[go: up one dir, main page]

WO2006060647A1 - Méthodes de traitement prophylactique et thérapeutique - Google Patents

Méthodes de traitement prophylactique et thérapeutique Download PDF

Info

Publication number
WO2006060647A1
WO2006060647A1 PCT/US2005/043602 US2005043602W WO2006060647A1 WO 2006060647 A1 WO2006060647 A1 WO 2006060647A1 US 2005043602 W US2005043602 W US 2005043602W WO 2006060647 A1 WO2006060647 A1 WO 2006060647A1
Authority
WO
WIPO (PCT)
Prior art keywords
odiparcil
administered
treatment
subjects
dose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2005/043602
Other languages
English (en)
Inventor
Jeffrey W. Dubb
Linda S. Henderson
Shunichiro S. Okada
Vincent Peyrou
Robert E. Samuels
Sunita Sheth
Patricia A. Spera
John R. Toomey
Douglas Wilson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratories Fournier SAS
Glaxo Group Ltd
Original Assignee
Laboratories Fournier SAS
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36565378&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2006060647(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Laboratories Fournier SAS, Glaxo Group Ltd filed Critical Laboratories Fournier SAS
Publication of WO2006060647A1 publication Critical patent/WO2006060647A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a method for treating and/or preventing thromboembolic disorders, comprising administration of 4-methyl-2-oxo-2H-1 -benzopyran- 7-yl-5-thio- ⁇ -D-xylopyranoside in effective amounts to a patient in need thereof.
  • the thromboembolic disorder is thromboses associated with atrial fibrillation, e.g., nonvalvular atrial fibrillation ("NVAF").
  • NVAF nonvalvular atrial fibrillation
  • the thromboembolic disorder is venous thromboses, e.g., associated with orthopedic surgery such as knee or hip replacement surgery.
  • thromboses Many medical problems relate to thromboses. For example, atrial fibrillation ("AF”), myocardial infarction (“Ml”), heart failure, surgery (especially major orthopedic surgery, including knee or hip replacement surgery), valvular heart disease, coronary artery disease, peripheral arterial occlusive disease, cerebrovascular disease, various cancers, and diabetes are associated with thrombogenesis and/or embolism, which can result in stroke or myocardial infarction.
  • AF atrial fibrillation
  • Ml myocardial infarction
  • heart failure especially major orthopedic surgery, including knee or hip replacement surgery
  • valvular heart disease coronary artery disease
  • peripheral arterial occlusive disease peripheral arterial occlusive disease
  • cerebrovascular disease various cancers
  • various cancers various cancers
  • diabetes are associated with thrombogenesis and/or embolism, which can result in stroke or myocardial infarction.
  • NVAF is a common cardiac dysrhythmia, with increased prevalence in the aging population.
  • Subjects with NVAF are at an overall 4-5 times greater risk of ischemic stroke and thromboembolic events, with subgroups having lower or higher risk.
  • Singer DE Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic Therapy in Atrial Fibrillation - The seventh ACCP Conference on antithrombotic and Thrombolytic Therapy. Chest. 2004;126:429S.
  • Thrombosis within the venous system is mostly related to blood stasis and endothelial damage, leading to activation of the clotting system.
  • Most ischemic strokes associated with atrial fibrillation are probably due to embolism of stasis-associated thrombi forming in the left atrium and particularly its appendage (see, e.g., Fuster, V. et al., 1997. Hemostasis, thrombosis, fibrinolysis, and cardiovascular disease. Heart Disease, Braunwald E 1809-1842. Philadelphia, PA: WB Saunders Company).
  • thromboses consist of platelets, fibrin (and often erythrocytes)
  • various approaches have been taken for the prevention and/or treatment of thromboses, including the use of antiplatelet drugs, anticoagulant drugs, and thrombolytic agents.
  • Anticoagulants are designed to inhibit or antagonize one or more aspects of the coagulation cascade, in order to ultimately inhibit the formation of fibrin. These effects may be achieved by targeting thrombin, which acts on fibrinogen and factor XIII to form fibrin and crosslinked fibrin polymer, respectively.
  • an anticoagulant may be designed to limit functional prothrombin synthesis, attenuate thrombin generation, or inhibit formed thrombin.
  • warfarin inhibits the synthesis of factors dependent on vitamin K, i.e., prothrombin, factors VII, IX and X, protein C, and protein S. Heparin binds to antithrombin III thereby inactivating thrombin Ha, factor IXa, and factor Xa (unfractionated heparin having action against XIIa, XIa, IXa, Vila and thrombin; low molecular weight heparin ("LMWH") having action primarily against Xa).
  • Direct thrombin inhibitors like melagatran, argatroban, and hirudin bind directly in the thrombin active site and thereby inhibit its formation.
  • HCII Heparin Cofactor Il
  • GAG(s) glycosaminoglycans
  • warfarin Current treatment for the prevention of stroke in the NVAF population with one or more risk factors for stroke is oral anticoagulation, and warfarin is the current standard of care for such treatment.
  • Numerous studies (AFASAK, BAATAF, EAFT, CAFA, SPAF I and SPINAF) have demonstrated the benefit of warfarin versus aspirin or placebo in the prevention of stroke in subjects with atrial fibrillation with one or more risk factors for stroke. These studies reported decreased mortality and a reduction in stroke, embolic event rates and death when NVAF subjects were treated with warfarin, compared to placebo or aspirin. While warfarin has been proven to be beneficial in reducing stroke and thromboembolic events, physicians face numerous challenges in managing NVAF subjects treated with warfarin.
  • the recommended treatment for atrial fibrillation patients with a low/intermediate risk for stroke is 325 mg aspirin, once daily (according to the American College of Chest Physicians ("ACCP”) and American Heart Association (“AHA”)/European Society of Cardiology (“ESC”)/American College of Cardiology (“ACC”) guidelines).
  • Orally active ⁇ -D-thioxylosides have been proposed as anticoagulants. See Millet J, Theveniaux J, Brown NL. The Venous Antithrombotic Effect of LF 1351 in the rat following oral administration. Thromb & Haemost 1992;67:176-179; Millet J, Theveniaux J, Brown NL. The Venous Antithrombotic profile of Naroparcil in the rabbit. Thromb & Haemost 1994;72:874-879; Bellamy F, Horton D, Millet J, Picart F 1 Samreth S, Chazan JB. Glycosylated derivatives of benzophenone, benzhydrol, and benzhydril as potential venous antithrombotic agents.
  • OdiparcN OdiparcN
  • Compound A Odiparcil and its preparation is disclosed in U.S. Patent No. 5,169,838, issued to Samreth et al. on Dec 8, 1992. This patent discloses, inter alia, the use of the disclosed benzopyranone- ⁇ -D- thioxyloside compounds in the treatment of venous and arterial thrombosis, and treatment and prevention of diseases associated with circulatory disorders. Without intending to be bound or limited by theory, the mechanism of action of odiparcil is postulated to involve an increased biosynthesis of GAGs and subsequent elevation of anti-lla activity via HCII, leading to prevention of thrombosis.
  • Anti-Ma activity expressed in dermatan sulphate units, may serve as a pharmacodynamic marker of the antithrombotic effect of odiparcil. See, e.g., JA Huntington, Journal of Thrombosis & Haemostasis. 1 (7):1535-49, JuI 2003, and Masson, PJ et al., The effect of the ⁇ -D- xyloside naroparcil on circulating plasma glycosaminoglycans, J. Biol Chem 1995; 270:2662-2668.
  • Odiparcil has shown efficacy when administered orally in experimental models of venous and arterial thrombosis, and limited effects on coagulation parameters and bleeding times in animals.
  • anti-thrombotic activity has been correlated with anti thrombin (anti-lla) activity expressed in dermatan sulphate units.
  • anti-lla anti thrombin
  • it is estimated that steady state, anti-lla trough levels in the range of > 0.5 ug (e.g., 0.5 to about 6, 0.5 to about 4, 0.5 to 3.5, 0.5 to 2 ⁇ g) dermatan sulfate/mL plasma may correlate with significant benefits in treating and/or preventing thromboembolism.
  • ID 50 S in these animal models provide a target anti-lla activity for clinical development. It is especially predicted that an anti-lla trough level of >1 ug, more especially >2 ug, dermatan sulfate/mL plasma, may correlate with significant benefits in treating and/or preventing thromboembolism.
  • Heparin sulphate and dermatan sulphate inhibit the generation of thrombin activity in plasma by complementary pathways. Blood, 1984;64:742-7), may result in a reduced bleeding risk compared with vitamin K antagonists, unfractionated, low molecular weight heparins (LMWHs) and direct thrombin inhibitors, while providing antithrombotic efficacy.
  • LMWHs low molecular weight heparins
  • odiparcil may be useful in the treatment and/or prevention of thromboembolism, particularly venous thromboembolism ("VTE") such as in acute or extended prophylaxis for prevention of VTE following orthopaedic surgery (e.g., knee or hip arthroplasty), and/or thromboembolism associated with atrial fibrillation (e.g., NVAF).
  • VTE venous thromboembolism
  • NVAF atrial fibrillation
  • the present invention relates to a method of treating and/or preventing VTE following orthopaedic surgery, comprising administering an effective amount of odiparcil to a patient in need thereof.
  • the invention also relates to a method of treating and/or preventing thromboses associated with atrial fibrillation, particularly NVAF, comprising administering an effective amount of odiparcil to a patient in need thereof.
  • the present invention relates to a method of treating and/or preventing thromboembolic disorders, comprising administering an effective amount of odiparcil to a patient in need thereof.
  • the present invention relates to a method of treating and/or preventing VTE, particularly following orthopaedic surgery (e.g., knee or hip arthroplasty), comprising administering an effective amount of odiparcil to a patient in need thereof.
  • orthopaedic surgery e.g., knee or hip arthroplasty
  • the present invention relates to a method of treating and/or preventing thromboembolism associated with atrial fibrillation, particularly NVAF, comprising administering an effective amount of odiparcil to a patient in need thereof.
  • the patient is at low or intermediate risk of stroke. In another embodiment, the patient is at high risk of stroke.
  • the odiparcil is administered in combination with aspirin or a heparin.
  • the odiparcil, and aspirin as applicable is administered in an oral dosage form, such as tablets and/or capsules.
  • the odiparcil is administered in an amount of from about 125 to about 1000 mg per day. In some embodiments, the odiparcil is administered about every 12 or 24 hours. In some embodiments, the odiparcil is administered in an amount of about 250, about 375 or about 500 mg twice daily. The odiparcil is administered for a period sufficient to treat and/or prevent the thromboembolic disorder. In some embodiments, the odiparcil is administered to treat acute thromboembolic disorders, e.g., for up to about 3 to 6 weeks (e.g., 1 to about 30 days, including about 8 to 12 days) following orthopaedic surgery. In some embodiments, the odiparcil is administered to treat a chronic thromboembolic disorder, e.g., for one or more months or years. 043602
