Incidence of recurrent venous thromboembolism of patients after termination of treatment with ximelagatran

Objective Recurrent thromboembolic events may occur after termination of anticoagulant therapy for acute venous thromboembolism (VTE) using oral direct thrombin inhibitor ximelagatran. Methods Patients with VTE recruited at the German study centres were followed-up for an additional 18 months, treated initially with 2×36 mg ximelagatran daily or with enoxaparin/warfarin over 6 months (THRIVE Treatment study) and 2×24 mg ximelagatran daily or placebo over 18 months (THRIVE III study). Recurrent VTE and the combined outcome events consisting of recurrent VTE, other thrombotic complication, major bleeding and mortality were analysed. Results In the THRIVE Treatment study, no patient suffered from a recurrent VTE, but 1 patient randomised to enoxaparin/warfarin experienced major bleeding. During follow-up, 4/32 and 3/32 patients initially randomised to ximelagatran and enoxaparin/warfarin developed recurrent VTE (p=0.7024). No major bleed occurred. One patient in each group died. The incidences of the combined outcome events were not different (p=0.9326). In the THRIVE III study, 0/9 versus 5/14 patients randomised to ximelagatran and placebo developed recurrent VTE including 1 fatal pulmonary embolism (p=0.0501). During follow-up, 3/9 and no patients initially randomised to ximelagatran and placebo developed recurrent VTE. One and 3 other outcome events occurred in patients initially randomised to ximelagatran or placebo. During follow-up, recurrent VTE (p=0.6893) and combined outcome events (p=0.3642) were not different between the groups. Conclusion The results of the follow-up studies suggest that thromboembolic events may re-occur in patients with acute VTE after termination of treatment with both vitamin K-antagonists and ximelagatran.     

Ximelagatran--recent comparisons with warfarin

Recently, ximelagatran and warfarin have been compared for stroke prevention in the Stroke Prevention using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) V trial in patients with non-valvular atrial fibrillation, and for the treatment of deep vein thrombosis in the Thrombin Inhibitor in Venous Thromboembolism (THRIVE) trial. In a mean follow-up of 20 months in SPORTIF V, the primary end point of stroke or systemic embolic events occurred in 37 patients in the warfarin group (of 1962) and 51 in the ximelagatran group (1960 patients). There was no difference between the groups in major bleeding. The rates of elevated alanine aminotransferase were much higher in the ximelagatran group (6%) than in the warfarin group (0.8%). In THRIVE, the primary efficacy end point of recurrent venous thromboembolism occurred in 26/1240 ximelagatran patients and 24/1249 patients in the enoxaparin/warfarin group. The incidence of alanine aminotransferase levels greater than three times the upper limit of normal was much higher with ximelagatran than with enoxaparin/warfarin (9.6 and 2.0%, respectively). In conclusion, although the trials comparing ximelagatran with warfarin as prophylaxis for stroke in atrial fibrillation and in the treatment of venous thromboembolism show noninferiority, concerns about the hepatic safety of ximelagatran remain.     

Direct thrombin inhibitors for treatment of heparin induced thrombocytopenia, deep vein thrombosis and atrial fibrillation

Thrombin is a central enzyme in hemostasis, exerting potent procoagulant effects and activating platelets. Recently, several small molecule direct thrombin inhibitors (DTI's) with important clinical applications have been developed. Both lepirudin and argatroban are effective in treatment of heparin-induced thrombocytopenia resulting in rapid normalization of platelet counts and a reduction in thrombotic events. Because of differences in clearance mechanisms, argatroban is preferable in patients with renal insufficiency and lepirudin if there is hepatic impairment. DTI's have also been evaluated in treatment of venous thromboembolism. Small studies with recombinant hirudin have shown promise. Ximelagatran is a new DTI in late-stage clinical trials with advantages for treatment of venous thromboembolism including oral administration and fixed dosing, making it convenient for long-term treatment. A Phase III trial demonstrated that ximelagatran was superior to placebo for preventing recurrent thrombosis in patients who had undergone six months of standard anticoagulant therapy for venous thromboembolism. Another large trial compared ximelagatran to standard treatment with enoxaparin and warfarin for treatment of symptomatic deep vein thrombosis in a Phase III trial of 2,528 patients. The results showed that ximelagatran administered twice daily was as effective as standard treatment in preventing recurrence with no increase in bleeding complications. Ximelagatran has also been evaluated in two Phase III trials in patients with atrial fibrillation. The primary analysis of both showed that ximelagatran was non-inferior to warfarin for preventing stroke and other embolic events with no increase in bleeding complications. Unexpectedly, elevated serum transaminase levels were observed in 5-10% of patients receiving ximelagatran for over 1 month, and routine monitoring may be necessary. The introduction of DTIs represents an important advance in treatment of heparin-induced thrombocytopenia. The oral direct thrombin inhibitor, ximelagatran, shows promise in providing simplified, effective therapy for venous thromboembolism and atrial fibrillation.     

