D-penicillamine Therapy Research Articles

Treatment of periocular hyperpigmentation due to lead of kohl (surma) by penicillamine: A single group non-randomized clinical trial

Background:Periocular hyperpigmentation is a condition in which skin of eyelids become darker in color than the normal surrounding skin. Lead and other heavy metals produce increased pigmentation because of deposition of metal particles in the dermis and increased epidermal melanin production.Aims:This study was conducted to evaluate the dual effect of chelation therapy in treating periocular hyperpigmentation and lead toxicity.Methods:The study population consisted of nine females complaining from dark coloration of their eyelids. The nine females were continuously using kohl as eyeliner. Lead levels in conjunctiva and serum before and after D-penicillamine (D-PCN) oral administration were estimated in relation to vertical, horizontal length, and degree of hyperpigmentation score.Results:Highly significant P values (0.000) were obtained as regard to the conjunctival lead levels, serum lead levels, horizontal length, and degree of darkness score before and after D-PCN therapy. A less significant P value (0.040) was recorded as regard to the vertical length.Conclusion:Regardless other causes, this study spots the light on a new concept for periocular hyperpigmentation from lead toxicity in adult females using kohl and suggests D-PCN in a low divided dose (750 mg/day) for its treatment.

A retrospective randomly selected cohort study of D-penicillamine treatment in rapidly progressive diffuse cutaneous systemic sclerosis of recent onset

Several uncontrolled studies in systemic sclerosis have shown that D-penicillamine may cause improvement in skin sclerosis, decrease the rate of new visceral organ involvement, and improve overall survival. To undertake a single-centre retrospective randomly selected cohort study to examine the effects of D-penicillamine treatment on skin and visceral organ involvement in patients with rapidly progressive systemic sclerosis of recent onset. Eighty-four patients with diffuse cutaneous systemic sclerosis who had received D-penicillamine within 24 months of clinically detectable onset of skin sclerosis were randomly selected from the systemic sclerosis cohort followed at the Scleroderma Center of Thomas Jefferson University. Employing a previously described severity scale, disease severity and skin involvement were compared from initiation of D-penicillamine to end of study and a correlated matched t-test was used to establish statistical significance. At a mean+/-SD duration of D-penicillamine therapy of 29.2+/-5.5 months and at a median dose of 750 mg per day statistically significant improvement in skin (P<0.01) and cardiac, pulmonary and renal involvement (P<0.05) was observed. At last follow-up, 17 (20%) patients were still receiving D-penicillamine, 25 (30%) had discontinued it owing to disease improvement, and 18 (21%) had discontinued it owing to side-effects. In a population of patients with diffuse cutaneous systemic sclerosis, with progressive disease of recent onset, D-penicillamine treatment at a median dose of 750 mg per day caused a statistically significant reduction in skin involvement and improvement of renal, cardiac and pulmonary involvement.

Wilson's disease with hepatic presentation in childhood

Diagnosis of Wilson's disease with hepatic presentation in childhood using clinical and common laboratory parameters is still challenging and is often missed or delayed. The aim of the study was to document the clinical and laboratory parameters of hepatic presentation of Wilson's disease in children. The study was conducted at a tertiary-care hospital in a developing country. Clinical and common laboratory parameters were recorded in 32 Wilson's disease children with hepatic presentation. The diagnosis was based on positive family history, Kayser-Fleischer ring, low serum ceruloplasmin level, elevated basal urinary copper excretion and favorable response to therapy with D-penicillamine. Mean age+/-SD at presentation was 9+/-2.97 years and 21 (65.6%) were boys. Chronic liver disease (21; 65.6%) followed by fulminant hepatic failure 1(6; 18.8%) were the commonest presentation. In the whole group, Kayser-Fleischer ring was found in 21 (65.6%), low serum ceruloplasmin in 16 (50%) and elevated basal urinary copper excretion in all 32 (100%) children. Diagnosis of Wilson's disease was made at presentation on the basis of i) Kayser-Fleischer ring, low serum ceruloplasmin, elevated basal urinary copper excretion and favorable response to D-penicillamine therapy in 11 (34.4%), ii) Kayser-Fleischer ring, elevated basal urinary copper excretion and favorable response to D-penicillamine therapy in 10 (31.2%), iii) elevated basal urinary copper excretion and favorable response to D-penicillamine therapy in 6 (18.8%) and iv) low ceruloplasmin, elevated basal urinary copper excretion and favorable response to D-penicillamine therapy in 5 (15.6%) children. Wilson's disease can not be excluded in children presenting with hepatic involvement using the commonly practiced clinical and laboratory parameters. A combination of various clinical and laboratory parameters were used for the diagnosis of Wilson's disease in the studied children with hepatic presentation.