  • Figure 1 represents 95% confidence intervals for incidence of VTE in a study of extended prophylaxis of VTE with odiparcil following THA.
  • Figure 2 represents box plots illustrating anti-lla activity data in different treatment groups at baseline and trough samples in a study of extended prophylaxis of VTE with odiparcil following THA.
  • Figure 3 represents box plots illustrating anti-lla activity data in different treatment groups at baseline and steady state trough samples in a study of extended prophylaxis of VTE with odiparcil following THA.
  • Figure 4 represents the dose-related effects of warfarin and odiparcil on thrombus formation and ex vivo pharmacodynamic indices.
  • Figure 5 represents the dose-related effects of warfarin and odiparcil on bleeding time and blood loss.
  • Figure 6 is a representative tracing demonstrating the effect of odiparcil on thrombin induced platelet aggregation.
  • Figure 7 represents the effect of protamine sulfate on odiparcil induced anti- thrombin and antithrombotic activity.
  • the present invention relates to a method of treating and/or preventing thromboembolic disorders comprising administration of an effective amount of odiparcil to a patient in need thereof.
  • thromboembolic disorder refers to disorders associated with inappropriate or undesired thromboses formation, resulting in undesired venous or arterial blockages or constriction of blood flow at the primary site of thrombosis and/or, in the case of embolisms, a more remote site.
  • embolism the initial thrombus which is formed, fragments at least partially and the part to fragment off (embolus) is transported in the plasma where it can sometimes occlude a remote blood vessel, often resulting in serious or even fatal consequences.
  • the thromboembolic disorder is thromboses associated with atrial fibrillation, including NVAF.
  • the thromboembolic disorder is thromboses following orthopedic surgery, including VTE, such as but not limited to deep vein thrombosis ("DVT"), symptomatic VTE, and pulmonary embolism ("PE").
  • VTE deep vein thrombosis
  • PE pulmonary embolism
  • the surgery is total or partial hip or knee replacement surgery.
  • the present invention relates to a method of treating and/or preventing a thromboembolic disorder comprising administering a combination of odiparcil and aspirin.
  • the disorder is thromboses associated with atrial fibrillation, including NVAF.
  • administered administration of a therapeutically effective dose of the active compound(s) (including in the form of corresponding pharmaceutical composition(s) thereof) to a patient in need thereof.
  • terapéuticaally effective dose herein is meant a dose that produces the effects for which it is administered.
  • effective amount is meant that amount of a compound (and/or corresponding pharmaceutical composition), which upon administration to a patient in need thereof provides a clinically desirable result in the treatment and/or prevention of a thromboembolic disorder.
  • an effective amount may inhibit partially or completely the formation of thromboses, including decreasing the size, weight and/or occurrence of thromboses.
  • an effective amount refers to an amount of the combined actives or their corresponding com position (s) which upon administration to a patient in need thereof provides a clinically desirable result in the treatment and/or prevention of a thromboembolic disorder.
  • "Patient” includes both mammals and other animals. Thus the methods are applicable to both human therapy and veterinary applications. In one embodiment the patient is a mammal, and in a particular embodiment the patient is a human.
  • odiparcil refers to the ⁇ -D-xylopyranoside and is normally provided consisting substantially of that enantiomer.
  • the odiparcil used herein has at least 60% of the D-xylopyranoside configuration; or at least 70%; or at least 80%; or at least 90%; or at least 95%; or at least 98%; or at least 99% of that configuration.
  • Odiparcil as referred to herein is preferred as its ⁇ -anomer.
  • odiparcil as used herein is at least 60% of its ⁇ -anomer; or at least 70%; or at least 80%; or at least 90%; or at least 95%; or at least 98%; or at least 99% of its ⁇ -anomer.
  • Odiparcil also includes all crystalline forms of the ⁇ -D- xylopyranoside.
  • aspirin refers to acetyl salicylic acid. Aspirin is readily available from commercial sources, generally in oral dosage forms such as tablets, caplets, capsules, powders, and the like. For example, aspirin marketed under the brands ST. JOSEPH (McNeil Consumer), ECOTRIN (GlaxoSmithKline Consumer), and ASPIRIN REGIMEN BAYER (Bayer Healthcare), ASPIRINE UPSA (Bristol-Myers Squibb), or equivalents thereof, may be used herein.
  • both actives are contained within a single packaging unit, but are in separate dosage forms.
  • the separate dosage forms are contained in separate packaging units.
  • the term “combination” can refer to the administration of a dosage form comprising both odiparcil and another active.
  • “Combination” in this regard also applies to administration of odiparcil and the other active wherein the odiparcil and other active are administered as separate dosage forms and wherein said administration may be substantially simultaneous or sequential, providing only that the combination is being administered for the treatment of a thromboembolic disorder.
  • the actives are administered in such a way that at least at some point, the odiparcil and other active are simultaneously present in the subject's plasma.
  • co-therapy in defining use of odiparcil and another active, may include the following examples: administration of each active agent in a sequential manner in a regimen to provide beneficial effects of the drug combination; and/or co-administration of each active agent in a substantially simultaneous manner (e.g., as in a single dosage form having a fixed ratio of these active agents or in multiple, separate dosage forms for each agent, etc.).
  • odiparcil is used in combination with aspirin.
  • odiparcil is used in combination with a heparin, e.g., LMWH or unfractionated heparin.
  • the odiparcil, and aspirin or other active as applicable may be administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition may further comprise one or more inactive ingredients or additional active ingredients, e.g., pharmaceutically acceptable excipients, and the like.
  • pharmaceutically acceptable means a compound which is suitable for pharmaceutical use.
  • the odiparcil and aspirin or other active may be in the same or 02
  • the present invention encompasses a pharmaceutical composition comprising an effective amount of odiparcil and aspirin, and a pharmaceutically acceptable excipient.
  • the active(s) and composition(s) may be provided in any dosage form suitable for the desired administration route.
  • administration may be peroral, lingual, sublingual, buccal, rectal, topical, intravenous, intraarterial, intracardiac, subcutaneous, intranasal, transdermal, intramuscular, or intraperitoneal.
  • the mode of administration, and thus the type of dosage form may be the same or different for the odiparcil and aspirin when used in combination according to some aspects of the present invention.
  • suitable dosage forms may be tablets (including caplets), capsules, powders, elixirs, syrups, solutions, suspensions, and others such as are known in the art.
  • the pharmaceutical composition(s) may comprise a wide variety and percentage of excipient(s) depending upon the particular drug, drug combination and/or method of delivery contemplated.
  • excipients and their use in pharmaceutical compositions are described, for example, in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (e.g., 2 nd Ed., Editors A. Wade and PJ. Weller, 1994); Handbook of Pharmaceutical Additives, Gower (e.g., M. and I. Ash, 1995); and Remington, The Science and Practice of Pharmacy, Lippincott Williams & Wilkins (e.g., 20 th Edition, Editor A. Gennaro et al., 2000).
  • the formulation may contain one or more excipients selected from starches, sugars, diluents, lubricants, disintegrants, binders, fillers, polymers (including rate- controlling polymers, swelling polymers, matrix polymers), glidants, pigments, colorants, dyes, waxes, coating agents, disintegrants, effervescent agents, floating agents, film- formers, stabilizing agents, suspending agents, viscosity-increasing agents, bulking agents, vehicles, adsorbents, anti-caking agents, humectants, plasticizers, solvents, preservatives, tonicity agents, surfactants, emulsifying agents, wetting agents, flavoring agents, sweetening agents, and other excipients such as are known in the art.
  • excipient may possess one or more properties, such as described above.
  • Solid oral dosage delivery forms may be coated or uncoated, and when coated, said coating might be, for example, a non-enteric coating or an enteric coating.
  • the odiparcil solid dosage form is coated; in a further embodiment, the coating is non-enteric.
  • the aspirin solid dosage form is uncoated.
  • the formulation will generally comprise a carrier which is typically a sterile aqueous solution, sometimes containing in addition to water T/US2005/043602
  • Injectable suspensions may also be prepared wherein a suspending agent is chosen along with a selected liquid vehicle carrier.
  • compositions of the invention may be prepared according to conventional pharmaceutical blending, compounding or mixing techniques. Such methods are well known in the art. For example, suitable techniques are described in Remington, The Science and Practice of Pharmacy, supra.
  • the odiparcil is provided in a solid dosage form.
  • the odiparcil is in the form of a tablet, further comprising a swelling polymer, a matrix polymer, a floating agent, and optionally a diluent, binder, glidant, and/or lubricant (e.g., in a modified release formulation).
  • a composition is suitably prepared by, in one or more steps, combining the components, blending the components together until appropriately homogeneous, and compressing the mixture into tablets.
  • the composition is prepared using a wet granulation method, such as are well known in the art.
  • the odiparcil, a portion of the diluent, binder, and sufficient amounts of a granulating fluid such as water are combined, granulated, dried and milled to form granules.
  • the granules are then combined with the remaining components and the mixture is compressed into tablets.
  • odiparcil tablets suitably comprise from about 5 to about 60% of odiparcil, based on the total weight of the tablet (unless otherwise stated, % compositions herein are based on the total weight of the composition).
  • the composition comprises from about 30 to about 50%, especially from about 35 to about 50%, e.g., about 37 to about 48%, odiparcil.
  • odiparcil tablets comprise about 125 to about 500 mg odiparcil (including about 125, 150, 200, 250, 375, 400, or 500 mg odiparcil).
  • odiparcil tablets comprise about 250, 375, or 500 mg odiparcil.
  • the odiparcil tablets are elongated, i.e., oblong (e.g., in the form of caplets). Caplets tend to promote ease of taking the medication and treatment compliance, and are particularly useful for dosage units containing higher active concentrations.
