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 in the small intestine, with an oral bioavailability of 20%. Metabolisms/Metabolites Cimeragatran is a prodrug and therefore needs to be converted into the active ingredient, melatonin, in vivo. Activation of cimeragatran occurs primarily in the liver and many other tissues through dealkylation and dehydroxylation reactions. Biological Half-Life 3-5 hours

The incidence of venous thromboembolism (VTE)[1] is shown in Table 3. The overall VTE incidence was 7.9% in the cimetidine group (62 out of 782 patients) and 4.6% in the enoxaparin group (36 out of 775 patients). The absolute difference in the overall VTE incidence between the two groups was 3.3%, with the enoxaparin group being superior to the cimetidine group (95% CI 0.9, 5.7). In the design of this trial, it was assumed that the VTE incidence after total hip arthroplasty would be 15% in the enoxaparin group and 13.5% in the cimetidine group, a reduction of 10%. We established a 95% CI for the absolute difference between the point estimates of the two treatment options. A 5% upper limit was pre-set, and non-inferiority could not be asserted if this limit was exceeded. Because the absolute incidence of total VTE was 3.3% lower in the enoxaparin group than in the simegaran group, and the upper limit of the 95% confidence interval for this difference was greater than the pre-specified >5.0%, this study cannot conclude that the efficacy of simegaran 24 mg bid is comparable to that of enoxaparin. Furthermore, because the lower limit of the 95% confidence interval is greater than 0, enoxaparin 30 mg bid was superior to simegaran 24 mg bid in this trial. In patients treated with simegaran, the incidence of proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) was 3.6% (28 out of 782), compared to 1.2% (9 out of 774) in patients treated with enoxaparin. During treatment, 0.5% of patients (4 out of 782) in the simeraga group developed confirmed symptomatic DVT, and 1.0% of patients (8 out of 775) in the enoxaparin group developed confirmed symptomatic DVT, with 2 cases of proximal DVT in each group. At the end of treatment, 11 patients developed confirmed symptomatic DVT (6 in the simeraga group and 5 in the enoxaparin group), all of which were proximal DVT. Four patients in the simeraga group developed confirmed PE during treatment, and 3 patients developed PE at the end of treatment (13, 15, and 21 days after treatment completion, respectively). Two patients in the enoxaparin group were diagnosed with pulmonary embolism 5 and 10 days after discontinuation of treatment. Subgroup analyses based on prespecified patient characteristics showed results similar to those in the overall population; no statistically significant interaction was found between treatment and any subgroup factor.

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Bleeding and Wound Complications[1]
The incidence of major bleeding, minor bleeding and total bleeding was low, and there were no statistically significant differences in these bleeding indicators or any other bleeding indicators (Tables 4 and 5). Of the 906 patients treated with cimetidine, 7 (0.8%) reported major bleeding during treatment, and of the 910 patients treated with enoxaparin, 8 (0.9%) reported major bleeding during treatment. Except for one patient treated with cimetidine whose major bleeding site was listed as "other", all other major bleeding events were wound hematomas; 6 major bleeding events occurred within 3 days postoperatively in both groups. 3 major bleeding events in each group were reported as serious adverse events, and 2 in each group led to treatment interruption. 3 additional patients experienced major bleeding events during follow-up (days 14, 28 and 36 postoperatively); these patients were all in the ...cimetidine group.

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Other safety assessments[1]
The most common adverse events during treatment were postoperative complications (35.2% of all patients), fever (16.0%), nausea (11.2%), constipation (8.1%), and urinary tract infection (7.9%). Only the difference between groups in postoperative complications exceeded 2% [37.0% in the simega group (335 out of 906 patients), 33.5% in the enoxaparin group (305 out of 910 patients)]. Eight patients in the simega group and seven patients in the enoxaparin group discontinued treatment prematurely due to serious adverse events. No patients died during treatment. One patient in each group died during the 6-week follow-up period; the investigators considered both deaths to be unrelated to treatment. Both deaths were determined by the center; autopsies were performed. No autopsies were performed.
Except for the elevation of gamma-glutamyl transferase (γ-GT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) on the day of intravenous angiography, the expected frequency of changes in laboratory parameters was similar in the two treatment groups. The frequency and magnitude of the elevation of these three enzymes were higher in the enoxaparin treatment group. Among the 840 patients with available data, 69, 6, and 2 patients treated with cimeragatine had these three enzymes elevated more than three times the upper limit of normal, respectively; while among the 847 patients with available data, 101, 42, and 22 patients treated with enoxaparin had the above three enzymes elevated, respectively.

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Safety[2]
During treatment, 6 patients in each of the two cimeragatine treatment groups and 5 patients in the warfarin group had major bleeding (Table 5). During follow-up, 4 patients in the low-dose group had other major bleeding events. One patient in each of the cimeragatine and warfarin groups had bleeding complications. One bleeding complication was fatal; a patient who had received two doses of 36 mg simergatan developed gastric ulcer bleeding. The bleeding led to multiple organ failure, and the patient died on postoperative day 46. This patient had also received enoxaparin (as part of the anesthesia regimen) and diclofenac preoperatively. Assessment of wound bleeding and wound appearance showed no significant differences between the simergatan and warfarin groups (Table 6), and there were no significant differences in other adverse events among the groups. The most common postoperative complication was anemia, with an incidence of 8% to 10% in all three groups. Six patients in the high-dose simergatan group and four patients in the low-dose simergatan group had alanine aminotransferase levels exceeding three times the upper limit of normal. On the day of venography, there were 12 patients in the simergatan group and 12 patients in the warfarin group; during a follow-up of 4 to 6 weeks, venography was performed in 4, 1, and 0 patients in the three groups, respectively (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.

