Effect Of Penicillamine Research Articles

Mechanisms of redox interactions of bilirubin with copper and the effects of penicillamine

Toxic effects of unconjugated bilirubin (BR) in neonatal hyperbilirubinemia have been related to redox and/or coordinate interactions with Cu2+. However, the development and mechanisms of such interactions at physiological pH have not been resolved. This study shows that BR reduces Cu2+ to Cu1+ in 1:1 stoichiometry. Apparently, BR undergoes degradation, i.e. BR and Cu2+ do not form stable complexes. The binding of Cu2+ to inorganic phosphates, liposomal phosphate groups, or to chelating drug penicillamine, impedes redox interactions with BR. Cu1+ undergoes spontaneous oxidation by O2 resulting in hydrogen peroxide accumulation and hydroxyl radical production. In relation to this, copper and BR induced synergistic oxidative/damaging effects on erythrocytes membrane, which were alleviated by penicillamine. The production of reactive oxygen species by BR and copper represents a plausible cause of BR toxic effects and cell damage in hyperbilirubinemia. Further examination of therapeutic potentials of copper chelators in the treatment of severe neonatal hyperbilirubinemia is needed.

Effects of penicillamine, hypotaurine, and epinephrine on motility, hyperactivity, acrosome reaction of fresh ram sperm

Objective: To determine the effects of different concentrations of penicillamine, hypotaurine, and epinephrine (PHE) as well as incubation time on motility, hyperactivity and acrosome reaction (AR) of ram sperm in vitro. Methods: Freshly ejaculated spermatozoa from three ram were collected, pooled and subjected to swim up technique in modified sperm Tyrode's albumin lactate pyruvate medium supplemented with different concentrations of PHE (10, 20, 30, 40, 50, 75 and 100 mM/mL). Then best concentrations were compared and examined for motility, hyperactivity and AR. Results: A high concentrations of PHE (30, 40, 50, 75 and 100mM/mL) showed a significant increase in motility when compared to control immediately after dilution and exist for the first and second hour of incubation period. However, when longer incubation time were used, a significant (P

The Interaction of Thiol Drugs and Urine pH in the Treatment of Cystinuria

Pharmacological therapy for cystinuria consists of alkali salts to increase urine pH and thiol drugs to form soluble cysteine-drug complexes. The effect of alkalinizing urine on thiol drug activity has not been well studied. Urine samples were obtained from 5 healthy subjects and pH was adjusted (range 6.0 to 8.0) in each urine aliquot. Urine samples were incubated with cystine crystals at 37C for 5, 15 and 60 minutes, and 48 hours. We compared cystine solubility in urine samples spiked with thiol drugs at a final concentration of 2 mM to that in control urine samples at the various pH levels and time points. In samples incubated for 48 hours, which is the standard time frame for solubility studies, cystine solubility more than doubled with thiol drugs compared to control and did not depend on pH. However, when incubation time was shortened to 5 minutes, representing the dwell time of urine in the renal pelvis, the effect of thiol drugs to solubilize cystine greatly depended on urine pH with less cystine dissolved at lower pH. Increasing urine pH greatly increased the efficacy of thiol drugs to solubilize cystine in a clinically relevant time frame. These findings suggest that to maximize the benefit of thiol drugs alkali therapy should be used in conjunction with thiol drugs with the goal of keeping urine pH at 7.5 or above. Clinical trials are needed to confirm these in vitro findings.

