Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.2 (alanine aminotransferase)
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Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 3,4-DAP; Adefovir dipivoxil, ADL-10-0101, alefacept, alemtuzumab, alosetron hydrochloride, ALT-711, aprepitant, atazanavir sulfate, atlizumab, atvogen; Bortezomib; CETP vaccine, clevudine, crofelemer; DAC:GLP-1, darbepoetin alfa, decitabine, drotrecogin alfa (activated), DX-9065a; E-7010, edodekin alfa, emivirine, emtricitabine, entecavir, erlosamide, erlotinib hydrochloride, everolimus, exenatide; Fondaparinux sodium, frovatriptan, fulvestrant; Gemtuzumab ozogamicin, gestodene; Homoharringtonine, human insulin; Imatinib mesylate, indiplon, indium 111 (111In) ibritumomab tiuxetan, inhaled insulin, insulin detemir, insulin glargine, ivabradine hydrochloride; Lanthanum carbonate, lapatinib, LAS-34475, levetiracetam, liraglutide, lumiracoxib; Maxacalcitol, melagatran, micafungin sodium; Natalizumab, NSC-640488; Oblimersen sodium; Parecoxib sodium, PEG-filgrastim, peginterferon alfa-2(a), peginterferon alfa-2b, pexelizumab, pimecrolimus, pleconaril, pramlintide acetate, pregabalin, prucalopride; rAHF-PFM, Ranelic acid distrontium salt, ranolazine, rDNA insulin, recombinant human soluble thrombomodulin, rhGM-CSF, roxifiban acetate, RSD-1235, rubitecan, ruboxistaurin mesilate hydrate; SC-51, squalamine; Tegaserod maleate, telbivudine, tesaglitazar, testosterone gel, tezosentan disodium, tipranavir; Vatalanib succinate; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zoledronic acid monohydrate.
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PMID:Gateways to clinical trials. 1467 84

Ximelagatran (Exanta, AstraZeneca), which is still investigational, is the first of a new category of direct inhibitors of thrombin which can be administered orally. SPORTIF III and V trials are both randomized studies; the first is open-label; the second, double-blind. They involved patients aged 18 or over with a non-valvular atrial fibrillation and, at least, one additional risk factor fot stroke (St) or systemic embolism (SE). They compared traditional warfarin anticoagulation (INR = 2-3) with fixed dose ximelagatran (36 mg twice daily) for the prevention of St/SE. These studies are non-inferiority trials. In the intention-to-treat analysis, SPORTIF III (3,407 patients [1,704 on on ximelagatran and 1,703 on warfarin]; mean follow-up of 17.4 months) observed 40 cases of St/SE in the ximelagatran group and 56 in the warfarin group. These data demonstrated the non-inferiority of ximelagatran. In addition, the per protocol analysis showed a superiority of ximelagatran (0.018). SPORTIF V (3,992 patients; mean follow-up of 20 months) observed 88 cases of St/SE. The incidence of these events was similar in both treatment-groups with an absolute difference no greater than 0.5%/yr. The non-inferiority of ximelagatran was thus confirmed. In both studies, bleedings were observed on both therapies with a slight trend in favor of ximelagatran. Additionally, some 6% of patients treated by ximelagatran experienced an increase to greater than three times the upper limit of normal of the liver enzyme alanine aminotransferase (ALT), compared to 0.7-0.8% in the warfarin group. Nearly all enzyme rises occurred during the first six months of therapy and decreased with or without drug discontinuation. The potential breakthrough that these data represent for oral anticoagulation is briefly outlined.
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PMID:[SPORTIF III and V trials: a major breakthrough for long-term oral anticoagulation]. 1497 54

Melagatran is a synthetic, small-peptide direct thrombin inhibitor with anticoagulant activity. Ximelagatran, an oral prodrug, undergoes rapid enzymatic conversion to melagatran. Melagatran has rapid onset of action, fixed twice-daily dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring drug levels or dose adjustment. There is no specific antidote, but the drug has a short plasma elimination half-life (about 4 hours). In clinical studies, melagatran/ximelagatran is not inferior to warfarin for stroke prevention in patients with non-valvular atrial fibrillation, to heparin-warfarin for acute treatment and extended secondary prevention of deep vein thrombosis, and superior to warfarin for prevention of venous thromboembolism after major orthopaedic surgery. Major bleeding with melagatran/ximelagatran occurred at rates similar to those in patients treated with warfarin. 6%-12% of patients taking ximelagatran develop asymptomatic elevated liver enzyme levels (predominantly alanine aminotransferase) after 1-6 months of therapy; this usually resolves with cessation of therapy. Less than 1% of patients develop abnormal liver function while taking ximelagatran; this rarely persists or develops into clinical illness.
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PMID:The direct thrombin inhibitor melagatran/ximelagatran. 1574 44

