Thrombin

Ximelagatran is an oral direct thrombin inhibitor that is being researched as an anticoagulant to prevent and treat thromboembolism. Ximelagatran is quickly absorbed and converted to its active form, melagatran, a reversible active site inhibitor of free and clot-bound thrombin with consistent pharmacokinetic features. Preliminary trials have demonstrated that ximelagatran is effective and safe in avoiding venous thromboembolism following total knee or total hip replacement [3].

Of the 1838 patients randomized, 1557 had either adequate venography or symptomatic, proven VTE (efficacy population). Overall rate of venography acceptable for evaluation was 85.4%. Overall rates of total VTE were 7.9% (62 of 782 patients) in the Ximelagatran group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference of 3.3% and a 95% confidence interval for the difference of 0.9% to 5.7%. Proximal DVT and/or PE occurred in 3.6% (28 of 782 patients) in the ximelagatran group and 1.2% (nine of 774 patients) in the enoxaparin group. Major bleeding events were observed in 0.8% (seven of 906) of the ximelagatran-treated patients and in 0.9% (eight of 910) of the enoxaparin-treated patients (P > 0.95). Non-inferiority of ximelagatran 24 mg bid based on a prespecified margin of 5% was not met, resulting in superiority of the enoxaparin regimen.
Conclusions: Both Ximelagatran and enoxaparin decreased the overall rate of VTE compared with that reported historically. However, in this study, enoxaparin 30 mg bid was more effective than ximelagatran 24 mg bid for prevention of VTE in THR. Oral ximelagatran was used without coagulation monitoring, was well tolerated, and had bleeding rates comparable to those of enoxaparin. Further refinement by testing a higher dose of ximelagatran in the patients undergoing THR is warranted. [1]

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Among the 1851 patients in the efficacy analysis, oral Ximelagatran at a dose of 36 mg twice daily was superior to warfarin with respect to the primary composite end point of venous thromboembolism and death from all causes (20.3 percent vs. 27.6 percent; P=0.003). There were no significant differences between these two groups with respect to major bleeding (incidence, 0.8 percent and 0.7 percent, respectively), perioperative indicators of bleeding, wound characteristics, or the composite secondary end point of proximal deep-vein thrombosis, pulmonary embolism, and death (2.7 percent vs. 4.1 percent; P=0.17).
Conclusions: The efficacy of oral Ximelagatran, administered starting the morning after total knee replacement, was superior to that of warfarin for prevention of venous thromboembolism. Rates of hemorrhagic complications with the two drugs were similar. [3]

Treatment regimens [1]
Patients were prescreened for eligibility 1–30 days before and on the day of their surgery. Their treatment was assigned according to a computer-generated randomization schedule after THR. Each patient received 26 tablets and 26 prefilled syringes (one active treatment and the other placebo). A Ximelagatran 24-mg tablet or enoxaparin 30-mg subcutaneous injection (Lovenox®; Aventis, Collegeville, PA, USA) was given, along with the corresponding placebo, in the morning and evening, starting on the morning after surgery (at least 12 h postoperatively) when adequate hemostasis had been achieved. The Ximelagatran dose was chosen on the basis of a previous dose-finding study. Patients remained in the hospital according to local practice, usually 3–4 days, after which they self-administered their medication, having been instructed in subcutaneous injection technique prior to hospital discharge. Treatment was given for 7–12 days, and unilateral venography of the leg on which surgery was performed was done on the last day of treatment.

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Assuming a total VTE incidence of 15% for enoxaparin and 13.5% (a 10% relative reduction) for Ximelagatran, approximately 1280 patients acceptable for evaluation were needed to provide > 90% power to demonstrate that the difference is no more than the 5% non-inferiority margin using a two-sided 95% CI. Approximately 1600 patients were to be enrolled in this study, anticipating that up to 20% of the randomized patients would not have a venogram adequate for evaluation.
Efficacy analyses included all patients who had a venogram adequate for evaluation or symptomatic, objectively confirmed DVT and/or PE during the treatment period. The proportions of patients with VTE were recorded; the differences in proportions of patients with verified VTE (Ximelagatran vs. enoxaparin) were assessed using a two-sided 95% CI. Non-inferiority was established if the upper border of the CI around the between-group difference in VTE frequency was <5%. Statistical superiority of Ximelagatran was established if the upper border of the CI for VTE was <0%. Statistical superiority of enoxaparin was established if the lower border of the CI was >0%.