Wilson Disease

The clinical manifestations of Wilson disease (WD) are varied and challenging. We conducted the current study to present the phenotypic characteristics and follow-up for a large cohort of patients with WD. We reviewed the medical records of 282 cases of WD (male:female ratio, 196:86) for clinical features, investigations, treatment, and outcome data. The clinical presentations were as follows: hepatic, 42 (14.9%); hepato-neurologic, 10 (3.5%); neurologic, 195 (69.1%); pure psychiatric, 7 (2.4%); osseomuscular, 6 (2.1%); and "presymptomatic," 15 (5.3%). Mean age was 15.9 years. Presymptomatic patients and those with the hepatic form of WD were younger and patients with osseomuscular and psychiatric forms were older than neurologic patients. The mean duration of illness at the time of diagnosis was 28 months. Predominant neurologic features were as follows: parkinsonism, 62.3%; dystonia, 35.4%; cerebellar, 28%; pyramidal signs, 16%; chorea, 9%; athetosis, 2.2%; myoclonus, 3.4%; and behavioral abnormalities, 16%. Kayser-Fleischer (KF) rings were seen as follows: neurologic patients, 100%; hepatic patients, 86%; and presymptomatic patients, 59%. Positive family history was noted in 47% and consanguinity in 54%. Patients born of consanguineous parents had an earlier age of onset and shorter duration of illness before presentation. Serum ceruloplasmin was decreased in 93% and 24-hour urinary copper excretion was increased in 70% of patients. Neuroimaging (computed tomography/magnetic resonance imaging) and electrophysiologic abnormalities were seen in many patients. Overall, 195 patients were on D-penicillamine therapy and 182 on zinc sulphate. Follow-up data, available for 225 patients, for a mean duration of 46 months, revealed improvement in 176, no change in 20, and deterioration in 6. Twenty-three patients died. To conclude, despite increased awareness and recognition and significant inroads into therapeutic frontiers, follow-up remains poor in developing countries and a return to previous level of functioning is not universal.

Scleroderma and chronic myeloid leukemia: a sheer coincidence, a consequence of long lasting d-penicillamine therapy or a plausible relationship of both diseases?

Systemic sclerosis is a chronic multisystem disorder of unknown etiology characterized by the involvement of skin and visceral organs caused by an accumulation of collagen. It has been reported that the incidence of solid and hematological malignancy increased in systemic sclerosis. Multiple myeloma and chronic lymphocytic leukemia are the most common hematological malignancies seen in patients with systemic sclerosis. Chronic myeloid leukemia (CML) has only rarely been reported so far. We here report a case with CREST (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactly, telangiectasia) who developed CML 7 years after the onset of CREST. Ours is the second case with CML developing after the onset of CREST in the literature. We also briefly discuss the possible tendency to hematological malignancy in systemic sclerosis.

Erythrocyte Metabolism and Antioxidant Status of Patients with Wilson Disease with Hemolytic Anemia

