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George J Brewer - One of the best experts on this subject based on the ideXlab platform.

  • the modern treatment of wilsons disease
    Journal of Gastrointestinal and Digestive System, 2014
    Co-Authors: George J Brewer
    Abstract:

    Wilson’s disease is an inherited defect in biliary copper excretion, causing a buildup of copper and copper toxicity, primarily in liver and brain. Presentation with liver disease and/or neurological disease usually occurs in the second and third decades of life. Recognition of the disease is often delayed, which is unfortunate, because once appropriate treatment is started, progression of the disease can be halted, and further damage avoided. Regarding current treatment, many physicians are only aware of penicillamine, because it was the first orally effective drug developed. However, penicillamine has outlived its usefulness, being more toxic than more recently developed drugs. For the hepatic presentation, a combination of Trientine and zinc should be used for 4-6 months, then Trientine stopped and zinc used for lifelong maintenance therapy. For the neurological presentation, tetrathiomolybdate should be used if available for 8-16 weeks, then zinc for maintenance. If tetrathiomolybdate is not available, zinc should be used. For presymptomatic patients, zinc should be used from the beginning. Zinc should also be used for pregnant and pediatric patients, with a reduced dose for the latter. Zinc causes gastric intolerance in some patients, so in all cases where zinc is the favored therapy, if it is not tolerated, then Trientine should be used as second choice. In too many cases, patients are put on zinc, compliance not monitored, and then papers are written about “zinc failures”. There are no zinc failures, just noncompliance problems.

  • treatment of wilson s disease with tetrathiomolybdate v control of free copper by tetrathiomolybdate and a comparison with Trientine
    Translational Research, 2009
    Co-Authors: George J Brewer, Frederick K Askari, Martha D Carlson, Karen J Kluin, John K. Fink, Robert B Dick, Julia Sitterly, Matthew T Lorincz
    Abstract:

    It has become clear that serum “free” copper (the copper not bound to ceruloplasmin in the blood) is the copper causing copper toxicity in Wilson's disease. But up until now, free copper has not been closely followed during initiation of anticopper therapy in neurologically presenting patients. During this period of initial therapy, the future fate of these patients hangs in the balance—if they worsen neurologically as often happens with penicillamine or Trientine therapy, many never recover. We hypothesize that free copper levels are a biological marker of clinical outcome in these patients. In this article, we evaluate the control of free copper in 3 studies of initial anticopper treatment in neurologically presenting Wilson's disease patients. The first (study 1) is a 55-patient open-label trial of tetrathiomolybdate, the second (study 2) is a 48-patient double-blind trial comparing tetrathiomolybdate and Trientine, and the third (study 3) is a 40-patient double-blind comparison of 2 disease regimens of tetrathiomolybdate. Free copper levels were determined by subtracting ceruloplasmin and tetrathiomolybdate bound copper from total serum copper. Tetrathiomolybdate showed very strong control of free copper levels over the 8 weeks of treatment in the 55-patient open-label study (study 1), reducing it to a mean value of about one fourth, or less, of baseline. In the tetrathiomolybdate/Trientine double blind (study 2), tetrathiomolybdate again showed good control of free copper levels over 8 weeks of treatment, which is significantly better than Trientine. In the Trientine arm of study 2, mean free copper levels actually went up during Trientine therapy. The 5 patients who neurologically worsened on Trientine therapy over 8 weeks of treatment showed significant spikes in serum free copper levels associated in time with their neurologic worsening. Patients who did not worsen neurologically generally did not show significant spikes in free copper. Tetrathiomolybdate controlled copper less well in the dose regimen study (study 3) than in the previous 2 studies of tetrathiomolybdate treatment, probably because of a change in the way “away from food” tetrathiomolybdate was given.

  • tetrathiomolybdate versus Trientine in the initial treatment of neurologic wilson s disease
    Progress in Neurotherapeutics and Neuropsychopharmacology, 2008
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    ABSTRACTBackground: The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus Trientine in the neurologically presenting Wilson's disease patient. Design and Methods: The study was a double blind design in which patients received either TM plus zinc, or Trientine plus zinc, for 8 weeksThis study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or Trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results: Twenty-three patients were entered into the Trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated (p < 0.05). One patient on Trientine had an adverse event while 7 on TM had adverse events. All adverse events were mild. Four patients in the Trientine arm died during follow-up, 3 having shown initial neurologic deterioration, 2 patients in the TM arm died. In those patients who did not deteriorate or die, neurologic and speech recovery over 3 years was good. Interpretation: TM is a superior choice to Trientine for the initial therapy of neurologic Wilson's disease.

