Combined sodium Dimercaptopropanesulfonate and zinc versus D-penicillamine as first-line therapy for neurological Wilson's disease.

BACKGROUND: Even though recent research has achieved significant advancement in the development of therapeutic approaches for Wilson's diseases (WD), the current treatment options available for WD are still limited, especially for WD patients with neurological symptoms. This study is intended to compare the therapeutic approaches for WD patients with neurological symptoms receiving either combined sodium 2, 3-dimercapto-1-propane sulfonate (DMPS) and zinc treatment or D-penicillamine (DPA) monotherapy as first-line therapy, and identify the more effective therapeutic approach. METHODS: The case records of 158 patients diagnosed with neurological WD were retrospectively analyzed. These patients treated with intravenous DMPS + Zinc and in combination with oral zinc as a maintenance therapy (Group 1) or DPA alone (Group 2) for 1 year. During the period of treatment, the neurological symptoms of the patients were assessed using the Global Assessment Scale (GAS) and Barthel index. The key hematological and biochemical parameters of the patients (such as the levels of aminotransferase, serum ceruloplasmin, 24-h urine copper excretion), as well as adverse effects were recorded and analyzed. RESULTS: Ninety-three patients in Group 1, displayed decreased GAS scores and increased Barthel indexes consistently in comparison with the baseline (P < 0.01). Among them, 82 patients (88.2%) exhibited significant neurological improvement after 1 year, while 8 patients (8.6%) experienced neurological deterioration. Among the 65 patients in Group 2, 37 patients (58.5%) exhibited neurological improvements, while 17 patients (26.2%) experienced neurological deterioration after 1-year follow up. Six patients discontinued their treatment midway due to their exacerbating neurological symptoms. A comprehensive comparison of the effectiveness of the two courses of treatment revealed that patients in group 1 demonstrated a higher improvement ratio (P < 0.01) and lower worsening ratio of the neurological symptoms for the patients (P < 0.01) in comparison to the patients in group 2. Meanwhile, renal function, liver enzyme and blood cell counts remained stabilized in group1. CONCLUSIONS: This study indicates that the combined therapeutic approach of DPMS and zinc may be a preferred first-line therapy in treating the neurological symptoms of WD, in comparison to the treatment with DPA.

A case report: Co-occurrence of Wilson disease and oculocutaneous albinism in a Chinese patient.

RATIONALE: Both Wilson disease (WD) and Oculocutaneous Albinism (OCA) are rare autosomal recessive disorders that are caused by mutations on chromosome 13 and chromosome 11, respectively. Here, we report on a patient with coexisting WD and OCA, initially presenting episodes of tremors. PATIENT CONCERNS: WD is a disorder of copper metabolism. The main sites of copper accumulation are the liver and the brain, resulting in hepatic symptoms. OCA is a disorder of melanin biosynthesis, characterized by a generalized reduction in pigmentation of the eyes (oculo-), skin (-cutaneous), and hair. DIAGNOSIS: The diagnosis of WD was confirmed by neurological symptoms, metabolism tests, and MRI scans. Interestingly, the patient also had very light skin color, blond hair and eyebrows, and dark brown eyelashes and irises. Because the association of dermatologic signs in WD has rarely been reported, OCA was highly suspected based on these clinical findings. Genetic analysis was subsequently conducted, and the results revealed the p. (Arg778Leu) mutation in 1 allele and the p. (Asn1270Ser) mutation in the other allele of the ATP7B gene, confirming the diagnosis of WD; the p. (D456fs) mutation in 1 allele and the p. (R299H) mutation in the other allele of the TYR gene, confirming the diagnosis of OCA. The family history was positive for WD with a 14-year-old younger brother also being diagnosed with it. Her parents are negative for OCA and WD. INTERVENTIONS: Sodium dimercaptopropanesulfonate (DMPS) was given during hospitalization. D-penicillamine and zinc sulfate treatment was initiated after discharge for long-term control. OUTCOMES: Postural and intention tremor disappeared, and other symptoms and signs markedly improved after treatment. LESSONS: In this study, we reported on the first case of a child who simultaneously presented WD and OCA, bringing up the possibility of a presumable link between these 2 rare diseases.

Evaluation of efficacy and safety of gandouling plus sodium dimercaptosulphonate in treatment of patients with neurological Wilson's disease from China.

