D-penicillamine Administration Research Articles

Protective role of silymarin and D-penicillamine against lead-induced liver toxicity and oxidative stress.

This study was performed to assess hepatotoxicity and alterations in liver antioxidant defence in acute lead (Pb) exposure and the protective effects of silymarin in comparison to D-penicillamine in rats. Forty eight Albino rats were divided in eight groups and received the following treatments in a 10-day experiment - group 1: normal saline as control; group 2: 25-mg/kg Pb acetate, intraperitoneally (IP) for the last 5 days; group 3: 100-mg/kg D-penicillamine, IP for the last 5 days; group 4: 200-mg/kg silymarin, orally for 10 days; and groups 5, 6, 7 and 8: in addition to Pb, they received D-penicillamine, for the last 5 days, silymarin for 10 days, a combination of silymarin for 10 days and D-penicillamine for the last 5 days and silymarin for the last 5 days, respectively. Pb acetate exposure induced significant elevation in serum alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzyme activities in group 2 compared to control group. Significant reductions in serum total protein and albumin in all Pb-exposed groups and in serum glucose in groups 2, 6 and 8 were also observed. Liver tissue superoxide dismutase and glutathione peroxidase were significantly lower in groups 2 and 8 compared to control group. Silymarin pretreatment and D-penicillamine administration in groups 5, 7 and 8 could significantly lower ALP, ALT and AST and improve liver antioxidant enzymes. Thus, acute Pb exposure induced hepatotoxicity with suppression of liver antioxidant defence system and silymarin, as an antioxidant could alleviate this effect.

Nutritional management of inherited copper-associated hepatitis in the Labrador retriever

Canine hereditary copper-associated hepatitis is characterized by gradual hepatic copper accumulation eventually leading to liver cirrhosis. Therapy is aimed at creating a negative copper balance with metal chelators, of which d-penicillamine is the most commonly used. d-penicillamine often causes gastro-intestinal side effects and life-long continuous therapy may lead to a deficiency of copper and zinc. The aim of the current study was to investigate the effect of a low-copper, high-zinc diet as an alternative to continuous d-penicillamine treatment for the long-term management of canine copper-associated hepatitis.Sixteen affected Labrador retrievers were followed for a median time period of 19.1months (range, 5.9–39months) after being effectively treated with d-penicillamine. The dogs were maintained on a diet containing 1.3±0.3mgcopper/1000kcal and 64.3±5.9mgzinc/1000kcal. Liver biopsies were taken every 6months for histological evaluation and copper determination. Plasma alanine aminotransferase (ALT) and alkaline phosphatase, as well as serum albumin were determined.Dietary treatment alone was sufficient to maintain hepatic copper concentration below 800mg/kg dry weight liver in 12 dogs during the study period. Four dogs needed re-treatment with d-penicillamine. ALT activity and albumin concentration were not associated with hepatic copper concentration, but showed a significant association with the stage and grade of hepatitis respectively. In conclusion, a low-copper, high-zinc diet can be a valuable alternative to continuous d-penicillamine administration for long-term management of dogs with copper-associated hepatitis. The copper re-accumulation rate of an individual dog should be considered in the design of a long-term management protocol and in determining re-biopsy intervals.

Urinary excretion of copper, zinc and iron with and without D-penicillamine administration in relation to hepatic copper concentration in dogs

Hereditary copper-associated hepatitis in dogs resembles Wilson’s disease, a copper storage disease in humans. Values for urinary copper excretion are well established in the diagnostic protocol of Wilson’s disease, whereas in dogs these have not been evaluated. The objectives of this study were to characterize both basal and D-penicillamine induced urinary copper, zinc and iron excretion in dogs in relation to hepatic copper concentration. Beagles, Beagle-Bedlington terrier cross-breeds homozygous for the COMMD1 gene mutation that causes copper toxicosis, and Labrador retrievers with normal or increased hepatic copper concentrations were investigated. The hepatic copper phenotype was determined by histological evaluation of liver biopsies and measurement of the hepatic copper concentration by instrumental neutron activation analysis. Urinary excretion of copper, iron and zinc was measured via inductively coupled plasma optical emission spectrometry under basal conditions and after oral administration of a single dose (20mg/kg bodyweight) of the chelator D-penicillamine.There was a rapid increase in urinary excretion of copper and zinc, but not iron after D-penicillamine administration. This increase was not different between dogs with high or normal hepatic copper concentrations. D-penicillamine-induced urinary copper excretion and the copper/creatinine ratio did not correlate with hepatic copper concentrations in the dogs studied, although basal urinary copper/zinc ratios did correlate with hepatic copper concentrations in Labrador retrievers. The latter parameter may be useful in diagnostic and follow-up protocols for copper-associated hepatitis in Labrador retrievers.