Ximelagatran/Melagatran: a review of its use in the prevention of venous thromboembolism in orthopaedic surgery

Ximelagatran (Exanta), the first available oral direct thrombin inhibitor, and its active form, melagatran, have been evaluated in the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement.After oral administration ximelagatran is rapidly bioconverted to melagatran. Melagatran inactivates both circulating and clot-bound thrombin by binding to the thrombin active site, thus, inhibiting platelet activation and/or aggregation and reducing fibrinolysis time.The efficacy of subcutaneous melagatran followed by oral ximelagatran has been investigated in four European trials and the efficacy of an all oral ximelagatran regimen has been investigated in five US trials. In a dose-ranging European study, preoperatively initiated subcutaneous melagatran 3 mg twice daily followed by oral ximelagatran 24 mg twice daily was significantly more effective than subcutaneous dalteparin sodium 5000IU once daily in preventing the occurrence of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing hip or knee replacement. In one study, there were no significant differences in VTE prevention between subcutaneous melagatran 3 mg administered after surgery followed by ximelagatran 24 mg twice daily and enoxaparin sodium (enoxaparin) 40 mg once daily. Compared with enoxaparin, significantly lower rates of proximal DVT and/or PE (major VTE) and total VTE were observed when melagatran was initiated preoperatively (2mg) then postoperatively (3mg) and followed by ximelagatran 24 mg twice daily. In the US, four studies showed that postoperatively initiated ximelagatran 24 mg twice daily was of similar efficacy to enoxaparin or warfarin in the prevention of VTE in patients undergoing hip or knee replacement. However, ximelagatran 36 mg twice daily was superior to warfarin (target international normalised ratio of 2.5) at preventing the incidence of VTE in patients undergoing total knee replacement in two studies.Ximelagatran alone or after melagatran was generally well tolerated. Overall, the incidence of bleeding events and transfusion rates were not markedly different from those documented for comparator anticoagulants. In a post-hoc analysis of one study, transfusion rates were lower in ximelagatran than enoxaparin recipients.CONCLUSIONS: Oral ximelagatran alone or in conjunction with subcutaneous melagatran has shown good efficacy and was generally well tolerated in the prevention of VTE in patients undergoing orthopaedic surgery. Furthermore, patients receiving ximelagatran/melagatran do not require anticoagulant monitoring. The drug has a low potential for drug interactions and can be administered either by subcutaneous injection or orally. Thus, on the basis of available evidence, ximelagatran/melagatran appears poised to play an important role in the prophylaxis of VTE in patients undergoing orthopaedic surgery.     

Melagatran and ximelagatran: new drug. No real simplification of anticoagulant therapy

