Penicillamine Research Articles

P-77D-PENICILLAMINE, A POTENTIAL ETHANOL ANTI-RELAPSE DRUG, DOES NOT REDUCE THE VOLUNTARY ETHANOL INTAKE IN LONG-TERM EXPERIENCED RATS

Experimental evidence has demonstrated that the reinforcing effects of ethanol crucially depend on the brain formation of acetaldehyde (ACD). Rationally supported by this basis, we previously evaluated a novel strategy to prevent relapse in alcoholism based on chemical ACD inactivation using D-Penicillamine (DP). Under our experimental …

Role of ethanol-derived acetaldehyde in operant oral self-administration of ethanol in rats.

The role of ethanol-derived acetaldehyde has not been examined yet on performance in a model of operant oral self-administration. However, previous studies reported that an acetaldehyde-sequestering agent, D-penicillamine (DP) and an inhibitor of catalase-mediated acetaldehyde production, 3-amino-1,2,4-triazole (3-AT) reduce voluntary ethanol consumption. The aim of our investigation was to evaluate the effects of DP and 3-AT on acquisition and maintenance of oral operant ethanol self-administration. Using operant chambers, rats learned to nose poke in order to receive ethanol solution (5-10 % v/v) under an FR1 schedule of reinforcement in which discrete light and tone cues were presented during ethanol delivery. DP and 3-AT impair the acquisition of ethanol self-administration, whereas its maintenance is not affected neither by drug given alone for both 10 or 5 % ethanol nor by drugs association for 5 % ethanol. Moreover, when the concentration of ethanol was diminished from 10 to 5 %, rats increased the rate of self-administration behaviour. These findings suggest that brain acetaldehyde plays a critical role during acquisition of operant self-administration in ethanol-naïve rats. In contrast, during the maintenance phase, acetaldehyde could contribute to ethanol self-administration by a combined mechanism: On one hand, its lack (by DP or 3-AT) might result in further ethanol-seeking and taking and, on the other, inhibition of ethanol metabolism (by 3-AT) might release an action of the un-metabolised fraction of ethanol that does not overall result in compromising maintenance of ethanol self-administration.

Acetaldehyde sequestration by D-penicillamine prevents ethanol relapse-like drinking in rats: evidence from an operant self-administration paradigm.

Previous experiments in our laboratory have shown that D-penicillamine (DP) (acetaldehyde sequestering agent) is able to block the increase in ethanol consumption observed after a period of imposed deprivation (the so-called alcohol deprivation effect (ADE)), using a non-operant paradigm in Wistar rats. This study is aimed at investigating the robustness and reproducibility of our previous data using an operant paradigm, which is considered to be a valid and reliable model of human drug consumption, and the ADE, probably the most often used measure of ethanol relapse-drinking behaviour in rats. Male Wistar rats with a limited (30-min sessions), intermittent and extended background of ethanol operant self-administration were used. In order to evaluate the efficacy of several DP doses (6.25, 12.5 and 25mg/kg i.p.) in preventing alcohol relapse, we set up a protocol based on the ADE. In a separate experiment, the effect of DP on spontaneous motor activity of rats was also tested. A significant ADE was observed in animals treated with saline. DP treatment blocked the increase in ethanol responses following the imposed abstinence period. The higher dose suppressed the ADE and provoked a significant reduction in ethanol consumption with respect to the baseline conditions. Basal motor activity was not altered after DP treatment. Our positive results with DP, using two different paradigms that evaluate relapse of ethanol drinking, will help to increase the positive predictive value of pre-clinical experiments and offer a solid base to inspire human studies with DP.

Optimal drug regimens for primary biliary cirrhosis: a systematic review and network meta-analysis.