Efficacy of d-penicillamine, a sequestering acetaldehyde agent, in the prevention of alcohol relapse-like drinking in rats

Nowadays, very few approved anti-relapse treatments for alcoholism exist, and their overall efficacy can be considered moderate. An exciting rationale drug development opportunity for the treatment of chronic alcoholism is the use of acetaldehyde sequestering agents. Although these compounds are able to attenuate or prevent most of the behavioral and neurochemical effects of ethanol, the efficacy of acetaldehyde sequestration, by using agents such as D-penicillamine (DP), in relapse prevention has not been studied yet. The aim of this study was to analyze the effects of DP treatment on the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats as a model of relapse behavior and measure drug plasma and brain levels during treatment. Rats were subcutaneously implanted with mini-osmotic pumps delivering 0, 0.25, or 1mg/h of DP during 1 week. The efficacy to prevent ADE was determined. DP plasma and brain levels achieved during its subcutaneous administration were measured. In a second experiment, animals received bilateral infusions of 0 or 1.5μg/h of DP directly into pVTA, and the appearance of ADE was evaluated. One milligram per hour, but not 0.25mg/h, DP infusion prevented ADE and reduced the total ethanol preference in animals. DP plasma concentrations associated with ADE suppression were around 3-4μg/ml, and brain DP levels in these conditions were about 2-3% of those found in plasma. Intra-pVTA DP administration also suppressed ADE. DP is able to prevent alcohol-relapse-like drinking in rats suggesting that this drug may be a useful new tool in the management of relapse in alcohol-dependent patients.

Anti-MuSK- and anti-AChR-positive myasthenia gravis induced by d-penicillamine

BackgroundMyasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction usually caused by antibodies to the nicotinic acetylcholine receptor (AChR) and occasionally to muscle-specific kinase (MuSK). d-penicillamine is a therapeutic agent for several diseases, but can also induce a number of immune-mediated disorders, including MG, as a side-effect. In most patients with d-penicillamine-induced MG, anti-AChR antibodies are detected, but the presence of anti-MuSK antibodies has not been reported previously. CaseThe case reported was a female patient who presented with myasthenic symptoms after d-penicillamine administration for scleroderma. ResultsBoth anti-AChR and anti-MuSK antibodies were identified in the patient's serum. The anti-MuSK antibodies were of the IgG4 subclass, as in idiopathic MG. Both types of antibody gradually disappeared after discontinuation of d-penicillamine. A significant improvement in symptoms was observed and the patient gradually became free of MG symptoms, without requiring any treatment for MG. Another four double-positive (anti-AChR and anti-MuSK antibodies) patients were identified during a retrospective study, but none had been treated with d-penicillamine. Conclusiond-penicillamine can cause anti-AChR and anti-MuSK antibody-positive MG, a rare phenomenon which is reversed after discontinuation of d-penicillamine treatment.

D-Penicillamine administration and the incidence of retinopathy of prematurity

We compared the development of retinopathy of prematurity (ROP) among 49 preterm neonates:; 15 who were treated during the first 2 weeks of life with D-penicillamine and 34 who were not. During a 15-month period beginning 1 March, 2005, 15 preterm neonates <1000 g birth weight or < or =29 weeks gestation enterally received a 14-day course of D-penicillamine, and 34 did not, in an open-label non-randomized trial. We compared the outcomes of developing 'ROP any stage' and 'ROP requiring surgery' in the recipients vs the non-recipients. Potential toxicities of the D-penicillamine were examined by comparing specific laboratory tests, growth velocities, transfusion requirements, discharge hemoglobin concentrations and supplemental O(2) at discharge. The 34 non-treated and the 15 D-penicillamine treated patients were of similar gestational age (26.5+/-1.8 vs 26.6+/-2.2 weeks, mean+/-s.d.) and birth weight (887+/-222 vs 849+/-187 g). Four of the 34 non-recipients died. Eighteen of the 30 survivors (60%) developed ROP and seven of the 30 (23%) had ROP surgery. One of the 15 D-penicillamine recipients died. Three of the 14 survivors (21%) developed ROP (P=0.01 vs non-recipients) and all three had ROP laser surgery. No increase in elevated creatinine, direct or indirect bilirubin, thrombocytopenia or neutropenia was apparent in those treated with D-penicillamine. The D-penicillamine recipients did not receive more transfusions and did not have lower hemoglobin concentrations at discharge. They did not have lower velocities of weight gain at 14, 28 and 56 days, and were not discharged on supplemental O(2) at a rate exceeding that of the non-recipients. In this non-randomized, single-centered comparison analysis, a 14-day course of D-penicillamine resulted in no apparent short-term toxicity. The treatment was associated with elimination of Stage I and Stage II ROP, decreasing the overall odds of developing ROP from 60 to 21%. However, this approach did not reduce the odds of ROP surgery. Perhaps higher doses of D-penicillamine or longer treatment periods or other prophylactic approaches will be required to reduce ROP surgery among the most immature neonates.

