Trientine Dihydrochloride Research Articles

Clinical experience on switching trientine tetrahydrochloride to trientine dihydrochloride in Wilson disease patients

AbstractThis study evaluates the effectiveness and safety of trientine dihydrochloride (TETA 2‐HCl) in patients with Wilson disease (WD) following a switch from trientine tetrahydrochloride (TETA 4‐HCl). A total of 30 WD patients with stable copper metabolism were identified for treatment with TETA 2‐HCl (Cufence™) after prior use of TETA 4‐HCl (Cuprior™). Biochemical markers including urinary copper, non‐ceruloplasmin bound copper (NCC) and liver function were analyzed at baseline and followed up over 12 months. Safety was assessed based on reported adverse events (AEs). Urinary copper levels and NCC remained stable across all follow‐ups, indicating adequate copper metabolism control. Reported AEs during TETA 2‐HCl treatment were mostly gastrointestinal discomfort (n = 6). In two patients, progressive elevation of transaminases occurred (despite stable copper metabolism). AEs led to discontinuation of treatment in five cases. Median baseline dose per day was 10.2 mg TETA 4‐HCl/kg bodyweight, whereas median baseline dose after therapeutic switch to TETA 2‐HCl was 12.8 mg/kg bodyweight. Median daily dose at 12 months did not differ significantly from TETA 2‐HCl dose at switching timepoint, with stable biochemical markers and markers of copper metabolism in most (25/30) of the patients. Transitioning from TETA 4‐HCl to TETA 2‐HCl maintained stable copper parameters and liver function in most of analyzed patients. TETA 2‐HCl treatment was generally well tolerated, suggesting that switching medications is safe and effective. In our real‐life cohort, adjustment factor of ~1.25× for the switch of TETA 4‐HCl to TETA 2‐HCl resulted in adequate copper metabolism control.

THU-335 - Quality of life in patients with Wilson disease treated with Trientine dihydrochloride: a prospective study

THU-335 - Quality of life in patients with Wilson disease treated with Trientine dihydrochloride: a prospective study

Exploring the potential of trientine tetrahydrochloride in the treatment of Wilson disease

Wilson disease is one of the uncommon, hereditary, slowly progressing, and autosomal recessive diseases that cause motion disorders. The pathogenesis of Wilson disease is attributed to the accumulation of copper in different parts of body mainly the brain, eyes, liver, etc. due to the mutation taking place in the ATP7B gene. This disease thus leads to dysfunction of liver, neurons, brain, eyes and infertility. Thus, there is a need of proper treatment for this disease. There are numerous treatments available, including penicillamine, zinc, ammonium tetrathiomolybdate, trientine, and combination drugs; however, these treatments have a variety of side effects and poor pharmacokinetics, leading to the approval of trientine salts, of which trientine tetrahydrochloride was found to be an efficient, safe, and drug with few side effects. In this review, various aspects related to the disease and trientine salts have been summarized including the pathogenesis of Wilson disease, treatments of Wilson disease, mechanism of trientine as well as comparative pharmacokinetics with the safety and efficacy of both the salts of trientine. We have also tried to explain the preference of usage of trientine tetrahydrochloride over trientine dihydrochloride with some drugs in clinical trials. Here various factors that lead to treatment failure and consideration of alternate therapies have been discussed. Clinical trials and investigations are still going on over gene therapy and stem cells usage in the treatment of Wilson disease which can be used as an effective treatment in future.

Efficacy and Safety of Two Salts of Trientine in the Treatment of Wilson's Disease.

