ABSTRACT
OBJECTIVES: Wilson disease (WD) is a rare genetic disease affecting copper metabolism and the biliary tract's copper excretion. Lifelong medication is necessary to prevent liver failure, neurological complications, and death. Although D-penicillamine (DPA), trientine, and zinc are used to treat WD, there is limited research on the long-term outcomes of these drugs, especially in children. This study aimed to evaluate the efficacy and safety of DPA, trientine, and zinc in patients diagnosed with WD during childhood. METHODS: Ninety out of 92 patients were included in the analysis, excluding two patients who underwent liver transplantation without drug treatment due to an acute liver failure diagnosis. Treatment outcomes and reasons for discontinuation of therapy in 148 treatment blocks (37 DPA, 50 trientine, and 61 zinc) were analyzed using Kaplan-Meier analysis. RESULTS: The median age at diagnosis was 8.3 years. There was a statistically significant difference in drug changes due to treatment ineffectiveness among the three drugs: trientine (22/50, 44%), zinc (15/61, 25%), and DPA (2/37, 5%) (all p < 0.05). Regarding drug changes due to adverse effects, the rate was the highest for DPA, followed by zinc and trientine. There were significant differences between DPA and zinc, zinc and trientine (all p < 0.05), but no significant difference was observed between DPA and zinc (p = 0.22). CONCLUSIONS: In pediatric WD, DPA, zinc, and trientine have therapeutic effects in that order. However, DPA and zinc are associated with more adverse effects compared to trientine.
Subject(s)
Hepatolenticular Degeneration , Penicillamine , Trientine , Zinc , Humans , Hepatolenticular Degeneration/drug therapy , Hepatolenticular Degeneration/metabolism , Penicillamine/therapeutic use , Penicillamine/adverse effects , Trientine/therapeutic use , Trientine/adverse effects , Child , Male , Female , Zinc/therapeutic use , Adolescent , Child, Preschool , Chelating Agents/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND AND AIM: This retrospective, multicenter study aims to assess the efficacy and safety in Wilson disease (WD) patients treated with trientine tetrahydrochloride (TETA 4HCl) after switch from trientine dihydrochloride (TETA 2HCl). METHODS: In total, 68 WD patients with stable copper metabolism were identified to receive TETA 4HCl (Cuprior™) after previous treatment with TETA 2HCl. We analyzed biochemical markers such as urinary copper, serum copper, non-coeruloplasmin bound copper (NCC), and transaminases as well as clinical scores (APRI; FIB-4 score) at baseline with a follow-up (FU) of 12 months. Safety of TETA 4HCl treatment was based on reported adverse events (AEs). RESULTS: The study cohort reflects a common WD cohort with a mean age of 20.3 years at diagnosis and 38.3 years at baseline. There are no significant differences concerning serum copper, NCC, transaminases, APRI, and FIB-4 score in the 3-month FU. Six-month FU revealed a decreased AST (P = 0.008), APRI (P = 0.042), and FIB-4 score (P = 0.039). GGT varied only borderline significantly in the 3-month, but not in the 6-month FU. Comparison of urinary copper within the subsets did not reveal a difference to baseline in all FUs, suggesting stable control of copper metabolism. Few AEs during TETA 4HCl treatment were reported, most commonly gastrointestinal discomfort. Only three treatments with TETA 4HCl were discontinued. CONCLUSION: Copper parameters and liver function were stable after treatment switch to TETA 4HCl. Treatment with TETA 4HCl was generally well tolerated. This study indicates that the switch from TETA 2HCl to TETA 4HCl is safe and viable.
Subject(s)
Hepatolenticular Degeneration , Trientine , Humans , Young Adult , Adult , Trientine/adverse effects , Hepatolenticular Degeneration/drug therapy , Copper , Retrospective Studies , Chelating Agents/adverse effects , TransaminasesABSTRACT
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.