Cimeragatran belongs to the azahexacyclic butane class of compounds. Its structure is similar to meragaratran, except that the carboxylic acid group is replaced by the corresponding ethyl ester, and the amidoyl group is replaced by the corresponding amidoxime. As a prodrug of meragaratran, simeratran was the first marketed oral direct thrombin inhibitor, but it was withdrawn from the market in 2006 due to reports of liver damage. It has multiple functions, including anticoagulation, prodrug, EC 3.4.21.5 (thrombin) inhibitor, and serine protease inhibitor. It belongs to the azahexacyclic butane class of compounds and is also an amidoxime, secondary amino compound, ethyl ester, carboxamide, tertiary carboxamide, and secondary carboxamide. Its function is related to meragaratran. It is a tautomer of simeratran (hydroxylamine form). Simeratran is an anticoagulant designed to replace warfarin by overcoming the dietary restrictions, drug interactions, and monitoring problems associated with warfarin. In 2006, its manufacturer, AstraZeneca, announced that it would no longer attempt to market cimetrazan and would cease distribution of the drug in countries where it had been approved, following reports of hepatotoxicity (liver injury) in clinical trials. Drug Indication For the treatment of acute deep vein thrombosis. Mechanism of Action Cimegrafran is the first orally administered direct thrombin inhibitor. Its mechanism of action involves only the inhibition of thrombin. As an oral medication, cimetrazan offers practical convenience in outpatient treatment, whereas continued prophylactic treatment with low molecular weight heparin after discharge requires outpatient follow-up or instruction in self-injection techniques for suitable patients. Secondly, unlike warfarin, cimetrazan does not require routine coagulation monitoring or dose adjustments to establish and maintain a safe and effective anticoagulation level. These advantages may become even more important if recent data show the benefit of prolonged prophylactic treatment, leading to changes in recommended treatment duration. In summary, although the incidence of venous thromboembolism (VTE) was low in both groups, the incidence was significantly lower in the enoxaparin treatment group than in the cimetidine treatment group. Cimetidine 24 mg bid and enoxaparin 30 mg bid were both well tolerated and had comparable bleeding rates. Based on the safety data observed in this study and previous studies, and the clear advantage of oral medications that do not require routine coagulation monitoring or dose adjustment, it is necessary to conduct more studies on the use of higher doses of cimetidine etexilate in patients undergoing orthopedic surgery. Such studies are currently underway. [1] Background: Complications such as early revision, infection/dislocation and venous thromboembolism (VTE) are common after joint replacement surgery. This study aimed to compare the efficacy of nine anticoagulants (edoxaban, dabigatan, apixaban, rivaroxaban, warfarin, heparin, bemiparin, cimetidine etexilate and enoxaparin) in preventing complications after joint replacement surgery through a network meta-analysis. Methods: PubMed, Embase, and Cochrane Library databases were searched from inception to November 2016, and randomized controlled trials were included. Direct and indirect evidence were integrated, and odds ratios and areas under the cumulative ranking curve were calculated. A total of 19 eligible randomized controlled trials were included. Results: Network meta-analysis showed that edoxaban, apixaban, and rivaroxaban had a lower incidence of asymptomatic deep vein thrombosis compared to warfarin, indicating that edoxaban, apixaban, and rivaroxaban were more effective in prevention. Similarly, edoxaban and rivaroxaban were more effective than enoxaparin; rivaroxaban was superior to cimetidine in prevention. Compared with apixaban, edoxaban, dabigatan, rivaroxaban, and enoxaparin had a higher incidence of clinically relevant non-major bleeding, indicating relatively poor preventive efficacy. In addition, the cumulative area under the curve results showed that rivaroxaban and bemiparin were the most effective in treating symptomatic deep vein thrombosis and pulmonary embolism. Apixaban and warfarin were better at preventing bleeding. Conclusion: Our results suggest that rivaroxaban may be more effective in treating symptomatic deep vein thrombosis and pulmonary embolism, while apixaban is better at preventing bleeding. [2] Background: In a previous study on the prevention of venous thromboembolism after total knee arthroplasty, the efficacy of oral direct thrombin inhibitor tamegatran (without monitoring of coagulation or dose adjustment) was found to be similar to that of warfarin at a dose of 24 mg twice daily. This study aimed to determine whether a higher dose of tamegatran was superior to warfarin. Methods: This randomized, double-blind trial compared the efficacy of oral tamegatran (24 or 36 mg twice daily for 7 to 12 days) started the morning after surgery with warfarin started the evening after surgery. The primary endpoint was a composite endpoint of venous thromboembolism and all-cause mortality, as well as the incidence of bleeding. [3]

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Our results showed that oral administration of cimetidine (36 mg twice daily) starting postoperatively (mean 20.4 hours postoperatively) was significantly superior to warfarin in preventing venous thromboembolism after total knee arthroplasty, with an absolute risk reduction of 7.3% and a relative risk reduction of 26.4%. The number of patients required for treatment was 14. This benefit was attributed to a reduction in the rate of asymptomatic deep vein thrombosis, while the incidence of proximal deep vein thrombosis and symptomatic venous thromboembolism was lower in all three treatment groups, and there was no significant difference between the 36 mg cimetidine group and the warfarin group. Studies of the natural history of venous thromboembolism have shown that asymptomatic deep vein thrombosis detected by postoperative venography is a predictor of the occurrence 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.)