Effect of penicillamine and zinc on iron metabolism in Wilson's disease

Objective. The physiology of iron metabolism in Wilson's disease is largely unknown, and there is a paucity of data on the real presence and progression of iron accumulation. The purpose of this study was to assess the iron metabolism parameters, including hepatic iron concentration, in follow-up liver biopsies and serum, and urinary pro-hepcidin. Material and methods. Twenty-three Wilson's disease patients undergoing long-term treatment were enrolled in the study. Results. Hepatic iron content was significantly increased in penicillamine-treated patients compared with zinc-treated patients. Serum and urinary pro-hepcidin concentrations were significantly higher in Wilson's disease patients than in healthy volunteers, despite a normal biochemical pattern of iron metabolism. Conclusions. Long-term penicillamine treatment seems to be responsible for a more marked iron accumulation in the liver. This observation may justify a revision of long-term Wilson's disease treatment modalities with penicillamine. The finding that serum and urinary pro-hepcidin is significantly increased in Wilson's disease patients compared with healthy volunteers suggests a role for hepcidin in iron metabolism in Wilson's disease, but this needs to be confirmed by a study of hepatic hepcidin expression in these patients.

Use of a monoclonal antibody specific for activated endothelial cells to quantitate angiogenesis in vivo in zebrafish after drug treatment

We have recently generated a monoclonal antibody (mAb), Phy-V002, which specifically labels activated vascular endothelial cells (EC) in zebrafish. Here, we show that this mAb labels activated EC in newly formed vessels in vivo without staining mature vessels or other tissues. Using this mAb, drug effects on in vivo EC migration and vessel formation were visually assessed by whole-mount immunochemical staining in the transparent embryo. In addition, we have developed a quantitative microplate-based ELISA that measures EC proliferation in vivo after drug treatment. We have validated the quantitative in vivo ELISA using several antiangiogenic small molecules with different mechanisms of action which were added directly to the fish water. Some of these drugs, including: 2-methoxyestradiol, flavopiridol, paclitaxel, and genistein, are currently in clinical trials. We also injected large molecule drugs, including 3TSR and TSR2+KRFK, recombinant human antiangiogenic peptides of thrombospondin-1, a natural protein. To demonstrate that proangiogenic effects can also be assessed in zebrafish, we assessed effects of penicillamine and simvastatin, two proangiogenic compounds shown to stimulate vessel formation in rodents. Using whole-mount immunochemical staining with Phy-V002, inhibition of EC migration and inhibition or stimulation of vessel formation were visually observed for each compound. Next, using the quantitative in vivo angiogenesis ELISA, we generated dose-response curves for each compound. Compared to conventional assays, advantages of using zebrafish to assess drug effects on angiogenesis include: (1) a short assay time; (2) easy animal maintenance; (3) use of small quantities of drug; (4) single dosing; (5) a quantitative assay format; and (6) use of statistically significant number of animals per test.

Electrochemical Investigations of the Nickel(II)-Penicillamine System. Inert and Labile Complexes Detected by Polarography

The effect of penicillamine on nickel diffusion current demonstrates that Ni22- is a kinetically inert complex whereas NiL is labile (L2- = (CH3)2C(S-)CH(NH2)COO-)). The difference in kinetic stability between the analogous bis-ligand complexes of Ni(II) with either penicillamine or cysteine is tentatively explained taking into account their structures. It is suggested that nickel detoxication by chelate ligands depends on the inert character rather than on the thermodynamic stability of the relevant nickel complex.

The effect of penicillamine, hypotaurine, epinephrine and sodium metabisulfite, on bovine in vitro fertilization

The effect of penicillamine, hypotaurine, epinephrine and sodium metabisulfite, on bovine in vitro fertilization

Oral cadmium chloride intoxication in mice: effects of penicillamine, dimercaptosuccinic acid and related compounds.

The antidotal efficacies of chelators during acute cadmium intoxication has previously been examined in experiments where both a soluble cadmium salt and the chelator were administered parenterally. In the present study, PA, DMSA and related compounds were studied as oral antidotes during oral CdCl2 intoxication. According to the antagonistic effects noted on mortality, peristaltic toxicity and intestinal cadmium uptake, the relative efficacies of the compounds tested were: DMSA greater than PAD greater than DMPS greater than MSA greater than PA greater than NAPA. None of the chelators induced major changes in the organ distribution of absorbed cadmium, in particular no increased cerebral deposition of cadmium. This study indicates that, in oral cadmium intoxication in humans, orally administered DMSA would be likely to offer protection against the local toxicity of cadmium in the gastrointestinal tract as well as to reduce the risk of systemic toxicity of absorbed cadmium.