Subject(s)
Hepatolenticular Degeneration , Adult , Humans , Chelating Agents/adverse effects , Copper , Hepatolenticular Degeneration/drug therapy , Penicillamine/adverse effects , Trientine/adverse effectsABSTRACT
OBJECTIVES: Trientine dihydrochloride (TETA-2HCl) has been used for the treatment of Wilson disease for over 30 years. The current study was designed to systematically evaluate existing data to further define the long-term outcome of the efficacy and tolerability of TETA-2HCl in Wilson disease patients. METHODS: Medical records of 77 Wilson disease patients were reviewed to collect data on hepatic and neurologic symptoms, copper (Cu) homeostasis and adverse events. Data were collected for 48 months after initiation of TETA-2HCl after withdrawal of D-penicillamine treatment. RESULTS: Mean duration of TETA-2HCl treatment was 8 years (range 5 months-32.5 years). Over the course of TETA-2HCl treatment, 35% of patients had no hepatic symptoms whereas in 49.4% of patients, hepatic symptoms improved. They remained unchanged in 10.4% of patients and worsened in 5.2% of patients. No patients progressed to acute hepatic failure or necessity of a liver transplant. During TETA-2HCl treatment, 46.7% of patients had no neurologic symptoms; in 14.3% of patients, neurologic symptoms improved whereas in 36.4% of patients, they remained stable and worsened in 2.6% of patients. During the evaluation period, 12 patients discontinued TETA-2HCl treatment due to: anemia ( N = 1), inadequate hepatic response ( N = 2), switch to zinc treatment ( N = 8) and patient's decision to withdraw from treatment ( N = 1). Treatment-emergent adverse events were reported by 24.7% of the patients of which gastrointestinal disorders (9.1%) and nervous system disorders (5.2%) were most reported. CONCLUSIONS: TETA-2HCl is well-tolerated and effective in Wilson disease patients following the withdrawal of treatment with D-penicillamine. ClinicalTrials.govIdentifier : NCT02426905.
Subject(s)
Hepatolenticular Degeneration , Trientine , Chelating Agents/adverse effects , Hepatolenticular Degeneration/chemically induced , Hepatolenticular Degeneration/diagnosis , Hepatolenticular Degeneration/drug therapy , Humans , Penicillamine/adverse effects , Retrospective Studies , Trientine/adverse effectsABSTRACT
Background. Available treatments for Wilson disease (WD) prevent longterm complications of copper accumulation. Current anti-copper agents include zinc salts, penicillamine, and trientine. Patients with WD may switch between the agents for a number of reasons. Due to the different mechanisms of action between the copper chelators and zinc salts, transitioning could require a period of overlap and increased monitoring. There are no large studies that investigate the best transition strategies between agents. In this article, we review the treatments for WD and how to monitor for treatment efficacy. Case Summary. The patient had been diagnosed with WD for over 20 years prior to establishing care in our Hepatology Clinic. During his initial course, he was transitioned from penicillamine to zinc due to evidence suggesting penicillamine had greater adverse effects in the long term. Later, he was switched to trientine. His liver enzymes and 24-hour urine copper were monitored. During these years, he intermittently had some financial hardship, requiring him to be on penicillamine rather than trientine. He also had developed acute kidney injury. Overall, his liver disease remained under control and he never had signs of decompensated cirrhosis, but had fluctuations of liver enzymes over the years. Conclusion. Anti-copper treatment for WD has to be tailored to medication side effects profile, patient's chronic and emerging comorbidities, as well as costs. Transitioning regimens is often challenging, and it requires closer monitoring, with no predictors of response.
Subject(s)
Acute Kidney Injury/chemically induced , Chelating Agents/adverse effects , Copper/urine , Hepatolenticular Degeneration/drug therapy , Adult , Chelating Agents/economics , Hepatolenticular Degeneration/urine , Humans , Liver/physiopathology , Male , Penicillamine/adverse effects , Treatment Outcome , Trientine/adverse effects , Zinc/therapeutic useABSTRACT
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.