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TREATMENT REGIMENS [1]
Warfarin or a warfarin placebo was administered each evening, with the first dose given on the evening of the day of surgery and with the dose adjusted to achieve an international normalized ratio (INR) of 2.5 (range, 1.8 to 3.0). Ximelagatran at a dose of 24 mg or 36 mg in tablet form or a Ximelagatran placebo was given in the morning and evening starting 12 hours or more after surgery, when adequate hemostasis had been achieved. The treatment was continued until venography was performed. To guide the adjustment of the warfarin dosage, INR values were measured in a blinded fashion on days 1 to 3 after surgery, on the day when venography was performed, and as needed. INR values were measured either at participating centers, with the use of encrypted point-of-care devices, or at local laboratories equipped with a system that prevented access to the INR values by local personnel. All INR values were reported to an anticoagulation management center, which relayed real or sham values to local study personnel. A warfarin-dosing nomogram was provided, but the dose of either warfarin or warfarin placebo was chosen at the investigator's discretion. For patients receiving Ximelagatran, sham INR values were generated to mimic the usual values in patients receiving warfarin. Compliance with oral treatment was assessed by counting tablets used in the hospital, dispensed at discharge, and returned after the treatment had ended.

Absorption, Distribution and Excretion
Rapidly absorbed by the small intestine with an oral bioavailability of 20%.

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Metabolism / Metabolites
Ximelagatran is a prodrug, and hence, it requires in vivo conversion to the active agent, melagatran. The activation of ximelagatran is produced in the liver and many other tissues mainly by reactions of dealkylation and dehydroxylation.

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Biological Half-Life
3-5 hours

Incidence of venous thromboembolism [1]
The overall incidence of VTE was 7.9% in the Ximelagatran group (62 of 782 patients) and 4.6% in the enoxaparin group (36 of 775 patients), as shown in Table 3. The absolute difference in total VTE rates was 3.3% in favor of enoxaparin (95% CI 0.9, 5.7). In designing this trial we assumed that, following THR, the resulting VTE incidence with enoxaparin would be 15% and with ximelagatran would be 13.5%, a 10% reduction. A 95% CI for absolute difference was established between the point estimates of the two treatments. An upper bound of 5% was prespecified, above which it could not be claimed that non-inferiority exists. Since there was an absolute difference of 3.3% for the total VTE rates in favor of enoxaparin, and since the upper bound for the 95% CI of the difference was greater than the prespecified margin of >5.0, it could not be claimed that ximelagatran 24 mg bid was comparable to enoxaparin in this study. Moreover, since the lower bound of the 95% CI was > 0, enoxaparin 30 mg bid was superior to ximelagatran 24 mg bid in this trial. Proximal DVT and/or PE was observed in 3.6% (28 of 782) and 1.2% (nine of 774) of the Ximelagatran and enoxaparin patients, respectively.
Confirmed symptomatic DVT occurred during treatment in 0.5% of patients (four of 782) in the Ximelagatran group and 1.0% (eight of 775) in the enoxaparin group, of which two cases each were proximal. Following the treatment period, 11 patients developed confirmed, symptomatic DVT (six ximelagatran and five enoxaparin), all proximal. Four ximelagatran patients had a verified PE during treatment and three following treatment (13, 15, and 21 days after the end of treatment). Two patients in the enoxaparin group had verified PE 5 and 10 days after discontinuing treatment.
Subgroup analyses based on prespecified patient characteristics showed results similar to those for the total population; no statistically significant interactions were found between treatment and any of the subgroup factors.

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Bleeding and wound complications [1]
The incidence of major, minor, and total bleeding was low, and there were no statistically significant differences in these or any of the other indicators of bleeding (Table 4, Table 5. Major bleeding during treatment was reported for seven of 906 (0.8%) Ximelagatran patients and eight of 910 (0.9%) enoxaparin patients. All of these were wound hematomas, apart from one Ximelagatran-treated patient whose site of major bleeding was listed as ‘other’; six major bleeding events in each group occurred within 3 days of surgery. Three of the major bleeding events in each group were reported as a serious adverse event, and two in each group led to treatment discontinuation. Three additional patients experienced major bleeding events during the follow-up period (on postoperative days 14, 28, and 36); each of these patients was in the ximelagatran group.

