-
Medicina Clinica Mar 2023Wilson's disease (WD) is an uncommon hereditary disorder caused by a deficiency in the ATP7B transporter. The protein codified by this gene facilitates the incorporation... (Review)
Review
Wilson's disease (WD) is an uncommon hereditary disorder caused by a deficiency in the ATP7B transporter. The protein codified by this gene facilitates the incorporation of the copper into ceruloplasmin. Therefore, WD accumulates copper primary in the liver and secondary in other organs, such as the central nervous system. It represents a wide spectrum of disease, ranging from being asymptomatic in some patients to promote an acute liver failure in others. The diagnosis requires a combination of clinical signs and symptoms, as well as some diagnostic tests such as the measurement of serum ceruloplasmin, the urinary excretion of copper, the liver biopsy or the genetic testing. The treatment must be maintained lifelong and includes some drugs such as chelating agents (penicillamine and trientine) and inhibitors of the copper absorption (zinc salts). Lastly, the liver transplant should be an option for patients with end-stage liver disease.
Topics: Humans; Ceruloplasmin; Chelating Agents; Copper; Hepatolenticular Degeneration; Penicillamine
PubMed: 36697289
DOI: 10.1016/j.medcli.2022.12.016 -
Clinics in Liver Disease Nov 2017Consideration of a diagnosis of Wilson disease is still the critical factor in testing for and establishing disease diagnosis. In association with other clinical and... (Review)
Review
Consideration of a diagnosis of Wilson disease is still the critical factor in testing for and establishing disease diagnosis. In association with other clinical and biochemical tests, liver biopsy results and molecular genetic testing can also be used to generate a score for diagnosing Wilson disease. Medical therapy is effective for most patients; liver transplant can rescue those with acute liver failure or those with advanced liver disease who fail to respond to or discontinue medical therapy. Treatment monitoring must be done at regular intervals and includes clinical evaluation, liver tests and blood counts, and copper metabolic parameters.
Topics: Aftercare; Biopsy; Ceruloplasmin; Chelating Agents; Copper; Copper-Transporting ATPases; Disease Management; Hepatolenticular Degeneration; Humans; Liver; Liver Failure, Acute; Liver Transplantation; Penicillamine; Trientine
PubMed: 28987261
DOI: 10.1016/j.cld.2017.06.011 -
Clinics in Liver Disease Aug 2022The silver anniversary of the discovery of the Wilson disease gene ATP7B was a couple of years ago, and we continue to make progress both in our understanding of copper... (Review)
Review
The silver anniversary of the discovery of the Wilson disease gene ATP7B was a couple of years ago, and we continue to make progress both in our understanding of copper transportation using animal models as well as earlier diagnosis by availing of genetic testing. Wilson disease is multisystemic and the hepatic manifestations are seen more frequently in childhood, whereas neurologic manifestations are more common in adults; presentation may range from subtle changes to end-stage liver disease with or without encephalopathy as well as neuropsychiatric manifestations. Treatment remains with zinc and chelating agents such as D-penicillamine and trientine but newer agents and gene therapy are in clinical trials. Liver transplantation becomes necessary when medical therapy is not enough. Molecular diagnosis and genetic counseling is important.
Topics: Chelating Agents; Copper; Hepatolenticular Degeneration; Humans; Penicillamine; Trientine
PubMed: 35868686
DOI: 10.1016/j.cld.2022.03.008 -
The Lancet. Gastroenterology &... Dec 2022Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease.
METHODS
We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18-75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25-150 μg/L), 24 h urinary copper excretion (100-900 μg/24 h), and alanine aminotransferase (ALT; <2 × upper limit of normal). Stable patients were randomly assigned (1:1) to continue receiving the maintenance twice daily dose of oral penicillamine or switched mg-for-mg to oral TETA4 centrally with a web-based system using minimisation. The primary endpoint, assessed 24 weeks after randomisation, was NCC by speciation assay. The non-inferiority margin of mean difference in NCC by speciation assay was -50 μg/L, as estimated by a general linear model for repeated visits, adjusted for baseline values. Further data on safety and efficacy were collected during a 24-week extension period. Data were analysed using an intention-to-treat approach. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03539952 (active, not recruiting).