  • the aspirin is microencapsulated with ethylcellulose and further comprises lactose monohydrate and glycerine behenate.
  • the method is for the treatment and/or prevention of thromboses following orthopedic surgery, including VTE (e.g., DVT, symptomatic VTE, and PE).
  • VTE e.g., DVT, symptomatic VTE, and PE
  • the surgery is total or partial hip or knee replacement surgery.
  • the method is for the treatment and/or prevention of thromboses associated with atrial fibrillation, particularly NVAF.
  • the method is for the prevention of stroke in atrial fibrillation.
  • the patient is one with chronic atrial fibrillation at high risk for stroke.
  • This may include patients who have had a previous ischemic stroke, transient ischemic attack ( 1 TIA"), or systemic embolism; patients greater than 75 years of age; patients with moderately or severely impaired left ventricular function and/or chronic heart failure; and patients with a history of hypertension or diabetes.
  • TIA transient ischemic attack
  • the patient is one with chronic atrial fibrillation at low or intermediate risk for stroke.
  • This may include patients: (1 ) ⁇ 60 years of age with no heart disease; (2) ⁇ 60 years of age with heart disease but no risk factors (i.e.,: heart failure, left ventricular ejection fraction less than 35%, diabetes, history of hypertension, and prior embolic event); or (3) >60 yrs and ⁇ 75 years of age with no risk factors and no heart disease.
  • treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms (e.g., a chronic disorder).
  • the odiparcil and aspirin or another active may be administered simultaneously or sequentially.
  • the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be administered in a single composition, provided that the active agents are not incompatible with other active agents or the formulation, or otherwise undesirably combined in a single composition.
  • the present invention is not limited in the sequence of administration; the odiparcil may be administered either prior to, at the same time with or after administration of the aspirin or other active.
  • administration is sequential.
  • the monitoring physician or health care worker may find it preferable to administer one of the components followed by a set period, or followed by a period determined on the basis of some determination or monitoring, and after that period administer the other component. This process may be repeated.
  • the administration where sequential, may occur over a number of iterations and with an order and frequency that is determined as the circumstances and judgment might dictate.
  • the second drug will be administered at a time where the patient being treated still has at least some of the first drug in his or her system (e.g., in plasma).
  • the odiparcil and aspirin are administered substantially simultaneously in part and/or sequentially in part. For example, about one half of the total daily dose of odiparcil is administered substantially simultaneously with the total daily dose of aspirin, and the other half of the total daily dose of odiparcil is administered sequentially at a different time.
  • the odiparcil, or odiparcil and aspirin or other active is administered in an amount effective to treat or prevent a thromboembolic disorder.
  • the optimal amount of a drug to be administered depends upon a particular combination and/or composition contemplated, the particular thromboembolic disorder being treated and its severity, relevant patient characteristics (sex, weight, age, general health including the presence or absence of other conditions, diet, etc), the mode of delivery (e.g., systemic vs local), the time of administration, drug interactions, etc.
  • from about 125 mg to about 1000 mg of odiparcil is administered per day.
  • about 125, 250, 300, 375, 400, 500, 750, 800 or 1000 mg of odiparcil are administered per day.
  • about 250, 300, 375, 400, 500, 750, or 800 to about 1000 mg of odiparcil are administered daily.
  • At least about 0.1 mg, to about 50 mg of odiparcil per kilogram patient body weight may be administered per day.
  • at least about 1 or 2 mg, to about 5, 10, 15, 20, 25, 30 or 35 mg odiparcil per kilogram patient body weight are administered per day.
  • the odiparcil is administered once daily or twice daily (e.g., about every 8-16, 10-14, or 12 hours).
  • twice daily administration e.g., 1000 mg per day administered as a 500 mg dose twice a day, or as two 250 mg dosage units twice a day, and the like).
  • each odiparcil dose is administered in 1-4 dosage units.
  • each dose is administered as a single dosage unit.
  • each dosage unit may comprise about 250, 375, 400, or 500 mg odiparcil.
  • about 250, 375, 400, or 500 mg odiparcil is administered twice daily (for a total daily dose of about 500, 750, 800 or 1000 mg).
  • the odiparcil is administered at least once a day, including a morning dose.
  • the odiparcil is administered in the fasted state (i.e, on an empty stomach, e.g., at least about 1 hour before eating or about 2 or more hours after eating).
  • the odiparcil is administered with food ("in the fed state"); e.g., concurrently with or shortly before or after eating a meal (e.g., within about 20-30 minutes after eating, e.g., within about 5 minutes of completing a meal).
  • Administering odiparcil with food tends to increase its systemic exposure and the maximum plasma concentration.
  • the aspirin or other active used in combination with odiparcil is generally used in accordance with its prescribing information.
  • aspirin may be administered in an amount of from about 50 to about 325 mg per day (including but not limited to about 100 to about 100 mg per day; 50, 75, 80, 81 , 100, 160, 162.5, and 325 mg/day).
  • the total daily dose may be achieved, e.g., in one or more doses per day (e.g., 1-6 doses per day).
  • about 325 mg of aspirin are administered per day, generally as a single dose.
  • LMWH such as enoxaparin, may for example be administered in an amount of about 30 mg BID or about 40 mg daily.
  • treatment with odiparcil is preceded by an initial treatment with an anticoagulant at standard regimen, e.g., low molecular weight heparin or unfractionated heparin (e.g., tinzaparin, enoxaparin, dalteparin, ardeparin).
  • Initial treatment with an anticoagulant is suitably utilized for acute VTE (e.g., DVT) therapy, e.g., in orthopaedic surgeries.
  • Initial treatment with anticoagulant is suitably started post-surgery, suitably once adequate hemostasis is achieved (generally within 12-24 hours).
  • initial treatment may be continued as needed, for example, for about 24 hours or for several days, e.g., up to 2 or 3 weeks, including 6-10 or 7-10 days, post-surgery.
  • initial treatment is started before surgery, e.g., about 9-24 hours prior.
  • the odiparcil, or odiparcil and aspirin or other active is administered for a period sufficient to treat or prevent a thromboembolic disorder, including acute and extended treatment. Duration of treatment will vary depending upon the particular thromboembolic disorder being treated, the patient being treated, the treatment setting, etc. In some cases, treatment might consist of a single administration.
  • the active(s) will be administered multiple times over a period of time sufficient to meet the needs of the particular situation.
  • the odiparcil, or odiparcil and aspirin or other active is given regularly or fairly regularly, for the entire duration of the patients need, without limit. In one embodiment, the period of treatment is for more than one year. In other embodiments, the odiparcil or odiparcil and aspirin is given regularly or fairly 2
  • Treatment for months or years may be particularly suitable for thromboembolic disorders which are typically chronic, such as those associated with atrial fibrillation. Treatment in the order of days to about 2 or 3 months may be particularly suitable for thromboembolic disorders following orthopedic surgery.
  • the odiparcil, or odiparcil and aspirin or other active is administered for a period of from between 6, 7, or 8 days to 10, 11 , or 12 days (e.g., 6-10, 7-10 or 8-12 days).
  • odiparcil is administered for a period of from about 1 to 60 days, e.g., 1 to 30 or 35 days, or 6-12 days, after an initial treatment with anticoagulant (e.g., LMWH) (such as described herein).
  • LMWH anticoagulant
  • Such methods may be particularly useful for acute treatment and prevention of VTE (e.g., DVT).
  • the administration of odiparcil is initiated as soon as possible following surgery (e.g., once adequate hemostasis is achieved, generally within about 24 hours, e.g., about 12 hours or about 6 hours after surgery). In a particular embodiment administration of odiparcil is initiated no later than 12 hours following completion of surgery.
  • the odiparcil, or odiparcil and aspirin or other active is administered on a need to treat basis. Accordingly, under such a regimen, the active(s) may not be administered regularly, but rather may be administered according to the need of the particular individual. In such a scenario, the individual being treated might be treated once, or a number of times and the effect of the treatment monitored, measured or otherwise diagnosed, and if necessary, additional treatment undertaken as needed or desired.
  • Example 1 Clinical study - Prevention of Venous Thromboembolism following Total Knee Replacement Surgery
  • a multi-center, double-blind, double dummy, randomized, dose ranging, comparator-controlled trial to assess the efficacy, safety, and tolerability of odiparcil in subjects who undergo total knee replacement ( 1 TKR") surgery is conducted.
  • Subjects will receive odiparcil or warfarin.
  • the study will consist of a screening period, a 10 +/- 2 day double-blind study medication period and two (2) follow-up visits, one at 14 ⁇ 2 days and the second at 28 ⁇ 2 days after discontinuation of study medication.
  • the treatment period includes randomization (day 1), in-hospital days on medication, and discharged days on medication. On the first day of the treatment period, eligible subjects are randomized to study medication following surgery.
  • TKR TKR following primary elective TKR, subjects will receive either 250mg, 375mg or 500mg odiparcil q12h for 10 +/- 2 days or dose adjusted warfarin for 10 +/- 2 days.
  • Study medication should be started as soon as possible following TKR surgery, but no later than 12 hours following completion of surgery. Study medication should be taken with food, i.e, it should not be taken on an empty stomach.
  • Subjects may be male or female >35 years of age who are scheduled for primary elective unilateral total knee arthroplasty (i.e., first time the knee is being replaced on the operative side). Subjects on the study will not be taking any other antithrombotic drug therapy such as a vitamin K antagonist, heparin (standard unf ractionated or low molecular weight), heparinoid, direct thrombin inhibitor, GPIIb/llla receptor antagonist, thrombolytic agent, dextran, aggrenox, clopidogrel, or ticlopidine. Subjects will not use compression stockings or intermittent pneumatic compression.
  • Any subject presenting with symptoms suggestive of PE or DVT at any time prior to randomization will be objectively assessed for symptomatic VTE and may remain a candidate for randomization if VTE is ruled out.