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Other safety assessments [1]
The most common treatment-emergent adverse events were postoperative complications (35.2% of all patients), fever (16.0%), nausea (11.2%), constipation (8.1%), and urinary tract infection (7.9%). Only postoperative complications showed a between-group difference of >2% [37.0% (335 of 906) in the Ximelagatran group vs. 33.5% (305 of 910) in the enoxaparin group]. Serious adverse events led to early treatment discontinuation in eight patients in the ximelagatran group and seven in the enoxaparin group. No patients died during treatment. One patient in each group died during the 6-week follow-up period; the study investigators judged both deaths unlikely to be related to treatment. Both deaths were centrally adjudicated; autopsies were not performed.
Expected changes in laboratory parameters were observed at similar frequencies in either treatment group, except for increases in γ-glutamyl transferase (γ-GT), alanine transaminase (ALT), and aspartate transaminase (AST) on the day of venography, which were more frequent and of greater magnitude in the enoxaparin-treated patients. Increases above three times the upper limit of normal for these three enzymes were found in 69, six, and two ximelagatran-treated patients, respectively (of 840 patients with available data), compared with 101, 42, and 22 enoxaparin-treated patients (of 847 patients with available data).

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SAFETY [2]
Major bleeding occurred during treatment in six patients in each of the two Ximelagatran groups and in five patients in the warfarin group (Table 5). Additional major bleeding events occurred during follow-up in four patients in the lower-dose ximelagatran group and in one patient in the warfarin group. One bleeding complication was fatal; gastric-ulcer bleeding developed in a patient who had received two 36-mg doses of ximelagatran. The bleeding led to multiorgan-system failure and death on day 46. This patient had also received perioperative enoxaparin (as part of the anesthesia protocol) and diclofenac.
Assessment of wound bleeding and of the appearance of the wound revealed no significant differences between either Ximelagatran group and the warfarin group (Table 6), and there were no appreciable differences among the groups with respect to other adverse events. The most common postoperative complication was anemia, which occurred in 8 to 10 percent of patients in each of the three groups. Alanine aminotransferase levels were more than three times the upper limit of the normal range in 6 patients in the higher-dose ximelagatran group, 4 patients in the lower-dose ximelagatran group, and 12 patients in the warfarin group on the day of venography and in 4, 1, and 0 patients in the three groups, respectively, at follow-up at four to six weeks (Table 7).

[1]. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study. J Thromb Haemost. 2003 Oct;1(10):2119-30.

[2]. Effects of different anticoagulant drugs on the prevention of complications in patients after arthroplasty: A network meta-analysis. Medicine (Baltimore). 2017 Oct;96(40):e8059.

[3]. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med. 2003 Oct 30;349(18):1703-12.

ximelagatran is a member of the class of azetidines that is melagatran in which the carboxylic acid group has been converted to the corresponding ethyl ester and in which the amidine group has been converted into the corresponding amidoxime. A prodrug for melagatran, ximelagatran was the first orally available direct thrombin inhibitor to be brought to market as an anticoagulant, but was withdrawn in 2006 following reports of it causing liver damage. It has a role as an anticoagulant, a prodrug, an EC 3.4.21.5 (thrombin) inhibitor and a serine protease inhibitor. It is a member of azetidines, an amidoxime, a secondary amino compound, an ethyl ester, a carboxamide, a tertiary carboxamide and a secondary carboxamide. It is functionally related to a melagatran. It is a tautomer of a ximelagatran (hydroxylamine form).
Ximelagatran is an anticoagulant intended to become a replacement for warfarin by overcoming the dietary restrictions, drug interaction, and monitoring issues associated with the former. In 2006, its manufacturer AstraZeneca announced that it would not attempt to market ximelagatran after reports of hepatotoxicity (liver damage) during trials, and to discontinue its distribution in countries where the drug had been approved.

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Drug Indication
For the treatment of acute deep vein thrombosis.

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Mechanism of Action
Ximelagatran was the first member of the drug class of direct thrombin inhibitors that can be taken orally. Its effect is solely related to the inhibition of thrombin.

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As an orally administered agent, ximelagatran offers practical convenience in outpatient settings, while continuation of prophylaxis with a LMWH after hospital discharge requires outpatient visits or teaching of self-injection technique to suitable candidates. Second, unlike warfarin, ximelagatran does not require routine coagulation monitoring or dose adjustment to establish and maintain safe and effective levels of anticoagulation. These advantages may become more important if recent data showing the benefits of extended prophylaxis lead to changes in the recommended duration of treatment.
In conclusion, although both patient populations had a low incidence of VTE, enoxaparin-treated patients had a significantly lower incidence than did ximelagatran-treated patients. Ximelagatran 24 mg bid and enoxaparin 30 mg bid were both well tolerated and had comparable bleeding rates. Based on the safety data seen in this and previous studies, and because of the obvious potential of an oral drug that does not require routine coagulation monitoring or dose adjustment, additional studies in orthopedic surgery patients using higher doses of ximelagatran are warranted and ongoing. [1]

