Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149871 (deep vein thrombosis)
 12,364 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of heparin as the most potent anticoagulant for the prevention of deep vein thrombosis and pulmonary embolism is nevertheless limited, because it is available to patients only by parenteral administration. Toward overcoming this limitation in the use of heparin, we have previously developed an orally active heparin-deoxycholic acid conjugate (LMWH-DOCA) in 10% DMSO formulation. The present study evaluates the anti-thrombogenic effect of this orally active LMWH-DOCA using a venous thrombosis animal model with Sprague-Dawley rats. When 5 mg/kg of LMWH-DOCA was orally administered in rats, the maximum anti-FXa activity in plasma was 0.35 +/- 0.02, and anti-FXa activity in plasma was maintained above 0.1 IU/ml [the minimum effective anti-FXa activity for the prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE)] for five hours. LMWH-DOCA (5 mg/kg, 430 IU/kg) that was orally administered reduced the thrombus formation by 56.3 +/- 19.8%;on the other hand, subcutaneously administered enoxaparin (100 IU/kg) reduced the thrombus formation by 36.4 +/- 14.5%. Also, LMWH-DOCA was effectively neutralized by protamine that was used as an antidote. Therefore, orally active LMWH-DOCA could be proposed as a new drug that is effective for the longterm prevention of DVT and PE.
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PMID:Prevention effect of orally active heparin derivative on deep vein thrombosis. 1689 57

The oral delivery of macromolecules is a topic of much interest as this would undoubtedly improve patient acceptance and compliance with chronic regimens. Heparin and insulin are perhaps among the first candidates that should be considered for oral macromolecule delivery systems. Heparin is the most potent anti-coagulant known for the prevention of deep vein thrombosis and pulmonary embolism, and an orally active heparin would undoubtedly effectively reduce chronic thrombotic events. Here, we report on the development of an orally administrable chemical conjugate of heparin and hydrophobic deoxycholic acid (DOCA), which we refer to as LHD. LHD was pre-formulated with dimethyl sulfoxide (DMSO) as solubilizer to further improve its oral bioavailability (9.1% in monkey). LHD was found to be absorbed mainly in the jejunum and ileum of the small intestine, although it is in the ileum that the absorption is most notable. From the mechanism studies of LHD absorption using Caco-2 cell monolayers for mimicking the intestine, we found that LHD highly permeated by passive diffusion through the transcellular route and its permeation was partially affected by bile acid transporters. This study demonstrates the feasibility of chemically modified heparin for long-term oral administration as an effective therapy for venous thromboembolism in clinical trials.
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PMID:Absorption study of deoxycholic acid-heparin conjugate as a new form of oral anti-coagulant. 1749 Jul 73

The development of orally active heparin will have tremendous clinical importance since it can be used to effectively prevent deep vein thrombosis (DVT) in a long-term chronic treatment. We developed in this study a new orally active heparin derivative (Db-LHD), which has heparin chemically conjugated with deoxycholic acid and DMSO molecules by secondary interactions. Db-LHD was prepared in the powder form in soft capsules. When we administered Db-LHD capsules to monkeys, its oral physiological availability was increased up to 16.6%. The maximum anti-FXa activity at 5 mg/kg of Db-LHD was more than twice the minimum effective anti-FXa activity (MEC, 0.1 IU/mL) for preventing DVT, and the anti-FXa activity in plasma was maintained for 10 h above the MEC in monkeys. Also, we evaluated anti-thrombogenic effect of Db-LHD in a rat thrombosis model. A subcutaneous administration of enoxaparin (100 IU/kg), which was the highest recommended dose for the prevention of venous thromboembolism, reduced thrombus formation by 38.9+/-14.2%. On the other hand, 5 mg/kg (425 IU/kg) of orally administered Db-LHD reduced thrombus formation by 51.0+/-2.0. We propose a new orally active heparin, Db-LHD, in a solid dosage form to effectively prevent DVT and PE.
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PMID:A newly developed oral heparin derivative for deep vein thrombosis: non-human primate study. 1788 30