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General Description:

Danaparoid, identified by CAS number 308068-55-5, is a notable compound with significant therapeutic applications. Danaparoid is a low-molecular-weight heparinoid with an average molecular weight of 5500 Daltons consisting of a mixture of glycosaminoglycans . The active constituents are heparan, dermatan and , and they are isolated from the porcine intestinal mucosa . Danaparoid possesses a potent antithrombic activity that works by inhibiting activated factor X (Factor Xa) and activated factor II (Factor IIa). It is chemically distinct from heparin by containing different protein binding properties, thus has lower cross-reactivity in heparin-intolerant patients. Danaproid is used in the treatment of heparin-induced thrombocytopenia (HIT) as an off-label indication and prevention of post-operative deep venous thrombosis (DVT). While it was initially approved by the FDA as Orgaran™, danaparoid was withdrawn by Organon International on August 14, 2002, due to a shortage in drug substance by the manufacturer. The use of Orgaran™ was discontinued in the United States however it is available in several other countries including European countries and Japan. Danaparoid sodium is the common salt form in therapeutic preparations and is typically administered subcutaneously.

Indications:

This drug is primarily indicated for: Indicated for the prophylaxis of post-operative deep venous thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing elective hip replacement surgery . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Danaparoid undergoes metabolic processing primarily in: There is no evidence of hepatic metabolism and danaparoid is unlikely to undergo cellular metabolism . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Danaparoid are crucial for its therapeutic efficacy: Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly antifactor Xa and antifactor IIa activities. The bioavailability of danaparoid is 100% following subcutaneous administration . Following administration of single subcutaneous doses of 750, 1500, 2250, and 3250 anti-Xa units of danaparoid, the peak plasma anti-Xa activities were 102.4, 206.1, 283.9, and 403.4 mU/mL, respectively . The time to reach maximum anti-Xa activity is approximately 2-5 hours . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Danaparoid is an important consideration for its dosing schedule: Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. The elimination half-life ranges from 19.2 to 24.5 hours during anti-Xa activity and ranges from 1.8 to 4.3 hours during anti-IIa activity . This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Danaparoid from the body primarily occurs through: Renal excretion is the main route of elimination, accounting for approximately 40-50% of the total clearance of antifactor Xa activity following intravenous administration of danaparoid . Therefore in patients with severe renal impairment, the elimination half-life of anti-Xa activity may be prolonged . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Danaparoid is distributed throughout the body with a volume of distribution of: Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. The volumes of distribution of anti-Xa and anti-IIa activities are 9.1 L and 7.3-9.0 L, respectively . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Danaparoid is a critical factor in determining its safe and effective dosage: Pharmacokinetic studies on danaparoid are based on the kinetics of its anticoagulant activities, which are mostly anti factor Xa and anti factor IIa activities. Total plasma clearance is about 0.36 L/h during anti-Xa activity, which may be accelerated with higher body surface area . Total plasma clearance during anti-IIa activity ranges from 2.3 to 3 L . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Danaparoid exerts its therapeutic effects through: Danaparoid contains a mixture of heparan sulfate, dermatan sulfate and chondroitin sulfate in amounts of approximately 84%, 12% and 4%, respectively . Danaparoid is as an antithrombotic agent that prevents the formation of fibrin in the coagulation pathway. It has a high antifactor Xa to antifactor IIa (thrombin) activity that primarily works via antithrombin III-mediated inhibition of factor Xa . The ratio of antifactor Xa to antifactor II activity is ≥ 20:1 . Danaparoid has a minor effect on platelet function and aggregation . In a worldwide compassionate-use programme involving a total of 667 patients with heparin-induced thrombocytopenia (HIT), treatment with danaparoid resulted in 93% of successful outcomes in resolving HIT . In healthy volunteers, danaparoid caused significantly less prolongation o f the activated partial thromboplastin time (APTT) and was associated with a significantly lower thrombin time than unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) . Danaparoid displays lower lipolytic activity than UFH _in vitro_ and in healthy individuals, leading to lower plasma levels of free fatty acids . Danaparoid has been associated with the cross-reactivity with pathogenic heparin-induced platelet-factor 4 (PF4) antibodies, which occurs in about 10 % or more by _in vitro_ testing . The clinical relevance of this effect is not fully understood . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Danaparoid functions by: In the coagulation cascade leading to clot formation, factor X and factor II requires activation to promote subsequent conversion of fibrinogen to fibrin. The mechanism of action of danaparoid resulting in anticoagulant and antithrombic effects involves a complex interaction between 2 components, factor IIa and in particular, factor Xa . Via binding to antithrombin and inducing a conformational change , danaparoid enhances and catalyzes the the binding of factor Xa to antithrombin, which induces antithrombin-mediated inactivation of factor Xa. This leads to inhibition of thrombin generation and subsequently, thrombus formation . Danaparoid also weakly enhances antithrombin III and heparin cofactor II inactivation of factor IIa . There is evidence that danaparoid also suppresses the activation of factor IX which, in conjunction with simultaneous inhibition of factor X, may lead to antithrombic effects . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Danaparoid is categorized under the following therapeutic classes: Agents causing hyperkalemia, Anticoagulants, Blood and Blood Forming Organs, Carbohydrates, Cardiovascular Agents, Chondroitin, Fibrin Modulating Agents, Glycosaminoglycans, Hematologic Agents, Heparin and similars, Heparinoids, Polysaccharides. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.