Myasthenia penicillamine

Xu et al. [5] described the effect of (z>)-penicillamine on the binding of several antiacetylcholine receptor monoclonal antibodies to the Torpedo acetylcholine receptor. Penicillamine is covalently incorporated into the acetylcholine receptor through SS exchange at the cysteine residues of the a-subunit, altering the antigenic structure of the receptor. This effect on the structure of the native receptor at the neuromuscular junction may be responsible for the establishment of the autoimmune response to the acetylcholine receptor in (i))-penicillamine-induced myasthenia gravis. Cysteine and penicillamine interact to form penicillamine-cysteine mixed disulfide complexes [6] ... 

Toxicity to the pulmonary system is uncommon, but severe dyspnea has been reported from penicillamine-induced bronchoalveolitis. Myasthenia gravis has been induced by long-term therapy with penicillamine. 

Penicillamine onset may be seen in 1 to 3 months, and most responses occur within 6 months. Early adverse effects include skin rash, metallic taste, hypogeusia, stomatitis, anorexia, nausea, vomiting, and dyspepsia. Glomerulonephritis may occur, which manifests as proteinuria and hematuria. Penicillamine is usually reserved for patients who are resistant to other therapies because of the rare but potentially serious induction of autoimmune diseases (e.g., Goodpasture s syndrome, myasthenia gravis). 

Drugs can cause a wide variety of other autoimmune reactions. One example is myasthenia gravis, which is characterized by muscle weakness and is mediated by antibodies against the acetylcholine receptor at the neuromuscular junction. It has been reported in association with penicillamine [66], gold salts [67], and procainamide [68]. Another form of drug-induced autoimmunity is polymyositis, which is an autoimmune disease... 

Guinea pigs D-Penicillamine Myositis, myasthenia gravis... 

Nitrofurantion D-Penicillamine Peripheral neuritis Autoimmunity drug-induced SLE, myasthenia gravis, pemphigus, glomerulonephritis, Goodpasture s disease... 

Fatalities Penicillamine has been associated with fatalities due to aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture s syndrome, and myasthenia gravis. 

Delrieu F, Menkes Cl, Sainte-Croix A, Babinet P, Chesneau AM, Delbarre F. Myasthenie et thyroidite auto-immune au course du traitements de la polyarthrite rhumato ide par la D-penicillamine. Etude anatomo-clini-que d un cas. [Myasthenia gravis and autoimmune thyroiditis during the treatment of rheumatoid polyarthritis with D-penicillamine. Anatomoclinical study of 1 case.] Ann Med Interne (Paris) 1976 127(10) 739-43. 

Patients should be advised to rest and to avoid extreme heat. They should be warned that symptoms may be aggravated by illness, stress, malnutrition, pain, or surgery. Various drugs have been shown to worsen symptoms of myasthenia gravis. These include the aminoglycoside antibiotics such as tobramycin, gentamicin, and neomycin tetracyclines such as doxycycline and minocycline class 1 antiarrhythmics such as lidocaine, quinidine, and procainamide magnesium in calcium and multivitamin supplements beta-blockers such as timolol and propranolol calcium channel blockers such as verapamil and penicillamine. 

In myasthenia gravis synaptic transmission at the neuromuscular junction is impaired most cases have an autoimmune basis and some 85% of patients have a raised titre of autoantibodies to the muscle acetylcholine receptor. The condition is probably heterogeneous, however, as about 15% do not have receptor antibodies, or have antibodies to another neuromuscular junction protein (muscle specific kinase) and rarely it occurs with penicillamine used for rheumatoid arthritis. 

Other drugs. Penicillamine causes some patients, especially those with rheumatoid arthritis, to form antibodies to the acetylcholine receptor and a syndrome indistinguishable from myasthenia gravis results. Spontaneous recovery occurs in about two-thirds of cases when penicillamine is withdrawn. Phenytoin may rarely induce or aggravate myasthenia gravis, or induce a myasthenic syndrome, possibly by depressing release of acetylcholine. Lithium may impair presynaptic neurotransmission by substituting for sodium ions in the nerve terminal. 

Penicillamine-induced myasthenia gravis (SED-10, 415) was probably the cause of extremely prolonged apnea... 

Fried Ml, Protheroe DT. D-penicillamine induced myasthenia gravis. Its relevance for the anaesthetist. Br J Anaesth 1986 58(10) 1191-3. 

Blanloeil Y, Baron D, Gazeau MF, Nicolas F. Cnrarisation prolongee an cours d un syndrome myasthenique induit par la D-penicillamine. [Prolonged neuromuscular blockade during D-penicillamine-induced myasthenia.] Anesth Analg (Paris) 1980 37(7-8) 441-3. 

A 53-year-old woman with rheumatoid arthritis who had reacted to D-penicillamine treatment by developing myasthenia gravis was given gold instead and 12 months later developed pemphigus vulgaris (60). 

Ciompi ML, Marchetti G, Bazzichi L, Puccetti L, AgeUi M. D-penicillamine and gold salt treatments were comphcated by myasthenia and pemphigus, respectively, in the same patient with rheumatoid arthritis. Rheumatol Int 1995 15(3) 95-7. 