  • Tetrathiomolybdate versus Trientine in the Initial Treatment of Neurologic Wilson's Disease
    Progress in Neurotherapeutics and Neuropsychopharmacology, 2007
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    ABSTRACT Background : The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus Trientine in the neurologically presenting Wilson's disease patient. Design and Methods : The study was a double blind design in which patients received either TM plus zinc, or Trientine plus zinc, for 8 weeks This study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or Trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results : Twenty-three patients were entered into the Trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated ( p Interpretation : TM is a superior choice to Trientine for the initial therapy of neurologic Wilson's disease.

  • treatment of wilson disease with ammonium tetrathiomolybdate iv comparison of tetrathiomolybdate and Trientine in a double blind study of treatment of the neurologic presentation of wilson disease
    JAMA Neurology, 2006
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    OBJECTIVE: To compare tetrathiomolybdate and Trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. DESIGN: A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of Trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received 50 mg of zinc 2 times per day. Patients were hospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. SETTING: A university hospital referral setting. PATIENTS: Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. INTERVENTION: Treatment with either Trientine plus zinc or tetrathiomolybdate plus zinc. MAIN OUTCOME MEASURES: Neurologic function was assessed by semiquantitative neurologic and speech examinations. Drug adverse events were evaluated by blood cell counts and biochemical measures. RESULTS: Six of 23 patients in the Trientine arm and 1 of 25 patients in the tetrathiomolybdate arm underwent neurologic deterioration (P<.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving Trientine had an adverse effect of anemia. Four patients receiving Trientine died during follow-up, 3 having shown initial neurologic deterioration. Neurologic and speech recovery during a 3-year follow-up period were quite good. CONCLUSION: Tetrathiomolybdate is a better choice than Trientine for preserving neurologic function in patients who present with neurologic disease.

Karen J Kluin - One of the best experts on this subject based on the ideXlab platform.

  • treatment of wilson s disease with tetrathiomolybdate v control of free copper by tetrathiomolybdate and a comparison with Trientine
    Translational Research, 2009
    Co-Authors: George J Brewer, Frederick K Askari, Martha D Carlson, Karen J Kluin, John K. Fink, Robert B Dick, Julia Sitterly, Matthew T Lorincz
    Abstract:

    It has become clear that serum “free” copper (the copper not bound to ceruloplasmin in the blood) is the copper causing copper toxicity in Wilson's disease. But up until now, free copper has not been closely followed during initiation of anticopper therapy in neurologically presenting patients. During this period of initial therapy, the future fate of these patients hangs in the balance—if they worsen neurologically as often happens with penicillamine or Trientine therapy, many never recover. We hypothesize that free copper levels are a biological marker of clinical outcome in these patients. In this article, we evaluate the control of free copper in 3 studies of initial anticopper treatment in neurologically presenting Wilson's disease patients. The first (study 1) is a 55-patient open-label trial of tetrathiomolybdate, the second (study 2) is a 48-patient double-blind trial comparing tetrathiomolybdate and Trientine, and the third (study 3) is a 40-patient double-blind comparison of 2 disease regimens of tetrathiomolybdate. Free copper levels were determined by subtracting ceruloplasmin and tetrathiomolybdate bound copper from total serum copper. Tetrathiomolybdate showed very strong control of free copper levels over the 8 weeks of treatment in the 55-patient open-label study (study 1), reducing it to a mean value of about one fourth, or less, of baseline. In the tetrathiomolybdate/Trientine double blind (study 2), tetrathiomolybdate again showed good control of free copper levels over 8 weeks of treatment, which is significantly better than Trientine. In the Trientine arm of study 2, mean free copper levels actually went up during Trientine therapy. The 5 patients who neurologically worsened on Trientine therapy over 8 weeks of treatment showed significant spikes in serum free copper levels associated in time with their neurologic worsening. Patients who did not worsen neurologically generally did not show significant spikes in free copper. Tetrathiomolybdate controlled copper less well in the dose regimen study (study 3) than in the previous 2 studies of tetrathiomolybdate treatment, probably because of a change in the way “away from food” tetrathiomolybdate was given.