Subject(s)
Chelating Agents/adverse effects , Chelating Agents/therapeutic use , Hepatolenticular Degeneration/drug therapy , Zinc/therapeutic use , Copper/metabolism , Humans , Liver/metabolism , Molybdenum/adverse effects , Molybdenum/therapeutic use , Penicillamine/adverse effects , Penicillamine/therapeutic use , Randomized Controlled Trials as Topic , Trientine/adverse effects , Trientine/therapeutic use , Zinc/adverse effectsABSTRACT
Wilson's disease (WD) is a rare inherited disorder of copper metabolism causing toxic hepatic and neural copper accumulation. Clinical symptoms vary widely, from asymptomatic disease to acute liver failure or chronic liver disease with or without neuropsychiatric symptoms. Continuation of specific medical treatment for WD is recommended during pregnancy, but reports of pregnancy outcomes in WD patients are sparse. In a retrospective, multicenter study, 282 pregnancies in 136 WD patients were reviewed. Age at disease onset, age at conception, and WD-specific treatments were recorded. Maternal complications during pregnancy, rate of spontaneous abortions, and birth defects were analyzed with respect to medical treatment during pregnancy. Worsening of liver function tests was evident during 16 of 282 (6%) pregnancies and occurred in undiagnosed patients as well as in those under medical treatment. Liver test abnormalities resolved in all cases after delivery. Aggravation of neurological symptoms during pregnancy was rare (1%), but tended to persist after delivery. The overall spontaneous abortion rate in the study cohort was 73 of 282 (26%). Patients with an established diagnosis of WD receiving medical treatment experienced significantly fewer spontaneous abortions than patients with undiagnosed WD (odds ratio, 2.853 [95% confidence interval, 1.634-4.982]). Birth defects occurred in 7 of 209 (3%) live births. CONCLUSION: Pregnancy in WD patients on anticopper therapy is safe. The spontaneous abortion rate in treated patients was lower than that in therapy-naïve patients. Although the teratogenic potential of copper chelators is a concern, the rate of birth defects in our cohort was low. Treatment for WD should be maintained during pregnancy, and patients should be monitored closely for hepatic and neurological symptoms. (Hepatology 2018;67:1261-1269).
Subject(s)
Hepatolenticular Degeneration/complications , Pregnancy Complications/epidemiology , Pregnancy Outcome/epidemiology , Adolescent , Adult , Female , Hepatolenticular Degeneration/drug therapy , Humans , Liver/physiopathology , Liver Function Tests , Pregnancy , Pregnancy Complications/etiology , Retrospective Studies , Trientine/adverse effects , Trientine/therapeutic use , Young Adult , Zinc/adverse effects , Zinc/therapeutic useABSTRACT
BACKGROUND AND AIMS: Current guidelines favor the use of chelating agents (d-penicillamine, trientine) in first line therapy of symptomatic Wilson disease patients. Development of chelator induced immunological adverse events are a concern especially under d-penicillamine therapy. This study assessed the prevalence of co-existing or therapy-related immune-mediated diseases in Wilson disease patients, and evaluated the role of antinuclear antibodies in therapy monitoring. METHODS: We retrospectively analyzed 235 Wilson disease patients. Medical regimens were classified and analyzed in relation to adverse events and antinuclear antibody courses. RESULTS: Coexisting immune-mediated diseases were evident in 19/235 (8.1%) patients, of which 13/235 (5.5%) had pre-existing autoimmune diseases. Six patients (2.6%) developed an autoimmune disease under therapy, all of them under long-term d-penicillamine treatment. Data relating to antinuclear antibody courses during treatment and adverse events were available for patients treated with d-penicillamine (n = 91), trientine (n = 58), and zinc salts (n = 58). No significant increase in antinuclear antibody titers in patients treated with d-penicillamine (16/91; 17.6%), trientine (12/58; 20.7%), and zinc (7/58; 12.1%) were found. CONCLUSION: Under long-term d-penicillamine therapy a minority of patients developed immune-mediated disease. Elevations in antinuclear antibodies were found frequently, but no correlations were evident between increases in antinuclear antibodies and the development of immune-mediated diseases or medical regimes. Thus, the value of antinuclear antibodies for monitoring adverse events under chelator therapy seems to be limited.