  • Subjects will be assessed for VTE at screening, prior to randomization, during treatment, and at the end of the study (day 10+2) or early withdrawal. Any subject who remains asymptomatic for VTE at the end of the study or at early withdrawal will receive a bilateral venogram.
  • Any subject who becomes symptomatic for VTE including PE during the treatment period should be objectively assessed to confirm the presence or absence of VTE.
  • Symptoms of DVT may include but are not limited to pain or swelling in the legs, and symptoms of PE may include shortness of breath or difficulty in breathing. If a VTE is confirmed then the subject should be withdrawn from the study medication.
  • Subjects who are symptomatic and objectively confirmed by a method other than venography including compression ultrasound (“CUS") for VTE or ventilation-perfusion (“V/Q”) scan for PE, spiral computerized tomography (“CT”) or some other objective method
  • CCS compression ultrasound
  • V/Q ventilation-perfusion
  • CT spiral computerized tomography
  • All events will be adjudicated by an independent central adjudication committee (“ICAC”).
  • IIC independent central adjudication committee
  • VTE proximal and distal DVT, non-fatal PE and death due to VTE.
  • Bilateral venography should be performed within 12 h of the last dose of oral medication according to a modification of the Rabinov and Paulin technique, requiring at least nine (9) images per leg.
  • Rabinov K Paulin S. Roentgen. Diagnosis of venous thrombosis in the leg. Arch Surg 1972; 104: 134-44; Kalebo P, Anthmyr BA, Eriksson Bl, Zachrisson BE. Phlebographic findings in venous thrombosis following total hip replacement. Acta Radiol 1990; 31: 259-63; Kalebo P, Ekman S, Lindbratt S, Eriksson Bl, Pauli U, Zachrisson BE.
  • metformin will be stopped the day before the patient undergoes venography and may not resume until 48 hours after venography.
  • the venography should be performed in a semiupright position (preferably 60% elevation from horizontal), using adequate volumes of contrast media (preferably 100 ml_ per leg), and without the use of lower limb tourniquets. Venograms will be judged adequate for evaluation if they demonstrate bilaterally complete visualization of all deep veins or if a DVT was found.
  • Symptomatic DVT during hospitalization or follow-up may be confirmed by ultrasound or venography.
  • DVT will be diagnosed by the ICAC using set criteria. DVT may be diagnosed, for example: when a constant intraluminal filling-defect is seen on at least two images. Proximal DVT is defined as DVT in or above the popliteal vein.
  • PE is diagnosed by ventilation-perfusion ("V/Q") scintigraphy, pulmonary angiography or spiral computerized tomography ("CT”) based on accepted criteria for diagnosis (See Biello DR, Mattar AG, McKnight RC, Siegel BA. Ventilation-perfusion studies in suspected pulmonary embolism. Am J Roentgenol 1979; 133: 1033-7). Subjects experiencing symptoms of a PE will undergo ventilation-perfusion scintigraphy, pulmonary angiography or spiral computerized tomography (CT) of the 02
  • Symptoms of PE include chest pain, dyspnea, hemoptysis, syncope, tachypnea, and a widened A-a DO2 difference (See Tierney LM Jr, Messina LM. 2000. Blood Vessels and Lymphatics. Current Medical Diagnosis and Treatment 2000, Tierney LM Jr, McPhee SJ, Papadakis MA. p 467. New York: Lange Medical Books/McGraw Hill). Subjects experiencing symptoms of DVT will undergo CUS or a venogram. If CUS findings confirm a proximal DVT, a venogram is not required, otherwise the subject will undergo bilateral venography to diagnose DVT.
  • Symptoms of DVT include calf pain or tightness, slight edema of the involved calf, distension of the superficial venous collaterals, tenderness over the femoral and iliac veins and marked edema of the involved leg, and cyanotic skin in severe obstruction (See Chestnutt MS, Prendergast TJ. 2000. Lung. Current Medical Diagnosis and Treatment 2000, Tierney LM Jr, McPhee SJ, Papadakis MA. p 264. New York: Lange Medical Books/McGraw-Hill).
  • VTE cardiovascular disease
  • All subjects without objectively confirmed VTE will undergo mandatory bilateral venography on day 10+2 or at early withdrawal from study medication. All subjects will participate in a population pharmacokinetic ("PK") analysis. Blood samples (approximately 2-3 mL) will be collected for analysis as follows: day 3 (i.e. predose (i.e., 15 minutes prior to dosing administration), 2, 4, 8, 10, and 12 hours post dose), day 5 (predose) and day 10 (predose). Samples will be collected in an EDTA tube and immediately chilled in ice. Plasma will be separated by centrifugation and frozen at approximately -20 0 C.
  • predose i.e., 15 minutes prior to dosing administration
  • predose day 5
  • day 10 predose
  • a pharmacodynamic (“PD") assessment will be based on anti Ua activity.
  • an additional blood sample (approximately 3 mL) will be collected at the time of other blood sampling as follows: Baseline, day 3 (i.e. predose, 2, 4, 8, 10, and 12 hours post dose), day 5 (predose), and day 10 (predose) for the assessment of anti-factor Ha activity. Samples will be collected in 3.8% sodium citrate tubes and immediately chilled in ice. Plasma will be centrifuged and frozen at approximately -20°C.
  • the pharmacodynamic response is determined by measurement of the biomarker anti-lla to detect changes in coaguability, and the relationship between odiparcil dosage, PK, and anti Ha activity is characterized. For example, anti-lla levels following periods of treatment, and proportions of subjects having defined anti-lla levels (e.g., at least 0.75 ug/mL, at least 2ug/mL) following periods of treatment, are assessed.
  • the pharmacokinetics and pharmacodynamics of odiparcil in the study can be evaluated as described herein.
  • the study medication will consist of 250mg, 375mg or 500mg odiparcil tablets and matching placebo as well as overencapsulated warfarin. Warfarin will be supplied at strengths of 1 mg and 5mg, with placebo to match. 5 043602
  • Odiparcil (250 mg) is provided as aqueous film-coated, bi-convex, modified release, round tablets.
  • the 500 and 375 mg strength odiparcil is provided as aqueous film-coated, modified release, bi-convex caplets.
  • Placebo tablets are provided to match the 250 mg, 375 mg and 500 mg active tablets.
  • the odiparcil tablets may be prepared using a wet granulation method.
  • a granulation is prepared using about 90% odiparcil, 7% microcrystalline cellulose (e.g., Avicel PH102 (NF)), 3% Povidone (e.g., Kollidon 30 (USP)), and purified water (USP) qs (purified water is used in the process and is removed by drying).
  • the granules are prepared using a high-shear granulator (e.g., 25L T.K. Fielder) followed by fluid bed drying (e.g., Glatt GPCG 5/9) and milling (e.g., Co-Mil).
  • Solid materials are screened (nominal 20 mesh using vibratory sieve if necessary) and transferred to the granulator in the following order: about half the odiparcil, the Avicel PH102, the povidone K30, and the remainder of odiparcil.
  • the mix is blended using low main impeller speed and chopper setting for about 2 minutes. Water sufficient for granulation is slowly added and the mass is mixed to granulate (e.g., about 3 min).
  • the granules are then dried, e.g. to a moisture content of ⁇ 5% (by loss at 105C), milled and screened through the mill using a nominal 039 screen and washer (spacer) size 250+200. (Using a Fitsch sieve shaker, not more than 5% should be retained on a 20 mesh screen and not less than 20% should pass through a 100 mesh screen.)
  • the milled granulation is screened through a 20 mesh screen.
  • Odiparcil tablets for use in the study may be prepared, nominally according to the following compositions:
  • 500 mg strength odiparcil tablets may be prepared nominally as follows.
  • the microcrystalline cellulose (Avicel PH200) and colloidal silicon dioxide are combined. This blend, and the NaCMC, Na bicarbonate, hypromellose, and magnesium stearate are separately screened through a nominal 30 mesh screen.
  • these components are added to a suitable blender (e.g., a PK blender): about half the granules, the NaCMC, the microcrystalline cellulose/colloidal silicon dioxide, the Na bicarbonate, and the hypromellose. The remainder of the granules are added and the mix is blended until sufficiently uniform, e.g., for 10 min at 25 RPM.
  • the magnesium stearate is then added and blended into the mixture until sufficiently uniform, e.g., for 3 min at 25 RPM.
  • the mixture is compressed into biconvex caplets using a suitable press with about 0.38" x 0.72" punches and dies.
  • the caplets are coated with Opadry White YS-1-7706-G (Colorcon, West Point PA) (comprising titanium dioxide, hypromellose, PEG, polysorbate 80), in an amount of about 1.8-1.9%, based on the weight of the uncoated tablet.
  • Formula 1B Formula 1B
  • 375 mg strength odiparcil tablets may be prepared, e.g., in a like manner as described for Formula 1 A, and coated with Opadry White YS-1-7706-G, in an amount of about 2% based on the uncoated tablet weight.
  • the sieved components are blended in the following manner: the hypromellose, and about 10% each of the
  • NaCMC, MCC/SiO2, and Na bicarbonate are blended; about 50% each of the remaining NaCMC, MCC/SiO2, and Na bicarbonate are blended in; about half the granulation, and the remainder of each of the NaCMC, MCC/SiO2, Na bicarbonate, and granulation are blended in (all the foregoing blending steps being, e.g., about 10 minutes at 24 +/- 3 rpm); and the magnesium stearate is blended in (e.g., about 3 minutes at 24 +/- 3 rpm).
  • the mixture is compressed into tablets using, e.g., a Stokes Tripact press with about 0.38" X 0.72" punches and dies.
  • Formula 1C 250 mg strength odiparcil tablets may be prepared nominally as follows. 1199 g of the microcrystalline cellulose Avicel PH200 and 27 g of the colloidal silicon dioxide are combined. 480 g NaCMC, the MCC/SiO2 blend, 383 g Na bicarbonate, and 60 g hypromellose are separately screened through a #30 mesh screen in that order. In the following order, these components are added to a PK crossflow blender: about 833.5 g of the granules of Example 1 , the NaCMC, microcrystalline cellulose/colloidal silicon dioxide, Na bicarbonate, hypromellose, and about another 833.5 g of the granulation (to total 1667 g).
  • the mix is blended for 10 min at 25 RPM.
  • 24 g of magnesium stearate is passed through a #30 mesh screen, added to the blender and mixed for 3 min at 25 RPM.
  • the mixture is compressed into 640 mg round, biconvex tablets using a Stokes B2 press with Vz" standard punches and dies.
  • the tablets are coated with Opadry White YS-1 -7706-G, in an amount of about 3% based on the uncoated tablet weight.
  • the comparator warfarin is provided as overencapsulated Warfarin Sodium Tablets, 1 mg and 5 mg strength.
  • the capsules used to overencapsulate are pink, opaque, hard gelatin capsules (size DB-AA) containing a white powder and the warfarin tablet.
  • the placebo comparator capsules visually match the active overencapsulated Warfarin Sodium Tablets and Capsules.
  • Warfarin will be dose adjusted to a target INR of 2 to 3 at the investigator's discretion according to their own practice and subject status. A pre-dose INR will be taken and subsequent INRs should be monitored on days 2 and 3 of treatment and then as needed (assuming the subject has not reached the target INR level and been placed on a maintenance dose by day 3) to achieve the target INR of 2-3. Subjects should be placed 02
