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At least 19 recordsLinked to original sources
PubMed1992

Wilson's disease treatment by triethylene tetramine dihydrochloride (trientine, 2HCl): long-term observations.

Wilson's disease is an autosomal recessive disorder characterized by an accumulation of a toxic amount of copper in the body. Triethylene tetramine dihydrochloride (trientine, 2HCl) is a new chelating agent that may be effective in the removal of excess copper but long-term efficacy has not yet been investigated. Here we report the use of trientine over more than 8 years in 2 patients with Wilson's disease who could not tolerate D-penicillamine. We found no significant side effect, except a decreased serum iron concentration without clinical symptoms of anemia. In annual examinations at a steady state, the serum copper levels remained below 20 micrograms/100 ml. The 24-hour urinary copper excretion was less than that found using D-penicillamine, while the basal copper excretion, after 5 days abstinence from trientine, was maintained below 100 micrograms/day. Both hepatic and neurological manifestations except bulbar symptoms were recovered without any initial deterioration.

Adolescent↗
PubMed1991

A comparison of the effects of penicillamine, trientine, and trithiomolybdate on [35S]-labeled metallothionein in vitro; implications for Wilson's disease therapy.

The synthesis of radiolabeled metallothionein was induced in rats in vivo by the injection of CuSO4 and [35S]-cysteine. Treatment of "cold" rat liver cytosol "spiked" with purified [35S] metallothionein with Penicillamine and Trientine showed that even at relatively high concentrations (up to 50 mg/g liver, wet weight), these compounds had no effect on the copper peak or the position of the [35S] label in the cytosol eluate after Sephadex G-75 gel filtration. By contrast, incubation of the "spiked" liver cytosol with Trithiomolybdate, even at relatively low concentrations (0.5 mg/g liver, wet weight), resulted in a transfer of metallothionein copper to high molecular weight protein fractions; the position of the [35S] apoprotein was unaffected. This copper "stripping" effect on metallothionein supports clinical and other evidence that thiomolybdates have a genuine decoppering effect in vivo whereas Penicillamine and Trientine have another mode of action and indicates that thiomolybdates might provide a more rational alternate therapy for Wilson's disease patients.

Animals↗
PubMed1987

The use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson's disease.

Penicillamine is known to be effective therapy for Wilson's disease. However, the clinical consequences of the abrupt and permanent withdrawal of penicillamine have not been investigated. We studied 11 patients who stopped their own treatment after having been treated successfully with penicillamine (1 to 2 g per day) for periods of 3 to 19 years. Eight died of hepatic decompensation or fulminant hepatitis after an average survival of only 2.6 years. In another 13 patients, penicillamine was discontinued by the physician because of serious adverse reactions. In these patients, penicillamine was replaced with trientine (1 to 1.5 g per day), a newer chelating agent. All but one of these patients (who was killed accidentally) are alive at this writing, from 2 to 15 years later. Our observations suggest that discontinuation of penicillamine in patients with Wilson's disease results in rapid clinical deterioration, which is often fatal. The replacement of penicillamine with trientine appears to prevent this adverse clinical course.

Ethylenediamines↗
PubMed1990

Treatment of Wilson's disease with triethylene tetramine hydrochloride (Trientine).

Penicillamine is the drug of choice for the treatment of Wilson's disease, whatever the stage of the illness. Toxic manifestations may preclude the use of this life-saving drug in some patients and discontinuation of penicillamine therapy usually leads to death. We report our experience with Trientine in seven patients, aged 13 to 33 years, with Wilson's disease who developed toxic manifestations with penicillamine that required discontinuation of therapy. These include two with nephrosis, one with neutropenia, two with thrombocytopenia, and one each with a SLE-like and a Henoch-Schonlein-like syndrome. The patients were treated for periods from 6 weeks to 16 years with a dose of 0.5 to 2 g/day. Trientine proved to be an effective alternative copper chelating agent in the treatment of Wilson's disease in patients with penicillamine-induced neutropenia, thrombocytopenia, SLE, and nephrosis. No serious untoward side effects were noted.