Subject(s)
Chelating Agents/adverse effects , Chelating Agents/therapeutic use , Drug-Related Side Effects and Adverse Reactions/immunology , Hepatolenticular Degeneration/drug therapy , Hepatolenticular Degeneration/immunology , Adolescent , Adult , Antibodies, Antinuclear/immunology , Autoimmune Diseases/chemically induced , Autoimmune Diseases/immunology , Child , Cross-Sectional Studies , Drug Monitoring/methods , Female , Humans , Male , Penicillamine/adverse effects , Penicillamine/immunology , Penicillamine/therapeutic use , Retrospective Studies , Trientine/adverse effects , Trientine/immunology , Trientine/therapeutic use , Young Adult , Zinc/adverse effects , Zinc/immunology , Zinc/therapeutic useABSTRACT
BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder of human copper metabolism characterized by copper accumulation in the liver due to impaired excretion of copper into the bile. Brain accumulation of copper may cause neuropsychiatric symptoms. Trientine (triethylenetetramine dihydrochloride) is a copper-chelating agent used to treat patients with WD. Trientine has been considered an option for initial treatment and maintentance therapy of WD due to its safety profile. CASE PRESENTATION: A 40 year old female with a recent diagnosis of WD was started on treatment with trientine for her WD. Within one month she developed profound bloody diarrhea unresponsive to medical treatment. Trientine was discontinued and a colonoscopy with biopsy showed moderately active ileitis and moderate to severe pancolitis, consistent with a drug induced mucosal injury. The colitis improved immediately upon withdrawal of trientine, and recurred when medication was rechallenged because of worsened WD symptoms. After second compulsory discontinuation of trientine, she remained on zinc therapy for her WD and her colitis resolved by time. CONCLUSION: Drug induced colitis is a very rare side effect of trientine. Although trientine therapy is well tolerated and less side effects are reported with this medication than penicillamine, colitis can occur during trientine treatment. Zinc therapy may be an effective alternative for treatment of WD in patients experiencing side effects from chelation therapy.
Subject(s)
Colitis/chemically induced , Hepatolenticular Degeneration/drug therapy , Trientine/adverse effects , Adult , Chelating Agents/adverse effects , Female , Humans , Withholding TreatmentABSTRACT
BACKGROUND: Wilson disease requires lifelong therapy, currently given daily in multiple divided dosages. AIM: To prospectively evaluate once-daily trientine as therapy for Wilson disease. STUDY GROUP: eight patients (seven males) aged 22-71 years with stable Wilson disease treated from 4 to 50 years. Patients were monitored for 3 months then for 12 months on a single daily dose of trientine (15 mg/kg). RESULTS: All patients remained clinically well. ALT and AST fluctuated in some, but none required treatment stoppages or side effects. Liver synthetic function was unchanged. Mean 24-h urine copper and zinc excretions at end of treatment were 313.4 ± 191.7 and 2,214 ± 1,346 µg, respectively. CONCLUSIONS: Once-daily trientine should be explored further for possible maintenance therapy for WD. Single daily dose may improve adherence to therapy. Larger trials and longer-term follow-up will establish the safety and treatment efficacy of this once-daily treatment regimen for WD (registration: NCT01472874).