Most comprehensive treatments for PBC include UDCA, combination of methotrexate (MTX), corticosteroids (COT), colchicine (COC) or bezafibrate (BEF), cyclosporin A (CYP), D-penicillamine (DPM), methotrexate (MTX), or azathioprine (AZP). Since the optimum treatment regimen remains inconclusive, we aimed to compare these therapies in terms of patient mortality or liver transplantation (MOLT) and adverse event (AE). We searched PubMed, Embase, Scopus and the Cochrane Library for randomized controlled trials until August 2014. We estimated HRs for MOLT and ORs for AE. The sensitivity analysis based on dose of UDCA was also performed. The search identified 49 studies involving 12 different treatment regimens and 4182 patients. Although no statistical significance can be found in MOLT, COT plus UDCA was ranked highest for efficacy outcome amongst all the treatment regimes. While for AEs, compared with OBS or UDCA, monotherapy with COC (OR 5.6, P < 0.001; OR 5.89, P < 0.001), CYP (OR 3.24, P < 0.001; OR 3.42, P < 0.001), DPM (OR 8.00, P < 0.001; OR 8.45, P < 0.001) and MTX (OR 5.31, P < 0.001; OR 5.61, P < 0.001) were associated with statistically significant increased risk of AEs. No significant differences were found for other combination regimes. Effect estimates from indirect comparisons matched closely to estimates derived from pairwise comparisons. Consistently, in the sensitivity analysis, results closely resembled our primary analysis. COT plus UDCA was the most efficacious among treatment regimens both for MOLT and AEs.

The Electrochemical Behavior of Au/AuNPs/PNA/ZnSe-QD/ACA Electrode Towards CySH Oxidation

This work describes the electrochemical behavior of azodicarboxamide (ACA) film immobilized on the surface of penicillamine (PNA)/ZnSe-quantum dot (ZnSe-QD) gold nanoparticle (AuNPs) Au electrode. Electrocatalytic activity of modified electrode toward the oxidation of cysteine (CySH) was investigated. The surface structure and composition of the sensor were characterized by scanning electron microscopy (SEM). Oxidation of CySH on the surface of modified electrode was investigated with cyclic voltammetry, electrochemical impedance spectroscopy (EIS), hydrodynamic voltammetry and chronoamperometry methods. The results show that the PNA/ZnSe-QD/ACA film displays excellent electrochemical catalytic activities towards CySH oxidation. The modified electrode shows reproducible behavior and high level of stability during the electrochemical experiments. Also it has short response time, low detection limit, high sensitivity and low operation potential, which can be used as an amperometric sensor for monitoring of CySH. The proposed modified electrode was successfully used for determination of CySH in real sample such as human serum.

Measurement of urinary copper excretion after 48-h d-penicillamine cessation as a compliance assessment in Wilson's disease.

Treatment of Wilson's disease (WD) with anti-copper agents is effective in most compliant patients. During long-term treatment with chelating agents, a two-day interruption of the treatment should result in normal urinary copper concentrations (<50 μg/dl). The aim of this study was to establish the usefulness of this method as a compliance assessment in these patients. We examined consecutive patients treated with d-penicillamine (DPA) undergoing routine follow-up studies at our center. We performed 24-h urinary copper excretion analysis 48 h after interruption of chelating therapy. Thirty-two patients were enrolled. After DPA cessation, normalization of copper excretion was observed in 91% of reportedly compliant patients. The specificity and sensitivity values of this test were 87% and 77%, respectively. Measurement of 24-h urinary copper excretion after a 48-h interruption of DPA therapy in patients with WD is a reliable method for confirming patients' compliance.

The development of a conjugated polyelectrolytes derivative based fluorescence switch and its application in penicillamine detection

A sensitive and simple method for detecting penicillamine (PA) has been developed based on fluorescence quenching and recovery. The fluorescence probe was designed based on poly 2,5-[3-(1,1-dimethyl-piperidine methylene) thiophene] chloride(PDPMT-Cl), a water-soluble cationic polythiophene derivative. The fluorescence of PDPMT-Cl was quenched by Au3+ due to the spontaneous formation of Au3+–PDPMT-Cl assembling dyads. The addition of PA created stable Au3+–PA complex leading the release of PDPMT-Cl and fluorescence recovery. The fluorescence intensity of PDPMT-Cl fluorescence “off–on” switch system was linear to PA concentration varying from 0.01 to 20μmol/L (γ=0.9981) with a detection limit of 3.26×10−9mol/L.