Administration, Oral↗
PubMed1992

Evaluation of the efficacy of d-penicillamine and trientine as copper chelators using an in vitro technique involving ovine red blood cells.

An in vitro technique for haemolysing ovine red blood cells with copper sulphate was standardized to induce c 50% haemolysis with 0.5 mM CuSO4 after incubation for 14 h at 38 degrees C. This technique was then applied to test the efficacy of trientine and d-penicillamine in preventing haemolysis. Trientine concentrations of 0.5; 1.0 and 1.5 mM were found to be the most effective (P < 0.05) in reducing copper-induced haemolysis. One and 1.5 mM concentrations of d-penicillamine were also effective (P < 0.05), but in this experiment a 0.5 mM concentration failed to protect the erythrocytes.

Animals↗
PubMed1986

Treatment of nickel dermatitis with Trientine.

23 nickel-sensitive patients with hand eczema were treated with Trientine 300 mg daily and a placebo in a double-blind, crossover trial. No significant improvement occurred in the hand eczema. A surprising finding was that there was no detectable increase in urinary nickel excretion, in contrast to animal studies.

Adult↗
PubMed1986

The management of pregnancy in Wilson's disease treated with trientine.

Seven patients with Wilson's disease, treated with trientine, have been followed during 11 pregnancies. Eight of these resulted in the delivery of normal infants, whilst one was very premature (31 weeks) and was later shown to have a chromosomal defect, isochromosome X. There was one therapeutic termination and one miscarriage associated with a contraceptive coil. The eight children are progressing satisfactorily and have been studied for periods varying from three months to nine years; all mothers are also doing well. The child with the isochromosome X is developing slowly; she shows no morphological abnormalities at this stage. The normal-for-age caeruloplasmin values found in the cord blood indicates that there was no significant copper depletion in the foetuses, as a result of treatment.

Adult↗
PubMed1992

Comparison of disposition behavior and de-coppering effect of triethylenetetramine in animal model for Wilson's disease (Long-Evans Cinnamon rat) with normal Wistar rat.

The disposition behaviors and de-coppering effect of triethylenetetramine dihydrochloride (trientine), a selective chelating agent for copper and an 'orphan drug' for Wilson's disease, have been evaluated in an animal model, Long-Evans Cinnamon (LEC) rats, and normal rats (Wistar). In LEC rats, urinary excretion of trientine was remarkably lower than that of Wistar rats. The absorption rates from the jejunal loop and in vitro metabolism in the liver S9 fraction (supernatant of 9000 x g) were approximately the same for both strains. The decline of urinary excretion of trientine in LEC rats is thought to be due mainly to the lowering of the functional activity of the kidney, because urinary excretion of creatinine and phenolsulfonphthalein were significantly lower in LEC rats than those in Wistar rats. Both acceleration of urinary excretion of copper and reduction of hepatic copper levels were observed with treatment of trientine in LEC rats aged 6 weeks. In LEC rats aged 13 weeks, however, no de-coppering effect from the liver was observed, though urinary excretion of copper was increased. These results suggest that trientine has a pharmacological effect in disease state, especially in the early stages of hepatitis.

Animals↗
PubMed1991

Prognosis of Wilsonian chronic active hepatitis.

