillamine is unlikely to cause zinc depletion in the presence of normal zinc intake (19c). Although this patient had a greatly increased excretion of copper, penicillamine did not influence the excretion of calcium, magnesium or iron. Camus and Kroeger have reviewed the pharmacological effects of penicillamine on collagen (SED- 10, 414; SEDA-11, 211 ; 20R), and Chamson and Frey have studied inhibition in vitro by penicillamine of collagen synthesis by fibroblasts (21c); their conclusions are similar to those presented earlier in this series. Hematological One further case has been described of thrombotic thrombocytopenic purpura (Moschcowitz syndrome), attributed to the use of penicillamine (only 250 mg/d) (SEDA-9,224; 22CR). A letter by the same authors in the Presse M~dicale of 31 May, 1986, apparently pertains to the same patient. Plasma exchange was not effective, but a lasting remission was achieved by treatment with corticosteroids and vincristine. The patient reported from the Netherlands with fatal aplastic anemia induced by penicillamine had sideroblastic changes. The findings indicated a stem cell injury (23CR). Hamilton and Williams demonstrated that in vitro development of both murine and human myeioid colonies from progenitor cells was markedly suppressed by d-penicillamine (or gold derivatives) in therapeutic concentrations (24c). These results, together with the earlier finding of inhibited megakaryopoiesis (SEDA-10,219), provide evidence that besides immunological processes - a pharmacological effect may be involved in the development of penicillamine-related bone marrow failure. Urinary system Penicillamine nephropathy with membranous glomerulitis as the characteristic lesion and nephrotic syndrome as the clinical manifestation - is a well-recognized entity (SED-10,412; 25R). Seherberich and coworkers have recently reviewed the occurrence of renal damage as part of rheumatoid arthritis, predominantly mesangioproliferative nephropathy (26CR). It may be difficult to distinguish
195 between rheumatic and drug-induced renal disease on the one hand, and also between penicillamine and NSAID-related renal damage on the other. This latter issue has also been adressed in a case-report by Feehally et al (27CR); in their patient acute tubulo-interstitial nephritis developed during the concomitant use of fenbufen and penicillamine. Although fenbufen was initially the suspected drug, a relapse on rechallenge with penicillamine showed that this drug was in fact the cause. In addition, another study described the spontaneous occurrence of membranous glomerulonephritis in rheumatic patients using neither penicillamine nor gold (28CR). Malaise and co-workers studied the titers of antigalactosyl antibodies in the serum of rheumatic patients (29CR). In this series high titers of antigalactosyl antibodies were strongly correlated with the prior development of proteinuria during penicillamine (and gold) therapy. Antigalactosyl antibodies may in the future be found to be useful for the monitoring of penicillamine nephropathy. Observations in 2 patients have underlined the fact that penicillamine-induced systemic lupus erythematosus (SLE) can be associated with diffuse crescentic glomerulonephritis and renal failure (SEDA-8, 237; SEDA-11, 213; 30CR). These 2 patients occurred in a series of only 52 patients treated for systemic sclerosis, giving a frequency of this complication of 4%. Skin and appendages A case-report on penicillamine-related cheilosis (31 c) is a reminder to the oral manifestations that can occur while using penicillamine (SED-10,411). Unfortunately, no details are given on the nature of the lesions in this patient. Two new case-reports describe penicillamine induced pemphigus (SED-10,413; SEDA-11,213; 32c, 33c). The predominance of penicillamine in iatrogenic pemphigus is illustrated in a review of the literature by Tholen (33R). Forty-two of 60 cases were associated with penicillamine, whereas in the remaining 18 patients 14 different drugs were involved. Kohn has commented upon the fatality rate of penicillamine-induced pemphigus, which appears to be in the range of 10 % (34R). Light and co-workers have described the collagen and elastin changes in pseudoxanthoma-elasticum-like lesions, induced by penicillamine (SEDA-I1,214; 35CR). A single report describes a further case of penicillamine-induced elastosis perforans serpiginosa (SED-10,413; 36CR). On histological exami-