(1) The reference drug for prophylaxis against venous thromboembolism after hip or knee replacement surgery is a low-molecular-weight heparin (LMWH), given subcutaneously for 1 to 5 weeks. Vitamin K antagonists, including warfarin, have similar risk-benefit balances. (2) Subcutaneous melagatran and its oral metabolic precursor ximelagatran have recently been granted marketing authorisation in France for use as prophylaxis after hip or knee replacement surgery. Melagatran, unlike LMWH, is a specific thrombin inhibitor. (3) There are four randomised double-blind trials in more than 9000 patients comparing these agents with a LMWH (enoxaparin in three trials, dalteparin in one). Melagatran was given subcutaneously for one or two days before being replaced with ximelagatran (as soon as oral feeding was possible) for 6 to 9 days. These trials showed no advantage of melagatran-ximelagatran in terms of clinical endpoints such as symptomatic deep venous thrombosis, pulmonary embolism, and death from all causes. (4) Three randomised double-blind trials have compared ximelagatran with warfarin in more than 5000 patients. Treatment lasted 7 to 12 days. Ximelagatran was no better than warfarin when assessed using clinical endpoints. (5) In these trials melagatran-ximelagatran did not increase the risk of bleeding compared with LMWH or warfarin. (6) Melagatran-ximelagatran can cause an increase in serum transaminase activity, and is contraindicated if pretreatment serum transaminase activity is more than twice the upper limit of normal. (7) Trials versus warfarin showed a higher risk of myocardial infarction in patients taking ximelagatran (0.7% versus 0.16%). (8) There are few data on the patient subgroups most likely to receive melagatran-ximelagatran, namely patients over 75, underweight and overweight patients, and patients with renal failure. (9) There is currently no clotting test that allows the melagatran-ximelagatran dose regimen to be adjusted in patients who have an increased risk of adverse effects due to overdosing. There is no available antidote if overdose occurs. (10) Erythromycin increases melagatran bioavailability, thereby increasing the bleeding risk. Melagatran and ximelagatran must not be combined with other anticoagulants, thrombolytic agents or antiplatelet drugs because of a increased bleeding risk. (11) In practice, low-molecular-weight heparin remains the reference prophylactic treatment for venous thromboembolism after hip or knee replacement surgery.     

Ximelagatran: an orally active direct thrombin inhibitor.

PURPOSE: The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, contraindications, and adverse effects of ximelagatran are reviewed. SUMMARY: Ximelagatran is the first orally active direct thrombin inhibitor to be tested in Phase III clinical trials. After oral administration, ximelagatran is rapidly converted to its active metabolite, melagatran. Melagatran (after oral ximelagatran administration) predictably inhibits thrombin function without need for routine anticoagulation monitoring. Melagatran effectively inhibits both free and clot-bound thrombin-a potential pharmacodynamic advantage over heparin products. Melagatran has a half-life of 2.4-4.6 hours, necessitating twice-daily administration. Melagatran is primarily eliminated by the kidneys and has not been studied clinically in patients with severe renal failure. Ximelagatran has undergone 10 Phase III trials (6 for prophylaxis of venous thromboembolism [VTE] due to orthopedic surgery, 1 for initial treatment of VTE, 1 for long-term prevention of VTE recurrence, and 2 for stroke prophylaxis due to atrial fibrillation). Results were generally positive. AstraZeneca applied in December 2003 for marketing approval of ximelagatran for prevention of VTE after total knee replacement surgery, long-term prevention of VTE recurrence after standard therapy, and stroke prevention due to atrial fibrillation. FDA denied approval of ximelagatran for all indications, mainly because of increased rates of coronary artery disease events in ximelagatran recipients in some studies and the possibility of hepatic failure when the medication is used for long-term therapy. CONCLUSION: Ximelagatran has shown promise as a possible alternative to warfarin and other anticoagulants but will require further study to ensure its safety.     

Ximelagatran

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.     

Ximelagatran, the new oral anticoagulant: would warfarin survive the challenge?

The last decade witnessed major advances in the prevention and treatment of venous as well as of arterial thrombosis. Limitations of existing anticoagulants led to the development of novel therapeutic approaches. Ximelagatran is a new direct thrombin inhibitor (DTI) that is given orally, without the need for close monitoring. This compound was tried in the treatment of active venous thromboembolism, and the results were encouraging. Randomized trials suggest that ximelagatran is not inferior to warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Multiple controlled, prospective trials compared ximelagatran with low molecular weight heparin or warfarin in prevention of venous thromboembolism in patients undergoing major orthopedic procedures. The results of these clinical trials are reviewed in this article. Because of certain safety concerns (increased liver enzymes, potential hepatonecrosis, and increased coronary events) ximelagatran has not yet been approved by the FDA. Additional studies may be required to address these concerns. Ximelagatran has been approved, however, by the European regulatory authorities for short-term thromboprophylaxis. The success of ximelagatran or other oral antithrombin agents would provide significant proof of the concept for the long-term use of oral antithrombins in the prevention and treatment of both arterial and venous thrombosis.     