Effective treatment of d-penicillamine induced elastosis perforans serpiginosa with ALA-PDT

A case of D-penicillamine(DPA) induced elastosis perforans serpiginosa(EPS) in a 32-year-old Chinese man was reported. The presentation lasted two years and was refractory to traditional medical treatment. He was then commenced on 7.6% 5-aminolevulinic acid (ALA) induced photodynamic therapy(PDT) by a LED light of 633 nm at dose levels of 130J/ cm2 for each session with total 3 sessions at one week interval. The patient was tolerated and responded well to this new approach for DPA-induced EPS without any adverse events. The etiology, pathophysiology, natural history, and treatment options for DPA-induced EPS are reviewed, and the authors suggest this method of treatment to be effective and safe for patients of DPA-induced EPS refractory to conventional therapy.

Ultrasensitive, highly selective and naked eye colorimetric recognition ofd-penicillamine in aqueous media by CTAB capped AgNPs: applications to pharmaceutical and biomedical analysis

Herein, we are going to report a straightforward, highly selective and ultra sensitive naked eye colorimetric probe for the detection of D-penicillamine (D-PA) in aqueous solution using cetyltrimethyl ammonium bromide (CTAB) capped colloidal silver nanoparticles (AgNPs) based on induced aggregation. The synthesized CTAB-AgNPs and their interaction with D-PA were characterized by different analytical techniques such as UV-Vis absorption spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS) measurements and zeta potential measurements. The color of the CTAB-AgNPs solution changed from yellowish brown to colorless within short period of time after the successive addition of D-PA, resulting in a blue shift with quenching in the absorption spectra. Under the optimal conditions, a calibration plot of (A0–A) against concentration of D-PA was linear in the range of 0.1–0.6 μg mL−1 with a correlation coefficient of 0.9901. The concentration of D-PA was quantitatively determined using an UV-Vis spectrophotometer with a limit of detection (LOD) of 0.056 μg mL−1 (56 ng mL−1). In addition, the method shows an excellent selectivity and sensitivity towards D-PA over the other interfering biomolecules and cations tested. The accuracy and reliability of the method were further ascertained from the detection of D-PA from pharmaceutical and biomedical samples via a standard addition method, with percentage recoveries in the range of 98.32–102.94%. A plausible reason for the observed color changes is also discussed. The proposed method is simple, rapid, specific and highly selective and sensitive with good precision.

The Effects of Daily Repeated Magnetic Field on S-Nitroso-N-acetyl-DL penicillamine Induced Hyperalgesia

Amac. Agri tedavisi tibbin en onemli hedeflerinden biridir. Bu arastirmada manyetik alan uygulamasinin S-Nitroso N-acetyl penicillamine (SNAP) tarafindan olusturulan agri uzerindeki etkilerini ve etki mekanizmasini arastirmayi amacladik. Yontem. Calisma iki kisim olacak sekilde tasarlandi. Birindi kisimda hayvanlar her birinde alti hayvan olacak sekilde 4 gruba bolundu. Birinci grup sham grubu olarak belirlendi ve bu hayvanlara 0,3 mL %0,9 NaCl tail flick latensleri olculmeden once uygulandi. Ikinci gruba (SNAP grubu) 2 mg/kg SNAP i.p. olarak enjekte edildi ve sham grubu ile ayni zaman noktalarinda tail flick olcumleri yapildi. Ucuncu grup (MF grubu) tekrarlayan alti gun boyunca manyetik alana maruz birakildi. Dorduncu grupta (SNAP+MF) hayvanlara manyetik alan uygulamasi yapilmadan hemen once 2 mg/kg SNAP i.p. olarak uygulandi. Calismanin ikinci kisminda ratlardan kan ornekleri alinarak kanlarinda supstance p ve B-endorfin seviyelerine ELISA yontemi ile bakildi. Bulgular. SNAP (2 mg/kg) anlamli bir hiperaljezi meydana getirerek tail flick latenleslerini kisaltti. Manyeteik alan uygulamasi (5 mT ve 165 dakika/gun) ozellikle 3. ve 4. gunlerde anlamli bir analjezi meydana getirdi. SNAP grubunda substance p seviyeleri yuksek bulunurken, manyetik alan grubunda B-endorfin seviyelerinin yuksek oldugu tespit edildi. Sonuc. Bu sonuclar manyetik alan uygulamasinin agri tedavisinde alternatif bir yaklasim olabilecegini gostermektedir. Fakat bu yontemin kullanilabilmesi icin gelisen toleransin ustesinden gelmenin yollarinin bulunmasi ve bunun icinde ileri arastirmalara gereksinim vardir.