Atrial fibrillation (AF) causes 50,000 to 100,000 ischemic strokes annually in the U.S., most of which could be prevented by oral anticoagulant treatment of the highest-risk patients. The greatest barrier to such treatment is the narrow therapeutic index of the vitamin K antagonists ([VKAs]: warfarin and related coumarin derivatives), the only oral anticoagulant agents currently available. Safe and effective treatment with the VKAs requires careful monitoring, because they interact with many other drugs and foods, and their anticoagulant action is unpredictable. Besides vitamin K, candidate targets for anticoagulant therapy include thrombin, a key prothrombotic mediator. Ximelagatran, the oral direct thrombin inhibitor at the most advanced stage of clinical development, is rapidly absorbed and bioconverted to its active moiety, melagatran-a potent, competitive inhibitor of both free and clot-bound thrombin. Two large clinical trials have demonstrated that fixed-dose oral ximelagatran, 36 mg twice daily, administered without coagulation monitoring, prevents stroke and systemic embolic events in patients with nonvalvular AF as effectively as well-controlled, adjusted-dose warfarin (international normalized ratio 2.0 to 3.0). The overall risk of bleeding was lower with ximelagatran than warfarin, although differences in rates of major hemorrhage were not statistically significant. Elevation of serum alanine aminotransferase levels above 3x the upper limit of normal occurred in approximately 6% of ximelagatran-treated patients but typically returned toward pretreatment levels without associated symptoms. In terms of preventing thromboembolism without hemorrhage, ximelagatran may have a more favorable benefit:risk profile than warfarin for patients with AF.
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PMID:Ximelagatran: oral direct thrombin inhibition as anticoagulant therapy in atrial fibrillation. 1562 64

The limitations of heparin and warfarin have prompted the development of new anticoagulant drugs for prevention and treatment of venous and arterial thromboembolism. Novel parenteral agents include synthetic analogs of the pentasaccharide sequence of heparin that mediates its interaction with antithrombin. Fondaparinux, the first synthetic pentasaccharide, is licensed for prevention of venous thromboembolism (VTE) after major orthopedic surgery and for initial treatment of patients with VTE. Idraparinux, a long-acting pentasaccharide that is administered subcutaneously once-weekly, is being compared with warfarin for treatment of VTE and for prevention of cardioembolic events in patients with atrial fibrillation. New oral anticoagulants include direct inhibitors of thrombin, factor Xa and factor IXa. Designed to provide more streamlined anticoagulation than warfarin, these agents can be given without routine coagulation monitoring. Ximelagatran, the first oral direct thrombin inhibitor, is as effective and safe as warfarin for prevention of cardioembolic events in patients with atrial fibrillation. However, ximelagatran produces a three-fold elevation in alanine transaminase levels in 7.9% of patients treated for more than a month, the long-term significance of which is uncertain. Whether other direct thrombin inhibitors or inhibitors of factors Xa or IXa also have this problem is under investigation. After a brief review of coagulation pathways, this paper focuses on new anticoagulants in advanced stages of clinical testing.
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PMID:New anticoagulants. 1610 51

Despite the significant advances over the last 50 years with regard to anticoagulant therapy, warfarin remains the definitive standard for the long-term prevention of thromboembolic events in at-risk patients, except those with acute coronary syndromes, in which antiplatelets are preferred. Ximelagatran, a prodrug of melagatran, is an orally administered direct thrombin inhibitor whose therapeutic potential has been investigated in venous thromboembolism, acute coronary syndromes and prevention of stroke in atrial fibrillation. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to the oral vitamin K antagonist warfarin and low molecular weight heparin for prophylaxis of venous thromboembolism, comparable to warfarin for stroke prevention in the setting of atrial fibrillation, and, when combined with aspirin, more effective than aspirin alone at preventing major adverse cardiovascular events in patients with a recent myocardial infarction. Double-blind trials have also revealed the efficacy of ximelagatran in the secondary prevention of venous thromboembolism and shown the agent to be as effective as enoxaparin/warfarin in treating patients with acute deep vein thrombosis. Adverse effects with ximelagatran include elevations in alanine transaminase (ALT), which may require monitoring, and bleeding complications. Bleeding complications appear to be less than or at least comparable to those occurring with standard anticoagulant treatments like warfarin or low molecular weight heparin. In addition to its favorable efficacy and safety profile in comparison with standard anticoagulant therapy, the convenience of its oral, fixed-dose administration without the need for anticoagulation monitoring might help encourage a wider use of appropriate anticoagulation using ximelagatran across the population at risk, reducing the incidence of thromboembolic events.
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PMID:Ximelagatran. 1651 7

