Penicillamine Research Articles

Joint toxic action of binary mixtures of osteolathyrogens at malformation‐inducing concentrations for Xenopus Embryos

The joint action of binary mixtures of the osteolathyrogens semicarbazide (SC), beta-aminopropionitrile (beta APN) and penicillamine (PNC) were determined at malformation-inducing concentrations for Xenopus embryos. Tests were static with renewal every 24 h for the 96-h test period. Simultaneous tests on each individual component of the binary mixtures alone gave baseline malformation data (EC50) for joint action analyses. Toxic unit analysis and isobole diagrams were used to determine the type of joint action for 3:1, 1:1 and 1:3 mixtures of each combination. The joint action was concentration additive (strictly additive) for SC with beta APN and response additive (less-than-additive) for SC with PNC and beta APN with PNC. The joint actions were not changed when only osteolathyrogenic lesions, rather than all types of malformations, were considered. The different specific location and character of PNC lesions, as opposed to those for SC and beta APN, may signify a different type of osteolathyrogenic effect for PNC. The mixture testing approach has potential value in determining compounds that act similarly.

Treatment of the eosinophilia-myalgia syndrome

The eosinophilia-myalgia syndrome (EMS) is a unique entity associated with products that contain l-tryptophan (L-trp). Studies of the underlying etiopathogenic processes are underway. EMS is a distinct syndrome, but shares features with eosinophilic fasciitis and other variants of systemic sclerosis. A wide spectrum of clinical manifestations has been described, but there is no consensus regarding treatment. We report the clinical and laboratory features of 12 patients. All were treated with nonsteroidal antiinflammatory drugs (NSAIDs) and analgesics with transient or minimal effect. Two received d-penicillamine (DP) and colchicine, with minimal improvement; one had no response to azathioprine (AZA). Eleven received corticosteroids and had improvement of general symptoms, arthralgias, arthritis, myalgias, skin changes, eosinophilia, and leukocytosis. Nevertheless, all but the latter two findings recurred when corticosteroids were tapered. Seven patients who were unresponsive to the former treatments received low-dose pulse oral methotrexate. Six exhibited continued improvement after a mean follow-up of 4.5 months, with good drug tolerance. Corticosteroids were tapered and, in some instances, discontinued without relapse or complications. One patient improved but later died of aspiration pneumonia. We conclude that methotrexate (MTX) is a therapeutic alternative for patients with severe or refractory EMS.

Triethylene-Tetramine(Trien) Therapy for Wilson's Disease.

Triethylene tetramine (trien), in increasing dose from 1.0-2.0 g/day to 2.5-3.0 g/day, was used for 4 Japanese patients with Wilson's disease who were intolerant of D-penicillamine (D-PC). Before the treatment, urinary copper excretion (UCE) was 70-96 micrograms/day. UCE increased to 1,512-2,352 micrograms/day on the day of initial administration, and remained at levels between 350-1,100 micrograms/day, thereafter. During 2 months of trien therapy, neurological deficits regressed in three patients, and only slightly in one patient. No adverse effects were observed. These results and the retrospective survey on 17 patients treated with D-PC confirmed that trien is less potent but a safer copper chelating agent than D-PC. The transient aggravation of neurological deficits seen in two patients during the early stage of the treatment suggested that trien, as D-PC, should be started in small doses and gradually increased.

Effect of some arsenic antagonists on the toxicity, distribution and excretion of arsenite and arsenate in rats

1. Arsenite and arsenate poisoned rats were treated with either BAL (2,3-dimercapto-1-propanol), penicillamine (PA) (β-β dimethyl cystein) or selenium (Se) (as sodium selenite). 2. The minimal dose of each antagonist that treated arsenic-induced lethality (causing 100% survival) was the same for both arsenite and arsenate. 3. Arsenic mobilization from the tissues (blood, kidney, liver, lungs, spleen, muscles, brain, heart) and its excretion in urine and feces were higher in arsenite-intoxicated animals than in arsenate-intoxicated ones. 4. The effect of each antagonist, when injected alone, on the urinary and fecal excretion of endogenous metals (Cu, Zn, Fe, Ca and Mg) was also examined. 5. The results indicated marked differences in the relative ability of BAL, PA and Se to increase the excretion of the metals.

Beneficial effects of zinc supplementation during chelation treatment of lead intoxication in rats

The ability of zinc to enhance the efficacy of commonly used chelating drugs in lead intoxication and to reduce the resulting zinc imbalance, was investigated in rats. The simultaneous zinc supplementation increased urinary lead elimination by calcium disodium ethylenediaminetetraacetate (Ca disodium EDTA) and 2,3 dimercaptosuccinic acid (DMSA). Combination therapy was also effective in potentiating the depletion of blood, hepatic and renal lead by calcium disodium EDTA and d-penicillamine (DPA), renal lead by DMSA and reveresed of inhibited blood δ-aminolevulinic dehydratase (ALAD) activity by calcium disodium EDTA and DPA. The body zinc status was also maintained as reflected by urinary, blood and tissue levesl of zinc.