Subject(s)
Chelating Agents/administration & dosage , Hepatolenticular Degeneration/drug therapy , Trientine/administration & dosage , Administration, Oral , Adult , Aged , Chelating Agents/adverse effects , Drug Administration Schedule , Female , Hepatolenticular Degeneration/diagnosis , Humans , Male , Medication Adherence , Middle Aged , Patient Dropouts , Patient Satisfaction , Pilot Projects , Prospective Studies , Surveys and Questionnaires , Time Factors , Treatment Outcome , Trientine/adverse effects , Young AdultABSTRACT
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.
Subject(s)
Chelation Therapy , Copper , Evidence-Based Medicine , Lead Poisoning/drug therapy , Mercury Poisoning/drug therapy , Succimer/therapeutic use , Unithiol/therapeutic use , Administration, Oral , Animals , Chelating Agents/administration & dosage , Chelating Agents/adverse effects , Chelating Agents/therapeutic use , Chelation Therapy/adverse effects , Drug Therapy, Combination , Free Radical Scavengers/therapeutic use , Humans , Infusions, Parenteral , Penicillamine/administration & dosage , Penicillamine/adverse effects , Penicillamine/therapeutic use , Succimer/administration & dosage , Succimer/adverse effects , Trientine/administration & dosage , Trientine/adverse effects , Trientine/therapeutic use , Unithiol/administration & dosage , Unithiol/adverse effectsABSTRACT
PURPOSE: Preclinical data showed that trientine, a copper-lowering agent, re-sensitized cancer cells to carboplatin through enhanced human copper transporter 1 (hCtr1) -mediated platinum uptake. EXPERIMENTAL DESIGN: We studied carboplatin and trientine in patients (n = 55; 45 who had failed platinum) with advanced malignancies (Phase I, modified 3 + 3 design). RESULTS: The most common cancers were head and neck (n = 13), non-small cell lung (n = 10) and epithelial ovarian (n = 8). The median number of prior regimens was four. No dose-limiting toxicity or treatment-related deaths were observed at doses up to carboplatin AUC 6 given with trientine. Eight patients achieved stable disease (SD) ≥ 6 months (six platinum failures) and one patient with platinum-resistant ovarian cancer, partial response (PR) (total SD ≥ 6 months/PR = 9, 16.4 %). The mean nadir serum copper level in the nine patients with SD ≥ 6 months/PR was 0.55 µg/mL (95 % CI, 0.34-0.75) versus 1.22 µg/mL (95 % CI, 1.02-1.42) (p < 0.001) in 38 tested patients with progression. In patients who maintained their ceruloplasmin (major copper-carrying protein) levels at 5-15 mg/dL (n = 9), the median progression-free and overall survivals were 9.2 and 15.2 months versus 1.9 (p = 0.001) and 5.7 months (p = 0.033) in patients who did not (n = 38), respectively. CONCLUSIONS: The combination of a copper-lowering agent with carboplatin was well tolerated and associated with antitumor activity, especially in patients in whom copper and/or ceruloplasmin levels were lowered. Further investigation of this strategy for reversing platinum resistance is warranted.