Background: Wilson’s disease (WD) is one of the few genetic disorders that can be successfully treated with pharmacological agents. Copper-chelating agents (D-penicillamine and Trientine salts) and zinc salts have been demonstrated to be effective. There are two salts of trientine. Trientine dihydrochloride salt (TETA 2HCL) is unstable at room temperature and requires storage at 2–8 °C. Trientine tetrahydrochloride (TETA 4HCL) is a more stable salt of trientine that can be stored at room temperature. No comparative study between both of the salts of trientine has been performed to date. As the two chemical forms were available in France between 1970 and 2009, we conducted a study to evaluate their efficacy and safety profiles. Methods: This retrospective cohort study was conducted by reviewing data from the national WD registry in France. Forty-three WD patients who received TETA 2HCL or TETA 4HCL monotherapy for at least one year until 2010 were included. The primary endpoints were hepatic and neurological outcomes. Secondary endpoints were the events leading to a discontinuation of medication. Results: Changes in medication were common, leading to the analysis of 57 treatment sequences of TETA 4HCL or TETA 2HCL. The mean duration of treatment sequence was significantly longer in the TETA 4 HCL group (12.6 years) than in the TETA 2HCL group (7.6 years) (p = 0.011). Ten patients experienced both trientine salts: eight stopped TETA 4 HCL (six had a hepatologic phenotype and two had a neurological phenotype) because this treatment was not available anymore (mean duration 7.4 years). Three of these patients already experienced TETA 2 HCL before the sequence. Two patients with a hepatologic phenotype (one had a previous sequence of TETA 4 HCL before) stopped TETA 2 HCL because of cold storage issues (mean duration 42.8 years). The total number of sequences was 57. All of the patients were clinically stable. No difference in efficacy was detected. Both treatments were well tolerated, except for a case of recurrence of lupus erythematosus-like syndrome in the TETA 2HCL group. The major reason for interruption of TETA 4HCL was due to a discontinuation in production of this salt. The reasons for stopping TETA 2HCL were mainly due to adherence issues largely attributed to the cold storage requirement. Conclusions: The two salts of trientine were effective in treating patients with WD. However, interruption of TETA 2HCL was frequent, linked to the cold storage requirement. As adherence to treatment is a key factor in the successful management of WD, physicians need to be even more vigilant in detecting adherence difficulties in patients receiving treatment with TETA 2HCL.

FRI258 - Gender dependent neurological and hepatic improvement in Wilson disease patients treated with Trientine dihydrochloride: post hoc results from a prospective study

FRI258 - Gender dependent neurological and hepatic improvement in Wilson disease patients treated with Trientine dihydrochloride: post hoc results from a prospective study

Multicentre, retrospective study to assess long-term outcomes of chelator based treatment with trientine in Wilson disease patients withdrawn from therapy with d -penicillamine.

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. 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. 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. TETA-2HCl is well-tolerated and effective in Wilson disease patients following the withdrawal of treatment with D-penicillamine. ClinicalTrials.govIdentifier : NCT02426905.

Copper chelation in patients with hypertrophic cardiomyopathy

BackgroundDisturbances of copper (Cu) homeostasis can lead to hypertrophic cardiac phenotypes (eg, Wilson’s disease). We previously identified abnormal Cu homeostasis in patients with hypertrophic cardiomyopathy (HCM) and, therefore, hypothesised that...

Trientine dihydrochloride for Wilson's disease.

Trientine dihydrochloride for Wilson's disease.

Optimized Trientine-dihydrochloride Therapy in Pediatric Patients With Wilson Disease: Is Weight-based Dosing Justified?

The aim of the study was to investigate the efficacy and safety of trientine-dihydrochloride (TD) in pediatric patients with Wilson disease (WD) and the effect of different weight-based dosages on their clinical and biochemical outcome. We retrospectively reviewed the clinical data of 31 children with WD receiving TD therapy ages under 18 years at the time of diagnosis. Outcome measures included parameters of copper metabolism and liver function tests. To examine the impact of different weight-based dosages, 2 dosage subgroups were analyzed. Group 1 received less than 20 mg/kg TD per day, group 2 more than 20 mg · kg-1 · day-1. Median follow-up was 60 (5-60) months in the total study group. During TD therapy, nonceruloplasmin-bound copper was reduced from mean 1.53 (0.01-6.95) at baseline to 0.62 (0.01-4.57) μmol/l. 24h-urinary copper excretion diminished to 1.85 (0.8-9.6) μmol/day approximating the therapeutic goal of 1.6 μmol/day. Seven of 31 patients (22.6%) required discontinuation of TD treatment, in 4 cases it was because of adverse events (ulcerative colitis, gingival and breast hypertrophy, hirsutism, elevation of transaminases).Investigations about weight-based dosage showed no significant difference of any laboratory parameter between the 2 cohorts. But in terms of clinical safety, adverse effects because of TD were only found in 6.7% of children in group 1 (<20 mg · kg-1 · day-1, median follow-up 60 [9-60] months), whereas in group 2 (>20 mg · kg-1 · day-1, median follow-up 60 [14-60] months), it was 63.6%. TD proves to be an efficacious alternative chelating agent for children with WD. Weight-based dosages above the recommended 20 mg · kg-1 · day-1 may increase the rate of adverse effects in pediatric patients.