OBJECTIVE: To evaluate the efficacy and safety of gandouling plus sodium dimercaptosulphonate (DMPS) on neurological Wilson's disease (WD) in patients. METHODS: We retrospectively evaluated the clinical records of 125 WD patients with neurological syndromes who were treated with gandouling plus sodium DMPS or DMPS used alone. All patients had a history of neurological deterioration during their diseases courses. The clinical efficacies, adverse reactions, and results of the various hematological and biochemical investigations were recorded for statistical analysis. RESULTS: 92.30% (60 patients) of the WD patients treated with the combined therapy experienced an improved or stable neurological condition paralleled by a significantly improved GAS score. Meanwhile, the WBC and PLT counts stabilized, liver function and renal function were improved or remained stable. The combined therapy also obviously promoted the 24-h urinary copper excretion. In particular, only 30.76% of the WD patients experienced mild adverse reactions, including neurological deterioration in 5 patients (7.69%), hepatic worsening in 1 subject (1.89%), which was less frequently than those in the control group treated with DMPS only. CONCLUSION: Our findings indicate that the safety and efficacy of gandou-ling plus DMPS is superior to those of DMPS used alone in the WD patients with neurological symptoms.

[Healing of Amyotrophic Lateral Sclerosis: A Case Report].

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to death within 3-5 years in most cases. New approaches to treating this disease are needed. Here, we report a successful therapy. CASE REPORT: In a 49-year-old male patient suffering from muscle weakness and fasciculations, progressive muscular atrophy, a variant of ALS, was diagnosed after extensive examinations ruling out other diseases. Due to supposed mercury exposure from residual amalgam, the patient's teeth were restored. Then, the patient received sodium 2,3-dimercaptopropanesulfate (DMPS; overall 86 × 250 mg in 3 years) in combination with α-lipoic acid and followed by selenium. In addition, he took vitamins and micronutrients and kept a vegetarian diet. The excretion of metals was monitored in the urine. The success of the therapy was followed by scoring muscle weakness and fasciculations and finally by electromyography (EMG) of the affected muscles. First improvements occurred after the dental restorations. Two months after starting therapy with DMPS, the mercury level in the urine was increased (248.4 µg/g creatinine). After 1.5 years, EMG confirmed the absence of typical signs of ALS. In the course of 3 years, the patient recovered completely. CONCLUSIONS: The therapy described here is a promising approach to treating some kinds of motor neuron disease and merits further evaluation in rigorous trials.

Chelation therapy in intoxications with mercury, lead and copper.

In the present review we provide an update of the appropriate use of chelating agents in the treatment of intoxications with compounds of mercury, lead and copper. The relatively new chelators meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-propanesulphonate (DMPS) can effectively mobilize deposits of mercury as well as of lead into the urine. These drugs can be administered orally and have relatively low toxicity compared to the classical antidote dimercaptopropanol (BAL). d-Penicillamine has been widely used in copper overload, although 2,3-dimercaptosuccinic acid or tetrathiomolybdate may be more suitable alternatives today. In copper-toxicity, a free radical scavenger might be recommended as adjuvant to the chelator therapy.

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.

Plasma and urine dimercaptopropanesulfonate concentrations after dermal application of transdermal DMPS (TD-DMPS).

2,3-Dimercaptopropane-1-sulfonate (DMPS) is a metal chelator approved in Europe for oral or intravenous use for heavy metal poisoning. Transdermally applied DMPS (TD-DMPS) is used by some alternative practitioners to treat autism, despite the absence of evidence for its efficacy. We found no literature evaluating the pharmacokinetics of the transdermal route of delivery or the ability of TD-DMPS to enhance urinary mercury elimination. We hypothesized that TD-DMPS is not absorbed. Eight adult volunteers underwent application of 1.5-3 drops/kg of TD-DMPS. Subjects provided 12-h urine collections the day before and day of application. Subjects underwent blood draws at 0, 30, 60,90, 120, and 240 min after TD-DMPS application. Plasma and urine were assayed for the presence of DMPS. Urine was assayed for any change in urinary mercury excretion after DMPS. One control subject ingested 250 mg of oral DMPS and underwent the same urine and blood collections and analyses. No subject had detectable urine DMPS or increased urine mercury excretion after TD-DMPS. One subject had detectable levels of DMPS in the 30-min plasma sample, suspected to be contamination. All other samples for that subject and the other seven subjects showed no detectable plasma DMPS. The control subject had detectable urine and plasma DMPS levels and increased urine mercury excretion. These results indicate that TD-DMPS is not absorbed. There was no increase in urine mercury excretion after TD-DMPS. Our results argue that TD-DMPS is an ineffective metal chelator.

Effect of DMPS and DMSA on the placental and fetal disposition of methylmercury.