Wilson disease (WD) is an autosomal recessive disorder due to the defect in ATP7B gene characterized by excessive accumulation of copper in the liver with progressive hepatic damage and subsequent redistribution to various extrahepatic tissues including the brain, kidneys, and cornea. Strikingly, the total serum copper concentration is always low in WD, even though the non-ceruloplasmin copper level is still expected to be high. To assess the role of free radical reactions catalyzed by non-ceruloplasmin copper, we investigated erythrocyte metabolism and oxidative stress as a mechanism for hemolysis in eight WD patients during episodes of acute hemolysis and compared them with eight follow-up cases of WD on d-penicillamine therapy and eight healthy, age-matched children. Elevated levels of non-ceruloplasmin copper were found in all the WD patients during an episode of hemolytic anemia. There was marked inhibition in erythrocyte enzymes, namely, hexokinase, total adenosine triphosphatase (ATPase), and glucose-6-phosphate dehydrogenase (G-6-PD) from WD patients compared with patients on penicillamine and healthy children, indicating altered erythrocyte metabolism during a hemolytic crisis. Antioxidant status was also found to be compromised as is evident from decreased glutathione (GSH) levels, decreased antioxidant enzymes (namely, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase), increased lipid peroxidation, and deranged plasma antioxidants. Uric acid showed maximum decrease followed by ascorbic acid. These findings suggest that the free radical production by elevated non-ceruloplasmin copper through transition metal catalyzed reactions leads to oxidative injury resulting in altered erythrocyte metabolism and severely compromised antioxidant status of WD patients during hemolytic anemia.

D-penicillamine for primary sclerosing cholangitis.

Primary sclerosing cholangitis is a cholestatic disease. D-penicillamine is suggested as a treatment option due to its copper reducing and immunomodulatory potential. To evaluate the beneficial and harmful effects of D-penicillamine for patients with primary sclerosing cholangitis. Eligible trials were identified through searches of The Cochrane Hepato-Biliary Group Controlled Trials Register (August 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 3, 2005), MEDLINE (1950 to August 2005), EMBASE (1980 to August 2005), Science Citation Index EXPANDED (1945 to August 2005), and reference lists of relevant articles. Authors of trials and pharmaceutical companies known to produce D-penicillamine were also contacted. Randomised clinical trials comparing D-penicillamine in any dose, duration, and route of administration versus placebo, no intervention, or other intervention(s). Trials were included irrespective of publication status, year of publication, language, or blinding. Both authors selected the trials, extracted data, and evaluated the methodological quality of the trials with respect to the generation of allocation sequence, allocation concealment, blinding, and follow-up. The results were reported by intention-to-treat analysis. The outcomes were presented as relative risk (RR) or weighted mean difference (WMD), both with 95% confidence intervals (CI). One randomised trial was identified and included in the review. It was of low methodological quality. The trial compared D-penicillamine versus placebo in 70 patients with primary sclerosing cholangitis. Compared with placebo, D-penicillamine therapy had no significant effect on mortality (RR 1.14, 95% CI 0.49 to 2.64), liver transplantation (RR 1.11, 95% CI 0.39 to 3.17), hepatic histologic progression (RR 1.17, 95% CI 0.79 to 1.74), or cholangiographic deterioration (RR 0.87, 95% CI 0.43 to 1.79). D-penicillamine led to a significant improvement in the serum aspartate aminotransferase (WMD -23.00 U/L; 95% CI -30.66 to -15.34), but not in serum bilirubin level (WMD 0.40 mg/L; 95% CI -0.19 to 0.99) and serum alkaline phosphatases activity (WMD 44.00 U/L; 95% CI -37.89 to 125.89). There were significantly more adverse events in patients receiving D-penicillamine (P = 0.013). There is not sufficient evidence to support or refute the use of D-penicillamine for patients with primary sclerosing cholangitis. We do not recommend the use of D-penicillamine for patients with primary sclerosing cholangitis outside randomised trials.

Elastosis perforans serpiginosa in a patient with trisomy 21

A 12-year-old girl with trisomy 21 (Downs syndrome) presented with an approximate 2-year history of an asymptomatic eruption on the right upper arm and left lateral neck that was clinically and histologically diagnostic of elastosis perforans serpiginosa (EPS). EPS is a perforating dermatosis affecting the face, ear, neck, extremities, or trunk. It occurs with greater frequency in persons with trisomy 21, as well as some other genetic syndromes and after D-penicillamine therapy. It has also been reported as a sporadic, presumably unrelated disorder in several acquired diseases.