  • tetrathiomolybdate versus Trientine in the initial treatment of neurologic wilson s disease
    Progress in Neurotherapeutics and Neuropsychopharmacology, 2008
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    ABSTRACTBackground: The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus Trientine in the neurologically presenting Wilson's disease patient. Design and Methods: The study was a double blind design in which patients received either TM plus zinc, or Trientine plus zinc, for 8 weeksThis study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or Trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results: Twenty-three patients were entered into the Trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated (p < 0.05). One patient on Trientine had an adverse event while 7 on TM had adverse events. All adverse events were mild. Four patients in the Trientine arm died during follow-up, 3 having shown initial neurologic deterioration, 2 patients in the TM arm died. In those patients who did not deteriorate or die, neurologic and speech recovery over 3 years was good. Interpretation: TM is a superior choice to Trientine for the initial therapy of neurologic Wilson's disease.

  • Tetrathiomolybdate versus Trientine in the Initial Treatment of Neurologic Wilson's Disease
    Progress in Neurotherapeutics and Neuropsychopharmacology, 2007
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    ABSTRACT Background : The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus Trientine in the neurologically presenting Wilson's disease patient. Design and Methods : The study was a double blind design in which patients received either TM plus zinc, or Trientine plus zinc, for 8 weeks This study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or Trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results : Twenty-three patients were entered into the Trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated ( p Interpretation : TM is a superior choice to Trientine for the initial therapy of neurologic Wilson's disease.

  • treatment of wilson disease with ammonium tetrathiomolybdate iv comparison of tetrathiomolybdate and Trientine in a double blind study of treatment of the neurologic presentation of wilson disease
    JAMA Neurology, 2006
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    OBJECTIVE: To compare tetrathiomolybdate and Trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. DESIGN: A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of Trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received 50 mg of zinc 2 times per day. Patients were hospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. SETTING: A university hospital referral setting. PATIENTS: Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. INTERVENTION: Treatment with either Trientine plus zinc or tetrathiomolybdate plus zinc. MAIN OUTCOME MEASURES: Neurologic function was assessed by semiquantitative neurologic and speech examinations. Drug adverse events were evaluated by blood cell counts and biochemical measures. RESULTS: Six of 23 patients in the Trientine arm and 1 of 25 patients in the tetrathiomolybdate arm underwent neurologic deterioration (P<.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving Trientine had an adverse effect of anemia. Four patients receiving Trientine died during follow-up, 3 having shown initial neurologic deterioration. Neurologic and speech recovery during a 3-year follow-up period were quite good. CONCLUSION: Tetrathiomolybdate is a better choice than Trientine for preserving neurologic function in patients who present with neurologic disease.

  • treatment of wilson disease with ammonium tetrathiomolybdate iv comparison of tetrathiomolybdate and Trientine in a double blind study of treatment of the neurologic presentation of wilson disease
    JAMA Neurology, 2006
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    Objective: To compare tetrathiomolybdate and Trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. Design:A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of Trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received50mgofzinc2timesperday.Patientswerehospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. Setting: A university hospital referral setting. Patients:Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. Intervention:Treatment with either Trientine plus zinc or tetrathiomolybdate plus zinc. Main Outcome Measures: Neurologic function was assessed by semiquantitative neurologic and speech examinations.Drugadverseeventswereevaluatedbyblood cell counts and biochemical measures. Results: Six of 23 patients in the Trientine arm and 1 of 25patientsinthetetrathiomolybdatearmunderwentneurologic deterioration (P.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving Trientine had an adverse effect of anemia.FourpatientsreceivingTrientinediedduringfollow-up, 3 having shown initial neurologic deterioration.Neurologicandspeechrecoveryduringa3-yearfollow-up period were quite good. Conclusion:Tetrathiomolybdate is a better choice than Trientine for preserving neurologic function in patients who present with neurologic disease. ClinicalTrials.gov Identifier: NCT00004339

Michael L. Schilsky - One of the best experts on this subject based on the ideXlab platform.

  • ORIGINAL ARTICLE Prospective Pilot Study of a Single Daily Dosage of Trientine for the Treatment of Wilson Disease
    2016
    Co-Authors: Aftab Ala, Michael L. Schilsky, Ermal Aliu, Alt Alananine Aminotransferase
    Abstract:

    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. Methods 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 lg, 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)

  • Trientine induced colitis during therapy for Wilson disease: a case report and review of the literature
    BMC pharmacology & toxicology, 2015
    Co-Authors: Salih Boga, Dhanpat Jain, Michael L. Schilsky
    Abstract:

    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. 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. 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.