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Background: After arthroplasty treatment, some complications commonly occur, such as early revision, infection/dislocation, and venous thromboembolism (VTE). This study aims to use a network meta-analysis to compare effects of 9 anticoagulant drugs (edoxaban, dabigatan, apixaban, rivaroxaban, warfarin, heparin, bemiparin, ximelagatran, and enoxaparin) in preventing postoperative complications in arthroplasty patients.
Methods: After retrieving PubMed, Embase, and Cochrane Library database from the inception to November 2016, randomized controlled trials were enrolled. The integration of direct and indirect evidences was performed to calculate odd ratios and the surface under the cumulative ranking curves. Nineteen eligible randomized controlled trials were included.
Results: The network meta-analysis results showed that compared with warfarin, edoxaban, apixaban, and rivaroxaban had a lower incidence rate in asymptomatic deep venous thrombosis, which indicated that edoxaban, apixaban, and rivaroxaban had better effects on prevention. Similarly, in comparison to enoxaparin, edoxaban and rivaroxaban had better effect; rivaroxaban was better than ximelagatran in preventive effects. Compared with apixaban, edoxaban, dabigatan, rivaroxaban, and enoxaparin had a higher incidence rate in clinically relevant non-major bleeding, which showed that preventive effects were relatively poor. In addition, the results of the surface under the cumulative ranking curves showed that rivaroxaban and bemiparin worked best on symptomatic deep venous thrombosis and pulmonary embolism. In terms of bleeding, apixaban and warfarin had better preventive effects.
Conclusion: Our findings suggested that rivaroxaban may work better in terms of symptomatic deep venous thrombosis and pulmonary embolism, whereas apixaban had better preventive effects in bleeding. [2]

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Background: In a previous study of the prevention of venous thromboembolism after total knee replacement, the efficacy of ximelagatran, an oral direct thrombin inhibitor that does not require monitoring of coagulation or dose adjustment, was found to be similar to that of warfarin at a dose of 24 mg of ximelagatran twice daily. The purpose of the present study was to determine whether a higher dose of ximelagatran is superior to warfarin. Methods: This randomized, double-blind trial compared a regimen of 7 to 12 days of oral ximelagatran, at a dose of 24 or 36 mg twice daily, starting the morning after surgery, with warfarin therapy started the evening of the day of surgery. The composite end point of venous thromboembolism and death from all causes and the incidence of bleeding were the primary outcome measures. [3]

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Our results show that ximelagatran given orally at a dose of 36 mg twice daily starting postoperatively (a mean of 20.4 hours after surgery) was significantly more effective than warfarin in preventing venous thromboembolism after total knee replacement, with an absolute risk reduction of 7.3 percent and a relative risk reduction of 26.4 percent. The number needed to treat was 14. This benefit was due to a reduction in the rate of asymptomatic deep-vein thrombosis, whereas the rates of proximal deep-vein thrombosis and of symptomatic venous thromboembolism were low in all three treatment groups and did not differ significantly between the group receiving 36 mg of ximelagatran and the warfarin group. Studies of the natural history of venous thromboembolism suggest that asymptomatic deep-vein thrombosis identified by postoperative venography is a predictor of the development of symptomatic venous thromboembolism.[3]

C24H35N5O5

473.5652

473.263

C, 60.87; H, 7.45; N, 14.79; O, 16.89

192939-46-1

192939-46-1;

9574101

White to beige solid powder

1.4±0.1 g/cm3

1.635

2.08

4

7

11

34

731

2

CCOC(CN[C@@H](C(N1CC[C@H]1C(NCC2=CC=C(C(N)=NO)C=C2)=O)=O)C3CCCCC3)=O

ZXIBCJHYVWYIKI-PZJWPPBQSA-N

InChI=1S/C24H35N5O5/c1-2-34-20(30)15-26-21(17-6-4-3-5-7-17)24(32)29-13-12-19(29)23(31)27-14-16-8-10-18(11-9-16)22(25)28-33/h8-11,17,19,21,26,33H,2-7,12-15H2,1H3,(H2,25,28)(H,27,31)/t19-,21+/m0/s1

N-[(1R)-1-cyclohexyl-2-[(2S)-2-[[[[4-[(hydroxyamino)iminomethyl]phenyl]methyl]amino]carbonyl]-1-azetidinyl]-2-oxoethyl]-glycine, ethyl ester

Exanta; H 376/95; Exarta; H 376-95; Ximelagatran; 192939-46-1; Exarta; H-376/95; xi-melagatran; Ximelagatran [USAN:INN]; H 376-95; ximelagatranum; H 37695; H-37695; H37695

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~250 mg/mL (~527.91 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.39 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.39 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.39 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)