196 nation, lesional and non-lesional skin showed the same changes. Special emphasis was given to the finding that elastic fiber alterations were also found in an artery. (See above for more information on the effects of penicillamine on collagen and elastin). Dermatomyositis is discussed below (Musculoskeletal system). Mnsenloskeletal system Earlier reports have discussed the possibility of penicillamine-associated arthralgia and arthritis (SED-10,415). Butler and Tiliakos have now provided details of 3 patients who apparently had penicillamineinduced acute exacerbations of rheumatoid arthrit/s, with severe, disabling febrile, symmetric polysynovitis. There were normal complement levels and negative antinuclear antibodies, and the patients recovered upon discontinuation of penicillamine. As the authors point out, the symptoms were not part of a (drug-induced) SLE reaction; the pathogenesis has remained unclear (37CR). Until recently, polymyositis and dermatomyositis were considered to be very rare complications of penicillamine therapy. Recently, however, 9 further cases have been described (38CR-41r In a series from Japan of 329 patients receiving penicillamine (for rheumatoid arthritis), 4 patients with myositis were observed (38cs). This gives an incidence of 1.2%, which is in the same range as for pemphigus and myasthenia (SEDA-8, 236). In one of these patients the causal involvement of penicillamine was proven when readministration was followed by a relapse of polymyositis. In a study by Matsumura the causal role of penicillamine was supported by a positive lymphocyte stimulation test (39CR). Dysphagia and muscle weakness may be the first signs of polymyositis, which can occur at any time during treatment with penicillamine and with doses as low as 100 mg (38c). Masson and co-workers focussed attention on the concomitant existence of antinuclear antibodies in 90% of the cases ofpenicillamineinduced polymyositis (40 CR) and suggested that this finding may be helpful in distinguishing it from spontaneous polymyositis. The patient described by Car and co-workers had dermatomyositis, probably induced by penicillamine (41cR). Recovery on stopping penicillamine and the absence of a neoplastic condition during 2 years of follow-up, were here arguments in favor of a causal relationship with penicillamine.
Chapter 24 R.H.B. Meyboom and I.A. Jaffe Immune system and autoimmune reactions Petersen has studied the complex in vitro effects of pharmacological concentrations of penicillamine, with or without copper, on the function of human lymphocytes (42cR). The results indicate that there are different processes by which penicillamine suppresses lymphocyte responses. It is concluded that penicillamine may modify the manifestations of rheumatoid arthritis by inhibition of antigeninduced and polyclonal lymphocyte responses. Another interesting in vitro study concerned the effect of penieiUamine on the production of antiDNA antibodies by lymphocytes from SLE patients and controls (43c). Panayi and McKenzie Mills found that peniciUamine (as well as sodium aurothiomalate) depresses the autologous mixed lymphocyte reaction and propose that this may be the mechanism whereby this drug decreases rheumatoid factor production (44c). In patients with spontaneous SLE an association has been found between disease activity and the reticuloendothelial system Fc receptor function. Fields and co-workers found that in patients with drug-induced SLE, on the contrary, Fc-receptor-mediated immune clearance did not differ significantly from that in normal controls (45cR). This difference in immune clearance may be relevant to the understanding of differences between spontaneous and druginduced SLE. In only one of their series of 16 patients was penicillamine the offending drug; symptoms were thrombocytopenia and pleuritis. An interesting finding was that in this patient the clearance of immune complexes was markedly delayed compared with the other patients (t,/2 of 80 min compared with a mean of 52 min in these patients, and a normal range of 34-60 min). Unfortunately, this observation is not discussed by the authors. The issue of drug-induced autoimmune disease has been reviewed by Spears and Batchelor (45R), with special reference to penicillamine (and gold and hydralazine). Genetic factors The associations between HLA antigens and susceptibility to penicillamine side effects has been reviewed previously (SEDA-11, 211). Two new studies of comparatively small series of patients did not reveal any such associations (47or, 48cr). Second-generation effects Rosa has recently reviewed the teratogenicity of penicillamine and the occurrence of cutis laxa in prenatally
197
Metal antagonists Chapter 24 exposed children (SED-10, 416; 49R). One further case is on record of a healthy baby born to a woman who had been treated with 500 mg penicillamine daily (for Wilson disease) (50c).
Another case-report described bullous lichen planus in association with the use oftiopronine (56c).
Interactions When taken concomitantly with
OTHER METAL ANTAGONISTS
iron salts, the absorption of penicillamine is strongly imp aired (S EDA- 10). Ifan and Welling have shown that also AI 3 § and Mg 2§ containing antacids may lower the absorption of penicillamine by up to 45% (51CR). Apparently this effect is not due to a decrease of the pH in the stomach but to chelation of penicillamine with these metal ions.
