Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease

Klein, Dominik; Arora, Uma; Lichtmannegger, Josef; Finckh, Matthias; Heinzmann, Ulrich; Summer, K

doi:10.1016/j.jhep.2003.11.034

Cited by 21 publications

(15 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Molybdenum toxicosis typically results in abnormalities consistent with copper deficiency such as hyporegenerative anemia and leukopenia . Infrequently, molybdenum can have a direct hepatotoxic effect . Furthermore, the ultimate consequences of accumulated molybdenum within liver or other tissues of dogs with CAH are unknown.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ammonium tetrathiomolybdate treatment of copper‐associated hepatopathy in dogs

Langlois

Querubin

Schall

et al. 2019

Veterinary Internal Medicne

View full text Add to dashboard Cite

Background Copper‐associated hepatopathy (CAH) is a common cause of liver disease in dogs. Although d ‐penicillamine can be an effective treatment, some dogs fail treatment or develop adverse effects. Ammonium tetrathiomolybdate (TTM) has been used to treat pathologic copper accumulation in other species, but its therapeutic potential for CAH is unknown. Objectives To investigate short‐term safety and efficacy of TTM for treatment of CAH. Animals Ten dogs with CAH. Methods Prospective study. All dogs were treated with TTM PO for 6 weeks, and hepatic biopsies were performed after the treatment course. Dog experiencing initial decreases in hepatic copper concentrations ([Cu] H ) received 6 additional weeks of TTM treatment and underwent 1 additional biopsy. Physical and laboratory examinations were performed every 2 weeks for study duration. Results Eight of 10 dogs had decreases in [Cu] H . Compared to baseline (median, 1606 μg/g; range, 572‐5158 μg/g), [Cu] H were decreased at 6 weeks (1033 μg/g, 450‐2975 μg/g; P = .04) and 12 weeks (931 μg/g, 218‐1677 μg/g; P = .02). Hepatic molybdenum concentrations increased >50‐fold ( P < 0.001). Changes in histologic scores and hematologic and biochemical test results were variable and not significantly different from baseline. One dog developed presumed immune‐mediated anemia and thrombocytopenia, but it was unclear if this was related to TTM administration. Conclusions and Clinical Importance Results suggest that TTM can effectively decrease [Cu] H in some dogs with CAH. Larger studies are needed to determine the overall safety and efficacy of TTM for treating CAH and how it compares with current treatments.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The effects of this degree of accumulation, if any, are unknown. Some of the hepatic molybdenum likely was complexed with copper in an inactive form . There may be benefit of TTM treatment beyond solely decreasing [Cu] H because TTM bound copper, even if still present within hepatic tissue, would not be expected to result in tissue injury.…”

Section: Discussionmentioning

confidence: 99%

Ammonium tetrathiomolybdate treatment of copper‐associated hepatopathy in dogs

Langlois

Querubin

Schall

et al. 2019

Veterinary Internal Medicne

View full text Add to dashboard Cite

show abstract

“…These complexes are initially deposited in the liver but subsequently result in the excretion of copper in bile (Lai and Sugawara 1997;Ogra et al 2000;George et al 2003). Tetrathiomolybdate given as a single intraperitoneal injection of 10 mg/kg after the onset of hepatitis results in clinical improvement of hepatitis and reduced hepatic copper within 4 days (Klein et al 2004). Given subcutaneously for 65 days from 8 weeks of age (before the onset of hepatitis), at a weekly dose of 5 mg/ kg, tetrathiomolybdate lowers hepatic copper but does not improve liver function parameters or weight.…”

Section: Treatment Studiesmentioning

confidence: 99%

Animal models of Wilson disease

Reed

Lutsenko²,

Bandmann

2018

Journal of Neurochemistry

View full text Add to dashboard Cite

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism manifesting with hepatic, neurological and psychiatric symptoms. The limitations of the currently available therapy for WD (particularly in the management of neuropsychiatric disease), together with our limited understanding of key aspects of this illness (e.g. neurological vs. hepatic presentation) justify the ongoing need to study WD in suitable animal models. Four animal models of WD have been established: the Long-Evans Cinnamon rat, the toxic-milk mouse, the Atp7b knockout mouse and the Labrador retriever. The existing models of WD all show good similarity to human hepatic WD and have been helpful in developing an improved understanding of the human disease. As mammals, the mouse, rat and canine models also benefit from high homology to the human genome. However, important differences exist between these mammalian models and human disease, particularly the absence of a convincing neurological phenotype. This review will first provide an overview of our current knowledge of the orthologous genes encoding ATP7B and the closely related ATP7A protein in C. elegans, Drosophila and zebrafish (Danio rerio) and then summarise key characteristics of rodent and larger mammalian models of ATP7B-deficiency.

show abstract

“…Another important, emerging treatment is tetrathiomolybdate (TTM) which binds excess copper and promotes biliary copper excretion . Contrary to DPen and trientine, it not only captures free plasma copper but also seems to have an additional protective activity component within cells . As it was too unstable for routine application in its original formulation as ammonium salt, it was never used widely.…”

Section: Introductionmentioning

confidence: 99%

Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta‐analysis of controlled studies

Appenzeller-Herzog

Mathes

Heeres

et al. 2019

Liver International

View full text Add to dashboard Cite

Background & aims Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD. Methods We included WD patients of any age or stage and the study drugs D‐penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non‐randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random‐effects meta‐analyses. Results The 23 included studies reported on 2055 patients and mostly compared D‐penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post‐decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D‐penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D‐penicillamine may have a greater impact on side effects and treatment discontinuations than zinc. Conclusions There are some indications that zinc is safer than D‐penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings.

show abstract

Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease

Cited by 21 publications

References 41 publications

Ammonium tetrathiomolybdate treatment of copper‐associated hepatopathy in dogs

Ammonium tetrathiomolybdate treatment of copper‐associated hepatopathy in dogs

Animal models of Wilson disease

Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta‐analysis of controlled studies

Contact Info

Product

Resources

About