Penicillamine induced pseudoxanthoma elasticum with elastosis perforans serpiginosa

Long term D-penicillamine therapy, especially when used to treat Wilson's disease has been shown to cause elastosis perforans serpiginosa, pseudoxanthoma elasticum perforans and other degenerative dermatoses. We report a 23-year-old male patient who presented with multiple firm papules, nodules over the neck, axillae, front of elbows for five years. He was a known case of Wilson's disease on long-term treatment with penicillamine for the past 12 years. The papulonodular lesions were non-tender and some were discrete while others were arranged in a circinate pattern. There was central scarring of the skin within the circinate lesions. In addition, there were several small yellowish papules on both sides of the neck which eventually became confluent to form plaques. Histopathology confirmed the diagnosis of elastosis perforans serpiginosa and pseudoxanthoma elasticum. He was treated with cryotherapy (using liquid nitrogen through cryojet) for former lesions. The lesions showed remarkable improvement after five sittings. Now the patient is under trientine hydrochloride (750 mg twice daily) for Wilson's disease.

Evolução para remissão clínica completa em esclerose sistêmica

OBJETIVO: mostrar a evolução de quatro pacientes para remissão clínica completa da esclerose sistêmica (ES), sem necessidade de tratamento medicamentoso atual, após uso de D-penicilamina como medicação principal. MÉTODOS: revisão dos prontuários de pacientes com diagnóstico de ES (ARA, 1980) que entraram em remissão após acompanhamento ambulatorial continuado. Foram relacionados dados como sexo, raça, idade do paciente quando do diagnóstico, manifestações iniciais, envolvimento sistêmico, perfil laboratorial, exames complementares, tratamento proposto, resposta medicamentosa e tempo total de tratamento. RESULTADOS: todos os pacientes eram brancos, sendo um homem e três mulheres, tendo como idade média 51,2 anos na instalação dos primeiros sintomas. O tempo médio decorrido entre o início dos sintomas e o diagnóstico foi de 8,2 meses. Todos os pacientes apresentaram alterações cutâneas, comprometimento sistêmico e FAN reagente em células HEp-2. Nenhum deles apresentou os auto-anticorpos específicos para ES (anticentrômero e anti Scl-70/topo I). Depois de instituída D-penicilamina, o tempo médio de tratamento para alcançar a remissão foi de 60,7±27,4 meses. Todos se encontram atualmente sem tratamento de qualquer natureza por períodos de 31 a 120 meses e sem manifestações que indiquem atividade da ES, mesmo fenômeno de Raynaud. CONCLUSÕES: a) no espectro clínico da ES há pacientes que entram em remissão com auxílio da D-penicilamina, permanecendo assintomáticos e sem medicação por muitos anos; b) nota-se na amostra a ausência dos auto-anticorpos mais característicos da ES (anticentrômero e anti-Scl-70/topo I) em todos os casos, um achado a ser explorado em amostra maior; c) a ausência de auto-anticorpos considerados como mais específicos da ES poderia ser indicativa de melhor resposta à terapia com D-penicilamina ou de possível evolução para remissão clínica espontânea.

Syndrome des ongles jaunes survenant au cours du traitement d’une polyarthrite rhumatoïde par dérivés thiolés : à propos de deux observations et revue de la littérature

Yellow nail syndrome is characterised by the following symptoms: yellow nails, lymphoedema of the lower limbs and pleuropulmonary manifestations as pleural effusions or bronchiectasies. This association with auto-immune disorders such as rheumatoid arthritis is well known. We report two new cases of yellow nail syndrome associated with rheumatoid arthritis with D-penicillamine therapy. Since 1979, eight similarly cases have been reported. Possible responsibility of D-penicillamine therapy in yellow nail syndrome is discussed.