Tumor-inducing effects Speit and Haupter have found that penicillamine is mutagenic in vitro and advise that further in vivo studies are needed to evaluate the risk to patients treated with penicillamine (52c). Their test results suggest that the induction ofpenicillamine of sisterchromatid exchanges may be complex and not based on a single mechanism. Up to the present time, however, there have been no clinical indications for an excess incidence of neoplasia in penicillamine users. RELATED COMPOUNDS
Tiopronine (N- (2-mercaptopropionyi)glycine) (SEDA-11,215) Ferraccioli and co-workers have studied the HLA antigens in patients experiencing adverse reactions to tiopronine (16 patients) or aurothiosulfate compared with those without adverse reactions (53c). There was an obvious correlation between tiopronine-induced nephropathy (11 patients) and dermatitis (4 patients) and antigens B35 and Cw4; one other patient had thrombocytopenia. The same group presented details of 9 patients with proteinuria in a series of 80 patients on tiopronine (i.e. 11 ~ ) (54c). Biopsies in 6patients showed predominantly membranous glomerulonephritis (as is usually the case in penicillamine nephropathy), with minimal changes on light microscopy. Two patients also had mesangial changes. On immunofluorescence depositions of IgG with C3 or IgM were found in the glomerular walls. Five patients had become ANA-positive when the nephropathy started. Assessment of the HLA antigens showed predominance of B35 (in 6 of 7 patients) and Cw4. One case has been described of a lupus-like syndrome, apparently induced by tiopronine (55c).
I)eferoxamine (SED-IO, 416; SEDA-8, 239; SEDA-9, 224; SEDA-IO, 223; SEDA-11,215) In the light of the increasing interest in deferoxamine, it may be useful to remind the reader of the review on iron chelation, which was published some years ago by Peter (57R). Reference has been made to the experimental use of deferoxamine in malignant disorders, i.e. neuroblastoma and acute neonatal leukemia (58 c, 59c). Since hemoglobin-derived iron compounds are neurotoxic, Sadrzadeh and co-workers have suggested the use of deferoxamine in hemorrhagic injuries to the CNS, in an attempt to limit brain damage (60 r Praga and co-workers have successfully used deferoxamine in a patient with hemodialysis-related porphyria cutanea tarda (61c). Further reports confirm the ocular toxicity of deferoxamine. Bournerais and co-workers described a patient with severe and persistent visual loss and macular pigmentation, developing after a total dose of deferoxamine of 18 g, administered over a period of 9 weeks, for treatment ofhemodialysis aluminium storage (62 oR). Another study by Rahi and co-workers, presents the light- and electron-microscopic findings in this condition. The changes include loss of microvilli from the apical surface, patchy depigmentation, vacuolation of the cytoplasm, swelling and calcification of mitochondria, and thickening of Bruch's membrane (63c). Taylor et al found that abnormally prolonged visual evoked potential (VEP) latencies may be indicative of early deferoxamine toxicity and suggest the use of VEPs for the monitoring of patients receiving chronic deferoxamine therapy (64cR). Pall and co-workers suggested that the neuroophthalmic toxicity of deferoxamine may be the result of oxidative damage by decompartmentalized copper (65 c) and has drawn attention to the possible interaction between deferoxamine and phenothiazine derivatives (which also have chelating properties) (SEDA-10, 224; 66c). Further reports describe Yersinia enterocolitica sepsis, probably facilitated by the ironmobilizing effect of deferoxamine (67c, 68 c, 69cr). This complication has been reviewed previously (SEDA-11, 215). Since iron - as
198 mobilized by deferoxamine - may also be a growth-promoting factor for a number of fungi, deferoxamine may also be suspected of being a contributing factor to systemic mycosis. Fatal rhinocerebral mucormycosis has recently been described in 2 non-diabetic patients on chronic hemodialysis, receiving deferoxamine (70r These authors advise that dialysis patients on deferoxamine presenting with fever, sinusitis or
Chapter 24
R.H.B. Meyboom and I.A. Jaffe
neuroiogic symptoms should undergo evaluation for mucormycosis. Another indication that iron may in one way or another impair immuno-protection is the recent finding of an intracellular defect in microbicidal mechanisms of monocytes, associated with iron overload in patients with thalassemia major (71cr).