Effect of penicillamine on luminol-dependent chemiluminescence in human leucocytes

Conference Article| October 01 1988 Effect of penicillamine on luminol-dependent chemiluminescence in human leucocytes RAYMOND C. FRENCH; RAYMOND C. FRENCH *Department of Biochemistry, The Medical College of St Bartholomew's Hospital, London EC1A 7BE, U.K. Search for other works by this author on: This Site PubMed Google Scholar KARL E. HERBERT; KARL E. HERBERT †Department of Rheumatology, The Medical College of St Bartholomew's Hospital, London EC1A 7BE, U.K. Search for other works by this author on: This Site PubMed Google Scholar DAVID L. SCOTT; DAVID L. SCOTT †Department of Rheumatology, The Medical College of St Bartholomew's Hospital, London EC1A 7BE, U.K. Search for other works by this author on: This Site PubMed Google Scholar DAVID PERRETT DAVID PERRETT ‡Department of Medicine, The Medical College of St Bartholomew's Hospital, London EC1A 7BE, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1988) 16 (5): 891. https://doi.org/10.1042/bst0160891 Article history Received: April 12 1988 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation RAYMOND C. FRENCH, KARL E. HERBERT, DAVID L. SCOTT, DAVID PERRETT; Effect of penicillamine on luminol-dependent chemiluminescence in human leucocytes. Biochem Soc Trans 1 October 1988; 16 (5): 891. doi: https://doi.org/10.1042/bst0160891 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1988 Biochemical Society1988 Article PDF first page preview Close Modal You do not currently have access to this content.

Effects of penicillamine on serum immunoglobulins and immune complex-reactive material in primary biliary cirrhosis

Although penicillamine is used in the treatment of primary biliary cirrhosis, its mechanism of action in this disease is unknown. As an immunologic action had been attributed to the drug, we investigated whether penicillamine might alter serum immunoglobulin levels or immune complex-reactive material in patients with primary biliary cirrhosis. Immunoglobulin levels and immune complex reactivity were measured and clinical tests were performed in 53 consecutive patients entering a double-blind randomized trial of 750 mg vs. 250 mg of penicillamine. Measurement of immune complex reactivity was determined by laser nephelometry, 125I-C1q binding, and Raji cell assays. Immune complex reactivity was detected by at least one assay in 75% of patients tested before treatment. Sixty-two percent were positive in the C1q assay, 28% in the Raji cell assay, and 39% by nephelometry. After therapy with either dose, we found no change in immune complex-reactive material by any assay. Concentrations of immunoglobulins G and M fell (p < 0.05) after 12 mo of therapy. Concentrations of immunoglobulin A decreased (p < 0.05) only in the high-dose group. Correlation was not consistent between results of immune complex assays and clinical liver tests. Although immunoglobulin levels fell during penicillamine therapy, no decrease in immune complex-reactive material was detected. The effect of penicillamine in primary biliary cirrhosis is not mediated through alteration of immune complex-reactive material.

Effect of penicillamine on blood levels and urinary excretion of gold.

Effect of penicillamine on blood levels and urinary excretion of gold.

Age-Related Difference in Radioprotective Effect of D-Penicillamine

D-Penicillamine, previously suspected to have a beneficial effect on the occurrence of severe retrolental fibroplasia among very low birth weight infants, was tested to determine the extent to which this drug modifies acute radiosensitivity on 3- to 4-day-old mice in comparison with adult animals. It was found that the radioprotective effect of penicillamine, given in doses of 3,000 mg/kg i.p. 60 min before whole-body exposure to 6-10 Gy of 60Co gamma rays, was greater in 3- to 4-day-old mice than in adult animals. These data seem to be compatible with the view that D-penicillamine, by virtue of its antioxidant action, may reduce the toxic effects associated with exposure of the newborn infant to hyperoxia, specifically retrolental fibroplasia and bronchopulmonary dysplasia.