Twenty of 320 patients with Wilson's disease initially presented with chemical and laboratory features of chronic active hepatitis, confirmed histologically in 17. When first seen, cirrhosis was present in all 20 and was complicated by ascites and/or jaundice in 11. Within 1 week to 8 years of the onset of over liver disease the diagnosis of Wilson's disease was established, and treatment with D-penicillamine was promptly initiated in 19 patients. One man refused treatment and died 4 months later. Treated patients received D-penicillamine or trientine for a total of 264 patient-years (median, 14 patient-years). Abnormal water retention, for which salt restriction and diuretics were added to penicillamine or trientine, disappeared in all but 1 of the patients so affected. Symptomatic improvement and virtually normal levels of serum albumin, bilirubin, aspartate aminotransferase, and alanine aminotransferase followed within 1 year in the majority of subjects. One woman died after 9 months of treatment. Two patients, who became noncompliant with the therapeutic regimen after 9 and 17 years of successful pharmacological treatment, required liver transplants. These results indicate that the prognosis of specifically treated Wilsonian chronic active hepatitis is very good in spite of the presence of cirrhosis.

Adolescent↗
PubMed1987

[New possibilities in the treatment of Wilson-Konovalov disease (hepatolenticular degeneration)].

The favourable therapeutic effect of a new copper chelator--trientine (triethylenetetramine dihydrochloride) is reported. The drug was applied to 3 patients, 18 to 25 years of age, with Wilson-Konovalov disease (hepatolenticular degeneration) who in the course of chronic D-penicillamine treatment developed drug intolerance with signs of nephrotoxicity (in one patient) and myelotoxicity with leucopenia and thrombocytopenia (in two patients). The treatment was carried out orally with optimal daily dose of 1.8 gr trientine which led to a 4-6 times increase of the 24 hour urine copper excretion. The drug is well tolerated and no side effects of allergic reactions have been registered up to now in the patients treated.

Adolescent↗
PubMed1991

Pathophysiology and treatment of Wilson's disease.

The pathophysiology, symptomatology, and treatment of Wilson's disease are reviewed, and new approaches to drug management are discussed. Wilson's disease is a rare, autosomal recessive disorder that occurs between the ages of 6 and 60 years. Disturbances in copper metabolism may result in the accumulation of excess copper in the liver, the basal ganglia of the brain (lenticular degeneration), the kidneys, the cornea (Kayser-Fleischer rings), and other tissues. The diagnosis of Wilson's disease is frequently overlooked; nonspecific symptoms and multisystem involvement may mimic other disease states, such as neurologic and psychiatric disorders, and hemolytic anemia. Screening tests for Wilson's disease include 24-hour urinary copper levels, serum ceruloplasmin and copper assays, radioactive uptake of 64Cu, and liver biopsy. Current methods of therapy include the use of a chelating agent--penicillamine or trientine--for initial rapid decoppering. Penicillamine therapy has been associated with many adverse reactions, including worsening of the neurologic symptoms of the patient. Zinc is a useful agent for maintenance therapy. Investigational studies exploring the use of ammonium tetrathiomolybdate for initial rapid decoppering have shown promising results. Unless it is recognized and treated, Wilson's disease can cause severe symptoms and, ultimately, death. Initial rapid decoppering with chelating agents, such as penicillamine and trientine, followed by lifelong maintenance therapy with zinc is the current method of treatment.

Hepatolenticular Degeneration↗
PubMed1992

Wilson's disease: current status.

OBJECTIVE: To review current concepts about the pathogenesis, clinical manifestations, and treatment of Wilson's disease, with an emphasis on recent developments. DATA IDENTIFICATION: Published information was identified using MEDLINE and through extensive manual searching of bibliographies in identified sources. RESULTS: The basic biochemical alteration responsible for deranged hepatobiliary copper homeostasis in Wilson's disease has yet to be identified. The gene for Wilson's disease has been mapped to chromosome 13, but the function of its gene product has not yet been determined. The clinical manifestations of Wilson's disease are varied and often nonspecific and include a range of hepatic, neurologic, and psychiatric findings. Penicillamine remains the drug of choice for the treatment of Wilson's disease, but recent experience suggests that trientine and zinc may be safe, effective alternatives. All three drugs are probably safe for use in pregnant patients with Wilson's disease. Liver transplantation is the only effective treatment for Wilsonian fulminant hepatic failure and corrects the underlying metabolic defect. CONCLUSIONS: Wilson's disease is a disorder of hepatobiliary copper excretion manifested predominantly by hepatic and neurologic copper toxicosis and inherited in an autosomal recessive pattern. Although the specific underlying biochemical defect remains to be defined, specific therapy is available and usually successful. Maintaining a high index of suspicion is critical in diagnosing this readily treatable inherited disease.