  • Other analyses may include but not be limited to: relative risk of any VTE after each dose of active, trend in total VTE incidence, anti-lla activity, and active plasma concentrations.
  • Plasma samples are assayed for odiparcil using a protein precipitation method followed by LC/MS/MS analysis (e.g., lower limit of quantification 5.00 ng/mL for a 50 ⁇ L aliquot plasma).
  • the odiparcil is isolated from human plasma by protein precipitation with acetonitrile and quantified by LC/MS/MS using a Turbo IonSpray interface.
  • Positive ion multiple reaction monitoring (MRM) is employed for the MS/MS detection of odiparcil and the internal standard, odiparcil [ 13 C 4 ] .
  • Rheos 4000 quaternary pumping system with degasser, (Flux Instruments AB (Karlskoga,
  • Sample Control version 1.3, PE/Sciex
  • MacQuan version 1.4, PE/Sciex
  • Working Standard Solutions Serial dilutions of odiparcil calibration and validation primary stock solutions are prepared in acetonitrile/water (50/50, v/v) to give working solution concentrations of 100 ug/mL, 10 ug/mL, 1.0 ug/ml_, and 0.1 ug/mL.
  • Working odiparcil [ ⁇ 3 C ⁇ solutions - stock solution of odiparcil [1 3 C ⁇ is diluted with acetonitrile to give a solution of 10 ug/mL, which is used to make a final solution of 250 ng/mL in acetonitrile.
  • the samples are assayed for dermatan sulfate concentration equivalents using a chromogenic assay technique, based on modifications of a method reported in the publication "A Simple Method to Measure Dermatan Sulfate at Sub-Microgram Concentrations in Plasma" by D. Dupouy, P. Sie, F. DoI and B. Boneu in Thrombosis and Haemostasis, 1988, 60:236-239.
  • Dermatan sulfate is a glycosaminoglycan found in abundance in human tissues, especially in skin, blood vessels and heart valves. Dermatan sulfate exhibits anticoagulant activity by indirectly inhibiting thrombin as it is formed in plasma. Dermatan sulfate activates heparin cofactor Il (HCII), a plasma protease inhibitor which specifically inhibits thrombin but not other proteases involved in hemostasis. Plasma levels of dermatan sulfate may increase in response to the administration of odiparcil. Therefore, plasma dermatan sulfate concentration may prove to be a useful biomarker for measuring antithrombotic activity after administration of odiparcil.
  • HCII heparin cofactor Il
  • Microplate reader - Dynex technologies MRX
  • Chantilly VA. Titer Plate Shaker, Model 4625 - Lab-Line Instruments, Inc., Melrose Park, IL Multichannel pipette, pipettors - Eppendorf (Brinkman), Westbury, CT EDOS 5221 Automatic Pipetter - Eppendorf (Brinkman), Westbury, CT
  • Tris 0.02 M Tris, pH 7.4 - 3.15 g Tris-HCI dissolved in 900 mL of deionized H2O, pH adjusted to 7.4 with 1 N NaOH, solution diluted to a final volume of 1 L with deionized H2O.
  • Bentonite Suspension - 10 g of Bentonite is added to 80 mL of 0.02 M Tris, pH 7.4, mixed, diluted to a final volume of 100 mL and stored at 4-8°C.
  • Heparin Cofactor II 10 ug/mL- 492 uL of HPLC water is added to a vial containing 8 uL of Heparin Cofactor Il stock to give a concentration of 200 ug/mL. 50 uL of this HCII solution is added to 950 uL HPLC water and vortexed (remaining 200 ug/mL solution is stored at 4-8 0 C). Thrombin- 2 mL of HPLC water is added to a vial of thrombin from the Stachrom HCII kit and mixed well, to give a final concentration of 2.75 Units/mL.
  • Substrate- 2 mL of HPLC water is added to a vial of Thrombin Substrate from the Stachrom HCII kit and mixed well, to give a final concentration of 1.25 umol/mL.
  • Dermatan Sulfate - Dermatan sulfate is prepared to a concentration of 100 ug/mL in HPLC water.
  • Normal plasma contains endogenous low levels of dermatan sulfate.
  • dermatan sulfate is added to pooled plasma (equal volumes of plasma from 4 normal volunteers) to give a concentration of 16.00 ug/mL above the endogenous level.
  • Serial dilutions of the 16.00 ug/mL standard are prepared to yield concentrations of 8.00, 4.00, 2.00, 1.00, 0.50, 0.25 ug/mL above endogenous level.
  • the plasma pool without addition of dermatan sulfate is used for the 0.00 ug/mL standard.
  • the standards are dispensed in 200 uL aliquots in 0.5 mL Safe-Lock Eppendorf tubes and stored at - 8O 0 C.
  • the Bentonite suspension is mixed on a stir plate for 30 min at room temperature. 200 uL of each plasma sample to be analyzed is dispensed into a 0.5 mL Safe-Lock Eppendorf tube. 200 uL of Bentonite suspension is added to each sample and standard tube (thawed to room temperature). The tubes are vortexed for 15 seconds, incubated for 5 minutes at room temperature, then centrifuged at 14,000 rpm for 2 min. 25 uL of HPLC water, 25 uL of Bentonite treated plasma or standard, and 50 uL of Heparin Cof actor Il is added in that order to appropriate wells in the microtiter plate. Standards and samples are assayed in duplicate.
  • the plate is covered, mixed for 15 - 30 seconds on the Titer-Tek rotator at 500 rpm at room temperature, then incubated for 10 min. at 150 rpm at 37°C using the Rotating Incubator. 25 uL of Thrombin is added per well. The plate is covered, mixed and incubated for 10 min. at 150 rpm at 37 0 C using the Rotating Incubator. 50 uL of substrate is added per well, then the plate is incubated at room temperature for 20-30 min. The plate is read using the DS-EP. asy program on the plate reader with the absorbance measured at 405 nm.
  • Example 2 Clinical study - Odiparcil + aspirin vs Placebo + aspirin in NVAF
  • a randomized, double-blind, double dummy, parallel group, placebo controlled, multi-center dose ranging study is conducted to assess the pharmacokinetics, pharmacodynamics (as defined by anti-lla activity), safety and tolerability of odiparcil in non-valvular atrial fibrillation patients at a low/intermediate risk for stroke.
  • Eligible patients are randomized to receive either odiparcil (250 mg, 375 mg or 500 mg) or placebo twice daily for 16 weeks in addition to aspirin, 325 mg once daily also for 16 weeks.
  • the PD response is determined by measurement of the biomarker anti-lla to detect changes in coaguability, and the relationship between odiparcil dosage, PK, and anti Ha activity is characterized. For example, anti-lla levels following periods of treatment, and proportions of subjects having defined anti-lla levels (e.g., at least 0.75 ug/mL, at least 2ug/ml_) following periods of treatment, are assessed.
  • Pharmacokinetic parameters are evaluated and correlated to safety and efficacy endpoints.
  • the study consists of a one week screening period, a 16 week treatment period and a 30 day follow-up period.
  • Study subjects are those who have a diagnosis of chronic non valvular atrial fibrillation with a low or intermediate risk for stroke within 6 months of the screening visit confirmed by either electrocardiogram (ECG) or telemetry (Subjects diagnosed with paroxysmal atrial fibrillation (AF), persistent AF or permanent AF may participate. Subjects with atrial flutter are excluded. The study excludes subjects with NVAF secondary to other reversible disorders such as thyrotoxicosis.).
  • ECG electrocardiogram
  • telemetry Subjects diagnosed with paroxysmal atrial fibrillation (AF), persistent AF or permanent AF may participate.
  • Subjects with atrial flutter are excluded.
  • a subject is considered at a low or intermediate risk for stroke if one of the following applies: Subject ⁇ 60 years of age with no heart disease;
  • Subject ⁇ 60 years of age with heart disease but no risk factors defined as: heart failure, left ventricular ejection fraction less than 35%, diabetes, history of hypertension and prior embolic event); Subject >60 yrs and ⁇ 75 years of age with no risk factors and no heart disease.
  • Subjects should not have had previous myocardial infarction, stroke (ischemic or hemorrhagic), TIA or other cardiovascular event, mechanical prosthetic valve or rheumatic valvular disease, history of hypertension (defined as medical treatment for the disease within the past year), diabetes (defined as medical treatment for the disease within the past year) or prior embolic event.
  • subjects are those not having LVEF less than 35%, and not requiring treatment with Class III anti-arrhythmic drugs.
  • Subjects are not receiving during the study any other antithrombotic drug therapy including vitamin K antagonist, heparin (standard unfractionated or low molecular weight), heparinoid, direct thrombin inhibitor, GPIIb/IIIA receptor antagonist, thrombolytic agent, intravenous dextran and clopidigrel; amiodarone; dofetilide; or a calcium channel blocker.
  • Blood samples (2 mL) for the assessment of population pharmacokinetics are collected from all subjects.
  • the PK blood samples are collected into tubes containing EDTA and immediately chilled in ice. Plasma is separated by centrifugation (preferably refrigerated)(e.g., 3000 rpm for approximately 10 minutes at 4 0 C) within 30 minutes following the blood draw. Plasma is then transferred immediately to appropriate specimen containers and frozen at approximately -2O 0 C until time of drug analysis. Plasma samples may be analyzed for odiparcil in accordance with the methodology described herein.
  • Plasma samples for evaluation of anti-lla via HCII are collected into 3.8% sodium citrate tubes. Plasma is separated, packaged and stored as for the PK samples. The plasma samples are assayed for anti-lla activity via chromogenic techniques in accordance with the methodology described herein.
  • a PD sample is collected just before the first morning dose at the beginning of the treatment period. PK and PD samples are obtained during the treatment period at week 1 (just before morning dose and 0.5-3 hrs after that dose); week 3 (7-12 hrs after the morning dose); week 4 and 8 (just before the morning dose); and week 16 (just before the morning dose and 4-6 hrs after that dose).
  • Odiparcil tablets/caplets and matching placebo are supplied and may be prepared using methods and nominally as described in Example 1. Open label 325 mg aspirin is provided in commercially packaged containers. Aspirin may be Aspirine UPSA, 325 mg available from Bristol-Myers Squibb.
  • the subjects are randomized in a 1 :1 :1:1 ratio to receive either: Odiparcil 250 mg bid, po and aspirin 325 mg qd, po; Odiparcil 375 mg bid, po and aspirin 325 mg qd, po; Odiparcil 500 mg bid, po and aspirin 325 mg qd, po; or Placebo bid, po and aspirin 325 mg qd, po.
  • subjects receive matching placebo for the other two odiparcil dose levels.
  • Subjects are instructed to self dose with the assigned odiparcil product twice a day, with food, with approximately 12 hours between doses, and aspirin 325 mg once daily, for a total of 16 weeks.
  • LMWH low molecular weight heparin
  • eligible subjects were randomized to odiparcil 125 mg twice daily (BID), odiparcil 500 mg BID, or matching placebo.
  • BID twice daily
  • odiparcil 500 mg BID or matching placebo.
  • the odiparcil was administered as a No. 0 opaque-white (white #9) capsule containing 125 mg or 250 mg of uniform, white to off-white granules of odiparcil. Placebo capsules were matched for weight, shape and color, comprising uniform white to off-white granules.
  • the granules were prepared using a high-shear granulator followed by fluid bed drying and milling nominally according to the following composition:
  • the granules were blended with magnesium stearate (lubricant; passed through a nominal 20-40 mesh screen using a vibratory sieve if required to de-aggregate), e.g., for 3 minutes at 24.4 RPM, or sufficient speed and/or time to achieve 60 +/- 10 revolutions, and filled into capsules according to the following target formulations:
  • 226 subjects were randomized to a treatment group and took at least one dose of study medication (79 to the placebo group, 72 to the odiparcil 125 mg BID group, and 75 to the odiparcil 500 mg BID group).
  • the majority of the randomized subjects (198) completed the study (i.e., received study medication for 28 +/- 3 days) (70 in the placebo group, 60 in the odiparcil 125 mg BID group, and 68 in the odiparcil 500 mg BID group).
  • the three treatment groups were well balanced with respect to the types of surgery (cemented (69%), hybrid, or uncemented) and anesthesia (general (54.4%) vs regional) used for THA.
  • the agent was either 1) started (first dose administered) on the last day of the on-therapy period, or 2) stopped (last dose administered) on the first day of the on-therapy period (the two subjects were not included in the efficacy evaluable population). Over 94% of the randomized subjects were considered compliant (took > 80% and
  • VTE venous thromboembolism
  • the last available assessment at the study screening visit was considered as the baseline value.
  • the endpoint value was defined as the last non-missing value in the on-therapy period.
  • Efficacy analysis was based on adjudication of VTE events by an independent central adjudication committee (ICAC).
  • the ICAC adjudicated mandatory venography reviewed and adjudicated the clinical and diagnostic investigations associated with the evaluation of reported, suspected symptomatic uv i and/or PE outcome events, and reviewed and classified the cause of any reported deaths. If an investigator recorded a VTE event that was not adjudicated as a VTE event by the ICAC, it was not counted as a VTE event. All efficacy data was analyzed descriptively.
  • the VTE event rates for each treatment group were described as 95% confidence intervals around the proportion of events. Pairwise comparisons of odiparcil against placebo were analyzed as 95% confidence intervals around the relative risk. The relative risks were calculated for each odiparcil treatment group as the percentage of subjects in the odiparcil group with a VTE divided by the percentage in the placebo group.
  • VTE data was analyzed using the evaluable population.
  • the anti-lla data was analyzed using the intent-to-treat population (i.e., subjects who had at least one dose of study medication).
  • Incidence of VTE events during the 28 (+3)-day treatment period included asymptomatic DVT assessed by bilateral venography on Day 28 or at early withdrawal (if applicable), symptomatic DVT confirmed by compression ultrasound or venography, or symptomatic PE confirmed by perfusion/ventilation scanning (VQ scanning), pulmonary angiography, or spiral computed tomography (CT) of the chest.
  • asymptomatic DVT assessed by bilateral venography on Day 28 or at early withdrawal (if applicable)
  • symptomatic DVT confirmed by compression ultrasound or venography
  • symptomatic PE confirmed by perfusion/ventilation scanning (VQ scanning), pulmonary angiography, or spiral computed tomography (CT) of the chest.
  • VQ scanning perfusion/ventilation scanning
  • pulmonary angiography pulmonary angiography
  • CT spiral computed tomography
  • Symptomatic deep vein thrombosis Subjects experiencing symptoms of DVT were required to undergo CUS or a venogram. If CUS findings confirmed a proximal DVT, a venogram was not required, otherwise the subject underwent bilateral venography to diagnose DVT. Symptoms of DVT included calf pain or tightness, slight edema of the involved calf, distension of the superficial venous collaterals, tenderness over the femoral and iliac veins and marked edema of the involved leg, and cyanotic skin in severe obstruction (Tierney LM Jr, Messina LM. Blood Vessels and Lymphatics. Current Medical Diagnosis and Treatment 2000, Tierney LM Jr, McPhee SJ, Papadakis MA. New York ⁇ ange Medical Books/McGraw Hill, 2000:467).
  • Asymptomatic deep vein thrombosis All subjects without objectively confirmed VTE were required to undergo mandatory bilateral venography on Day 28 or at early withdrawal from study medication. If a DVT was objectively confirmed, study medication was discontinued and treatment initiated according to local practice.
  • Pulmonary embolism Subjects experiencing symptoms of a PE underwent a ventilation/perfusion scan (V/Q scan) or spiral CT of the chest. Symptoms of PE included chest pain, dyspnea, hemoptysis, syncope, tachypnea, and a widened alveolar-arterial difference in oxygen (A-a DO 2 difference). In subjects who had a non-high probability V/Q scan or normal findings on spiral CT, further testing was to be performed using CUS.
  • CUS did not confirm a proximal DVT, then serial CUS, venography, or pulmonary angiography was to be performed. Positive findings were considered diagnostic for PE; negative findings were considered to exclude PE. If a suspected PE was objectively confirmed, study medication was discontinued and treatment initiated according to local practice.
  • a subject was considered to have experienced a VTE if the VTE event occurred at any time following the first dose of study medication through the Day 28 visit.
  • VTE Venous Thromboembolism
  • the efficacy evaluable population is defined as only those subjects who took at least one dose of study medication, did not violate the protocol, and had an evaluable venogram following 28 +/- 3 days of treatment. In addition, subjects who were withdrawn from the study with an adjudicated diagnosis of symptomatic VTE were included in the evaluable population.
  • VTE Venous Thromboembolism
  • DVT Deep Vein Thrombosis
  • PE Pulmonary Embolism
  • Asymptomatic DVT 3 ( 5.56) 2 ( 5.26) 0 Non-proximal 2 ( 3.70) 0 0 Proximal 1 ( 1.85) 2 ( 5.26) 0
  • Symptomatic DVT 1 ( 1.85) 0 1 ( 2.33) Non-proximal 1 ( 1.85) 0 1 ( 2.33) Proximal 1 ( 1.85) 0 0
  • Anti-lla activity was measured as a possible surrogate marker for efficacy.
  • blood was collected at baseline and on Days 5, 7, 14, and 21 (approximately 3 ml. in 3.8% sodium citrate tubes, which was centrifuged, and stored until analyzed).
  • the Days 5 and 7 samples were mixed samples (i.e., they could have been trough or peak samples).
  • Odiparcil elicited an increase in anti-lla activity that appeared to be proportional to dose.
  • Anti-lla activity was detected in both odiparcil treatment groups at all visits (days 5, 7, 14 and 21), but was markedly elevated in the higher, 500 mg BID group.
  • the median anti-lla activity was 0.41 and 0.42 ⁇ g/mL at Days 14 and 21 , respectively in the odiparcil 125 mg bid group and 3.52 and 3.64 ⁇ g/mL at Days 14 and 21, respectively in the odiparcil 500 mg bid group.
  • Two subjects in the odiparcil 125 mg bid group experienced asymptomatic VTE at Day 21 , having an anti-lla activity of 0.32 and 2.14 ⁇ g/mL.
  • One subject in the odiparcil 500 mg bid group experienced symptomatic VTE on Day 2; the anti-lla activity was not determined.
  • Elevated anti-lla activity was also demonstrated for both odiparcil treatment groups on Days 5 and 7. The tendency for higher values on Days 5 and 7 compared with Days 14 and 21 (trough samples) appears to be due to the difference in sampling.
  • Table 3 Number and Percentage of Subjects with Anti-lla Activity Greater Than 2 Micrograms per Milliliter odiparcil odiparcil
  • n/n Number of subjects with activity >2 ⁇ g/mL /number of subjects with nonmissing results.
  • Example 4 Comparison of odiparcil to warfarin in a rat model of venous thrombosis, and other characterizations of odiparcil
  • the antithrombotic and bleeding profile of odiparcil was compared to warfarin in a rat model of venous thrombosis. Additionally, the ex vivo antithrombin and antiplatelet activity of odiparcil, and the potential of protamine sulphate to function as an antidote to odiparcil, were assessed.
  • Materials: Bentonite, H 2 O 2, protamine sulfate, Adenosine diphosphate (ADP), Thrombin, and 3,3',5,S 1 tetramethylbenzidine were purchased from Sigma-AIdrich (St.
  • Deep Vein Thrombosis Model The thrombotic stimulus in this model is through the mechanical restriction of blood flow, coupled with induced endothelial lesions in the inferior vena cava brought on by the transient exposure to hypotonic saline. This model has been shown to result in thrombus formation which was sensitive to anticoagulants (and a more limited sensitivity to antiplatelet agents). See Millet J, Theveniaux J 1 Pascal M. A new experimental model of venous thrombosis in rats involving partial stasis and slight endothelium alterations. Thromb Res 1987;45:123-133; Feuerstein GZ, Toomey JR, Valocik R, Koster P, Patel A, Blackburn MN. An inhibitory anti-factor IX antibody effectively reduces thrombus formation in a rat model of venous thrombosis. Thromb & Haemost 1999;82:1443-1445).
  • odiparcil and warfarin were administered prior to the thrombotic challenge, warfarin daily over 4 days, and odiparcil 3 hours prior to the challenge.
  • the antithrombotic activity of odiparcil had been shown previously to peak 2-4 hours following a single oral dose (not shown).
  • mice Male Sprague-Dawley rats (350-400 g) were anaesthetised with sodium pentobarbital (50 mg/kg, i.p.). The trachea was surgically exposed and an endotrachael tube (PE tubing 240) was inserted. The left carotid artery was cannulated for withdrawal of blood samples at the end of the experiment. Blood was centrif uged at 3000 rpm for 10 minutes to obtain plasma for quantification of dermatan sulphate-like GAGs. For thrombus formation, a ventral midline incision was made and the descending vena cava was exposed and separated from the descending aorta.
  • sodium pentobarbital 50 mg/kg, i.p.
  • a suture was placed under the vena cava just distal to the renal veins and the vessel was tied against a 26g needle. The vessel was then clamped with a non-serrated clamp just proximal to the iliac veins. The section of vena cava between the ligature and the clamp formed a "vena cava (venous) sac". Thrombus formation was induced by injecting 2.0 ml hypotonic saline (0.25%) into the venous sac using a second 26g needle attached to a syringe via PE20 tubing. After saline injection, the distal clamp was released and the 26g needle was removed from the proximal ligature (time 0). The remaining suture restricts the vena cava to a 26g (opening) non-occlusive stenosis. The experiment continued for 60 minutes, after which blood 005/043602
  • PS protamine sulfate
  • venous thrombosis procedure utilized for this assessment was as described above, with the following modifications.
  • PS protamine sulfate
  • the right jugular vein was cannulated with a 22GA intravenous catheter (Becton, Dickinson, UT).
  • PS infusion began 5 minutes prior to thrombus induction and continued for a total of 60 minutes (see dosing regimen for details).
  • Odiparcil was prepared as a suspension in 0.5% carboxymethylcellulose (15 mg/ml stock concentration), and administered by oral gavage 3 hours prior to thrombus induction.
  • the dose groups were as follows: vehicle, 1.9 mg/kg, 3.8 mg/kg, 7.5 mg/kg, 15.0 mg/kg and 30 mg/kg (bleeding study only).