REFERENCES 1. Brewer EJ, Giannini EH, Kuzmina N, Alekseev L (1986) Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis. N. Engl. J. Med.. 314, 1269. 2. Prieur AM, Piussan C, Manigne P e t al (1985) Evaluation of d-penicillamine in juvenile chronic arthritis. Arthritis Rheum., 28, 376. 3. Kay A (1986) European League Against Rheumatism study of adverse reactions to d-penicillamine. Br. J. Rheumatol., 25, 193. 4. Cartier H, Chevallier J, Ghoussoub K, Paolaggi JB (1986) Enqu~tes du Rrsean Epidemioiogique de la Soci6t6 Francaise de Rhumatologie (RESFR) sur Ia prescription de la d-penicillamine dans le traitement de la polyarthrite rhumatoide. Rev. Rhum., 53, 331. 5. Kutsuna T, Maeda K, Okamoto T (1986) Longterm results of d-penicillamine treatment in rheumatoid arthritis. Ryumachi, 26, 270. 6. Multicentre Trial Group (1986) A prospective five-year comparison of treatment which included penicillamine with that excluding penicillamine in early rheumatoid arthritis. Br. J. Rheumatol. , 25, 184. 7. Sheikh IA, Kaplan AP (1987) Assessment of kininases in rheumatic diseases and the effect of therapeutic agents. Arthritis Rheum., 30, 138. 8. Hendel L, Ammitzbo T, Kreuzig F et al (1986) Bioavailability of d-penicillamine in a patient with gastrointestinal progressive systemic sclerosis. Scand. J. RheumatoL, 15, 91. 9. Hoogenraad TU, Van Hattum J, Van den Hamer CJ (1987) Management of Wilson's disease with zinc sulphate: experience in a series of 27 patients. J. Neurol. Sci., 77, 137. 10. SchulofRS, Scheib RG, Parenti DM et al (1986) Treatment of HTLV-III/LAV-infected patients with peniciltamine. Arzneim.-Forsch., 36, 1531. 11. Louie S, Gamble CN, Cross CE (1986) Penicillamine associated pulmonary hemorrhage. J. RheumatoL, 13, 963. 12. Kuncle RW, Pestronk A, Drachman DB, Rechthand E (1986) The pathophysiology of penicillamineinduced myasthenia gravis. Ann. Neurol., 20, 740. 13. Kolarz G, Maida EM (1986) AzetylcholinRezeptorantik6rper unter D-Penieillamintherapie. Z. Rheumatol., 45, 118. 14. Carter H, Job-Deslandre C, Delrieu F e t a l (1986) Myasthrnie induite par la d-prnicillamine au
cours du traitement de la polyarthrite rhumatoide. Rev. Rhum., 53, 341. 15. Fried M J, Protheroe DT (1986) D-Penicillaminr induced myasthenia gravis: its relevance for the anaesthetist. Br. J. Anaesth., 58, 1191. 16. Hearn J, Tiliakos NA (1986) Myasthenia gravis caused by penicillamine and chloroqnine therapy for rheumatoid arthritis. South. Med. J., 79, 1185. 17. Huaux JP, Delreux V (1986) Myasth6nie induite par la d-p6nicillamine: /L propos de deux observations. Acta Neurol. Belg., 86, 297. 18. Weismann K (1986) Chelating drugs and zinc. Dan. Med. Bull., 33, 208. 19. Datsych M, Jezek P, Richtrova M (1986) Der Einfluss einer Penicillamintherapie auf die Konzentration von Zink, Kupfer, Eisen, Kalzium und Magnesium im Serum und anf deren Ausscheidung im Urin. Z. Gastroenterol., 24, 157. 20. Camus JP, Kroeger AC (1986) D-P6nicillamine et collag~ne. Ann. Biol. Clin., 44, 296. 21. Chamson A, Frey J (1985) Effects of d-penicillamine on collagen biosynthesis by fibroblast cell cultures. Clin. Exp. Pharmacol. Physiol., 12, 549. 22. Masson C, Dion L, Myhal D etal (1986) Purpura thrombotique thrombop6nique induit par la d-prnicillamine lors de la polyarthrite rhumatoYde. Sere. Hdp., 62, 3639. 23. Ramselaar ACP, Dekker AW, Huber-Bruning O, Bijtsma JWJ (1987) Acquired sideroblastic anaemia after aplastic anaemia caused by d-penicillamine therapy for rheumatoid arthritis. Ann. Rheum. Dis., 46, 156. 24. Hamilton JA, Williams N (1985) In vitro inhibition of myelopoiesis by gold salts and d-penicillamine. J. RheumatoL, 12, 892. 25. Hill GS (1986) Drug-associated glomerulopathies. Toxicol. Pathol., 14, 37. 26. Scherberich JE, Sniehotta KP, Miehlke K, Schoeppe W (1987) Nierenbeteiligang bei rheumatoider Arthritis. Nieren- u. Hochdrukkr., 16, s.69. 27. Feehally J, Wheeler DC, Mackay EH et al (1987) Recurrent acute renal failure with interstitial nephritis due to d-penicillamine. Renal Fail., 10, 55. 28. Honkanen E, Toernroth T, Petterson E, Skrifvars B (1987) Membranous glomerulonephritis in rheumatoid arthritis not related to gold or d-penicillamine therapy: a report of four cases and review of the literature. Clin. Nephrol., 27, 87.