  • tetrathiomolybdate versus Trientine in the initial treatment of neurologic wilson s disease
    Progress in Neurotherapeutics and Neuropsychopharmacology, 2008
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    ABSTRACTBackground: The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus Trientine in the neurologically presenting Wilson's disease patient. Design and Methods: The study was a double blind design in which patients received either TM plus zinc, or Trientine plus zinc, for 8 weeksThis study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or Trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results: Twenty-three patients were entered into the Trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated (p < 0.05). One patient on Trientine had an adverse event while 7 on TM had adverse events. All adverse events were mild. Four patients in the Trientine arm died during follow-up, 3 having shown initial neurologic deterioration, 2 patients in the TM arm died. In those patients who did not deteriorate or die, neurologic and speech recovery over 3 years was good. Interpretation: TM is a superior choice to Trientine for the initial therapy of neurologic Wilson's disease.

  • Tetrathiomolybdate versus Trientine in the Initial Treatment of Neurologic Wilson's Disease
    Progress in Neurotherapeutics and Neuropsychopharmacology, 2007
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    ABSTRACT Background : The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus Trientine in the neurologically presenting Wilson's disease patient. Design and Methods : The study was a double blind design in which patients received either TM plus zinc, or Trientine plus zinc, for 8 weeks This study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or Trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results : Twenty-three patients were entered into the Trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated ( p Interpretation : TM is a superior choice to Trientine for the initial therapy of neurologic Wilson's disease.

  • wilson disease in children serum aminotransferases and urinary copper on triethylene tetramine dihydrochloride Trientine treatment
    Journal of Pediatric Gastroenterology and Nutrition, 2007
    Co-Authors: Ronen Arnon, Michael L. Schilsky, Judith Flores Calderon, Sukru Emre, Benjamin L Shneider
    Abstract:

    Objectives To evaluate the efficacy of and adherence to Trientine and/or zinc therapy in children with Wilson disease (WD). Materials and methods We retrospectively reviewed the clinical records of all children with WD in the pediatric liver/liver transplant program at our institution between 1998 and 2006. Results A total of 22 children with WD were evaluated and treated. Seven with fulminant disease required liver transplantation and 15 were treated with Trientine and/or zinc. Ten of those 15 had follow-up for 12 to 60 months and 6 of the latter 10 were followed for 12 to 18 months. All 10 patients were started on a Trientine treatment regimen. Mean alanine aminotransferase (ALT) levels decreased from 183 +/- 103 IU at presentation (n = 10) to 80 +/- 46 IU at 12 months (n = 10) and 66 +/- 40 IU at 18 months (n = 7). Mean 24-hour urinary copper levels increased from 156 microg at presentation to 494 microg at 1 to 2 months, then decreased to 71 microg after 21 to 24 months of treatment. Three of 10 patients had normalized ALT levels and 1 patient with cirrhosis continued with normal ALT levels since presentation. Four of 10 patients were documented to be nonadherent, as manifested by increased ALT levels (99 +/- 31 IU); 1 patient had previously normalized ALT levels. In 3 of 10 patients, ALT level decreased but remained at an abnormal level (93 +/- 53 IU). Conclusions Trientine and/or zinc therapy is effective for children with WD. Nonadherence is a common cause of increased aminotransferase levels in patients with WD.

John K. Fink - One of the best experts on this subject based on the ideXlab platform.

  • treatment of wilson s disease with tetrathiomolybdate v control of free copper by tetrathiomolybdate and a comparison with Trientine
    Translational Research, 2009
    Co-Authors: George J Brewer, Frederick K Askari, Martha D Carlson, Karen J Kluin, John K. Fink, Robert B Dick, Julia Sitterly, Matthew T Lorincz
    Abstract:

    It has become clear that serum “free” copper (the copper not bound to ceruloplasmin in the blood) is the copper causing copper toxicity in Wilson's disease. But up until now, free copper has not been closely followed during initiation of anticopper therapy in neurologically presenting patients. During this period of initial therapy, the future fate of these patients hangs in the balance—if they worsen neurologically as often happens with penicillamine or Trientine therapy, many never recover. We hypothesize that free copper levels are a biological marker of clinical outcome in these patients. In this article, we evaluate the control of free copper in 3 studies of initial anticopper treatment in neurologically presenting Wilson's disease patients. The first (study 1) is a 55-patient open-label trial of tetrathiomolybdate, the second (study 2) is a 48-patient double-blind trial comparing tetrathiomolybdate and Trientine, and the third (study 3) is a 40-patient double-blind comparison of 2 disease regimens of tetrathiomolybdate. Free copper levels were determined by subtracting ceruloplasmin and tetrathiomolybdate bound copper from total serum copper. Tetrathiomolybdate showed very strong control of free copper levels over the 8 weeks of treatment in the 55-patient open-label study (study 1), reducing it to a mean value of about one fourth, or less, of baseline. In the tetrathiomolybdate/Trientine double blind (study 2), tetrathiomolybdate again showed good control of free copper levels over 8 weeks of treatment, which is significantly better than Trientine. In the Trientine arm of study 2, mean free copper levels actually went up during Trientine therapy. The 5 patients who neurologically worsened on Trientine therapy over 8 weeks of treatment showed significant spikes in serum free copper levels associated in time with their neurologic worsening. Patients who did not worsen neurologically generally did not show significant spikes in free copper. Tetrathiomolybdate controlled copper less well in the dose regimen study (study 3) than in the previous 2 studies of tetrathiomolybdate treatment, probably because of a change in the way “away from food” tetrathiomolybdate was given.