Penicillamine unexpectedly caused myasthenia gravis when present as an unrecognized additive in Chinese herbs (141). 

Raynauld JP, Lee YS, Komfeld P, Fries JF. Unilateral ptosis as an initial manifestation of D-penicillamine induced myasthenia gravis. J Rheumatol 1993 20(9) 1592-3. 

Hypersensitivity reactions are frequent early in a course of penicillamine, with urticarial or maculopapular rashes, fever, and lymphadenopathy. Cross-allergy to penicillin can occur. In addition, the use of penicillamine can be complicated by a unique variety of often serious autoimmune reactions, involving the skin, kidneys, liver, lungs, muscles, or other organs. Proteinuria is found in more than 10% of patients and sometimes develops into the nephrotic syndrome. Pemphigus, myasthenia gravis, polymyositis, or a lupus-like syndrome occur in smaller percentages. 

In addition, several autoimmune reactions to penicillamine can secondarily affect pulmonary function. PeniciUamine-induced polymyositis (56) or myasthenia gravis can cause respiratory failure, even requiring ventilatory support (57). The diagnosis and management of lupus-induced pleurisy have been reviewed (58). 

In spite of the similarities, there are some differences between spontaneous and penicillamine-induced myasthenia in respect to genetics. Myasthenic reactions to penicillamine appear to occur in a special genetic subgroup of patients, in whom there is a higher prevalence of the HLA antigens DRl and Bw35, and a lower prevalence of the antigens DR3 (which is associated with idiopathic myasthenia) and DR4 (which is increased in rheumatoid arthritis) (112,113). 

In penicillamine-induced polymyositis, weakness can be the presenting symptom and it may at first be mistaken for myasthenia (56). 

A 47-year-old woman developed concurrent pemphigus and myasthenia gravis (with ptosis and diplopia), apparently induced by penicillamine (500 mg/day for rheumatoid arthritis) (376). 

Several studies have shown an increased frequency of penicillamine adverse effects in patients with low sulfoxidation activity, especially with regard to proteinuria and probably thrombocytopenia and myasthenia gravis (SED-12, 547) (3,196,387,388). The sulfoxidation capacity is expressed as the sulfoxidation index, calculated as the percentage of administered 5-carboxymethyl-L-cysteine (750 mg), excreted as sulfoxides in the urine in 8 hours. A sulfoxidation index above 6% is taken as indicative of relative impairment of sulfoxidation capacity. 

Drosos AA, Christou L, Galanopoulou V, Tzioufas AG, Tsiakou EK. D-penicillamine induced myasthenia gravis clinical, serological and genetic findings. Clin Exp Rheumatol 1993 11(4) 387-91. 

Liu GT, Bienfang DC. Penicillamine-induced ocular myasthenia gravis in rheumatoid arthritis. J Qin Neuroophthalmol 1990 10(3) 201-5. 

Katz LJ, Lesser RL, Merikangas JR, Silverman JP. Ocular myasthenia gravis after D-penicillamine administration. Br J Ophthalmol 1989 73(12) 1015-18. 

Ferbert A. D-Penicillamin-induzierte okulare Myasthenic bei Psoriasisarthritis. [D-peniciUamine-induced ocular myasthenia in psoriatic arthritis.] Nervenarzt 1989 60(9) 576-9. 

Cikes N, Momoi MY, Williams CL, Howard FM Jr, Hoagland HC, Whittingham S, Lermon VA. Striational autoantibodies quantitative detection by enzyme immunoassay in myasthenia gravis, thymoma, and recipients of D-penicillamine or allogeneic bone marrow. Mayo Qin Proc 1988 63(5) 474-81. 

Jan V, Callens A, Machet L, Machet MC, Lorette G, VaUlant L. Pemphigus polymyosite et myasthenie induites par la D-penicillamine. [D-peniciUamine-induced pemphigus, polymyositis and myasthenia.] Ann Dermatol Venereol 1999 126(2) 153-6. 

Garlepp MI, Dawkins RL, Christiansen FT. HLA antigens and acetylcholine receptor antibodies in penicillamine induced myasthenia gravis. BMJ (CUn Res Ed) 1983 286(6375) 1442-3. 

Jones E, Sobkowski WW, Murray SJ, Walsh NM. Concurrent pemphigus and myasthenia gravis as manifestations of penicillamine toxicity. J Am Acad Dermatol 1993 28(4) 655-6. 

Seideman P, Ayesh R. Reduced sulphoxidation capacity in D-penicillamine induced myasthenia gravis. Clin Rheumatol 1994 13(3) 435-7. 

In usual doses, 600-800 mg/day, pyritinol has a profile of adverse reactions reminiscent of that of penicillamine (2,3). Some 40% of users have adverse reactions, leading to withdrawal in about 23% of the total. The most common are non-specific rashes and stomatitis in addition, pemphigus, lichen planus, and photosensitivity have occurred. Gastrointestinal symptoms (diarrhea, gastral-gia, nausea, loss of taste) can occur, but are less frequent than with penicillamine. Thrombocytopenia, reversible extramembranous glomerulonephritis with nephrotic syndrome (4), a myasthenia-like picture, and acute polymyositis with positive rechallenge have also been described (5). 

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