Hepatic findings in long-term clinical trials of ximelagatran.

OBJECTIVE: In clinical trials, the efficacy and safety of the oral direct thrombin inhibitor ximelagatran have been evaluated in the prevention or treatment of thromboembolic conditions known to have high morbidity and mortality. In these studies, raised aminotransferase levels were observed during long-term use (>35 days). The aim of this analysis is to review the data regarding these hepatic findings in the long-term trials of ximelagatran. PATIENTS AND METHODS: The prospective analysis included 6948 patients randomised to ximelagatran and 6230 patients randomised to comparator (warfarin, low-molecular weight heparin followed by warfarin or placebo). Of these, 6931 patients received ximelagatran for a mean of 357 days and 6216 patients received comparator for a mean of 389 days. An algorithm was developed for frequent testing of hepatic enzyme levels. A panel of four hepatologists analysed all cases of potential concern with regard to causal relation to ximelagatran treatment using an established evaluation tool (Roussel Uclaf Causality Assessment Method [RUCAM]). RESULTS: An elevated alanine aminotransferase (ALT) level of >3 x the upper limit of normal (ULN) was found in 7.9% of patients in the ximelagatran group versus 1.2% in the comparator group. The increase in ALT level occurred 1-6 months after initiation of therapy and data were available to confirm recovery of the ALT level to <2 x ULN in 96% of patients, whether they continued to receive ximelagatran or not. There was some variability in the incidence of ALT level elevation between indications, those with simultaneous acute illnesses (acute myocardial infarction or venous thromboembolism) having higher incidences. Combined elevations of ALT level of >3 x ULN and total bilirubin level of >2 x ULN (within 1 month of the ALT elevation), regardless of aetiology, were infrequent, occurring in 37 patients (0.5%) treated with ximelagatran, of whom one sustained a severe hepatic illness that appeared to be resolving when the patient died from a gastrointestinal haemorrhage. No death was observed directly related to hepatic failure caused by ximelagatran. CONCLUSION: Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.     

The therapeutic potential of ximelagatran to become the anticoagulant of choice in medicine: a review of recently completed clinical trials

Ximelagatran (Exanta, AstraZeneca) is a novel oral direct thrombin inhibitor that inhibits the final step in the coagulation process - namely, the conversion of fibrinogen to insoluble fibrin by thrombin. Recently completed large clinical trials have evaluated the efficacy and safety of ximelagatran compared to standard anticoagulation therapy with warfarin and heparins in several thrombotic disorders including the treatment and prevention of venous thromboembolism following major orthopaedic surgery; stroke prevention in atrial fibrillation; and after acute myocardial infarction. This article reviews these recent clinical trials and explores the therapeutic potential of ximelagatran to become the oral anticoagulant of first choice in medicine.     

Hepatotoxicity following nevirapine-containing regimens in HIV-1-infected individuals.

To determine the incidence of hepatotoxicity and to investigate whether plasma concentrations of nevirapine, in addition to other risk factors, could predict hepatotoxicity during treatment with nevirapine-containing regimens, we conducted a retrospective analysis with data from 174 individuals infected with human immunodeficiency virus-1 (HIV-1). During regular visits to the clinic, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters including liver enzymes (LEs) and total bilirubin (TBR). Severe hepatotoxicity was defined as a grade > or =3 elevation in at least one of the tested LEs or TBR levels while on therapy. Analysis of predictive factors was focused on increases in aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) to grade > or =2. Grade > or =3 elevation developed with an incidence of 0.15 per patient year (PY); only 3.4% of the patients developed grade > or =3 values for ASAT and/or ALAT (incidence 0.03 per PY). We found that patients who use a protease inhibitor (PI) in a nevirapine-containing regimen and patients who have chronic hepatitis B (HBV) infection are at a higher risk for the development of increases in ASAT and/or ALAT to grade > or =2. In contrast, the plasma concentration of nevirapine does not appear to be a predictive factor in this study population.     