  • tetrathiomolybdate versus Trientine in the initial treatment of neurologic wilson s disease
    Progress in Neurotherapeutics and Neuropsychopharmacology, 2008
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    ABSTRACTBackground: The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus Trientine in the neurologically presenting Wilson's disease patient. Design and Methods: The study was a double blind design in which patients received either TM plus zinc, or Trientine plus zinc, for 8 weeksThis study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or Trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results: Twenty-three patients were entered into the Trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated (p < 0.05). One patient on Trientine had an adverse event while 7 on TM had adverse events. All adverse events were mild. Four patients in the Trientine arm died during follow-up, 3 having shown initial neurologic deterioration, 2 patients in the TM arm died. In those patients who did not deteriorate or die, neurologic and speech recovery over 3 years was good. Interpretation: TM is a superior choice to Trientine for the initial therapy of neurologic Wilson's disease.

  • Tetrathiomolybdate versus Trientine in the Initial Treatment of Neurologic Wilson's Disease
    Progress in Neurotherapeutics and Neuropsychopharmacology, 2007
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    ABSTRACT Background : The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus Trientine in the neurologically presenting Wilson's disease patient. Design and Methods : The study was a double blind design in which patients received either TM plus zinc, or Trientine plus zinc, for 8 weeks This study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or Trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results : Twenty-three patients were entered into the Trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated ( p Interpretation : TM is a superior choice to Trientine for the initial therapy of neurologic Wilson's disease.

  • treatment of wilson disease with ammonium tetrathiomolybdate iv comparison of tetrathiomolybdate and Trientine in a double blind study of treatment of the neurologic presentation of wilson disease
    JAMA Neurology, 2006
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    OBJECTIVE: To compare tetrathiomolybdate and Trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. DESIGN: A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of Trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received 50 mg of zinc 2 times per day. Patients were hospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. SETTING: A university hospital referral setting. PATIENTS: Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. INTERVENTION: Treatment with either Trientine plus zinc or tetrathiomolybdate plus zinc. MAIN OUTCOME MEASURES: Neurologic function was assessed by semiquantitative neurologic and speech examinations. Drug adverse events were evaluated by blood cell counts and biochemical measures. RESULTS: Six of 23 patients in the Trientine arm and 1 of 25 patients in the tetrathiomolybdate arm underwent neurologic deterioration (P<.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving Trientine had an adverse effect of anemia. Four patients receiving Trientine died during follow-up, 3 having shown initial neurologic deterioration. Neurologic and speech recovery during a 3-year follow-up period were quite good. CONCLUSION: Tetrathiomolybdate is a better choice than Trientine for preserving neurologic function in patients who present with neurologic disease.

  • treatment of wilson disease with ammonium tetrathiomolybdate iv comparison of tetrathiomolybdate and Trientine in a double blind study of treatment of the neurologic presentation of wilson disease
    JAMA Neurology, 2006
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    Objective: To compare tetrathiomolybdate and Trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. Design:A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of Trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received50mgofzinc2timesperday.Patientswerehospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. Setting: A university hospital referral setting. Patients:Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. Intervention:Treatment with either Trientine plus zinc or tetrathiomolybdate plus zinc. Main Outcome Measures: Neurologic function was assessed by semiquantitative neurologic and speech examinations.Drugadverseeventswereevaluatedbyblood cell counts and biochemical measures. Results: Six of 23 patients in the Trientine arm and 1 of 25patientsinthetetrathiomolybdatearmunderwentneurologic deterioration (P.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving Trientine had an adverse effect of anemia.FourpatientsreceivingTrientinediedduringfollow-up, 3 having shown initial neurologic deterioration.Neurologicandspeechrecoveryduringa3-yearfollow-up period were quite good. Conclusion:Tetrathiomolybdate is a better choice than Trientine for preserving neurologic function in patients who present with neurologic disease. ClinicalTrials.gov Identifier: NCT00004339

Roberta M Tankanow - One of the best experts on this subject based on the ideXlab platform.