Subject(s)
Antineoplastic Agents/administration & dosage , Carboplatin/administration & dosage , Chelating Agents/administration & dosage , Copper/blood , Neoplasms/drug therapy , Trientine/administration & dosage , Adult , Aged , Antineoplastic Agents/adverse effects , Carboplatin/adverse effects , Ceruloplasmin/metabolism , Chelating Agents/adverse effects , Female , Humans , Male , Middle Aged , Neoplasms/blood , Treatment Outcome , Trientine/adverse effectsSubject(s)
Copper/deficiency , Deficiency Diseases/chemically induced , Hepatolenticular Degeneration/drug therapy , Nervous System Diseases/chemically induced , Spinal Cord Diseases/chemically induced , Adult , Copper/metabolism , Deficiency Diseases/metabolism , Deficiency Diseases/pathology , Hepatolenticular Degeneration/metabolism , Hepatolenticular Degeneration/pathology , Humans , Male , Nervous System Diseases/metabolism , Nervous System Diseases/pathology , Spinal Cord/pathology , Spinal Cord Diseases/metabolism , Spinal Cord Diseases/pathology , Trientine/adverse effects , Trientine/therapeutic use , Zinc Sulfate/adverse effects , Zinc Sulfate/therapeutic useABSTRACT
BACKGROUND & AIMS: Wilson disease is a genetic copper storage disorder that causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine, trientine) are used as first-line therapies for symptomatic patients, but there are few data from large cohorts. We assessed the safety of D-penicillamine and trientine therapy and outcomes of patients with Wilson disease. METHODS: We performed a retrospective analysis of data on 380 patients with Wilson disease from tertiary care centers in Germany and Austria, and 25 additional patients from the EUROWILSON registry. Chelator-based treatment regimens were analyzed for their effect on neurologic and hepatic symptoms and for adverse events that led to discontinuation of therapy (Kaplan-Meier estimation; data were collected for a mean of 13.3 y after therapy began). RESULTS: Changes in medication were common, resulting in analysis of 471 chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141 patients given trientine underwent liver transplantation. Adverse events leading to discontinuation of treatment were more frequent among those receiving D-penicillamine than trientine (P = .039). Forty-eight months after therapy, hepatic deterioration was reported in only 4 of 333 patients treated initially with a chelating agent. Hepatic improvements were observed in more than 90%, and neurologic improvements were observed in more than 55%, of therapy-naive patients, and values did not differ significantly between treatments. However, neurologic deterioration was observed less frequently in patients given D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P = .018). CONCLUSIONS: Chelating agents are effective therapies for most patients with Wilson disease; D-penicillamine and trientine produce comparable outcomes, although D-penicillamine had a higher rate of adverse events. Few patients receiving chelation therapy had neurologic deterioration, which occurred more frequently in patients who received trientine.
Subject(s)
Chelating Agents/administration & dosage , Chelating Agents/adverse effects , Hepatolenticular Degeneration/drug therapy , Penicillamine/administration & dosage , Penicillamine/adverse effects , Trientine/administration & dosage , Trientine/adverse effects , Adolescent , Adult , Austria , Child , Child, Preschool , Cohort Studies , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Germany , Hepatolenticular Degeneration/pathology , Humans , Infant , Male , Middle Aged , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
Trientine (triethylenetetramine dihydrochloride) is a copper-chelating agent used to treat patients with Wilson's disease (WD). It has been considered safe, rarely causing neurological deterioration during initial treatment. We describe a patient diagnosed with WD who became neurologically disabled after treatment with trientine. On a fluid attenuated inversion recovery sequence, brain MRI showed increased areas of high signal intensity compared with initial brain MRI. The patient's neurological signs partially resolved after cessation of trientine treatment. Our findings suggest that treatment with trientine is associated with a risk of neurological deterioration in patients with WD.
Subject(s)
Chelating Agents/adverse effects , Hepatolenticular Degeneration/complications , Nervous System Diseases/chemically induced , Trientine/adverse effects , Brain/pathology , Chelating Agents/therapeutic use , Copper/metabolism , Dystonia/etiology , Gait Disorders, Neurologic/etiology , Gait Disorders, Neurologic/pathology , Hepatolenticular Degeneration/drug therapy , Hepatolenticular Degeneration/pathology , Humans , Magnetic Resonance Imaging , Male , Nervous System Diseases/complications , Nervous System Diseases/pathology , Trientine/therapeutic use , Young Adult , Zinc/therapeutic useABSTRACT
A 37-year-old man was diagnosed with Wilson disease at the age of 14. His first manifestations were neurological. He was treated with trientine for more than 10 years and suffered from anemia and liver dysfunction. Wilson disease is a genetic disorder characterized by accumulation of copper in the body. Excess copper is toxic, but copper is an essential trace element. Copper-binding ceruloplasmin is important for iron metabolism. Excess copper chelating treatment-induced anemia and iron deposition in the liver was suspected. Proper monitoring of copper status is important for the management of Wilson disease.