Clinical experience with ximelagatran in orthopaedic surgery

Patients who undergo orthopaedic surgery are at substantially increased risk for venous thromboembolic events. These include proximal and distal deep vein thrombosis, with the former more likely to lead to pulmonary embolism and fatal complications. Anticoagulants are routinely used for venous thromboembolism prophylaxis in patients undergoing total hip or total knee replacement surgery. Although current treatments offer effective prophylaxis, they have disadvantages. Warfarin is limited by the requirement for coagulation monitoring to ensure effective and safe use. Similarly, low-molecular-weight heparins (LMWHs) have disadvantages, including the need for parenteral administration. This article brings together data from clinical trials of the novel oral direct thrombin inhibitor, ximelagatran, in the prevention of venous thromboembolism in patients undergoing elective total hip or total knee replacement. The ximelagatran clinical trial programme in orthopaedic surgery has focused primarily on five large multicentre studies in Europe (the Melagatran Thromboprophylaxis in Orthopaedic surgery II and III and Expanded Prophylaxis Evaluation Surgery Study studies) and in the United States (the Exanta Used to Lessen Thrombosis A and B studies), which enrolled more than 8000 patients. In addition, the USA clinical trial programme included three other trials that investigated ximelagatran in orthopaedic surgery; two of these studies focused on prevention of venous thromboembolism after total knee replacement, and one study investigated prevention of venous thromboembolism after total hip replacement. These studies compared ximelagatran with the LMWHs dalteparin and enoxaparin and with warfarin, and were designed to reflect regional differences in venous thromboembolism prophylaxis and to build on findings from previous studies. Generally, ximelagatran has been shown to possess comparable or greater efficacy relative to comparators. The timing and dose of ximelagatran have been shown to be important determinants of its efficacy and safety. As ximelagatran can be given in fixed oral dosing without coagulation monitoring, it is an attractive choice for the prevention of venous thromboembolism in major elective orthopaedic surgery.     

Prediction of drug-induced liver injury in humans by using in vitro methods: the case of ximelagatran.

OBJECTIVE: To investigate the possible mechanisms underlying the liver enzyme elevations seen during clinical studies of long-term treatment (>35 days) with ximelagatran, and investigate the usefulness of pre-clinical in vitro systems to predict drug-induced liver effects. METHODS: Ximelagatran and its metabolites were tested for effects on cell viability, mitochondrial function, formation of reactive metabolites and reactive oxygen species, protein binding, and induction of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) gene expression or nuclear orphan receptors. Experimental systems included fresh and cryopreserved hepatocytes, human hepatoma cell lines (HepG2 and HuH-7) and subcellular human liver fractions. RESULTS: Loss of cell viability was only seen in HepG2 cells at ximelagatran concentrations 100 microM and in cryopreserved human hepatocytes at 300 microM, while HuH-7 cells were not affected by 24 h exposure at up to 300 microM ximelagatran. Calcium homeostasis was not affected in HepG2 cells exposed to ximelagatran up to 300 microM for 15 min. There was no evidence for the formation of reactive metabolites when cell systems were exposed to ximelagatran. ALT and AST expression in human hepatoma cell lines were also unchanged by ximelagatran. Mitochondrial functions such as respiration, opening of the transition pore, mitochondrial membrane depolarization and beta-oxidation were not affected by ximelagatran or its metabolites. CONCLUSION: Ximelagatran at concentrations considerably higher than that found in plasma following therapeutic dosing had little or no effect on cellular functions studied in vitro. The in vitro studies therefore did not elucidate the mechanism by which ximelagatran induces liver effects in humans, possibly because of limitations in the experimental systems not reflecting characteristics of the human hepatocyte, restricted exposure time, or because the primary mechanism for the observed clinical liver effects is not on the parenchymal liver cell.     

Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or crushed tablets or dissolved formulation

OBJECTIVE: To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders. RESEARCH DESIGN AND METHODS: This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20-33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube. RESULTS: The plasma concentrations of ximelagatran, its intermediates and the active form melagatran were determined. Ximelagatran was rapidly absorbed and the bioavailability of melagatran was similar after the three different administrations, fulfilling the criteria for bioequivalence. The mean area under the plasma concentration-versus-time curve (AUC) of melagatran was 1.6 micromol.h/L (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (C(max)) was 0.3 micromol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t(1/2)) was 2.8 h for all treatments. The time to C(max) (t(max)) was 2.2h for the whole tablet and approximately 0.5 h earlier when the tablet was crushed or dissolved (1.7-1.8 h), due to a more rapid absorption. The study drug was well tolerated as judged from the low incidence and type of adverse events reported. CONCLUSION: The present study showed that the pharmacokinetics (AUC and C(max)) of melagatran were not significantly altered whether ximelagatran was given orally as a crushed tablet mixed with applesauce or dissolved in water and given via nasogastric tube.     