Effect ofD-penicillamine on rat lung elastin cross-linking during the perinatal period

This study was designed to clarify the effects of D-penicillamine (DPA), a drug used for treatment of various pathological events, on lung elastin formation and maturation of the newborn in the perinatal period. The investigation was conducted on 20 newborn rats bred from 40 female and six male rats. DPA doses 400 mg kg(-1) day(-1) and physiological saline were given intraperitoneally (i.p) to experimental and control groups. To assess newborn maturation, their body and lung weights were determined. Serum Cu levels were measured by atomic absorption spectroscopy and ceruloplasmin (Cp) activities were measured spectrophotometrically. Newborn lung tissue elastin, desmosine (DES) and isodesmosine (IDES) levels were measured by HPLC. The results showed that DPA treatment caused loss of skin elasticity and reduction in body and lung weight in newborns of the experimental group. The serum Cu levels and Cp activity were found to be significantly lower in both maternal and newborn of the experimental groups compared with the control group. The lung DES, IDES and elastin values of newborns in the experimental group were decreased compared with the control group. In conclusion, our results indicate that 400 mg kg(-1) day(-1) DPA, a dose that is used in the treatment of Wilson's disease, rheumatoid arthritis and cystinuria, caused the retardation of newborn maturation, a decrease in DES-IDES cross-links and levels of lung elastin of offspring in the perinatal period. Another conclusion to be drawn from this study is that even low levels of Cu depletion due to DPA administration induces a change in cross-linking in lung elastin during the perinatal period.

FSH, TSH, T3 and T4 changes in relation to plasma copper and zinc alterations during D-penicillamine administration in female Wistar rats

Zinc and copper are considered to antagonize each other in several organs, while they play a significant role in the regulation and function of many systems. D-penicillamine was administered to 19 female Wistar rats for 68 days, 1 g/d/kg B.W. Plasma copper and zinc levels, as well as serum T3, T4, TSH and FSH were measured at days 50, 53, 54, 58, 62 and 68. Copper concentration presented a significant decrease. Zinc showed an initial increase by day 54, followed by a subsequent decrease. FSH levels decreased, presenting a pattern identical with that of copper. T3 and —especially— T4 alterations were similar to that of zinc and copper, whereas TSH alterations were inverse to them. It is concluded that copper and zinc alterations, induced by d-penicillamine administration, can significantly affect pituitary sex hormones (TSH) and hypothalamic-pituitary-thyroid axis in rats.

Appropriate administration schedule of D-penicillamine for pediatric Wilson's disease patients based on urinary copper excretion

The purpose of this study was to increase the amount of copper excreted resulting from the administration of D-penicillamine(DP) in pediatric Wilson's disease(WD) patients. By measuring the urinary copper excretion after adjusting the administration schedules, the appropriate timing for DP administration was investigated. The subjects were three brothers with pediatric WD. The initial daily dose of DP was 5 mg/kg/day, and gradually increased to the maintenance dose of 20 mg/kg/day. Until the maintenance daily dose was reached, DP was administered 2 h after the morning and evening meal. After reaching the maintenance daily dose of DP, the appropriate timing for taking DP was investigated in both the morning and evening. Three schedules of DP administration were compared: 2 h after meals; 30 min before meals (with fasting); and 1 h before the morning and 1.5 before the evening meal (direction 1). The resulting urinary copper excretion on each dosing schedule was compared. Little difference was found in urinary copper excretion on the first two schedules, i.e., 2 h after meals and 30 min before meals. When DP was administered 30 min before meals, urinary copper excretion [microgram/day] was 1173 in the first brother, 918 in the second, and 875 in the third. When DP was administered according to direction 1, however, urinary copper excretion was increased significantly to 1701 in the first brother, 2701 in the second, and 3808 in the third. It is known that the efficiency of urinary copper excretion with DP administration depends on the maintenance of chelating ability after absorption from the gastrointestinal tract. Our results indicate that the excretion was lower when DP was administered 2 h after or 30 min before meals (with fasting), as recommended in the package insert. Thus to achieve better copper excretion efficiency, direction 1 is recommended for WD patients.