An examination of various mechanisms for ethanol-induced testicular injury: studies utilizing the isolated perfused rat testes.

The effect of ethanol, acetaldehyde, and acetate upon testicular production of testosterone was studied utilizing the isolated perfused rat testes. In addition, effects of 4-methylpyrazole (an inhibitor of alcohol dehydrogenase) and methylene blue (a proton acceptor) were evaluated alone and with addition of ethanol. Finally, the effect of penicillamine (a drug that forms a Schiff base with acetaldehyde) alone and with the addition of acetaldehyde to the perfusion medium was assessed. No changes in testicular light microscopic appearance and ATP content were noted as a result of the 2 h of perfusion. Testosterone production by the isolated perfused testes was reduced in a dose-related manner by the addition of ethanol over a range of concentrations from 50–150 mg/dl. Moreover, both acetaldehyde and acetate, products of ethanol and acetaldehyde metabolism, respectively, also inhibited testicular production of testosterone. In contrast, the addition of 4-methylpyrazole or methylene blue to the perfusion medium did not alter testosterone production significantly when compared to control perfusions without these additives. Both agents however, completely prevented the adverse effects of ethanol upon testosterone production. Finally, penicillamine was found to prevent completely the reduction of testosterone production associated with the addition of acetaldehyde to the perfusate. From these results we conclude that 1) ethanol is a gonadal toxin; 2) acetaldehyde and acetate can reduce testosterone production by the isolated perfused rat testes; and 3) the toxic effects of these materials can be prevented by the addition of drugs known to inhibit alcohol dehydrogenase activity, prevent redox changes, or form Schiff bases with acetaldehyde.

The effect of penicillamine and 2,3-dimercaptosuccinic acid on urinary excretion and tissue distribution of gold.

In order to study interactions in vivo between Au+ and SH-containing agents, groups of mice were given 35 mumol/kg of radiolabelled [195Au] thiomalate (Myocrisin) intramuscularly. The administration of Myocrisin is known to result in protein-bound gold and free thiomalate (mercaptosuccinate). High doses of dimercaptosuccinate (1 mmol/kg daily) increased the urinary excretion of radiolabelled gold [195Au] for several days. Treatment for 7 days with 1 mmol/kg of penicillamine or dimercaptosuccinate reduced the blood and kidney levels of gold to 30--50% of the controls. The oral administration of penicillamine in high doses, 1--10 mmol/kg, increased significantly the urinary excretion of [195Au] the first day after the Myocrisin injection, but on the subsequent days the radio-metal excretion was unaffected by the treatment. A lower dose level of penicillamine (0.3 mmol/kg daily) gave rise to only a small and insignificant increase in the urinary excretion of gold. The present results indicate that penicillamine at low clinical doses is an inefficient chelator of gold, while high doses (presumably comparable to about 1 200 mg daily in humans) may mobilize certain amounts of the metal deposits.

The Effect of Penicillamine on Radiation-Induced Pulmonary Lethality in Mice

The collagen inhibitor D-penicillamine was evaluated as a potential radiation reaction preventive agent by studying its effect on deaths attributed to pulmonary damage in mice. Long-term administration of D-penicillamine at a rate of 100 mg/kg/day had no significant effect on the LD50/160 in mice following pulmonary irradiation.