A sensitive and selective colorimetric method for detection of copper ions based on anti-aggregation of unmodified gold nanoparticles

A highly sensitive and selective colorimetric method for detection of copper ions, based on anti-aggregation of D-penicillamine (D-PC) induced aggregated gold nanoparticles (AuNPs) was developed. Copper ions can hinder the aggregation of AuNPs induced by D-PC, through formation of mixed-valence complex with D-PC that is a selective copper chelator. In the presence of a fixed amount of D-PC, the aggregation of AuNPs decreases with increasing concentrations of Cu2+ along with a color change from blue to red in AuNPs solution and an increase in the absorption ratio (A520/A650). Under the optimum experimental conditions (pH 7, [AuNPs] =3.0nmolL−1 and [NaCl]=25mmolL−1), a linear calibration curve for Cu2+ was obtained within the range of 0.05–1.85µmolL−1 with a limit of detection (3Sb) of 30nmolL−1. Excellent selectivity toward Cu2+ was observed among various metal ions due to a specific complex formation between Cu2+ and D-PC. The proposed method has been successfully applied for the detection of Cu2+ in various real samples.

Detection of hydrogen sulfide through photoluminescence quenching of penicillamine-copper nanocluster aggregates

We have developed a one-pot, inexpensive, simple and rapid method to synthesize photoluminescent copper nanocluster (Cu NC) aggregates from Cu2+ ions in 65% (v v−1) dimethylformamide aqueous solution containing penicillamine (PA) as a capping and reducing agent. As-prepared PA-Cu NC aggregates emit at 580 nm when excited at 326 nm, with a quantum yield of 2.0%. The photoluminescence of PA-Cu NC aggregates originate from ligand-to-metal charge transfer, which is supported by a long lifetime (126.5 ns) and a large Stokes shift (254 nm). As-prepared PA-Cu NC aggregates have different emission wavelengths with the same excitation wavelength in various organic-aqueous solutions. The PA-Cu NC aggregates are highly selective and sensitive to the detection of hydrogen sulfide (H2S), based on analyte-induced photoluminescence quenching through the formation of CuS nanoparticles. The probe allows the detection of H2S, with a linear range of 1–100 μM and a limit of detection (signal-to-noise ratio = 3) of 500 nM. The practicality of this probe has been validated through the analysis of hot spring water samples.

Covalent attachment of Ni-2,3-pyrazine dicarboxylic acid onto gold nanoparticle gold electrode modified with penicillamine- CdS quantum dots for electrocatalytic oxidation and determination of urea

This work describes the electrochemical behavior of Ni-2,3-pyrazine dicarboxylic acid (Ni-PDA) film immobilized on the surface of penicillamine (PNA)/CdS-quantum dots (CdS-QDs) gold nanoparticle (AuNPs) Au electrode and its electrocatalytic activity toward oxidation of urea. The surface structure and composition of the sensor was characterized by scanning electron microscopy (SEM). Oxidation of urea on the surface of modified electrode was investigated with cyclic voltammetry, electrochemical impedance spectroscopy (EIS), hydrodynamic voltammetry and chronoamperometry methods and the results showed that the PNA/CdS-QDs/PDA-Ni film displays excellent electrochemical catalytic activities towards urea oxidation. The modified electrode indicated reproducible behavior and high level of stability during the electrochemical experiments. Also it has short response time, low detection limit, high sensitivity and low operation potential. It can be used as an amperometric sensor for monitoring of urea. The proposed modified electrode was successfully used for determination of urea in real sample such human serum.