Ximelagatran: the first oral direct thrombin inhibitor

Oral anticoagulants are often prescribed for long-term prevention and treatment of venous or arterial thromboembolism. The only orally active anticoagulants currently available are the vitamin K antagonists. Although effective, they have a narrow therapeutic window and require routine coagulation monitoring to ensure that a therapeutic level has been achieved. Furthermore, genetic differences in metabolism and multiple food and drug interactions affect the anticoagulant response to vitamin K antagonists. These factors add to the need for routine coagulation monitoring, which is problematic for patients and physicians and costly for the healthcare system. Ximelagatran, the first oral direct thrombin inhibitor, was designed to overcome many of the drawbacks of vitamin K antagonists. Since it produces a predictable anticoagulant response, ximelagatran does not require coagulation monitoring. Phase III clinical trials have evaluated the efficacy and safety of ximelagatran for the prevention and treatment of venous thromboembolism and for the prevention of thromboembolic events in patients with atrial fibrillation. Focusing on ximelagatran, this review will discuss the appropriateness of thrombin as a target for new anticoagulants, compare and contrast direct and indirect thrombin inhibitors and describe the theoretical advantages of direct thrombin inhibitors. It will also review the pharmacology of ximelagatran, discuss the clinical trial results with ximelagatran and provide perspective on the advantages and potential limitations of ximelagatran.     

The therapeutic potential of ximelagatran to become the anticoagulant of choice in medicine: a review of recently completed clinical trials

Ximelagatran (Exanta^?, AstraZeneca) is a novel oral direct thrombin inhibitor that inhibits the final step in the coagulation process – namely, the conversion of fibrinogen to insoluble fibrin by thrombin. Recently completed large clinical trials have evaluated the efficacy and safety of ximelagatran compared to standard anticoagulation therapy with warfarin and heparins in several thrombotic disorders including the treatment and prevention of venous thromboembolism following major orthopaedic surgery; stroke prevention in atrial fibrillation; and after acute myocardial infarction. This article reviews these recent clinical trials and explores the therapeutic potential of ximelagatran to become the oral anticoagulant of first choice in medicine.     

Fumonisin B1-induced DNA damage in rat liver and spleen: effects of pretreatment with coenzyme Q10, L-carnitine, alpha-tocopherol and selenium.

Active oxygen radical species are reported to cause organ damage. This study was designed to determine whether oxidative stress contributed to the initiation or progression of hepatic and splenic cell DNA damage induced by fumonisin B1 (FB1) in rats. Another aim was to investigate the protective effects of the antioxidants coenzyme Q10 (CoQ10), L-carnitine, vitamin E (alpha-tocopherol) and selenium against DNA damage in the liver and spleen of rats treated with FB1. Fasted rats were injected intravenously with a single dose of fumonisin B1 at 1.55 mg kg-1 body wt. into the tail vein. Treatment with FB1 led to splenic and hepatic DNA fragmentation in 85% of the test animals. DNA fragmentation was investigated as a critical event in toxic cell death by testing total Ca2+ in liver. FB1 administration caused total Ca2+ in liver to increase within 4 h (204% of control). Measurement of liver enzyme activities showed an increase in aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT). FB1 also markedly decreased splenic and hepatic glutathione (GSH) levels. Pretreatment with CoQ10 (30 mg CoQ10 kg-1 diet) together with L-carnitine (2.8 mg carnitine kg-1 diet), alpha-tocopherol (30 IU vitamin E kg-1 diet) and selenium (1 mg selenium as sodium selenite kg-1 diet), decreased DNA damage and the activities of Ca2+, ASAT and ALAT in the liver. On the other hand, the level of GSH was slightly increased. The CoQ10 alone did not significantly protect against toxic cell death and glutathione depletion caused by FB1. Oxidative damage caused by FB1 may be one of the underlining mechanisms of FB1-induced cell injury and DNA damage.     