  • protamine sulphate study only a single dose of odiparcil (15 mg/kg) was administered.
  • Protamine sulphate was prepared in saline and infused as a 1.0 mg/kg bolus (over 5 minutes) + 1.0 mg/kg infusion (over 55 minutes).
  • Warfarin (Aldrich; Milwaukee, Wl) was prepared in 0.2 M NaHCO 3 (1 mg/ml stock concentration). Warfarin administration was initiated by oral gavage 72 hours prior to the start of the study, followed by subsequent dosing at 24 hour intervals. The last dose was administered 1 hour prior to thrombus induction.
  • the dose groups were as follows: vehicle, 0.06 mg/kg, 0.2 mg/kg and 0.6 mg/kg/day.
  • Bleeding Time Model A rat tail transection model was used to assess hemostasis effects. This model has been shown to be sensitive to the effects of anticoagulants as well as antiplatelet agents. See, Dejana E, Villa S, de Gaetano G. Bleeding time in rats: A comparison of different experimental conditions. Thromb & Haemost 1982;48:108-111. In a separate cohort of animals, bleeding was induced by tail transection of the anesthetized rat with a size 21 disposable scalpel blade 5mm from the tail tip. The bleeding tail was immediately placed in 1.0 liter of saline (37°C) where blood was collected.
  • Bleeding was monitored visually until blood flow stopped for a complete 15 second interval, or if bleeding did not stop, for a maximum of 30 minutes. After recording the time to stop bleeding, the liter of saline plus collected blood was mixed. The samples were collected and frozen (-2O 0 C) for blood volume/hemoglobin analysis.
  • Hemoglobin Analysis (Blood Loss): To quantitate and compare blood loss in the bleeding time experiments, the samples were assessed for hemoglobin content using a colorimetric hemoglobin detection assay. Determination of hemoglobin concentration was based upon the catalytic action of hemoglobin on the oxidation of 3,3',5,5' tetramethylbenzidine (TMB) by hydrogen peroxide (H 2 O 2 ). The rate of color formation in US2005/043602
  • this assay is proportional to the hemoglobin concentration and is detectable at wavelength of 600 nm.
  • 3 ⁇ l_ of each sample was added to 122 ⁇ l_ TMB and 125 ⁇ l_ H 2 O 2 .
  • Optical density readings were recorded 15 minutes after H 2 O 2 addition.
  • O.D.s derived from samples were compared to similarly prepared standards from known volumes of pooled rat blood and total blood loss per rat was calculated.
  • Coagulation tests Blood samples withdrawn via the cannulated left carotid artery at the end of the stenosis period were collected in 2 ml vacutainer tubes containing 3.8% sodium citrate, mixed gently, and then centrifuged at 3000 rpm for 10 minutes at room temperature to separate plasma. Coagulation tests were then performed using the Dade Behring BCS Coagulation System (Newark, DE).
  • PT prothrombin time
  • R is the patient PT/normal PT
  • ISI International Sensitivity Index of the reagent.
  • the target INR range is between 2.0- 3.0.
  • Platelet aggregation Rats were administered 15 mg/kg odiparcil or vehicle by oral gavage four hours prior to blood withdrawal. Blood was drawn into 3.8% citrated vacutainers (9 parts blood: 1 part citrate) via a carotid artery cannula and centrifuged at 2000 rpm for 4 minutes to obtain platelet rich plasma (PRP). PRP was removed and pooled from all rats in the same treatment group. The remaining sample was then centrifuged at 3000 rpm for 10 minutes to obtain platelet poor plasma (PPP).
  • PRP platelet rich plasma
  • PPP platelet-poor plasma
  • Plasma dermatan sulfate assay The assay is a modification of Dupouy D, Sie P, DoI F, Boneu B. A simple method to measure dermatan sulfate at sub-microgram concentrations in plasma. Thromb & Haemost 1988;60:236-239. An HCIl assay kit (Diagnostica Stago, Parsippany, NJ) was used to determine the concentration of 2005/043602
  • dermatan sulfate-like GAGs in plasma samples obtained in the odiparcil venous thrombosis study.
  • This assay was configured to detect HCII mediated thrombin inhibition as a function of dermatan sulfate concentration.
  • a standard curve was prepared by spiking pooled rat plasma with purified dermatan sulfate (0-100ug/ml). This was added in equal volume to a 10% bentonite suspension prepared in 0.02 M Tris, pH 7.4. The bentonite step was used to defibrinate the plasma and remove endogenous antithrombin III (ATIII) and HCII.
  • ATIII endogenous antithrombin III
  • the combination was vortexed, incubated for 5 minutes at room temperature, and then centrifuged for 2 minutes at 14,000 rpm. After centrifugation, the plasma supernatant was removed and assessed for HCII-dependent antithrombin activity according to the manufacturer's instructions.
  • plasma supernatant was combined with 0.5 ug of HCII, mixed and incubated for 10 minutes at 37 0 C, followed by an additional 10 minute incubation with thrombin (0.1 unit), and then finally residual thrombin activity detected using a thrombin specific chromogenic substrate (CBS61.50 - 0.36 mM) with an O. D. read-out at 405 nm.
  • CBS61.50 - 0.36 mM thrombin specific chromogenic substrate
  • O. D. read-out O. D. read-out at 405 nm.
  • the standard curve was prepared by plotting the observed O.D. values (thrombin activity) as a function of the dermatan
  • a desirable feature of any antithrombotic therapy is either rapid reversibility and/or an antidote.
  • the ability of protamine sulfate to suppress odiparcil-induced antithrombin activity was determined using a modification of the HCII kit described above. The assay was performed with plasma from rats treated with 15 mg/kg odiparcil. In this modified assay, bentonite treated plasma was incubated with HCII for 10 minutes, followed by a 10 minute incubation with PS (0-2OuM), and then finally an additional 10 minute incubation with thrombin. The addition of substrate, detection, and data analysis were as described above.
  • Warfarin had abrupt and pronounced effects on the prothrombin time, extending the INR to ⁇ 1.9 at the ID 50 and to -3.0 at the ID 65 (figure 4C) and beyond assay limitations (> 10) at the ID 90 .
  • the target INR for warfarin therapy in humans is in the range of 2.0 - 3.0
  • a therapeutically relevant dose-range of warfarin in this rat model would maximally suppress thrombus formation by approximately 65%.
  • DS-HCII dependent antithrombin assay The anti-thrombin effects of odiparcil were followed with the DS-HCII dependent antithrombin assay.
  • the readout in the assay was in DS equivalent units (ug/ml) (figure 4D).
  • DS concentration ranged from -2.0 ug/ml at the ID 50 to -4.0 ug/ml at the ID 65 with maximal DS concentration plateauing between 4-6 ug/ml.
  • odiparcil induced DS levels of 2.0 - 4.0 ug/ml approximated the efficacy of warfarin when dosed to an INR of 1.9 - 3.0 in this rat venous thrombosis model.
  • No ATIII dependent anti-thrombin activity was detected in odiparcil samples, nor were effects on aPTTs or PTs observed.
  • odiparcil did not cause dose-related changes in bleeding time or blood loss.
  • Odiparcil effects on thrombin, ADP, and collagen induced platelet aggregation To evaluate potential effects of odiparcil on platelet function, platelets were collected as platelet rich plasma (PRP) from rats treated with odiparcil (15mg/kg) and vehicle. The PRP was then tested in conventional platelet aggregation studies. By comparison to vehicle treated animals, platelets collected from odiparcil-treated rats did not respond differently to the platelet agonist ADP or collagen. ADP was tested in a range of 1-10 uM and collagen from 1 -8 ug/ml. In contrast thrombin-induced aggregation and subsequent clot formation was blocked by the odiparcil treatment (Figure 6). Odiparcil completely prevented aggregation and clot formation induced by 1.0 unit/ml thrombin, and caused reversible aggregation at 2.5 units/ml thrombin.
  • PRP platelet rich plasma
  • the triangle symbols represent an assay order of addition of plasma, HCII, thrombin, and then PS added as the last step;
  • the ability of protamine sulfate to neutralize the antithrombin and antithrombotic activity of odiparcil was assessed ex vivo and in vivo.
  • PS was evaluated in vivo for its potential to neutralize the antithrombotic effects of odiparcil.
  • the experimental protocol was as the previously described venous thrombosis studies, with the exception that PS administration was initiated 5 minutes prior to and then continued throughout the thrombus induction period.
  • the PS dose and regimen were selected through a limited dose-finding optimization effort. The most effective dose and regimen tested are illustrated in Figure 7B.
  • no dose or regimen tested in vivo completely neutralized the odiparcil antithrombotic activity.
  • the odiparcil antithrombotic mechanism may at least in part be through the actions of dermatan sulfate-like GAGs. Whether all of the antithrombotic activity of odiparcil is mediated by a DS-HCII antithrombin mechanism remains to be determined.
  • Prior studies with purified preparations of chondroitin and dermatan sulfate suggested antithrombotic potential through profibrinolytic and antiplatelet mechanisms (Kariya Y, Sakai T, Kaneko T, Suzuki K, Kyogashima M.
  • the present invention encompasses the use of protamine sulfate to neutralize the antithrombin and/or antithrombotic activity of odiparcil.
  • both odiparcil and warfarin demonstrated dose-related suppression of thrombus formation.
  • In vitro analysis of plasma from odiparcil treated rats demonstrated an increase in dermatan sulfate-like molecules at antithrombotic doses. This suggests increased heparin cofactor Il activity yielding an increase in thrombin inhibition. This indicates that DS-HCII mediated antithrombin activity could be used as a pharmacodynamic marker of odiparcil antithrombotic activity. 5 043602
  • odiparcil and warfarin demonstrated a pronounced difference in their effect on bleeding time and blood loss.
  • Odiparcil had no significant effect on bleeding time within an efficacious dose range and hemoglobin content analysis showed no significant blood volume loss.
  • warfarin significantly prolonged bleeding time in a dose range that overlapped antithrombotic effect and was accompanied by a significant loss in blood volume at doses > 0.2 mg/kg.
  • odiparcil is an orally active antithrombotic which has the potential to match the efficacy of warfarin (e.g., when dosed to an INR of 2-3), without incurring a significant bleeding liability.
  • efficacy in venous thrombosis could represent a marker of its efficacy in atrial thrombosis.
  • the above demonstrations of efficacy of odiparcil in venous thrombosis could represent a marker of or suggest its efficacy in atrial thrombosis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des méthodes de traitement prophylactique et/ou thérapeutique de troubles thromboemboliques, comprenant l’administration de 4-méthyl-2-oxo-2H-1-benzopyran-7-yl-5-thio-β-D-xylopyranoside en quantité significative.
PCT/US2005/043602 2004-12-01 2005-12-01 Méthodes de traitement prophylactique et thérapeutique Ceased WO2006060647A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US63215304P 2004-12-01 2004-12-01
US60/632,153 2004-12-01
US69172805P 2005-06-17 2005-06-17
US60/691,728 2005-06-17
US72169105P 2005-09-29 2005-09-29
US60/721,691 2005-09-29
US72471005P 2005-10-07 2005-10-07
US60/724,710 2005-10-07