D‐penicillamine versus zinc sulfate as first‐line therapy for Wilson's disease

To compare the course of treatment in patients with symptomatic Wilson's disease (WD) receiving either D-penicillamine (DPA) or zinc sulfate (ZS) as first-line therapy. In all, 143 consecutive patients diagnosed with symptomatic WD from January 2005 to December 2009, followed until December 2010, were included. The decision about first-line therapy was made individually after discussion with the patient. Physicians had no clear preference of one drug over the other. Data were analyzed in subgroups with predominantly neurological (DPA, 35; ZS, 21) and hepatic (DPA, 36; ZS, 51) presentation of WD. According to Kaplan-Meier analysis, neurological WD patients scheduled for DPA had a similar probability of not remaining on first-line therapy as patients receiving ZS (20% vs. 24% at the end of follow-up), with adjusted odds ratio (OR) of 0.9 (95% CI 0.2-3.5). In patients with hepatic WD, this probability was significantly higher for DPA (31% vs. 12%; adjusted OR 3.0, 95% CI 0.9-9.9), especially in the first 6 months. Early worsening occurred only in neurological WD patients, with no differences between both treatment groups (35% vs. 19%; OR 2.8, 95% CI 0.7-10.8). Neurological improvement and decrease of liver enzymes were achieved with similar frequency. Compliance with DPA was better in hepatic (97% vs. 80%) but not in neurological patients (91% vs. 81%). Drug adverse effects were more common on DPA (15% vs. 3%). DPA and ZS are effective in the majority of WD patients. Neither therapy appears to be clearly superior. Therefore ZS may be considered a reasonable alternative to DPA as a first-line therapy.

Detection of D‐penicillamine in skin lesions in a case of dermal elastosis after a previous long‐term treatment for Wilson's disease

Skin adverse events associated with D-Penicillamine (DPA) are common and multi-faceted, although the presence of DPA or its metabolites has never been documented in the skin, because of inherent difficulties in determining its tissue levels. Thus, the association between DPA and DPA-related dermatoses has been only hypothesized on the basis of careful history, clinical observation and typical histopathological findings. To detect DPA in biopsy specimens in a unique case of 25-year-late-onset elastosis perforans serpiginosa and pseudo-pseudoxanthoma elasticum associated with a history of long-term high dose DPA, by applying a recently described analytical method to assess the presence of DPA in skin. We used a reliable analytical method based on high-performance liquid chromatography coupled with amperometric detection to look for the presence of DPA in skin biopsy specimens. A chromatographic peak corresponding to DPA was evidenced in some affected skin samples collected from the patient. We documented the effective presence and the persistence after 25 years of DPA in the skin of a woman affected by elastotic cutaneous change due to a long-term therapy with DPA. This report provides further evidence of the relationship between DPA deposit in affected skin and clinical manifestation.

Compliant treatment with anti‐copper agents prevents clinically overt Wilson's disease in pre‐symptomatic patients

Wilson's disease (WD) is an inherited copper metabolism disorder that leads to dysfunction of affected tissues, mostly in the liver and brain. Anti-copper treatment should prevent clinically overt WD in pre-symptomatic patients but this has not been supported by strong evidence. Our aim was to evaluate the long-term effectiveness of treatment in clinically pre-symptomatic patients, with particular emphasis on patient compliance with treatment. Data were analyzed for 87 consecutive patients with no clinical symptoms of WD who were identified between 1957 and 2009 by family screening. All of them since diagnosis were treated with either zinc sulphate (Zn) (66.7%) or D-penicillamine (DPA) (33.3%). During a median follow-up of 12 years (range 3-52), 55 (63%) patients remained without clinical symptoms, 13 (15%) developed neuropsychiatric symptoms and 21 (24%) developed hepatic dysfunction, including five deaths from hepatic failure. Non-compliance for at least three consecutive months was observed in 39 patients, and in 29 cases this extended for more than 12 months. Multivariate analysis showed that the odds of developing symptomatic WD were independently increased by non-compliance (odds ratio 24.0, 95% confidence interval 6.0-99.0). According to Kaplan-Meier analysis patients who were compliant to treatment had a significantly higher likelihood of remaining symptom-free, and their overall survival was similar to the survival rate observed in the general population. The use of anti-copper agents in clinically pre-symptomatic patients diagnosed with WD allows clinically overt disease to be effectively prevented. However, compliance with therapy is extremely important.