The comparative efficacy and toxicity of second‐line drugs in rheumatoid arthritis results of two metaanalyses

We performed 2 metaanalyses of placebo-controlled and comparative clinical trials to examine the relative efficacy and toxicity of methotrexate (MTX), injectable gold, D-penicillamine (DP), sulfasalazine (SSZ), auranofin (AUR), and antimalarial drugs, the second-line drugs most commonly used to treat rheumatoid arthritis (RA). For the efficacy study, we applied a set of inclusion criteria and focused on trials which provided information on tender joint count, erythrocyte sedimentation rate, or grip strength. We found 66 clinical trials that contained 117 treatment groups of interest, and for each drug, we combined the treatment groups. For each outcome, results showed that AUR tended to be weaker than other second-line drugs. The results of the 3 outcome measures were synthesized into a composite measure of outcomes, and AUR was significantly weaker than MTX (P = 0.006), injectable gold (P less than 0.0001), DP (P less than 0.0001), and SSZ (P = 0.009) and was slightly, but not significantly, weaker than antimalarial agents (P = 0.11). We also found heterogeneity among antimalarial agents, in that patients treated with chloroquine did better than those treated with hydroxychloroquine. We found little difference in efficacy between MTX, injectable gold, DP, and SSZ. A power analysis showed that a trial should contain at least 170 patients per treatment group to successfully differentiate between more effective and less effective (e.g., AUR) second-line drugs. None of the reported interdrug comparative trials we reviewed were this large. For the toxicity study, our inclusion criteria captured RA trials which reported the proportion of patients who discontinued therapy because of drug toxicity and the total proportion who dropped out. We found 71 clinical trials that contained 129 treatment groups. The average proportion who dropped out and the average proportion who dropped out because of drug toxicity were computed for each drug. Overall, 30.2% of the patients in these trials dropped out; 50% of them did so because of drug toxicity. Injectable gold had higher toxicity rates (P less than 0.05) and higher total dropout rates (P less than 0.01) than any other drug; 30% of gold-treated patients dropped out because of side effects versus 15% of all trial patients. Antimalarial drugs and AUR had relatively low rates of toxicity; the rate for MTX was imprecise because of discrepancies between trials. Thus, of the commonly used second-line drugs, AUR is the weakest, and injectable gold is the most toxic. Agents introduced in the future will be compared with these drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

D-Penicillamine-induced copper deficiency in suckling mice: neurological abnormalities and brain mitochondrial enzyme activities

Brain mitochondrial enzyme activities were examined in 15-day-old suckling mice which were daily injected with d-penicillamine (DP), a chelating agent of copper. Newborn mice treated with DP (1 g/kg/day) showed retarded weight gain, hyperelasticity of skin, and a bizarre forelimb posture with subcutaneous edema on experimental day (ED) 7. Paraparesis or dragging of the hindlimbs was observed by ED 15. Brain copper contents of DP-treated mice decreased to 34% of the controls on ED 15. Cytochrome c oxidase activity (complex IV) in the brain showed 51% decrease of the controls, on the contrary, rotenone-sensitive NADH cytochrome c reductase (complex I + III) and succinate cytochrome c reductase (complex II + III) were normal. Histochemistry of cytochrome c oxidase in the cerebellum of DP-treated mice disclosed diffuse reduction of staining, especially in Purkinje cells. These data show that DP-induced copper deficiency in the brain subsequently disturbs mitochondrial electron transport system, selectively cytochrome c oxidase activity. This seems to be a useful animal model not only for Menkes' kinky hair disease but also for mitochondrial encephalomyopathy.

Penicillamine may have a niche

Penicillamine may have a niche

Addition of hypotaurine can reactivate immotile golden hamster spermatozoa.

Hamster epididymal spermatozoa became virtually immotile following washing and dilution in chemically defined medium (TLP-PVA). The sperm motility factors (penicillamine, hypotaurine, and epinephrine: PHE) were examined for their ability to reactivate immotile sperm. Sperm could be reactivated by addition of PHE at 1 h of incubation. Hypotaurine alone was capable of reactivating sperm motility, but epinephrine and penicillamine together were not. However, overall sperm motility and percentage of motile sperm during incubation were higher when PHE components were used in combination than when hypotaurine was used alone. Addition of hypotaurine to immotile sperm suspensions could be postponed for up to 6 h with subsequent recovery of sperm motility, although the degree of recovery of motility declined progressively with each hour that addition of hypotaurine was delayed. The rescuing effect of hypotaurine was due to an increase both in the percentage of motile sperm and in the quality (grade) of sperm motility. The data show that hypotaurine is required for expression of sperm motility in the hamster, and support the concept that the loss of hypotaurine from sperm following washing and dilution is responsible for the sperm-immobilizing effect of these procedures. Additionally, the data demonstrate that hamster sperm can remain viable for several hours after becoming immotile, and that many of the immotile sperm are capable of being reactivated.