MECHANISM OF ACTION OF PENICILLAMINE IN THE TREATMENT OF AVIAN MUSCULAR DYSTROPHY *

Penicillamine, a cysteine analog with a reduced sulfhydryl group, has been used in this laboratory for the treatment of hereditary avian dystrophy. The drug delays the onset of symptoms and alleviates the debilitating aspects of the disease. To study the mechanism of drug action, the effects of penicillamine on white and red muscles of dystrophic chickens were examined with regard to the specific activities of the soluble enzymes glyceraldehyde-3-phosphate dehydrogenase, acetylphosphatase, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, glutathione reductase, glutathione preoxidase, superoxide dismutase, and catalase. The sulfhydryl contents of the soluble proteins and the concentration of myoglobin were also determined. In white dystrophic muscle (pectoral), there were large alterations in the various enzymatic activities compared to normal levels. In the DISCUSSION, these changes are related to the pathogenesis of the disease and to the adaptive response for protection of the severely affected fast fibers. Red dystrophic muscles (thigh) were minimally involved, in accordance with the known sparing action of the slow fiber type. The results suggested that the disease process in dystrophic muscle may be due to oxidation of the essential sulfhydryl groups of proteins. Penicillamine may produce therapeutic effects by altering the intracellular redox status, thereby promoting better regulation of enzymatic activity, membrane stability, and improved muscle function.

The Effect Of Penicillamine On Blood Pressure And Vascular Disease In Mice With Infarct-Kidney Hypertension

Treatment with penicillamine was capable of bringing down the elevated systemic arterial pressure in the thymus-dependent phase of infarct-kidney hypertension in mice; a marked improvement in the clinical condition of the treated animals was observed as compared with untreated hypertensive mice. No pathological changes in either kidney or heart could be attributed to toxic side effects of penicillamine either in normotensive or in hypertensive mice treated for several months with penicillamine. It is concluded that penicillamine may have an effect on thymus-dependent reactions, such as the increased blood pressure in the chronic phase of infarct-kidney hypertension in mice. In mice, the treatment can be extended over a considerable part of the animal's life span without apparently giving rise to toxic side effects on vital organs.

The effect of penicillamine on immune complexes and immunoglobulins in primary biliary cirrhosis

The effect of penicillamine on immune complexes and immunoglobulins in primary biliary cirrhosis

Effects of Penicillamine and Hydroxyquinoline on Absorption of Orally Ingested 65Zinc in the Rat

The influence of high doses of 2 chelating agents, D-penicillamine and iodochlorohydroxyquin, on the metabolism of orally ingested 65 Zn was studied on rats by means of whole body counting assay technique. Both drugs were found to increase zinc absorption in a dose-dependent way to values significantly above those of the untreated control group. At identical doses D-penicillamine had a significantly stronger enhancing effect than the 8-hydroxyquinoline derivate, except for the highest dosage which was 100 mg daily. The turnover of the absorbed 65Zn fraction was followed during the time of observation which was 11 days. The elimination rate was practically identical in all experimental groups, except for the 100 mg D-penicillamine group in which the biological half-life of 65Zn was significantly decreased as compared to the control group.

Metabolism of airborne particulate lead in continuously exposed rats: Effect of penicillamine on mobilization

Sprague-Dawley rats of both sexes were exposed to airborne particulate lead at a level of about 20 μg/m3 for periods up to 15 months. Blood lead plateaued at a level of about 26 μg/100 ml within 5 months, as compared to a nearly constant level of 4 μg/100 ml in the controls. On discontinuance of the exposure, the blood lead fell (within 3 months) to a level of about 6 μg/100 ml; treatment with penicillamine (20 mg/kg, twice daily, 5 days per week for 6 weeks) greatly accelerated the rate of decline of this parameter. Urinary and fecal outputs of lead (as micrograms/day) in the treated animals during the exposure period exceeded those in the controls by about 100–300%. There was little increase in tissue lead between the sixth and fifteenth months of exposure; however, in femur the increase during this period was nearly 70%. The level of exposure in these experiments, in terms of micrograms per cubic meter of air far exceeded the yearly mean in most American cities (1–3 μg/m3).