A Case of Minimal Change Nephrotic Syndrome Associated with D-penicillamine Therapy of Wilson's Disease

A Case of Minimal Change Nephrotic Syndrome Associated with D-penicillamine Therapy of Wilson's Disease

The HLA-DRB1*0401 Allele and the Development of Methotrexate-Induced Accelerated Rheumatoid Nodulosis

The HLA-DRB1*0401 Allele and the Development of Methotrexate-Induced Accelerated Rheumatoid Nodulosis

Efficacy of d-Penicillamine in Reducing Lead Concentrations in Children: A Prospective, Uncontrolled Study

Objective: To evaluate the efficacy of oral d-penicillamine therapy in children with high blood lead concentrations. Design: A prospective, uncontrolled study. Methods and Patients: Seven children (2–16 y old; mean 8.7) with elevated blood lead concentrations but no symptoms of lead poisoning were treated with oral d-penicillamine. Lead-contaminated homemade flour as found to be the source of poisoning. Mean ± SD blood lead concentrations prior to therapy were 60.3 ± 12.9 μg/dL (range 47.8–83). Mean blood zinc protoporphyrin (ZPP) was 337.86 ± 58.55 μmol/mol hemoglobin (Hb) (range 247–394). Results: Ninety days of treatment with d-penicillamine lowered the mean blood lead concentration by 31.7% to a mean of 40.7 ± 8.6 μg/dL (range 30–53) and lowered mean ZPP blood concentrations by 40% to a mean of 201.14 ± 14 μmol/mol Hb (range 150–278). Three patients with blood lead concentrations &gt;45 μg/mL at the end of this therapy were subsequently treated with succimer, an alternative oral chelator; the blood lead concentrations were further reduced to &lt;45 μg/mL. Conclusions: d-Penicillamine therapy significantly reduced blood lead concentrations but did not achieve acceptable lead and ZPP concentrations for young children. Therefore, we conclude that 90 days of d-penicillamine treatment is of limited effectiveness in young children who have high blood lead concentrations and also show symptoms of lead poisoning.

Hypersomnia in Wilson's disease:an unusual symptom in an unusual case

Wilson's disease (WD) shows a wide heterogeneity in symptoms. In this case report we present hypersomnia as a symptom of WD. The male patient's complaints as fatigue, decreased level of concentration, and highly increased demand of sleeping started at his age of 21 years. No abnormality was found at physical examination. A moderate elevation in liver function tests was found, but all the other laboratory findings were within the normal range. The marked hypersomnia was verified by 24-h cassette EEG polisomnographic monitoring. No abnormality was found at physical examination. EEG, brain CT and MRI were normal. Neither toxic nor infectious disease was detectable. The diagnosis of WD was based on decreased coeruloplasmin level, increased baseline and forced urinary excretion of copper, and decreased level of serum copper. Kayser-Fleischer ring was not detectable. D-penicillamine (DPA) was introduced. At 8-10 months after the initiation of the therapy the patient's complaints gradually resolved. The control sleep record 14 months after the initiation of the DPA therapy was normal. Five years later the patient is currently on penicillamine treatment and he is free of any symptom.

Pemphigus vulgaris induced by D-penicillamine therapy in a patient with systemic sclerosis

D -Penicillamine–induced pemphigus occurs infrequently, typically in patients with rheumatoid arthritis. We describe a patient with systemic sclerosis who experienced this complication 3 months after starting D -penicillamine therapy. Nikolsky’s sign, histopathologic findings, and direct immunofluorescence all confirmed the diagnosis. Termination of disease progression required intravenous pulse glucocorticoids, azathioprine, and 3 courses of plasmapheresis. The presentation, treatment, and etiology of D -penicillamine-induced pemphigus are reviewed, and the incidence of this complication in scleroderma patients is examined. (J Am Acad Dermatol 2000;42:297-9.)

A critical evaluation of copper metabolism in Indian Wilson's disease children with special reference to their phenotypes and relatives.

Wilson's disease is an autosomal recessive disorder of copper accumulation in various organs, with most common clinical manifestations such as hepatic, neurological, and renal dysfunctions. Serum copper and ceruloplasmin in Wilson's disease were significantly lower as compared to normals, controls, and relatives of Wilson's disease patients, whereas marked hypercupriuria (145+/-7 microg/24 h) was observed in Wilson's children only. A good correlation (r=0.92) was found between non-ceruloplasmin-bound copper and 24-h urinary copper excretion in Wilson's disease patients. Further, copper studies among the different phenotypes of Wilson's disease revealed substantially low serum ceruloplasmin and a marked hypercupriuria in Wilson's disease children associated with renal tubular acidosis as compared to the patients with either hepatological or neurological manifestations. Serum ceruloplasmin levels in 14 patients of Wilson's disease were between 14 and 20 mg/dL. These patients of Wilson's disease were confirmed by measuring liver biopsy copper, which was about nine times higher than normal hepatic copper content. During the family screening by copper studies, four asymptomatic siblings were diagnosed for Wilson's disease. These subjects were then started on D-penicillamine therapy because presymptomatic treatment prevents progression of the disease complications.

Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis.

To determine whether the initiation of corticosteroids or other types of therapy affects the development of scleroderma renal crisis (SRC). Using a case-control study, 110 patients with systemic sclerosis who developed SRC between 1981 and 1993 were closely matched with controls on sex, race, age, disease duration, skin score, levels of creatine phosphokinase, and presence of tendon friction rubs. Corticosteroid use was determined prior to the onset of SRC in cases or prior to the first visit in controls. Cases were compared with matched controls using McNemar's matched-pair analysis and conditional logistic regression analysis. The effects of other drugs, including D-penicillamine, nonsteroidal antiinflammatory drugs (NSAIDs), calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors, were also evaluated. In the 6 months prior to SRC onset or to the first visit, high-dose corticosteroids (> or =15 mg/day prednisone or equivalent) were administered significantly more frequently in SRC patients (36%) than in the controls (12%) (McNemar's odds ratio 4.37, 95% confidence interval 2.03-9.43, P < 0.0001). New use of low-dose steroids, continuous use of any steroid dose, NSAIDs, calcium channel blockers, and ACE inhibitors were not associated with an increased risk of SRC. Antecedent D-penicillamine therapy may have been protective against the development of SRC in controls. This retrospective case-control study has shown a significant association between antecedent high-dose corticosteroid therapy and the development of SRC. These results should discourage the use of high-dose corticosteroids in patients with early diffuse scleroderma who are at increased risk of developing SRC.

A novel approach to reduce the unwanted gastric side-effects of orally administered non-steroidal anti-inflammatory drugs in rats

Among experimental circumstances both cysteine and glutathione, given in the same time as indomethacin or piroxicam, are capable to decrease the unwanted gastric side-effects of the non-steroidal anti-inflammatory drugs. Similar effects were encountered with prostacyclin or D-penicillamine therapy as well but additional prostacyclin therapy is expensive and complicated (its biological half-life is too short;) D-penicillamine has numerous other, non gastrointestinal side-effects, therefore these two latter substances seem to be inferior compared to the previously mentioned ones. Therefore we conclude that in the human non-steroidal anti-inflammatory therapy it would be worthwhile to apply those drugs with a small amount of either cysteine or glutathione to decrease their unwanted side-effects. This assumption is strengthened by the fact that neither cysteine nor glutathione is an unnatural material in the body.

Present interpretation of the role of copper in Indian childhood cirrhosis

A common killer disease of the past, Indian childhood cirrhosis (ICC), which became preventable and treatable in the early 1990s, is now rare. ICC must be clearly distinguished in Indian children from other chronic liver disorders including Wilson disease. Grossly increased hepatic, urinary, and serum copper concentrations are characteristic of ICC. These increased concentrations are easily demonstrated histologically with orcein-rhodanine staining. Environmental ingestion of copper appears to be the most plausible explanation for ICC, as shown by feeding histories, the prevention of ICC is siblings and in the Pune district by a change in feeding vessels, and the dramatic reduction in incidence of ICC throughout India. The nature and role of a second factor in the causation of ICC remains unclear, although an inherited defect in copper metabolism is strongly suspected. ICC, however, does not appear to be a straightforward early onset of Wilson disease because ceruloplasmin is consistently normal and clinical and histologic recovery is maintained in the long term despite withdrawal of D-penicillamine therapy. Descriptions of an ICC-like illness in the West suggest that different mechanisms (environmental, genetic, or both) can lead to the same end-stage liver disease: copper-associated childhood cirrhosis. ICC probably represents a specific form of copper-associated childhood cirrhosis that requires high environmental copper ingestion for its full expression.