Metal antagonists Chapter 24 29. Malaise MG, Davin JC, Mahieu PR, Franchimont P (1986) Elevated antigalactosyl antibody titers reflect renal injury atter gold or d-penicillamine in rheumatoid arthritis. Clin. Immunol. lmmunopathoL, 40, 356. 30. Ntoso KA, Tomaszewski JE, Jimenez SA, Neilson EG (1986) Penicillamine-induced rapidly progressive glomerulonephritis in patients with progressive systemic sclerosis: successful treatment of two patients and a review of the literature. Am. J. Kidney Dis., 8, 159. 31. Rajendran N, Koteeswaran A, Kala M (1985) Penicillamine-induced cheilosis. Indian J. Dermatol. Venereol. Leprol., 51, 50. 32. Komatsu H, Inatani M, Ikezawa Z (1986) Pemphigus following d-penicillamine. Skin Res., 28, 400. 33. Tholen S (1987) Arzneimittelbedingter Pemphigus. Z. Hautkr., 61,719. 34. Kohn SR (1986) Fatal penicillamine-induced pemphigus foliaceus-like dermatosis. Arch. DermatoL, 122, 17. 35. Light N, Meyrick Thomas RH, Stephens Aet al (1986) Collagen and elastin changes in d-penicillamine-induced pseudoxanthoma elasticum-like skin. Br. J. DermatoL, 114, 381. 36. Price RG, Prentice RS (1986) Penicillamineinduced elastosis perforans serpiginosa: tip of the iceberg? Am. J. Dermatopathol., 8, 314. 37. Butler D, Tiliakos NA (1986) Penicillamineinduced exacerbation of rheumatoid arthritis. South. Med. J., 79, 778. 38. Takahashi D, Ogita T, Okudaira H et al (1986) D-Penicillamine-induced polymyositis in patients with rheumatoid arthritis. Arthritis. Rheum., 29, 560. 39. Matsumura T, Yuhara T, Yamane K et al (1986) D-PeniciUamine-induced polymyositis occurring in patients with rheumatoid arthritis: a report of two cases and demonstration of a positive lymphocyte stimulation test to d-penicillamine. Henry Ford Hosp. Med. J., 34, 123. 40. Masson CJ, M6nard HA, Audran M et al (1986) Polymyosite induite par la d-p6nicillamine lors d'arthrite rhumatoide: ~tpropos de deux cas avec des anticorps anti-nucl6aires. Un. M~d. Can., 115, 855. 41. Car J, Lorette G, Jacob C (1987) Dermatomyosite induite par la d-p6nicillamine. Sere. H6p., 63, 399. 42. Petersen J (1987) Inhibition ofT cell-dependent antibody production by d-penicillamine. Allergy, 42, 37. 43. Mach PS, Brouilhet H, Amor B (1986) D-Penicillamine: a modulator of anti-DNA antibodies production. Clin. Exp. Immunol., 63, 414. 44. Panayi GS, McKenzie Mills M (1986) Secondline drug treatment in rheumatoid arthritis associated with depressed autologous mixed lymphocyte reaction. Rheumatol. Int., 6, 25. 45. Fields TR, Zarrabi MH, Gerardi EN et al (1986) Reticuloendothelial system Fc receptor function in the drug-induced lupus erythematosus syndrome. J. RheumatoL, 13, 726.
