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Toxicology Mechanisms and Methods Nov 2020Copper storage disease occurs in multiple dog breeds and is one of the most common causes of chronic hepatitis in this species. The disease is caused by hereditary...
Copper storage disease occurs in multiple dog breeds and is one of the most common causes of chronic hepatitis in this species. The disease is caused by hereditary defects in copper metabolism in conjunction with high dietary copper levels. The progressive copper accumulation leads to hepatitis, cirrhosis, and eventually death if left untreated. Copper chelators are critical in modulating the effects of this disease. It is therefore of significant practicality to understand the pharmacokinetic (PK) parameters of chelating agents, particularly since they are oftentimes quite expensive. A liquid chromatography-tandem mass spectrometric (LC/MS/MS) method was developed to measure plasma levels of one of the most common chelators, d-penicillamine. The compound was discovered to exist in two forms, monomeric and dimeric, and various chemical derivatizations were tried to force the compound into one form or the other. Eventually, the simplest approach was individual determination of penicillamine and its dimer, with summation of the two quantities. This enabled determination of canine PK parameters for penicillamine based on comparison of oral and intravenous administration of the drug, including time to maximum drug level (Tmax), concentration at maximum (Cmax), clearance (Cls) and volume of distribution (Vdss). The drug was found to exist predominantly in the dimeric form in plasma, which is incapable of chelating copper owing to lack of free sulfhydryl groups and must therefore provide a storage form of the drug in equilibrium with its monomeric form . Mechanisms are discussed for the electrospray-induced fragmentation of penicillamine as well as of its dimer.
Topics: Administration, Intravenous; Administration, Oral; Animals; Chelating Agents; Chromatography, Liquid; Dogs; Drug Monitoring; Female; Male; Models, Biological; Penicillamine; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 32854553
DOI: 10.1080/15376516.2020.1814467 -
Therapie 1967
Review
Topics: Hepatolenticular Degeneration; Humans; Liver Diseases; Penicillamine
PubMed: 4863259
DOI: No ID Found -
Zeitschrift Fur Rheumatologie 1988The present paper reviews the different therapeutic uses of D-penicillamine and outlines the dosage regimen of D-penicillamine for treatment of rheumatoid arthritis.... (Review)
Review
The present paper reviews the different therapeutic uses of D-penicillamine and outlines the dosage regimen of D-penicillamine for treatment of rheumatoid arthritis. While many open clinical trials are published, only a few controlled, double-blind studies investigate the "optimal" dosing of D-penicillamine. From these findings, a uniform regimen cannot be named but the heterogenous appearance of chronic polyarthritis requires an individual therapy. In order to minimize the risk of side effects, however, it is necessary to follow the guideline "go low--go slow" as postulated by Jaffe.
Topics: Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Penicillamine
PubMed: 3063002
DOI: No ID Found -
Orvosi Hetilap Nov 1991D-penicillamine was introduced to treat neonatal hyperbilirubinaemia in 1973 and to prevent retinopathy of prematurity in 1980. In this study we investigated the renal... (Review)
Review
D-penicillamine was introduced to treat neonatal hyperbilirubinaemia in 1973 and to prevent retinopathy of prematurity in 1980. In this study we investigated the renal and liver functions of neonates treated with DPA and the in vitro effect of the drug on superoxide anion generation and beta-glucuronidase release as well as on phagocytic and intracellular killing activation on human peripheral blood granulocytes. Our data concerning the renal and liver functions before and after 3 to 4 days DPA treatment reveal no pathological change during short-term administration in the neonatal period. Furthermore, none of the examined DPA concentrations influenced the phagocytic or killing activity of neutrophils.
Topics: Humans; Hyperbilirubinemia; In Vitro Techniques; Infant, Newborn; Kidney; Liver; Penicillamine; Phagocytes; Retinopathy of Prematurity
PubMed: 1945383
DOI: No ID Found -
Rheumatology and Rehabilitation Nov 1977D-Penicillamine alters the normal metabolism of collagen by inhibiting cross-linking and protein synthesis. This could affect wound healing, accelerate skin thinning and...
D-Penicillamine alters the normal metabolism of collagen by inhibiting cross-linking and protein synthesis. This could affect wound healing, accelerate skin thinning and possibly exaggerate the osteoporosis of rheumatoid disease. The mean time to wound healing after 42 orthopaedic surgical operations in 21 patients treated with penicillamine was 19.8 (+/- 13.1) days. Compared with an earlier study, these results suggest that the drug has a comparable effect on would healing to corticosteroids given for three years. Skinfold thickness over the fourth metacarpal of the dominant hand was measured in 28 cases before and during penicillamine treatment. There was a significant decrease both in the first and second four-month periods of treatment (P less than 0.005 and P less than 0.01). Corticosteroids in constant dose did not have an additive effect. In view of the wound healing findings the significance of these results must await further sequential measurements. The normal progression of osteoporosis over three years was documented in 70 patients who had not received penicillamine. Penicillamine reversed this trend in 35 patients after one year of treatment (P less than 0.005). The results confirm that the osteoporosis is related to disease severity rather than drug therapy.