Improved effect of the combination naltrexone/D-penicillamine in the prevention of alcohol relapse-like drinking in rats

Opioid antagonists are licensed drugs for treating alcohol use disorders; nonetheless, clinical studies have evidenced their limited effectiveness. Preclinical findings indicate that opioid receptor (OR) antagonists, such as naltrexone (NTX), reduce the alcohol deprivation effect (ADE). However, a detailed analysis of published data shows the existence of a delayed increase in ethanol consumption after continuous OR blockade, a phenomenon originally called as 'delayed ADE'. We have recently reported that D-penicillamine (DP) is able to prevent ADE through a mechanism dependent on the inactivation of acetaldehyde, the main metabolite of ethanol. Hypothetically, OR activation would be triggered by acetaldehyde after ethanol consumption. Hence, we conjecture that the combination of NTX and DP, due to their distinct but complementary mechanisms to impede OR activation, may be more efficacious in the prevention of the ADE and, specifically, the 'delayed ADE'. Herein, we compare the effects of the combination NTX/DP (NTX: 2×5 mg/kg SC injection daily/DP: SC infusion (0.25 mg/h)) versus NTX on the ADE in long-term ethanol-experienced rats. As expected, NTX-treated animals displayed a delayed ADE. However, NTX/DP treatment prevented this delayed effect. Our present data indicate that this combination therapy shows an adequate anti-relapse preclinical efficacy being able to overcome the preclinical limitations of NTX alone.

Wilson’s disease

Wilson s disease (WD) is a genetically determined, autosomal recessive disorder of copper metabolism. The gene ATP7B encodes a copper carrier that both transports copper from hepatocyte to bile and ceruloplasmin copper incorporation. WD may present with almost any variety of liver disease at an age ranging from 4–12 years, or with neurological and psychiatric symptoms in adolescence. Less commonly, haemolysis and/or fulminant hepatic failure may be an initial presentation. Low plasma ceruloplasmin, a positive penicillamine challenge test, and a high hepatic copper content suggest the diagnosis. Molecular methods help in diagnosing WD. If diagnosed early, it is treatable with chelators and/or zinc, and has a good prognosis. Fulminant hepatic disease has a poor outcome without transplantation.

Clinical efficacy and safety of chelation treatment with typical penicillamine in cross combination with DMPS repeatedly for Wilson’s disease

The aim of this study was to assess the clinical efficacy and safety of chelation treatment with penicillamine (PCA) in cross combination with sodium 2, 3-dimercapto-1-propane sulfonate (DMPS) repeatedly in patients with Wilson's disease (WD). Thirty-five patients with WD were enrolled. They were administrated intravenous DMPS in cross combination with oral PCA alternately which was practiced repeatedly, all with Zinc in the meantime. During the treatment, clinical observations and 24-h urine copper excretion as well as adverse effects of medicines were recorded and analyzed. Although the incidence of adverse effects was not significantly different after either intravenous DMPS or oral PCA treatment, levels of 24-h urine copper tended to be higher after short-term intravenous DMPS than that of oral PCA. Adverse effects in the course of intravenous DMPS were mainly neutropenia, thrombocytopenia, allergic reaction and bleeding tendency. As compared with oral PCA alone or intravenous DMPS alone, such repeated cross combination treatment could as much as possible avoid continued drug adverse effects or poor curative effect and had less chance to stop treatment in WD patients. Improved or recovered liver function in 71% of the patients, alleviated neurologic symptoms in 50% of the patients, and disappeared hematuria in 70% of the patients could be observed during the follow-up period of 6 months to 5 years after such combined chelation regimen. Chelation treatment repeatedly with oral penicillamine in cross combination with intravenous DMPS alternately could be more beneficial for WD patients to relieve symptoms, avoid continued drug adverse effects and maintain lifelong therapy.

Trientine or D-Penicillamine for Wilson Disease?

In a recent study, zinc monotherapy, an inhibitor of intestinal copper uptake, was not as effective as chelating agents in the treatment of Wilson