Subject(s)
Anemia/chemically induced , Chelating Agents/adverse effects , Chelation Therapy/adverse effects , Copper , Hepatolenticular Degeneration/drug therapy , Liver Diseases/etiology , Adult , Anemia/blood , Ceruloplasmin/metabolism , Chelating Agents/administration & dosage , Copper/metabolism , Hemochromatosis/etiology , Hemochromatosis/metabolism , Hepatolenticular Degeneration/complications , Hepatolenticular Degeneration/metabolism , Humans , Iron/metabolism , Liver Diseases/metabolism , Male , Trientine/administration & dosage , Trientine/adverse effectsABSTRACT
The selective Cu(II)-chelator, triethylenetetramine (TETA), is undergoing clinical trials for the treatment of heart failure in patients with diabetes. Recently, the authors showed that 2 acetylated metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT), are formed in humans following oral TETA administration. Thus, it became necessary to determine whether the N-acetyltransferase (NAT) 2 phenotype has any effects on the pharmacological properties and safety profile of TETA. Twelve fast and 12 slow NAT2-phenotype healthy participants were recruited. After oral drug administration, the authors collected plasma and urine samples, measured plasma concentrations of TETA and its 2 metabolites along with concomitant urinary copper concentrations, and performed safety tests. They present, for the first time, the complete 24-hour pharmacokinetic profiles of TETA, MAT, and DAT in humans. There was no evidence for clear-cut differences in pharmacokinetic profiles between fast and slow acetylators. Pharmacodynamic analysis showed no significant differences in cupruresis between the 2 NAT2 phenotypes. Safety results were consistent with TETA being well tolerated, and no significant differences in safety profiles were observed between the 2 phenotypes. Based on these data, NAT2 phenotype does not affect TETA's pharmacokinetic, pharmacodynamic, or safety profiles. TETA may be acetylated via an alternative mechanism, such as that catalyzed by spermidine/spermine N(1)-acetyltranferase.
Subject(s)
Chelating Agents/pharmacology , Chelating Agents/pharmacokinetics , Trientine/metabolism , Trientine/pharmacology , Trientine/pharmacokinetics , Adult , Arylamine N-Acetyltransferase/genetics , Chelating Agents/adverse effects , Copper/urine , Female , Humans , Male , Middle Aged , Phenotype , Time Factors , Trientine/adverse effects , Trientine/analogs & derivatives , Trientine/bloodABSTRACT
The population pharmacokinetics (PK) and pharmacodynamics (PD) of triethylenetetramine (TETA) dihydrochloride (trientine, GC811007) administered orally as 100-, 300-, 600-, or 1800-mg twice-daily doses were assessed in healthy adult male and female volunteers. This study was a randomized, double-blind, placebo-controlled, group-sequential, dose-escalating design. Forty participants, 10 per dose level (8 receiving TETA, 2 receiving placebo), received twice-daily doses for 14 consecutive days. A 2-compartment model for the PK and a linear direct effect model for drug-induced copper excretion (PD) were employed. The population PK/PD model was applied using the NONMEM software. Covariates tested were glomerular filtration rate (GFR), body weight, and gender. Multiple daily doses of TETA were safe and generally well tolerated. The linear 2-compartment model with first-order absorption well characterized the serum concentration data. Although its role was small, GFR had a statistically significant (P < .05) influence on systemic clearance (CL/F). The augmentation of copper excretion was well described by a direct linear model in which the slope was related to GFR and gender (P < .001). The intersubject coefficient of variation was 22.2% for slope (SL) and 82.5% for intercept (ER0). TETA has consistent single/multiple-dose pharmacokinetics and dose-proportional and serum concentration-proportional effects on enhancing copper excretion.