Human medicines European public assessment report (EPAR): Cufence, trientine dihydrochloride, Hepatolenticular Degeneration, Date of authorisation: 25/06/2019, Status: Authorised

Human medicines European public assessment report (EPAR): Cufence, trientine dihydrochloride, Hepatolenticular Degeneration, Date of authorisation: 25/06/2019, Status: Authorised

Orphan designation: trientine dihydrochloride, Treatment of Wilson's disease

Orphan designation: trientine dihydrochloride, Treatment of Wilson's disease

Summary of opinion: Cufence,trientine dihydrochloride

Summary of opinion: Cufence,trientine dihydrochloride

Copper chelation by trientine dihydrochloride inhibits liver RFA-induced inflammatory responses in vivo.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. Radiofrequency ablation (RFA) is currently performed widely for managing HCC. RFA treatment causes damage around the ablation. Trientine dihydrochloride has been used to reduce the copper in liver. The rats were treated with trientine dihydrochloride for 5days before liver RFA. Liver function, copper concentration, inflammation biomarkers and MDA, SOD were analyzed after RFA treatment for 2h, 2 and 5days. The results indicated that trientine dihydrochloride reduced the copper in plasma and liver tissue significantly. And trientine dihydrochloride significantly inhibited RFA-induced inflammatory gene expression in liver. Similar inhibitory effects of trientine dihydrochloride were observed on ROS-induced malondialdehyde production in liver tissues. These results suggest that pre-treatment with the selective copper chelator trientine dihydrochloride can inhibit inflammatory response effectively during and after liver RFA in vivo. Chelation of copper to a lower level before liver RFA may be a novel strategy to prevent or ameliorate inflammatory responses in liver induced by RFA and to protect the parenchyma tissues in liver during and after RFA in HCC patients.

Edema and Cirrhosis Caused by Wilson's Disease

Figure 1 Kayser-Fleischer ring, copper deposition in Descemet’s membrane, was revealed as a crescent at the top of the cornea (arrow) by ocular slit-lamp examination. A previously healthy 11-year-old boy had puzzling pitting edema of his lower legs for 5 weeks prior to presentation, as well as progressive weight gain (46e52 kg), puffy eyelids, and scrotal edema. Laboratory tests showed severe hypoalbuminemia (1.67 g/dL), absence of urinary protein, and hypertransaminasemia (AST 311 IU/L, ALT 72 IU/L, bilirubin 0.97/0.26 mg/dL). Ocular slit-lamp examination revealed yellowish cloudy crescent Kayser-Fleischer rings at the upper cornea (Figure 1). An axial computed tomography scan of the abdomen demonstrated cirrhotic liver with encapsulated and intraperitoneal ascites (Figure 2). Wilson’s disease with Child’s class C cirrhosis was confirmed by low serum ceruloplasmin (8.65 mg/dL; normal range, 20e35 mg/dL) and high urinary copper excretion (353.8 mg in 24 hours; normal <100 mg). After the penicillamine challenge test, the 24-hour urinary copper significantly increased to 2782 mg. The patient received a low copper diet and chelating therapy with 6 weeks of D-penicillamine, which was followed by trientine dihydrochloride and zinc acetate because of pancytopenia. Normal liver function

Normal Cerebellar Metabolism in a Patient with Superficial Siderosis

Normal Cerebellar Metabolism in a Patient with Superficial Siderosis

Trientine Dihydrochloride Encapsulated Nanoparticles for Copper Chelation Therapy in Rat Model of Non-Wilsonian Brain Copper Toxicosis

Trientine is unable to mitigate the brain copper overload and neurological manifestations in Wilson's disease patients. The aim of this study was to assess the therapeutic efficacy of orally administered Trientine loaded nanoparticles to that of conventional Trientine for 90 days in Wistar rat model for non-Wilsonian brain copper toxicosis. High performance liquid chromatography, atomic absorption spectrophotometry, biochemical estimations, neurobehavioral and histopathological studies, and nanoparticles preparation and their physicochemical characterization were carried out.

An Early Sign of Wilson's Disease: Dysarthria.