199 46. Spears CJ, Batchelor JR (1987) Drug-induced autoimmune disease. Adv. Nephrol., 16, 219. 47. Nuotio P, Nissil/l M, Ilonen J (1986) HLA-D antigens in rheumatoid arthritis and toxicity to gold and penicillamine. Scand. J. Rheumatol., 15, 255. 48. Gladman DD, Anhorn KA (1986) HLA and disease manifestations in rheumatoid arthritis - a Canadian experience. J. Rheumatol., 13, 274. 49. Rosa FW (1986) Teratogen update: penicillamine. Teratology, 33, 127. 50. Morimoto I, Ninomiya H, Komatsu K, Satho M (1986) Pregnancy and penicillamine treatment in a patient with Wilson's disease. Jpn. J. Med., 25, 59. 51. Ifan A, Welling PG (1986) Pharmacokinetics of oral 500-rag penicillamine: effect of antacids on absorption. Biopharm. Drug Disposit., 7, 401. 52. Speit G, Haupter S (1987) Cytogenetic effects of penicillamine. Mutat. Res., 190, 197. 53. Ferraccioli G, Peri F, Nervetti A e t al (1986) Toxicity due to remission inducing drugs in rheumatoid arthritis: association with HLA-B35 and Cw4 antigens. J. Rheumatol,, 13, 65. 54. Ferracciole GF, Peri F, Nervetti A e t al (1986) Tiopronine nephropathy: clinical, pathological, immunological and immunogenetic characteristics. Clin. Exp. Rheumatol., 4, 9. 55. Katayama I, Nishioka K (1986) Lupus like syndrome induced by 2-mercaptopropionylglycine. J. Dermatol. (Tokyo), 13, 151. 56. Hsiao L, Yoshinaga A, Ono T (1986) Druginduced bullous lichen planus in a patient with diabetes mellitus and liver disease. J. Am. Acad. Dermatol., 15, 103. 57. Peter HH (1983) Eisenchelierung, biologische Bedeutung und medizinische Anwendungen. Schweiz. Med. Wochenschr., 113, 1428. 58. Blatt J, Stitley S (1987) Antineuroblastoma activity ofdesferoxamine in human cell lines. Cancer Res., 47, 1749. 59. Estrov Z, Tawa A, Wang XH et al (1987) In vitro and in vivo effects of deferoxamine in neonatal acute leukemia. Blood, 69, 75. 60. Sadrzadeh SM, Anderson DK, Panter SS et al (1987) Hemoglobin potentiates central nervous system damage. J. Clin. Invest., 79, 662. 61. Praga M, Enriques de Salamanca R, Andres A et al (1987) Treatment of hemodialysis-related porphyria cutanea tarda with deferoxamine. N. Engl. J. Med., 316, 547. 62. Bournerais F, Monnier N, Duffer JL, R~veillaud RJ (1987) Toxicit~ oculaire s~v~re de la desferrioxamine chez l'h6modialys6. N~phrologie, 8, 27. 63. Rahi AH, Hungerford JL, Ahmed AI (1986) Ocular toxicity of desferrioxamine: light microscopic, histochemical and ultrastructural findings. Br. J. OphthalmoL, 70, 373. 64. Taylor MJ, Keenan NK, Gallant T et al (1987) Subclinical VEP abnormalities in patients on chronic deferoxamine therapy: longitudinal studies. Electroencephalogr. Clin. Neurophysiol., 68, 81. 65. Pall H, Blake DR, Good PA et al (1986) Copper chelation and the neuro-ophthalmic toxicity of desferrioxamine. Lancet, 2, 1279.
200 66. Pall HS, Williams AC, Blake DR (1986) Iron, akathisia and antipsychotic drugs. Lancet, 2, 1469. 67. Hughes RT, Keidan J, Janmohamed R, Leyland MJ (1987) Yersinia and iron. Lancet, 1,929. 68. Mofenson HC, Caraecio TR, Sharieff N (1987) Iron sepsis: Yersinia enterocolitica septicemia possibly caused by an overdose of iron. N. Engl. J. Med., 316, 1092. 69. Gallant TSVI, Freedman MH, Vellend H et al (1986) Yersinia sepsis in patients with iron overload
Chapter 24
R.H.B. Meyboom and I.A. Jaffe
treated with deferoxamine. N. Engl. J. Med., 314, 1643. 70. Veis JH, Contiguglia R, Klein M e t al (1987) Mucormycosis in deferoxamine-treated patients on dialysis. Ann. Intern. Med., 107, 258. 71. BaUart IJ, Estevez ME, Sen L et al (1986) Progressive dysfunction of monocytes associated with iron overload and age in patients with thalassemia major. Blood, 67, 105.