The treatment of acute venous thromboembolism and prophylaxis of recurrent events with heparin/low molecular weight heparin followed by vitamin K antagonists is limited by several factors. Oral direct thrombin inhibitors (ODTIs) showed a better pharmacological activity and might be an alternative in the treatment of venous thromboembolism. The Thrombin Inhibition in Venous Thromboembolism (THRIVE) program performed some studies developing the ODTI ximelagatran for this indication, and it is presented in the overview. The aim of the THRIVE I study was the dose finding, and that of the THRIVE IV study the applicability in hemodynamic stabile pulmonary embolism. A prospective, randomized, double blind trial was performed to compare oral ximelagatran with enoxaparin/warfarin for a 6-month treatment of acute venous thrombosis (THRIVE II and V). A second double blind study compared ximelagatran with placebo over 18 months after a 6-month anticoagulant therapy of acute deep vein thrombosis. The efficacy and safety of treatment of patients with acute deep venous thrombosis who received 2 infinity 36 mg ximelagatran was not inferior to that of patients who received a conventional anticoagulant for prophylaxis of recurrent events over 6 months. Ximelagatran 2 infinity 24 mg significantly reduced recurrent thromboembolic events compared to placebo without increasing the risk for hemorrhage. A reversible symptomless increase of alanine aminotransferase occurs in 6% to 9.6% of patients between months 2 and 4. The results of the follow-up studies suggest that thromboembolic events may recur in patients with acute venous thromboembolism after termination of treatment with both vitamin K antagonists and ximelagatran.
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PMID:Ximelagatran for treatment and prophylaxis of recurrent events in deep vein thrombosis. 1763 92

Ximelagatran was developed for the prevention and treatment of thromboembolic conditions. However, in long-term clinical trials with ximelagatran, the liver injury marker, alanine aminotransferase (ALT) increased in some patients. Analysis of plasma samples from 134 patients was carried out using proteomic and metabolomic platforms, with the aim of finding predictive biomarkers to explain the ALT elevation. Analytes that were changed after ximelagatran treatment included 3-hydroxybutyrate, pyruvic acid, CSF1R, Gc-globulin, L-glutamine, protein S and alanine, etc. Two of these analytes (pyruvic acid and CSF1R) were studied further in human cell cultures in vitro with ximelagatran. A systems biology approach applied in this study proved to be successful in generating new hypotheses for an unknown mechanism of toxicity.
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PMID:A systems biology approach to understanding elevated serum alanine transaminase levels in a clinical trial with ximelagatran. 1978 Jun 43

Ximelagatran was the first orally available direct thrombin inhibitor under clinical development that also reached the market. Ximelagatran was tested in an extensive clinical programme. Short-term use (<12 days) in humans including the phase III clinical trials did not indicate any hepatotoxic potential. Increased hepatic enzyme levels were first observed at a higher frequency when evaluating the long-term (>35 days) use of ximelagatran (incidence of >3x upper limit of normal (ULN) plasma ALT was 7.9%). The frequency of elevated total bilirubin levels was similar in the ximelagatran and the comparator groups. However, the combination of ALT > 3x ULN and total bilirubin > 2xULN was 0.5% among patients treated with ximelagatran and 0.1% among patients in the comparator group. Symptoms such as fever and rash potentially indicating hypersensitivity (immunologic type of reaction) were low and did not differ between ximelagatran and the comparators. The withdrawal of ximelagatran from the market and termination of the ximelagatran development program was triggered by safety data from a 35-day study, indicating that severe hepatic injury in a patient could develop after exposure to the drug has been completed and that regular liver function monitoring may not mitigate the possible risk of severe hepatic injury. As for many drugs causing liver injury, the standard preclinical toxicological studies provided no indication that ximelagatran affected hepatic functions. In addition, extensive investigations using human-based in vitro models have not been able to define mechanisms explaining the pattern of hepatic injury observed in long-term clinical trials. A pharmacogenomic study provided evidence that the ALT increases were associated with major histocompatibility complex (MHC) alleles DRB1'07 and DQA1*02 suggesting a possible immunogenic pathogenesis. This example provides important clues to the mechanism of idiosyncratic drug-induced liver toxicity.
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PMID:Drug-induced liver injury in humans: the case of ximelagatran. 2002 Feb 69