Methylmercury (CH3Hg+) is a serious environmental toxicant. Exposure to this metal during pregnancy can cause serious neurological and developmental defects in a developing fetus. Surprisingly, little is known about the mechanisms by which mercuric ions are transported across the placenta. Although it has been shown that 2,3-dimercaptopropane-1-sulfonate (DMPS) and 2,3-dimercaptosuccinic acid (DMSA) are capable of extracting mercuric ions from various organs and cells, there is no evidence that they are able to extract mercury from placental or fetal tissues following maternal exposure to CH3Hg+. Therefore, the purpose of the current study was to evaluate the ability of DMPS and DMSA to extract mercuric ions from placental and fetal tissues following maternal exposure to CH3Hg+. Pregnant Wistar rats were exposed to CH3HgCl, containing [203Hg], on day 11 or day 17 of pregnancy and treated 24 h later with saline, DMPS or DMSA. Maternal organs, fetuses, and placentas were harvested 48 h after exposure to CH3HgCl. The disposition of mercuric ions in maternal organs and tissues was similar to that reported previously by our laboratory. The disposition of mercuric ions in placentas and fetuses appeared to be dependent upon the gestational age of the fetus. The fetal and placental burden of mercury increased as fetal age increased and was reduced by DMPS and DMSA, with DMPS being more effective. The disposition of mercury was examined in liver, total renal mass, and brain of fetuses harvested on gestational day 19. On a per gram tissue basis, the greatest amount of mercury was detected in the total renal mass of the fetus, followed by brain and liver. DMPS and DMSA reduced the burden of mercury in liver and brain while only DMPS was effective in the total renal mass. The results of the current study are the first to show that DMPS and DMSA are capable of extracting mercuric ions, not only from maternal tissues, but also from placental and fetal tissues following maternal exposure to CH3Hg+.

MRP2 involvement in renal proximal tubular elimination of methylmercury mediated by DMPS or DMSA.

2, 3-Dimercaptopropane-1-sulfonic acid (DMPS) and meso-2, 3-Dimercaptosuccinic acid (DMSA) are dithiols used to treat humans exposed to methylmercury (CH(3)Hg(+)). After treatment, significant amounts of mercury are eliminated rapidly from the kidneys and are excreted in urine. In the present study, we extended our previous studies by testing the hypothesis that MRP2 mediates the secretion of DMPS or DMSA S-conjugates of CH(3)Hg(+). To test this hypothesis, the disposition of mercury was assessed in control and Mrp2-deficient (TR(-)) rats exposed intravenously to a 5.0-mg/kg dose of CH(3)HgCl. Twenty-four and 28 h after exposure, groups of four control and four TR(-) rats were injected with saline, DMPS, or DMSA. Tissues were harvested 48 h later. Renal and hepatic contents of mercury were greater in saline-injected TR(-) rats than in controls. In contrast, the amounts of mercury excreted in urine and feces by TR(-) rats were less than those by controls. DMPS and DMSA significantly reduced the renal and hepatic content of mercury in both groups of rats, with the greatest reduction in controls. A significant increase in urinary and fecal excretion of mercury (which was greater in the controls) was also observed. Our findings in inside-out membrane vesicles prepared from hMRP2-transfected Sf9 cells show that uptake of DMPS and DMSA S-conjugates of CH(3)Hg(+) was greater in the vesicles containing hMRP2 than in control vesicles. Overall, these dispositional findings indicate that MRP2 does play a role in DMPS- and DMSA-mediated elimination of mercury from the kidney.

Severe iatrogenic bismuth poisoning with bismuth iodoform paraffin paste treated with DMPS chelation.

BACKGROUND: Bismuth iodoform paraffin paste (BIPP) is used for the packing of wound and surgical cavities. Features of both bismuth and iodoform toxicities have been associated with the use of BIPP, but there are no previous reports of 2,3-dimercaptopropane-1-sulphonate (DMPS) chelation therapy for bismuth poisoning secondary to its use. CASE REPORT: A 67-year-old man presented with a pelvic tumor requiring extensive surgical resection. BIPP packing was required post-operatively for surgical wound breakdown. A few days after insertion, the patient developed neurological features of bismuth toxicity (blood and urine bismuth concentrations were 340 microg/L and 2800 microg/L, respectively), which was treated with removal of the BIPP packing and DMPS chelation [27 days of intravenous DMPS (5 mg/kg 4 times daily for 5 days, 5 mg/kg three times daily for 5 days followed by 5 mg/kg twice a day for 17 days) followed by 24 days of oral DMPS (200 mg three times a day for 10 days, followed 200 mg twice daily for 14 days)]. This resulted in improvement in his symptoms and a decline in his pre-chelation bismuth concentration of 480 microg/L to 5 microg/L following chelation. There were no adverse effects during chelation. CONCLUSIONS: DMPS chelation appears to be a potentially effective chelating agent in bismuth toxicity.

Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice.

Chelating therapy has been reported as a useful approach for counteracting mercurial toxicity. Moreover, 2,3-dimercapto-1-propanesulfonic acid (DMPS), a tissue-permeable metal chelator, was found to increase urinary mercury excretion and decrease mercury content in rat brain after methylmercury (MeHg) exposure. We evaluated the capability of DMPS to reduce MeHg-induced motor impairment and cerebellar toxicity in adult mice. Animals were exposed to MeHg (40 mg/L in drinking water, ad libitum) during 17 days. In the last 3 days of exposure (days 15-17), animals received DMPS injections (150 mg/kg, i.p.; once a day) in order to reverse MeHg-induced neurotoxicity. Twenty-four hours after the last injection (day 18), behavioral tests related to the motor function (open field and rotarod tasks) and biochemical analyses on oxidative stress-related parameters (cerebellar glutathione, protein thiol and malondyaldehyde levels, glutathione peroxidase and glutathione reductase activities) were carried out. Histological analyses for quantifying cellular damage and mercury deposition in the cerebellum were also performed. MeHg exposure induced a significant motor deficit, observed as decreased locomotor activity in the open field and decreased falling latency in the rotarod apparatus. DMPS treatment displayed an ameliorative effect toward such behavioral parameters. Cerebellar glutathione and protein thiol levels were not changed by MeHg or DMPS treatment. Conversely, the levels of cerebellar thiobarbituric acid reactive substances (TBARS), a marker for lipid peroxidation, were increased in MeHg-exposed mice and DMPS administration minimized such phenomenon. Cerebellar glutathione peroxidase activity was decreased in the MeHg-exposed animals, but DMPS treatment did not prevent such event. Histological analyses showed a reduced number of cerebellar Purkinje cells in MeHg-treated mice and this phenomenon was completely reversed by DMPS treatment. A marked mercury deposition in the cerebellar cortex was observed in MeHg-exposed animals (granular layer>Purkinje cells>molecular layer) and DMPS treatment displayed a significant ameliorative effect toward these phenomena. These findings indicate that DMPS displays beneficial effects on reversing MeHg-induced motor deficits and cerebellar damage in mice. Histological analyses indicate that these phenomena are related to its capability of removing mercury from cerebellar cortex.

Increase of renal excretion of organo-mercury compounds like methlymercury by DMPS (2,3-Dimercapto-1-propanesulfonic acid, Dimaval).

In a highly mercury-burdened, small scale gold mining area in the Philippines, spontaneous urine samples were taken from 75 Hg intoxicated volunteers before (U1), and 2-3 hours after (U2) the oral application of 200 mg DMPS (2,3-Dimercapto-1-propanesulfonic acid, Dimaval). In the urine samples, the concentrations of organic and inorganic bound mercury were determined separately by CV-AAS. In U1, median concentrations of 15.7 microg inorganic Hg/g crea. and 2.2 microg organic Hg/g crea. were found. In U2, these values increased to 262 for inorganic Hg and 14.5 for organic Hg. Maximum concentrations (microg/g crea.) as high as 7,593 for inorganic Hg and 2,011 for organic Hg were observed after DMPS. The mean (median) increasing factor (U2/U1) was 16.0 for inorganic Hg and 5.1 for organic Hg. There was a trend that females responded better to DMPS than males. It was concluded that DMPS increases the renal excretion of organic bound Hg as it does for inorganic Hg, but to a lesser extent.

Evaluation of protective ointments used against dermal effects of nitrogen mustard, a vesicant warfare agent.

Mustard, a vesicant warfare agent, has cytotoxic, mutagenic, and cytostatic effects via alkylation of DNA and inhibition of DNA replication. Since symptoms appear following a latent period, it can cause some subacute and chronic effects to occur and delay in the treatment. Therefore, the main approach should be the use of protective preparation to reduce the skin toxicity. Thus, this study was conducted in guinea pigs (350-400 g) shaved in areas of 10 x 10 cm. Mechlorethamine HCl (100 mg), a nitrogen mustard derivative, in ethanol was applied by spraying on hairless regions where previously prepared pharmaceutical topical formulations were medicated before. The experimental regions of the animals were kept preserved from environmental factors. Forty-eight hours after the application of the protective ointments and mechlorethamine consecutively, skin-damaging effects were macroscopically evaluated in terms of erythema formation, ulceration, necrosis, and inflammation occurrences. Then, punch biopsy was performed from these damaged sites for histopathological evaluation. Although numerous topical formulations were prepared and tested for protection, according to microscopic examination of the pathologic sections, tissue specimen treated with the ointment containing the mixture of zinc oxide, zinc chloride, dimethylpolysiloxane in a base of petroleum jelly was determined as being the most effective protective against skin injury caused by the vesicant agent.