Publications (1)

Publication Number Publication Date
WO2006060647A1 true WO2006060647A1 (fr) 2006-06-08

Family

ID=36565378

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/043602 Ceased WO2006060647A1 (fr) 2004-12-01 2005-12-01 Méthodes de traitement prophylactique et thérapeutique

Country Status (5)

Country Link
AR (1) AR053789A1 (fr)
PE (1) PE20061246A1 (fr)
TW (1) TW200635580A (fr)
UY (1) UY29237A1 (fr)
WO (1) WO2006060647A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6602899B1 (en) * 1999-11-17 2003-08-05 Fournier Industrie & Sante β-D-5 thioxylose derivatives, preparation method and therapeutic use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6602899B1 (en) * 1999-11-17 2003-08-05 Fournier Industrie & Sante β-D-5 thioxylose derivatives, preparation method and therapeutic use

Also Published As

Publication number Publication date
UY29237A1 (es) 2006-05-31
AR053789A1 (es) 2007-05-23
TW200635580A (en) 2006-10-16
PE20061246A1 (es) 2006-11-08

Similar Documents

Publication Publication Date Title
O'Dell et al. New oral anticoagulants for atrial fibrillation: a review of clinical trials
EP2374456B1 (fr) Posologie d'edoxabane
US20100322869A1 (en) Method for treating or preventing thrombosis using dabigatran etexilate or a salt thereof with improved safety profile over conventional warfarin therapy
Olsson et al. Safety and tolerability of an immediate-release formulation of the oral direct thrombin inhibitor AZD0837 in the prevention of stroke and systemic embolism in patients with atrial fibrillation
US20100322870A1 (en) Method for treating or preventing thrombosis using dabigatran etexilate or a salt thereof with improved efficacy over conventional warfarin therapy
Thachil The newer direct oral anticoagulants: a practical guide
US20220105065A1 (en) METHOD OF TREATING PATIENTS WITH A FACTOR Xa INHIBITOR, ASPIRIN, AND VERAPAMIL
Harenberg et al. Prophylaxis of embolic events in patients with atrial fibrillation using low molecular weight heparin
US7608640B2 (en) Glycine betaine and its use
Rupprecht et al. Clinical pharmacology of direct and indirect factor Xa inhibitors
Patadiya et al. A high profile review on new oral clotting factor Xa inhibitor: betrixaban
US20130005683A1 (en) Glycine betaine and its use
KR20110082563A (ko) 통상의 와파린 요법에 비해 효능이 향상된 다비가트란 에텍실레이트 또는 이의 염을 사용하여 혈전증을 치료하거나 예방하는 방법
Bendel et al. Dabigatran: an oral direct thrombin inhibitor for use in atrial fibrillation
Ahmed et al. Dabigatran-a new chapter in anticoagulation
WO2006060647A1 (fr) Méthodes de traitement prophylactique et thérapeutique
Goubran et al. Coagulation and Anticoagulants
US20230338413A1 (en) Oral delivery of heparins
CN115120606A (zh) 治疗局部缺血事件、减少局部缺血事件的发生和/或预防局部缺血事件的方法
Heidbuchel et al. Dabigatran for stroke prevention in atrial fibrillation: from RE-LY to daily clinical practice
Brampton PrTARO-TICAGRELOR
Dahl Dabigatran etexilate: an oral direct thrombin inhibitor
K Turagam et al. Apixaban in Venous Thromboembolism in an Era of New Oral Anticoagulants
WO2024220809A1 (fr) Utilisation de milvexian pour le traitement et la prévention d'états thrombotiques chez des patients atteints d'une maladie cardiovasculaire ou cérébrovasculaire
HK40073112A (en) Methods of treating, reducing the incidence of, and/or preventing ischemic events

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 05852739

Country of ref document: EP

Kind code of ref document: A1