Dear Editor, We would like to present here, a case of Wilson’s disease (WD), who was having a history of dysarthria since 3 months. A 10-year-old male child was admitted to Neurology Department of a tertiary care hospital in northeast India. As per the medical history of patient which was narrated by his mother, patient had been having episodes of high grade fever, loose motions and difficulty in speaking, for around 3 months. After consulting a private practitioner, fever and loose motions of the patient subsided, but slurred speech was persistent. Gradually, patient developed a low pitched voice, was unable to hold his footwear because of abnormal posturing of left leg toe and he had difficulty in chewing and swallowing. On examination, his vital signs were normal, except icterus and pallor. Ceruloplasmin is a serum glycoprotein which carries majority of copper in the blood and the patients with WD have low levels of ceruloplasmin [1]. In contrast, in our case, serum ceruloplasmin was within normal range, i.e. 324mg/l (normal 200-350mg/l), whereas serum copper was 46μg/dl (normal 70-140μg/dl). The haemoglobin concentration was 16gm%, white blood cell count was 9.1×103/mm3 and platelet count was 106×103/mm3. The serum concentrations of electrolytes were normal, creatinine was 0.36mg% and total bilirubin was 0.3mg% (direct fraction 0.2mg). Serum levels of AST, ALT and alkaline phosphatase were 88, 65 and 242U/L respectively. The 24 hour urine copper level was 835.48μg/day (normal 32-64μg/day). The diagnosis was made on the basis of urine copper levels, Kayser-Fleischer ring and face of giant panda on T2-weighted images seen on Magnetic Resonance Imaging. The penicillamine test was not performed in this case. At the hospital, tablet distamine (penicillamine 250mg) and tablet zincolac (folic acid 1.5mg, pyridoxine 3mg, riboflavin 10mg, thiamine 10mg, calcium pantithenate 5mg, lacto bacillus sporegens -60 million spores, niacinamide 45mg and zince sulphate 45mg) were prescribed to the patient and he was then discharged after one week. Thus, we can depict that tablet distamine was prescribed as a chelator to form penicillamine-copper complexes, while tablet zincolac was prescribed to block copper absorption from the intestinal track. However, after a few days, patient was again admitted with the complaint of aggravated abnormal behaviour and dystonia which involved tongue, right upper limb, left lower limb and right foot. The clinical features indicated potential intolerance to penicillamine and physician advised the patient’s mother to withdraw the tablet distamine. Tablet trientine dihydrochloride (triethylenetetramine 1000mg) was prescribed instead. In WD, copper accumulates in gray and white matter along with the basal ganglia, resulting in improper modulation of the basal ganglia by the subthalamic nucleus [2]. The mixed dysarthria with hypotonia and dystonia is common, because copper damages the extrapyramidal pathways as well as various components of motor system [3]. Initially, patient had difficulty in pronouncing lingual and he gradually developed a slower speech rate, hypophonia, variation in loudness, abnormal stress patterns on words, stuttering and palilalia. Thus, dysarthria in patients can be considered as an effective monitor of progress in the treatment of this disease [4]. This case indicated that dysarthria should not be overlooked in patients and that its cause should be figured out, for early detection of disease and to begin appropriate treatment.

The copper-chelating agent, trientine, attenuates liver enzyme-altered preneoplastic lesions in rats by angiogenesis suppression

It has been shown that angiogenesis plays an important role not only in tumor growth, but also in carcinogenesis. We previously reported that the copper-chelating agent, trientine dihydrochloride (trientine), exerted strong anti-angiogenic activity and inhibited hepatocellular carcinoma (HCC) tumor growth. The aim of the current study was to elucidate the effect of trientine on liver enzyme-altered preneoplastic lesions in rats, especially in conjunction with angiogenesis alteration in the liver. In a diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis model, trientine treatment, even at a clinically comparable low dose, significantly suppressed glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions associated with a decrease in copper content in the liver. Trientine also markedly suppressed neovascularization in the liver to a similar level as that of development of the preneoplastic lesions. On the contrary, the proliferative cell nuclear antigen (PCNA)-positive cells were not altered with or without trientine treatment. These results suggested that the copper-chelating agent, trientine, exerted chemopreventive effects against rat liver carcinogenesis due to the suppression of angiogenesis, and suggest that it might be useful clinically as a chemopreventive agent of HCC.

The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.

Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.

Oxidative stress in LEC rats evaluated by plasma antioxidants and free fatty acids

The Long-Evans cinnamon (LEC) rat, an animal model of Wilson's disease, develops hepatitis and liver cancer, Since LEC rats accumulate copper especially in the liver and since copper is a good catalyst of oxidation, selected plasma markers of oxidative stress in LEC rats and control Long-Evans agouti (LEA) rats were measured. Significant decrease in the plasma ascorbate level was observed even at the onset of hepatitis, suggesting that LEC rats are under oxidative stress because ascorbate is very susceptible to oxidation. The ratio of plasma ubiquinol-9, another oxidatively vulnerable antioxidant, to ubiquinone-9 in LEC rats also decreased significantly after the onset of hepatitis. Oxidative damage in the liver of LEC rats after the onset of hepatitis was also suggested by a decrease in the ratio of polyunsaturated fatty acids (PUFA) to free fatty acids (FFA) and an increase in the palmitoleic acid to FFA ratio in plasmas of LEC rats when compared with LEA rats since PUFA are vulnerable to oxidation and δ9 desaturase is activated in order to compensate for the loss of PUFA. All of the above changes and hepatitis were prevented by adding a copper chelating agent, trientine dihydrochloride, to the drinking water of LEC rats. These data suggest that oxygen radicals may play an important role in the development of hepatitis and the subsequent liver cancer. J. Trace Elem. Exp. Med. 10:129–134, 1997. © 1997 Wiley-Liss, Inc.