Penicillamine toxicity

Matsukawa Y, Saito N, Nishinarita S, Horie T, Ryu J. Therapeutic effect of tiopronin following D-penicillamine toxicity in a patient with rheumatoid arthritis. Clin Rheumatol 1998 17(1) 73. ... 

Vlachoyiannopoulos PG, Zerva LV, Skopouli FN, Drosos AA, Moutsopoulos HM. D-penicillamine toxicity in Greek patients with rheumatoid arthritis anti-Ro(SSA) antibodies and cryoglobuhnemia are predictive factors. J Rheumatol 1991 18(l) 44-9. 

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. 

An established and elinieally important interaetion. For maximal absorption give the iron at least 2 hours after the penicillamine. This should reduce their admixture in the gut. Do not withdraw iron suddenly from patients stabilised on penicillamine because the marked increase in absorption that follows may precipitate penicillamine toxicity. The toxic effects of penicillamine seem to be dependent on the size of the dose and possibly also related to the rate at which the dosage is increased. Only ferrous sulfate and fumarate have been studied but other iron compounds would be expected to interact similarly. 

Penicillamine plasma levels are increased by chloroquine and an increase in penicillamine toxicity is possible. Penicillamine should not be used with gold. Indometacin slightly increases penicillamine levels, and its use with any NSAD) might increase the risk of renal damage. An isolated report describes penicillamine-induced breast enlargement in a woman taking a combined oral contraceptive. 

Studies in which chloroquine was given to patients taking penicillamine found that it was more effective, less effective, or indistinguishable from penicillamine alone. However in some instances penicillamine toxicity was reported to be increased. A pharmacokinetic study in patients with rheumatoid arthritis taking penicillamine 250 mg daily found that a single 250-mg dose of chloroquine phosphate increased the AUC by 34%, and raised the peak plasma levels by about 55%. It therefore seems possible that any increased toxicity is simply a reflection of increased plasma pen-... 

Tan SS, Latif SA, Poh WY. Concurrent massive breast enlargement, myasthenia gravis and dermopathy as manifestations of penicillamine toxicity in a V fflson s disease patient. Med J Malays June 2012 67(3) 323-5. 

One enantiomer of penicillamine (D-) exhibits antiarthritic properties but foe other is highly toxic (Figure 8.3). The teratogenic effects of thalidomide were induced by one enantiomer, foe other exhibited foe beneficial effects against morning sickness. 

The adverse reactions seen with penicillamine include pruritus, rash, anorexia, nausea, vomiting, epigastric pain, bone marrow depression, proteinuria, hematuria, increased skin friability, and tinnitus. Penicillamine is capable of causing severe toxic reactions. 

There is an increased risk of toxicity of MTX when administered with the NSAIDs, salicylates, oral antidiabetic drugs, phenytoin, tetracycline, and probenecid. There is an additive bone marrow depressant effect when administered with other drug known to depress the bone marrow or with radiation therapy. There is an increased risk for nephrotoxicity when MTX is administered with other drug that cause nephrotoxicity. When penicillamine is administered with digoxin, decreased blood levels of digoxin may occur. There is a decreased absorption of penicillamine when the dmg is administered with food, iron preparations, and antacids. 

Penicillamine. The primary healHi care provider will explain Hie treatment regimen and adverse reacHons before therapy is started. You must know which toxic reactions require contacting Hie primary healHi care provider immediately. Take penicillamine on an empty stomach, 1 hour before or 2 hours after a meal. If other drugp are prescribed, penicillamine is taken 1 hour apart from any other drug. Observe skin areas over Hie elbows, shoulders, and buttocks for evidence of bruising, bleeding, or break in the skin (delayed wound healing may occur). If Hiese occur, do not self-treat the... 

In addition to relying on safety and efficacy data, the initial DMARD choice depends on disease severity, patient characteristics (i.e., comorbidities, likelihood of adherence), cost, and clinician experience with the medication.1,7 Methotrexate alone or in combination therapy is the initial treatment of choice for patients with aggressive disease. Patients with early, mild disease may receive monotherapy with sulfasalazine or hydroxychloroquine. Agents such as azathioprine, D-penicillamine, and gold salts are used rarely today because of concerns about toxicity and reduced efficacy.1,15... 

The enantiomers of this drug differ in their efficacy and activity, with (D)-penicilla-mine being the enantiomer required for pharmaceutical preparations. The (l)-enantiomer is toxic, and its absorption by the human body is more than the (D)-enantiomer. While both enantiomers of penicillamine are desulfhydrated by (r.)-cysteine desulfhydrase, only the (l)-isomer inhibits the action of this enzyme [2], The reported optical rotation values for (D)-penicillamine are ... 