Administration, Oral↗
PubMed1991

Mode of action of triethylenetetramine dihydrochloride on copper metabolism in Wilson's disease.

The drug of choice for the initial treatment of "decoppering" in Wilson's disease, an inherited disorder of copper metabolism, is the chelating agent D-penicillamine. In the case of harmful side-effects an alternative drug is triethylenetetramine dihydrocholoride (trien or trientine). Using the 24-h-urine excretion of copper and the oral copper loading test with copper-64, a double function for trien was found: trien increases the urine copper excretion and decreases the intestinal copper absorption respectively.

Adult↗
PubMed1990

[Intestinal absorption and urinary excretion of triethylenetetramine for Wilson's disease in rat].

Triethylenetetramine.2.HCl (trientine, TE) is an orphan drug for the treatment of Wilson's disease. There has been no reports regarding the absorption, distribution, metabolism, and excretion in the body. In the current study, the absorption and excretion of TE in rats were examined. The observed mean percentage amount of TE absorbed at the jejunum and ileum with the loop method for 1 h was 42.0% and 22.5%, respectively. Tight junction blocking agent inhibited the absorption of TE from the jejunum loop with 27%, but the absorption of TE from the ileum loop was not affected by this blocking agent. Therefore, the main absorption route for TE might be permeation across the plasma membrane of intestinal epithelial cells. TE and amikacin, a polycationic compound like TE, bound to the brush border membrane (BBM) of rat small intestine in the absence of inorganic ions such as Na+, K+, Ca2+, Mg2+ and Cu2+. But the binding of TE to BBM was inhibited markedly under the physiological concentration of these ions. The bioavailability of TE was below 10% and the plasma levels of TE in non-fasted rats were significantly lower than that observed in fasted rats. The urinary excretion of unchanged TE during 24 h was only 3.5% of the orally administered dose. However, the urinary excretion of total TE including metabolites, though they have not been identified, was 35.7%. These results suggest that low bioavailability of TE might be due to the rapid metabolism in the body after absorption from the gastrointestinal tract.

Administration, Oral↗
PubMed1989

Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients.

An analysis has been made of presenting symptoms and course in 87 patients with predominantly hepatic Wilson's disease. In 30 patients, in whom the diagnosis was made relatively quickly, response to treatment was excellent and all recovered although two had severe haemolytic crises. Mean age of onset was 11 years (range five to 22). Nine patients suffered toxic reactions to penicillamine and were then treated with trientine. In 22 patients the diagnosis was made after neurological symptoms had supervened; in 20 the signs of hepatic damage had disappeared despite the lack of treatment but in two hepatic signs persisted until the central nervous system was affected. In the 20 patients in whom signs of liver disease resolved spontaneously there was a time interval of from one to eight years before neurological signs developed. All 22 patients in a third group died of hepatic disease without central nervous system involvement. In 19 cases duration of the illness was brief and the diagnosis was made very late or at post-mortem examination. One patient survived with chronic progressive liver damage for 20 years; diagnosis was also made at post-mortem examination. Mean age at death was 15 years. The diagnosis was made retrospectively in 13 patients who died. In two of these the diagnosis was confirmed by determination of the liver copper concentration on tissue saved at postmortem examination; in the other 11 the diagnosis is probable since other siblings developed a similar illness, proven to be Wilson's disease. Age range for these patients was eight to 13 years. Duration of the illness from onset to death was nine days to four years (mean 10 weeks). There was no example of primary carcinoma of the liver in this series.

Adolescent↗