Ximelagatran,an oral direct thrombin inhibitor,has a low potential for cytochrome P450-mediated drug-drug interactions

BACKGROUND: Ximelagatran is an oral direct thrombin inhibitor currently in clinical development for the prevention and treatment of thromboembolic disorders. After oral administration, ximelagatran is rapidly absorbed and extensively bioconverted, via two intermediates (ethyl-melagatran and hydroxy-melagatran), to its active form, melagatran. In vitro studies have shown no evidence for involvement of cytochrome P450 (CYP) enzymes in either the bioactivation or the elimination of melagatran. OBJECTIVE: To investigate the potential of ximelagatran, the intermediates ethyl-melagatran and hydroxy-melagatran, and melagatran to inhibit the CYP system in vitro and in vivo, and the influence of three CYP substrates on the pharmacokinetics of melagatran in vivo. METHODS: The CYP inhibitory properties of ximelagatran, the intermediates and melagatran were tested in vitro by two different methods, using heterologously expressed enzymes or human liver microsomes. Diclofenac (CYP2C9), diazepam (CYP2C19) and nifedipine (CYP3A4) were chosen for coadministration with ximelagatran in healthy volunteers. Subjects received oral ximelagatran 24mg and/or diclofenac 50mg, a 10-minute intravenous infusion of diazepam 0.1 mg/kg, or nifedipine 60mg. The plasma pharmacokinetics of melagatran, diclofenac, diazepam, N-desmethyl-diazepam and nifedipine were determined when administered alone and in combination with ximelagatran. RESULTS: No inhibition, or only minor inhibition, of CYP enzymes by ximelagatran, the intermediates or melagatran was shown in the in vitro studies, suggesting that ximelagatran would not cause CYP-mediated drug-drug interactions in vivo. This result was confirmed in the clinical studies. There were no statistically significant differences in the pharmacokinetics of diclofenac, diazepam and nifedipine on coadministration with ximelagatran. Moreover, there were no statistically significant differences in the pharmacokinetics of melagatran when ximelagatran was administered alone or in combination with diclofenac, diazepam or nifedipine. CONCLUSION: As ximelagatran did not exert a significant effect on the hepatic CYP isoenzymes responsible for the metabolism of diclofenac, diazepam and nifedipine, it is reasonable to expect that it would have no effect on the metabolism of other drugs metabolised by these isoenzymes. Furthermore, the pharmacokinetics of melagatran after oral administration of ximelagatran are not expected to be altered by inhibition or induction of CYP2C9, CYP2C19 or CYP3A4. Together, the in vitro and in vivo studies indicate that metabolic drug-drug interactions involving the major human CYP enzymes should not be expected with ximelagatran.     

Ximelagatran: the first oral direct thrombin inhibitor

Oral anticoagulants are often prescribed for long-term prevention and treatment of venous or arterial thromboembolism. The only orally active anticoagulants currently available are the vitamin K antagonists. Although effective, they have a narrow therapeutic window and require routine coagulation monitoring to ensure that a therapeutic level has been achieved. Furthermore, genetic differences in metabolism and multiple food and drug interactions affect the anticoagulant response to vitamin K antagonists. These factors add to the need for routine coagulation monitoring, which is problematic for patients and physicians and costly for the healthcare system. Ximelagatran, the first oral direct thrombin inhibitor, was designed to overcome many of the drawbacks of vitamin K antagonists. Since it produces a predictable anticoagulant response, ximelagatran does not require coagulation monitoring. Phase III clinical trials have evaluated the efficacy and safety of ximelagatran for the prevention and treatment of venous thromboembolism and for the prevention of thromboembolic events in patients with atrial fibrillation. Focusing on ximelagatran, this review will discuss the appropriateness of thrombin as a target for new anticoagulants, compare and contrast direct and indirect thrombin inhibitors and describe the theoretical advantages of direct thrombin inhibitors. It will also review the pharmacology of ximelagatran, discuss the clinical trial results with ximelagatran and provide perspective on the advantages and potential limitations of ximelagatran.