Gotti et al. [42] reported an analytical study of penicillamine in pharmaceuticals by capillary zone electrophoresis. Dispersions of the drug (0.4 mg/mL for the determination of (/q-penicillaminc in water containing 0.03% of the internal standard, S -met hy I - r-cystei ne, were injected at 5 kPa for 10 seconds into the capillary (48.5 cm x 50 pm i.d., 40 cm to detector). Electrophoresis was carried out at 15 °C and 30 kV, with a pH 2.5 buffer of 50 mM potassium phosphate and detection at 200 rnn. Calibration graphs were linear for 0.2-0.6 pg/mL (detection limit = 90 pM). For a more sensitive determination of penicillamine, or for the separation of its enantiomers, a derivative was prepared. Solutions (0.5 mL, final concentration 20 pg/mL) in 10 mM phosphate buffer (pH 8) were mixed with 1 mL of methanolic 0.015% 1,1 -[ethylidenebis-(sulfonyl)]bis-benzene and, after 2 min, with 0.5 mL of pH 2.5 phosphate buffer. An internal standard (0.03% tryptophan, 0.15 mL) was added and aliquots were injected. With the same pH 2.5 buffer and detection at 220 nm, calibration graphs were linear for 9.3-37.2 pg/mL, with a detection limit of 2.5 pM. For the determination of small amounts of (L)-penicillamine impurity, the final analyte concentration was 75 pg/mL, the pH 2.5 buffer contained 5 mM beta-cyclodextrin and 30 mM (+)-camphor-10-sulfonic acid, with a voltage of 20 kV, and detection at 220 nm. Calibration graphs were linear for 0.5-2% of the toxic (L)-enantiomer, with a detection limit of 0.3%. 

Penicillamine is reported to be more than 80% bound to plasma protein. The compound is metabolized in the liver. N-acetylpenicillamine is more effective than penicillamine in protecting against the toxic effect of mercury, presumably because it is even more resistant to metabolism [7,2]. 

Penicillamine Gold salts A Patients who have had gold salt therapy discontinued due to a major toxic reaction may be at greater risk of serious adverse reactions with penicillamine, but not necessarily of the same type. However, this is controversial. 

Renal toxicity induced by penicillamine is usually manifested as reversible proteinuria and hematuria, but may progress to nephrouritic syndrome with membraneous glomerulopathy. 

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. 

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

Thiono and sulfhydryl drugs are also associated with a significant incidence of a lupus-like syndrome. Propylthiouracil is associated with a significant incidence of lupus [18] as well as liver toxicity [19, 20] and agranulocytosis [21], Penicillamine is associated with lupus, agranulocytosis [22] and a variety of autoimmune syndromes as discussed later. 

Although chelation is not helpful for Alzheimer s disease patients, it is the key to treating patients with dementia due to Wilson s disease. Wilson s disease is a genetically inherited disorder that usually strikes before age 30. The disease causes toxic levels of copper to accumulate in the liver, brain, eyes, and kidney. Untreated, Wilson s disease leads to tremors, cirrhosis, depression, psychosis, dementia, and ultimately death. Chelation with penicillamine (Cuprimine) can stop and even reverse the accumulation of copper. 

Combination with penicillamine is contraindicated as penicillamine is a metal chelator. However penicillamine can be used to treat gold toxicity. N-acetylcysteine can also increase the excretion of gold. 

Sulfasalazine has been used for the management of RA and ankylosing spondylitis with apparently similar effectiveness as penicillamine and with less toxicity. While 5-aminosalicylic acid is the active agent in inflammatory bowel disease, it is believed that sulfapyridine is mostly responsible for the antirheumatoid effects. Gastrointestinal complaints, dizziness and photosensitivity are the most frequently observed adverse events. With levamisole and also with sulfasalazine and olsalazine a delay of 2-3 months is to be expected before positive responses will be observed. 

Sulfasalazine (Azulfidine) is approved for the treatment of rheumatoid arthritis and ulcerative colitis. It is also used to treat ankylosing spondylitis and Crohn s disease. Comparisons of sulfasalazine with other DMARDs suggest that it is more effective than hydroxychloroquine, azathioprine, and oral gold compounds. It is at least as effective as intramuscular gold and penicillamine. It has a greater degree of toxicity than hydroxychloroquine but less than gold compounds and penicillamine. After 5 years, approximately 75% of patients have discontinued sulfasalazine therapy, primarily because of a lack of efficacy as opposed to intolerable side effects. 

Aminoquinolines can increase plasma concentrations of penicillamine, hence the potential for serious hematological or renal toxicity. Similarly, aminoquinolines can increase digoxin levels. Gold and an amino-quinoline probably should not be administered concurrently because of the propensity of each to produce dermatitis. 

For patients who are unable to tolerate penicillamine, trientine, another chelating agent, may be used in a daily dose of 1-1.5 g. Trientine appears to have few adverse effects other than mild anemia due to iron deficiency in a few patients. Zinc acetate administered orally increases the fecal excretion of copper and is sometimes used for maintenance therapy. The dose is 50 mg three times a day. Zinc sulfate (200 mg/d orally) has also been used to decrease copper absorption. Zinc blocks copper absorption from the gastrointestinal tract by induction of intestinal cell metallothionein. Its main advantage is its low toxicity compared with that of other anticopper agents, although it may cause gastric irritation when introduced. 

Penicillamine (Figure 57-3) is a white crystalline, water-soluble derivative of penicillin. D-Penicillamine is less toxic than the l isomer and consequently is the preferred therapeutic form. Penicillamine is readily absorbed from the gut and is resistant to metabolic degradation. 

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