Topics: Arthritis, Rheumatoid; Arthroplasty; Humans; Osteoporosis; Penicillamine; Postoperative Care; Skinfold Thickness; Wound Healing
PubMed: 601432
DOI: 10.1093/rheumatology/16.4.223 -
Lancet (London, England) Jul 1975
Topics: Humans; Kidney Diseases; Penicillamine; Rheumatic Diseases
PubMed: 49668
DOI: 10.1016/s0140-6736(75)90516-4 -
Agents and Actions Nov 1990The transformation of D-penicillamine (D-pen) was studied in orally- and intravenously-dosed rats and in human plasma in vitro. In each case, low molecular weight (LMW)...
The transformation of D-penicillamine (D-pen) was studied in orally- and intravenously-dosed rats and in human plasma in vitro. In each case, low molecular weight (LMW) metabolites (previously identified as disulphides) and a mixed disulphide between D-pen and albumin (D-pen-protein) formed. The rates of D-pen elimination, other than through protein conjugation, were comparable in the rat groups to the rate of oxidation to LMW metabolites in vitro. The rates of transformation to D-pen-protein were also comparable in the in vitro preparations and in orally-treated rats. These qualitative and quantitative similarities suggest blood plasma may be an important site of transformation in vivo. Extracellular oxidation of D-pen may be linked to its antirheumatic action, either through reduction of oxygen species or through formation of D-pen-protein disulphides at surfaces of mononuclear leukocytes.
Topics: Administration, Oral; Animals; Biotransformation; Disulfides; Humans; Injections, Intravenous; Kinetics; Male; Molecular Weight; Penicillamine; Rats; Rats, Inbred Strains; Serum Albumin
PubMed: 2085148
DOI: 10.1007/BF01997631 -
European Journal of Drug Metabolism and... 1988Radiolabelled [35S]-D-penicillamine was administered orally to DA-strain rats. After 72 hours approximately 65% of the dose was excreted with no significant differences...
Radiolabelled [35S]-D-penicillamine was administered orally to DA-strain rats. After 72 hours approximately 65% of the dose was excreted with no significant differences between male and female animals. The major urinary product was inorganic sulphate with small amounts of D-penicillamine. Penicillamine disulphide, penicillamine-cysteine, S-methyl penicillamine and N-acetyl penicillamine were also found as metabolites. The female rat excreted significantly less sulphate (P less than 0.1) and more penicillamine disulphide (P less than 0.01) than the male. The residual radioactivity was found in the carcass, with slight concentration in the gut, skin, kidney, bladder and liver.
Topics: Animals; Autoradiography; Chromatography, Paper; Female; Male; Mass Spectrometry; Penicillamine; Rats; Rats, Inbred Strains; Tissue Distribution
PubMed: 3208797
DOI: 10.1007/BF03191310 -
The Journal of Rheumatology. Supplement 1981This paper evaluates the usefulness of different methods for measuring aminothiols and disulfides in biological fluids. The major approaches usually involve liquid or... (Review)
Review
This paper evaluates the usefulness of different methods for measuring aminothiols and disulfides in biological fluids. The major approaches usually involve liquid or gas-liquid chromatography. Techniques tested and currently used by the authors are discussed.
Topics: Chromatography, Gas; Chromatography, Liquid; Chromatography, Thin Layer; Cysteine; Humans; Penicillamine; Radioimmunoassay; Spectrophotometry
PubMed: 7014874
DOI: No ID Found -
Lancet (London, England) Sep 1976A prospective study involving 87 patients was carried out to evaluate the necessity for a high dose of contrast material in addition to delayed computed tomographic (CT)...
A prospective study involving 87 patients was carried out to evaluate the necessity for a high dose of contrast material in addition to delayed computed tomographic (CT) scanning for optimal detection of the lesions of multiple sclerosis in the brain. In patients with either clinically definite multiple sclerosis or laboratory-supported definite multiple slerosis, CT scans were obtained with a uniform protocol. Lesions consistent with multiple sclerosis were demonstrated on the second scan in 54 patients. In 36 of these 54 patients, the high-dose delayed scan added information. These results are quite similar to those of a previous study from this institution using different patients, in whom the second scan was obtained after the bolus injection of contrast material containing 40 g of organically bound iodine. The lack of real difference in the results of the two studies indicates that the increased dose, not just the delay in scanning, is necessary for a proper study.
Topics: Anemia, Aplastic; Arthritis, Rheumatoid; Bone Marrow; Female; Humans; Middle Aged; Penicillamine; Scleroderma, Systemic
PubMed: 60533
DOI: No ID Found