Fulminant hepatic failure during perinatal period in a pregnant woman with Wilson’s disease

Wilson's disease associated with hepatic failure is not common and the underlying mechanism triggering the event is not known at present. We treated a 28-year-old Japanese woman with Wilson's disease who developed hepatic failure associated with hemolytic crisis just after delivery. She was diagnosed as having Wilson's disease at 12 years of age, at which time she started taking D-penicillamine. She had previously delivered two children without difficulty. When she found out she was pregnant this time, she stopped taking D-penicillamine in contrast to taking it faithfully during her first two pregnancies. On the day of delivery of her full-term baby, jaundice developed accompanied with severe hemolytic crisis. Plasma exchanges and blood transfusion were performed and D-penicillamine administration was started again. She gradually recovered and apparently was following a good clinical course. However, on day 30 the second hemolytic crisis occurred and subsequent liver failure led her to death on day 50. At autopsy her liver was cirrhotic and showed massive necrosis. Prophylactic oral administration of D-penicillamine and careful observation are therefore recommended to prevent hemolytic crisis during the perinatal period.

Effects of prolonged administration of d-penicillamine or captopril in various strains of rats : Brown Norway rats treated with d-penicillamine develop autoantibodies, circulating immune complexes, and disseminated intravascular coagulation

d-Penicillamine and captopril, two drugs that induce autoimmune manifestations in man, were administered orally for 5 to 10 months to various strains of rats. Three to eight weeks after d-penicillamine administration in a dosage of 20 to 50 mg per day, 73% of Brown Norway (BN) rats became ill. The disease was characterized by weight loss, dermatitis, and a high mortality presumably caused by disseminated intravascular coagulation. Microscopy revealed widespread granulomatous and necrotic lesions. The plasma of these animals contained antinuclear antibodies and immune complexes. In the kidney deposits of IgG were found in a linear pattern along the glomerular basement membrane. IgG eluted from diseased kidneys bound both “ in vitro” and “ in vivo” to kidney basement membranes. BN rats initially receiving 5 mg of d-penicillamine per day and subsequently 20 and 50 mg per day did not develop disease. No adverse effects were noted in Lewis (LEW) and Sprague-Dawley (SD) rats treated with 20 or 50 mg of d-penicillamine per day, nor in BN and LEW rats treated with 20 mg of captopril per day.

D-Penicillamine-induced neuromuscular disease in guinea pigs

We found that chronic d-penicillamine administration in guinea pigs may induce a variety of electrophysiologic, histologic, and serologic changes that are reminiscent of features of both experimental allergic myositis and experimental allergic myasthenia gravis. These include (i) electromyographic decrement following repetitive stimulation that is reversible with edrophonium, and augmentation of twitch tension with edrophonium; (ii) nonspecific inflammatory and necrotic changes in muscle; and (iii) significant elevation of acetylcholine receptor antibody. The guinea-pig model raises several questions that must be answered before it can be regarded as a reliable model of d-penicillamine-induced neuromuscular disease in humans.

Plasma amine oxidases in Wilson's disease

Plasma Mono- and Diamine-Oxidase activities (MAO and DAO), two copper containing enzymes, were estimated in 5 patients with Wilson's disease, without treatment and during D-Penicillamine treatment. Ceruloplasmin and “free” copper plasma levels were simultaneously measured. MAO was elevated in all cases, while DAO was within normal limits. D-Penicillamine administration did not result in significant reductions of these enzyme activities. It is likely that alterations of copper metabolism induced by Wilson's disease and by D-Penicillamine administration do not affect the activity of MAO or DAO. The increase in MAO activity in Wilson's disease probably results from the hepatic fibrosis.

Increased radiation morbidities, hypocupremia and hyperlipoperoxidemia in the rat induced by D-penicillamine administration.

Increased radiation morbidities, hypocupremia and hyperlipoperoxidemia in the rat induced by D-penicillamine administration.

Effect of d-Penicillamine Treatment on Mineral Balance in Guinea Pigs

Experiments were conducted to study the effect of d-penicillamine on the metabolism of iron, magnesium, calcium and phosphorus in guinea pigs as measured by changes in absorption, retention and excretion of these elements. d-Penicillamine administration for 10 days did not change the iron and magnesium metabolisms as compared with the controls. Calcium absorption and urinary excretion were increased, but 50% of the guinea pigs had a negative calcium balance during the penicillamine treatment. A decreased phosphorus absorption and an increased urinary excretion were observed during the penicillamine treatment. Only 3 out of 16 guinea pigs, however, were in a negative phosphorus balance. The body weight of the guinea pigs was also decreased during the penicillamine administration, though feed consumption remained unchanged. The increased calcium and phosphorus urinary excretion, the loss of body weight and the normal blood levels of calcium and phosphorus suggested a decreased tubular reabsorption of these two minerals and the mobilization of calcium and phosphorus from the bone stores.