FINDINGS
Between June 4, 2018, and March 10, 2020, 77 patients were screened. 53 patients were randomly assigned (27 to the penicillamine group and 26 to the TETA4 group). After 24 weeks, the mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was -9·1 μg/L (95% CI -24·2 to 6·1), with the lower limit of the 95% CI within the defined non-inferiority margin. At 24 weeks, urinary copper excretion was lower with TETA4 than with penicillamine (mean difference 237·5 μg/24 h (99% CI 115·6 to 359·4). At 48 weeks, TETA4 remained non-inferior to penicillamine in terms of NCC by speciation assay (mean difference NCC -15·5 μg/L [95% CI -34·5 to 3·6]). Urinary copper excretion at 48 weeks remained in the expected range for well treated patients in both study groups, and the mean difference (124·8 μg/24 h [99% CI -37·6 to 287·1]) was not significantly different. At 24 weeks and 48 weeks, masked clinical adjudication of stability assessed by three independent clinicians confirmed clinical stability (100%) of all participants, in agreement with the stability seen with the NCC by speciation assay. There were no notable changes in either the Clinical Global Impression of Change or Unified Wilson Disease Rating Scale (neurological assessment) from baseline (pre-randomisation) at weeks 24 and 48. The mean change in serum total copper from baseline to 24 weeks was 17·6 μg/L (99% CI -9·5 to 44·7) with penicillamine and -6·3 μg/L (-34·7 to 22·1) with TETA4, and the mean change in serum total caeruloplasmin from baseline to 24 weeks was 1·8 mg/L (-19·2 to 22·8) with penicillamine and -2·2 mg/L (-6·1 to 1·7) with TETA4. All liver enzymes were similar at 24 weeks and 48 weeks, with the exception of elevated ALT concentration at 48 weeks for patients in the TETA4 group. Penicillamine was associated with three post-randomisation serious adverse events (leukopenia, cholangiocarcinoma, and hepatocellular cancer); none were reported for TETA4. The most common treatment-emergent adverse events were headache for penicillamine (five [19%] of 27 patients vs two [8%] of 26) and abdominal pain for TETA4 (one [4%] vs four [15%]); all treatment-emergent adverse events resolved and were mild to moderate. One patient developed a rash with TETA4 that resolved on discontinuation of therapy.
INTERPRETATION
The efficacy of TETA4 as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease.
FUNDING
Orphalan.
Topics: Adult; Humans; Chelating Agents; Copper; Hepatolenticular Degeneration; Penicillamine; Trientine
PubMed: 36183738
DOI: 10.1016/S2468-1253(22)00270-9 -
Nephrologie & Therapeutique Apr 2021Cystinuria is the most common monogenic nephrolithiasis disorder. Because of its poor solubility at a typical urine pH of less than 7, cystine excretion results in... (Review)
Review
Cystinuria is the most common monogenic nephrolithiasis disorder. Because of its poor solubility at a typical urine pH of less than 7, cystine excretion results in recurrent urinary cystine stone formation. A high prevalence of high blood pressure and of chronic kidney disease has been reported in these patients. Alkaline hyperdiuresis remains the cornerstone of the preventive medical treatment. To reach a urine pH between 7.5 and 8 and a urine specific gravity less than or equal to 1.005 should be the goal of medical treatment. D-penicillamine and tiopronin, two cysteine-binding thiol agents, should be considered as second line treatments with frequent adverse events that should be closely monitored.
Topics: Cystine; Cystinuria; Humans; Kidney Calculi; Penicillamine; Tiopronin
PubMed: 33910689
DOI: 10.1016/j.nephro.2020.03.001 -
Methods in Molecular Biology (Clifton,... 2022Serine/threonine ligation (STL) and cysteine/penicillamine ligation (CPL) are highly chemo- and regioselective reactions between unprotected peptides with C-terminus...
Serine/threonine ligation (STL) and cysteine/penicillamine ligation (CPL) are highly chemo- and regioselective reactions between unprotected peptides with C-terminus salicylaldehyde esters and unprotected peptides with N-terminus serine/threonine or cysteine/penicillamine, which serve as powerful tools for cyclic peptide natural product and chemical protein synthesis. Herein, we introduce the preparation of C-terminal peptide salicylaldehyde esters, serine/threonine ligation, cysteine/penicillamine ligation, and subsequent acidolysis.
Topics: Cysteine; Esters; Penicillamine; Peptides; Serine; Threonine
PubMed: 35761040
DOI: 10.1007/978-1-0716-2489-0_3 -
Biology of Reproduction Dec 2022Methods for standard in vitro fertilization have been difficult to establish in the horse. We evaluated whether prolonged sperm pre-incubation would support subsequent...