Effect of N‐Acetyl‐cysteine, D‐Penicillamine and Buthionine Sulfoximine on Glutathione Levels and CNS Oxygen Toxicity in Rats

The effect of glutathione (GSH) synthesis modulators - L-buthionine sulfoximine (BSO), N-acetyl cysteine (NAC) and D-penicillamine (DPA) - on the susceptibility of rat CNS to O2 toxicity was investigated. The animals were given 5% sucrose or 40 mM solutions of BSO, NAC or DPA in 5% sucrose as drinking water for one week and sacrificed prior to or after exposure to 4.5 ATA O2. The GSH content in brain, liver, lung and blood, and the activity of glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glucose-6-phosphate dehydrogenase (G-6-PD) and superoxide dismutase (SOD) in brain and lungs were measured. The brain GSH content and the enzyme activities were not changed by any of the drugs. BSO decreased the GSH content in all the other tissues; NAC and DPA treatments increased the GSH content in lungs, blood and/or liver. The CNS toxicity threshold as measured by the time of appearance of first electrical discharge (FED) on ECoG recording was not changed by NAC or DPA, but BSO brought about a significant delay in FED time. It is suggested that increased extracerebral GSH levels do not protect against CNS oxygen toxicity, and that BSO provides some protection, probably via a glutathione-independent mechanism.

Ｄ‐ｐｅｎｉｃｉｌｌａｍｉｎｅのヒト血管内皮細胞および滑膜線維芽細胞に対する影響

The effect of D-penicillamine (D-P) on proliferation of human endothelial cells (ECs) and synovial fibroblastic cells (SFCs) was examined. D-P inhibited DNA synthesis of both ECs and SFCs in the presence of copper sulfate. Inhibition of DNA synthesis occurred in a dose-dependent fashion and a significant inhibition was attained at 60 μM D-P, a level which is attained in the serum of treated patients. Similar inhibition was observed by other thiols but not by disulfides. D-P, in vitro, produced hydrogen peroxide in the presence of copper sulfate. As the inhibition observed by D-P and copper sulfate was reversed almost to the control level by simultaneous addition of catalase and horseradish peroxide, it is suggested that inhibition of EC and SFC DNA synthesis is due to the action of hydrogen peroxide produced by D-P and cupric ion.D-P, therefore, may suppress the growth of pannus and synovial fibrosis by inhibition of synovial vessel growth and SFC proliferation and in this way, may reduce rheumatoid inflammation.

The effects of D-penicillamine on the renal and liver functions in neonates and the in vitro influence on granulocytes.

D-Penicillamine (DPA) was introduced to treat neonatal hyperbilirubinemia 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 phagocytic and intracellular killing activation of human peripheral blood granulocytes. Our data concerning the renal and liver functions before and after 3 to 4 days DPA treatment reveal that the drug does not produce any pathological change during short-term administration in the neonatal period. Furthermore, it was found that superoxide anion generation was slightly increased, and beta-glucuronidase release markedly increased by preincubation with DPA at concentrations of 0.5-5 mM. The rise was directly proportional to the concentration in the examined range. On the other hand, none of the examined DPA concentrations influenced the phagocytic or killing activity of neutrophils.

Little to differentiate between sulfasalazine and penicillamine in RA

Little to differentiate between sulfasalazine and penicillamine in RA

Induction of anticentromere antibody in patients receiving treatment with D-penicillamine.

Anticentromere antibody (ACA) was previously described as a specific marker for CREST, progressive systemic sclerosis (PSS), scleroderma (SCL), Raynaud's phenomenon (RP) and primary biliary cirrhosis (PBC). In this present investigation ACA was observed appearing and disappearing due to D-penicillamine (DPA) treatment in 7 patients without any features of CREST, PSS, SCL, RP or PBC. HLA-DR3 was found in 5/7 of these patients. DPA induced ACA should be added to adverse immunologic drug reactions.

Influence of triethylenetetramine and D-penicillamine on zinc metabolism in mice.