  • tetrathiomolybdate versus Trientine in the initial treatment of neurologic wilson s disease
    Progress in Neurotherapeutics and Neuropsychopharmacology, 2008
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    ABSTRACTBackground: The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus Trientine in the neurologically presenting Wilson's disease patient. Design and Methods: The study was a double blind design in which patients received either TM plus zinc, or Trientine plus zinc, for 8 weeksThis study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or Trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results: Twenty-three patients were entered into the Trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated (p < 0.05). One patient on Trientine had an adverse event while 7 on TM had adverse events. All adverse events were mild. Four patients in the Trientine arm died during follow-up, 3 having shown initial neurologic deterioration, 2 patients in the TM arm died. In those patients who did not deteriorate or die, neurologic and speech recovery over 3 years was good. Interpretation: TM is a superior choice to Trientine for the initial therapy of neurologic Wilson's disease.

  • Tetrathiomolybdate versus Trientine in the Initial Treatment of Neurologic Wilson's Disease
    Progress in Neurotherapeutics and Neuropsychopharmacology, 2007
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    ABSTRACT Background : The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus Trientine in the neurologically presenting Wilson's disease patient. Design and Methods : The study was a double blind design in which patients received either TM plus zinc, or Trientine plus zinc, for 8 weeks This study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or Trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results : Twenty-three patients were entered into the Trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated ( p Interpretation : TM is a superior choice to Trientine for the initial therapy of neurologic Wilson's disease.

  • treatment of wilson disease with ammonium tetrathiomolybdate iv comparison of tetrathiomolybdate and Trientine in a double blind study of treatment of the neurologic presentation of wilson disease
    JAMA Neurology, 2006
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    OBJECTIVE: To compare tetrathiomolybdate and Trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. DESIGN: A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of Trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received 50 mg of zinc 2 times per day. Patients were hospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. SETTING: A university hospital referral setting. PATIENTS: Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. INTERVENTION: Treatment with either Trientine plus zinc or tetrathiomolybdate plus zinc. MAIN OUTCOME MEASURES: Neurologic function was assessed by semiquantitative neurologic and speech examinations. Drug adverse events were evaluated by blood cell counts and biochemical measures. RESULTS: Six of 23 patients in the Trientine arm and 1 of 25 patients in the tetrathiomolybdate arm underwent neurologic deterioration (P<.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving Trientine had an adverse effect of anemia. Four patients receiving Trientine died during follow-up, 3 having shown initial neurologic deterioration. Neurologic and speech recovery during a 3-year follow-up period were quite good. CONCLUSION: Tetrathiomolybdate is a better choice than Trientine for preserving neurologic function in patients who present with neurologic disease.

  • treatment of wilson disease with ammonium tetrathiomolybdate iv comparison of tetrathiomolybdate and Trientine in a double blind study of treatment of the neurologic presentation of wilson disease
    JAMA Neurology, 2006
    Co-Authors: George J Brewer, Frederick K Askari, Matthew T Lorincz, Michael L. Schilsky, Martha D Carlson, Peter Hedera, Karen J Kluin, John K. Fink, Paolo Moretti, Roberta M Tankanow
    Abstract:

    Objective: To compare tetrathiomolybdate and Trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. Design:A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of Trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received50mgofzinc2timesperday.Patientswerehospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. Setting: A university hospital referral setting. Patients:Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. Intervention:Treatment with either Trientine plus zinc or tetrathiomolybdate plus zinc. Main Outcome Measures: Neurologic function was assessed by semiquantitative neurologic and speech examinations.Drugadverseeventswereevaluatedbyblood cell counts and biochemical measures. Results: Six of 23 patients in the Trientine arm and 1 of 25patientsinthetetrathiomolybdatearmunderwentneurologic deterioration (P.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving Trientine had an adverse effect of anemia.FourpatientsreceivingTrientinediedduringfollow-up, 3 having shown initial neurologic deterioration.Neurologicandspeechrecoveryduringa3-yearfollow-up period were quite good. Conclusion:Tetrathiomolybdate is a better choice than Trientine for preserving neurologic function in patients who present with neurologic disease. ClinicalTrials.gov Identifier: NCT00004339

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