Methods for standard in vitro fertilization have been difficult to establish in the horse. We evaluated whether prolonged sperm pre-incubation would support subsequent fertilization. Fresh sperm were pre-incubated with penicillamine, hypotaurine, and epinephrine (PHE) for 22 h. Co-incubation of cumulus-oocyte complexes (COCs) for 6 h yielded 43% fertilization; culture of presumptive embryos yielded 21% blastocysts. Sperm incubated similarly, but without PHE, did not fertilize oocytes. Use of extended semen in the system yielded 54% blastocysts and was applied in subsequent experiments. Transfer of three in vitro fertilization-produced blastocysts to recipient mares resulted in birth of three normal foals. When sperm were pre-incubated for 22 h, 47-79% of oocytes were fertilized after 1 h of co-incubation. Sperm pre-incubated for 15 min or 6 h before co-incubation yielded no fertilization at 1 h, suggesting that capacitation in this system requires between 6 and 22 h. Sperm assessed after 15 min, 6 h, or 22 h pre-incubation showed increasing protein tyrosine phosphorylation of the midpiece, equatorial band, and apical head; this pattern differed from that induced by high pH conditions and may denote functional equine sperm capacitation. Use of the final devised system, i.e., extended semen, with 22 h of sperm pre-incubation and 3 h of COC co-incubation, yielded 90% fertilization with a blastocyst rate of 74%. This is the first report of efficient and repeatable standard in vitro fertilization in the horse and the first report of in vitro production of blastocysts and resulting foals after in vitro fertilization.
Topics: Horses; Animals; Female; Male; Semen; Fertilization in Vitro; Spermatozoa; Blastocyst; Sperm Capacitation; Oocytes; Penicillamine; Epinephrine
PubMed: 36106756
DOI: 10.1093/biolre/ioac172 -
The Veterinary Clinics of North... May 2017Copper-associated hepatitis is recognized with increasing frequency in dogs. The disease is characterized by centrolobular hepatic copper accumulation, leading to... (Review)
Review
Copper-associated hepatitis is recognized with increasing frequency in dogs. The disease is characterized by centrolobular hepatic copper accumulation, leading to hepatitis and eventually cirrhosis. The only way to establish the diagnosis is by histologic assessment of copper distribution and copper quantification in a liver biopsy. Treatment with the copper chelator d-penicillamine is the most commonly used treatment. In addition, a low-copper/high-zinc diet can help prevent accumulation or reaccumulation of hepatic copper. Mutations in the copper metabolism genes COMMD1 or ATP7A and ATP7B have been associated with hepatic copper concentrations in Bedlington terriers and Labrador retrievers respectively. In the Labrador retriever, dietary copper intake contributes strongly to the disease phenotype.
Topics: Animals; Biomarkers; Chelating Agents; Copper; Dog Diseases; Dogs; Hepatitis, Animal; Humans; Penicillamine
PubMed: 28063745
DOI: 10.1016/j.cvsm.2016.11.011 -
Annals of Translational Medicine Apr 2019The availability of effective therapies distinguishes Wilson disease (WD) from other inherited neurometabolic diseases. The cause of hepatic, neurologic or psychiatric... (Review)
Review
The availability of effective therapies distinguishes Wilson disease (WD) from other inherited neurometabolic diseases. The cause of hepatic, neurologic or psychiatric symptoms is copper overload and subsequent copper toxicity. Diagnosed WD patients require life-long pharmacologic therapy that is focused on reversal of copper overload with maintenance of a long-term negative copper balance. This is associated with the rapid control of free or non-ceruloplasmin bound copper that is mostly responsible for acute cytotoxic effects. Currently available therapies can be divided into chelators and zinc salts. They have different mechanisms of action and the onset of efficacy that influences their selection in acute and chronic stages of therapy. We review the use of D-penicillamine and trientine for chelation therapies, including the required monitoring of therapy for its efficacy and possible overtreatment with iatrogenic copper deficiency. Additionally, the use of zinc salts is also discussed, including a possibility of its use for the initial therapy in an acute stage of the disease. Supportive and symptomatic therapies for liver failure and neuropsychiatric symptoms are also reviewed.
PubMed: 31179303
DOI: 10.21037/atm.2019.03.18