Analysis of time-dependent recovery from beryllium toxicity following chelation therapy and antioxidant supplementation.

Efforts have been made to minimize the toxic effect caused by beryllium. Adult cyclic rats of Sprague Dawley strain were administered a bolus dose of 50mg/kg beryllium nitrate intramuscularly. The chelation therapy with glutathione (GSH), dimercapto propane sulfonic acid (DMPS)+ selenium (Se) and D-Penicillamine (DPA) + Se was given for 3 days followed by a rest of 1,3 and 7 days respectively. The results revealed a significant fall in the blood sugar level, serum alkaline phosphatase activity, serum proteins. A significant rise in the transaminases i.e. aspartate aminotranferase and alanine aminotranferase pattern is indicative of leakage of enzymes from liver resulting in alterations in the cell permeability. A rise in the hepatic lipid peroxidation activity is a direct indication of oxidative damage resulting in free radical generation. Results of the distribution studies by atomic absorption spectrophotometry reveal an increased concentration of beryllium in liver and kidney followed by lung and uterus. The relative ability of 3 chelating agents to act as antagonists for acute beryllium poisoning have been examined in liver, kidney, lungs and uterus. The appreciable change in the beryllium concentration in various organs is duration-dependent during the entire period being highly significant after 7 days rest. From the biochemical assays, and distribution studies it can be assumed that DPA+Se was the most effective therapeutic agent followed by DMPS+Se and GSH. Thus it can be concluded that DPA+Se is a better therapeutic agent as compared to DMPS+Se and GSH.

Evaluation of the mercury exposure of dental amalgam patients by the Mercury Triple Test.

AIMS: To establish and analyse reference data for the mercury burden of patients with and without amalgam fillings. METHODS: Atomic absorption spectroscopy was used to quantify Hg concentrations in the scalp hair and urine (before and after application of dimercaptopropane sulphonate), and Hg release from dental amalgams (using a newly developed, amalgam specific chew test), in 2223 subjects. RESULTS: 50th centiles were 1.3 microg Hg/g creatinine in basal urine, 32 microg Hg/g creatinine after DMPS application, 454 ng Hg/g in hair, and 27 microg Hg per g of chewing gum, which corresponds to about 1 micro g Hg released per minute of chewing. Total Hg intake (from ambient air, drinking water, food, and amalgams) of most patients is well below the provisioned tolerable weekly intake (PTWI) defined by the WHO, unless extremely Hg rich food is consumed on a regular basis. However, for patients exceeding the 75th centile in chew tests, total Hg intake exceeds the PTWI by about 50%, even at the low limit of intake from food. In the absence of occupational exposure, significant Hg release from dental amalgams is a necessary but insufficient condition to obtain a high long term body burden. After removal of dental amalgams, chew tests no longer exhibit oral Hg exposure, while basal urine Hg content and DMPS induced excretion display a exponential decrease (half life about 2 months in both cases). CONCLUSIONS: A standardised procedure for evaluation of the magnitude and origin of the Hg burden of individuals has been developed, which, by comparison with the database presented here for the first time, can serve as a diagnostic tool.

Blood mercury following DMPS administration to subjects with and without dental amalgam.

The use of DMPS as a diagnostic tool in patients with symptoms allegedly caused by mercury from dental amalgam fillings is disputed. We have previously shown that the mercury concentrations in urine cannot be used in such a way. In the present study, we wished to evaluate the effect on blood mercury levels (B-Hg) following intravenously injected DMPS in four groups of subjects: 19 controls without amalgam experience; 21 healthy controls with amalgam fillings; 20 patients with self-reported symptoms from existing dental amalgams; and 20 patients who had removed amalgam fillings. A single dose of DMPS (2 mg/kg) was injected. Blood samples were collected prior to the injection and after 15, 30, 120 min, and after 24 h, and mercury was analyzed by cold vapor atomic absorption spectrophotometry. All groups showed an initial drop of 24 to 30% in the blood levels, approaching baseline values (2.5-5.5 microg/l) after 2 h. The subjects with no amalgam experience had the lowest mercury values. There was no significant difference between the three groups with such experience. There were no significant differences between the two groups with amalgam fillings present. Patients with symptoms allegedly caused by amalgam were not different from the control groups. There were indications that part of the urinary mercury excreted during the first 30 min originated from blood.