Triethylenetetramine (TETA) is a copper chelator used in the treatment of Wilson’s disease. It is applied primarily to patients with adverse reactions to D-penicillamine (DPA) (Walshe 1973). DPA influences the metabolism of the essential trace element zinc (Klingberg et al 1976). Several adverse effects including teratogenicity may be caused by the zinc depletion. It was also suggested that the teratogenicity of TETA may be due at least partly through induction of zinc toxicity (Keen et al 1983). However, the affinity of TETA for zinc in vivo was not systematicaly investigated.

In vitro induction of acantholysis by addiction of piroxicam, captopril and D-penicillamine to human keratinocytes cultured on dead deepidermized dermis

In vitro induction of acantholysis by addiction of piroxicam, captopril and D-penicillamine to human keratinocytes cultured on dead deepidermized dermis

Effect of sulphydryl drugs on paracetamol-induced hepatotoxicity in mice.

It has been shown that the major in vivo biotransformation of thiol-containing drugs such as captopril (CP) and penicillamine (PA) involve mixed disulphide formation with endogenous thiols derived from cysteine. At high doses, both drugs produced a dose-dependent depletion of glutathione (GSH) and may perturb GSH and related GSH-enzymes. In this study the possible interactions of these drugs with paracetamol, which produce hepatotoxicity after GSH depletion, were investigated. Following co-administration of CP (50-250 mg/kg) or PA (43-257 mg/kg) with paracetamol (300 mg/kg), the hepatotoxic effect produced by paracetamol was diminished. The protective effect was comparable to that produced by N-acetylcysteine (500 mg/kg) and L-cysteine (500 mg/kg). However, pre-treatment with buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, abolished the protective effects of CP, N-acetylcysteine and L-cysteine while the protective effect of PA was unaffected. This suggests that, although both CP and PA may act as alternative sulphydryl nucleophiles to GSH to prevent arylation of essential cellular macromolecules by the reactive metabolite of paracetamol, the underlying mechanisms of these drug interactions may be distinctly different.

Temporal patterns of response to D-penicillamine, hydroxychloroquine, and placebo in juvenile rheumatoid arthritis patients.

We calculated the time required for therapeutic benefit to become apparent following initiation of treatment with D-penicillamine (DP), hydroxychloroquine (HCQ), or placebo (each administered concomitantly with a nonsteroidal antiinflammatory drug) using data from a double-blind, randomized 12-month trial in 162 patients with juvenile rheumatoid arthritis. Using previously published criteria to classify the outcome, we found that 60% of the HCQ group, 46% of the DP group, and 39% of the placebo group responded favorably after 12 months of therapy. Data from examinations between the initial and final assessments were used to determine when the response first occurred. Approximately 50% of all patients who showed improvement at 12 months had already done so by 2 months. After 6 months, 96% of the DP group, 88% of the HCQ group, and 85% of the placebo group responders had met the criteria for response. The average time until response was attained was 105 days for the DP group, 129 days for the HCQ group, and 140 days for the placebo group. Our results indicate that a favorable response to these slow-acting antirheumatic drugs is unlikely if improvement has not occurred within the first 6 months of therapy.

Suppression of human fibroblast proliferation by D-penicillamine and copper sulfate in vitro.

We examined the effect of D-penicillamine (DP) and copper sulfate (CuSO4) on human fibroblast proliferation in vitro. DP plus CuSO4 inhibited both basal and interleukin-1 (IL-1)-induced tritiated thymidine incorporation into fibroblasts in a dose- and time-dependent manner. Significant inhibition was observed at the level of 60 microM in the presence of 4 microM CuSO4. At this range of concentrations, which is attained in serum and in tissues of treated patients, DP alone or CuSO4 alone did not affect fibroblast proliferation. Similar inhibition was observed with various thiols in the presence of copper, but not with disulfides such as DP disulfide or oxidized glutathione. Inhibition of fibroblast DNA synthesis induced by DP and CuSO4 was reversed by the simultaneous addition of catalase or horseradish peroxidase, but not by boiled catalase or superoxide dismutase. The inhibition by DP and CuSO4, therefore, may be attributable to hydrogen peroxide produced by these 2 agents. DP, in the presence of CuSO4, did not affect IL-1 secretion from human peripheral mononuclear phagocytes. These observations indicate that hydrogen peroxide produced by DP plus CuSO4 inhibits IL-1-induced fibroblast proliferation by directly affecting fibroblasts, without alteration of IL-1 secretion from mononuclear phagocytes. Thus, DP may play a role in inhibiting the growth of rheumatoid pannus and excessive collagenation in scleroderma by direct inhibition of fibroblast proliferation.

NEPHROPATHY FROM PENICILLAMINE TREATMENT FOR RHEUMATOID ARTHRITIS.

To clarify the natural course of penicillamine nephropathy, Hall and colleagues prospectively studied 33 patients with rheumatoid arthritis who