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ABSTRACT: Pleiotrophin, also known as heparin affin regulatory peptide (HARP), is a growth factor expressed in various tissues and cell lines. In this work, HARP was tested for its capacity to modulate the anticoagulant activity of heparin and heparan sulphate mimetics (OTR4120). We used both in vitro and in vivo assays. HARP was found to be differently effective for neutralization of the anticoagulant activity of the mimetic heparan sulphate (OTR4120) and heparin in purified system and human plasma. HARP was shown to compete with both antithrombin and thrombin for binding to heparin and to OTR4120, respectively. In the presence of OTR4120, the V(max) was constant and the calculated maximum velocity was 1.56 U/min; the thrombin Km value (0.011 nM) was affected by HARP concentrations. The Km (HARP) value was 0.085 nM, which is consistent with high affinity of HARP to OTR4120. Under the same conditions, initial velocity patterns for antithrombin-heparin were determined in the presence or in the absence of HARP. The antithrombin value Km (0.022 nM) was affected by HARP (0.077 nM). HARP exhibits efficacy equivalent to or greater than protamine. Interestingly, intraperitoneally administered HARP decreased the anticoagulant activity of heparin and of OTR4120 in mice. Taken together, these data provide the first evidence for a physiological role of HARP in the modulation of anticoagulant activity of heparin and heparin-like material.
Basic & Clinical Pharmacology & Toxicology 06/2012; 111(5):296-302. · 2.18 Impact Factor
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ABSTRACT: Bexarotene, (LGD1069, Targretin), is an antitumoral agent used as chemotherapy in the treatment of cutaneous T-cell lymphoma. Therapy with bexarotene is accompanied by adverse events, such as, bleeding, hemorrhage, and coagulopathy
In order to design applications for bexarotene, it was very important to gain an understanding of how bexarotene inhibits blood clotting
We investigated the interaction between bexarotene or vehicle alone, and coagulation factors or blood cells. We used both in vitro and in vivo assays. Anticoagulant activity of bexarotene or vehicle was assessed by clotting time tests (TT, RT, APTT, and PT). Coagulation factors activity was measured by adding diluted test plasma to artificially prepared factor-deficient plasma. Direct interactions between bexarotene and factor Xa were studied by chromogenic substrate assay. A mouse model was used to investigate in vivo effects of the drug on blood system and for evaluation of clinical hematology and organ pathology.
Increases in clotting times (prothrombin time and activated thromboplastin time) occurred with bexarotene in in vitro and in vivo experiments. We detected no significant influence of bexarotene on factors II, V, VII, VIII, XI and XII, while factor IX and factors X were affected. Bexarotene exerts anticoagulant effects and acts mainly as a direct factor IX and factor X inhibitor. On the contrary, the vehicle is remarkably inert toward the coagulation system. The number of blood cells was unaffected in mice treated with bexarotene or with the vehicle.
Monitoring of the coagulation factors profile should be considered in cancer patients receiving bexarotene, particularly those with a known diagnosis of coagulation factors deficient.
Cancer Chemotherapy and Pharmacology 01/2011; 68(4):847-54. · 2.83 Impact Factor
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ABSTRACT: The aim of this study was to investigate the development of an oral dextran derivative OTR4120. Pharmacokinetics (PK) parameters of OTR4120 were determined after treatment with intravenous injection (i.v.) at dose 5 mg/kg, intraperitoneal injection (i.p.) at dose 50 mg/kg or oral administration at dose 70 mg/kg. To study distribution at dose 70 mg/kg after oral administration, OTR4120 was given by gavage to mice. In ex vivo experiments, SDS-PAGE showed that plasma of mice treated orally at dose 70 mg/kg induced the formation of covalently linked complexes between antithrombin III and thrombin. OTR4120 were absorbed and metabolized following oral administration. OTR4120 given i.v., i.p. and oral had relatively small volume of distribution 0.95 L/kg and 4.68 L/kg respectively, plasma clearance was 45, 520 and 514 ml/h per kg after i.v., i.p. or oral administration respectively. Short elimination half-life was 80 min after i.p. administration and 383 min after oral administration. OTR4120 was distributed in the spleen and kidney and accumulated there over a long period, whereas the OTR4120 levels in liver were negligible a 24 hours after oral administration. Food do not change the oral bioavailability of OTR4120 in mice, AUC, C(max) and T(max) of OTR4120 were not significantly different when mice received the oral dose with food compared with under fasting conditions. This work presents another therapeutic agents administration way using dextran delivery system.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 09/2010; 64(9):627-32. · 2.24 Impact Factor
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ABSTRACT: Heparan sulfate mimetic polymers promotes tissue repair when injected locally in doses of 1-2mg/kg by various routes. These biopolymers, have been extensively studied for their diverse biological activities. However, there is no detailed report investigating the toxicity of OTR4120. In this study, the acute and subchronic (30 days) toxicity of varying levels of OTR4120 was investigated in mice after intraperitoneal administration. The results showed that no significant toxicological changes were observed when 50mg/kg body weight per day OTR4120 was administered to mice. But when the dose was increased to 60 and 70 mg/kg body weight per day, the clotting time was significantly prolonged. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities were reduced female and male at dose 70 mg/kg body weight per day. These blood biochemistry data suggest that OTR4120 have a hepatoprotective effect. Based on these results, it can be concluded that the no adverse effect level of OTR4120 is 50 mg/kg body weight per day.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 05/2010; 48(7):1965-8. · 2.99 Impact Factor
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ABSTRACT: OTR4120, which belongs to a family of heparan sulfate-mimetic polymers, promotes tissue repair when injected locally in doses of a few micrograms. As OTR4120 is a sulfated polysaccharide, we investigated its possible role on the coagulation cascade. We used both in vitro and in vivo assays. Increases in clotting times (thrombin time, prothrombin time, and activated partial thromboplastin time) occurred with OTR4120 in doses at least 10 times lower than heparin. OTR4120 dose-dependently inhibited the biological activity of thrombin and bound thrombin with an affinity of 14 +/- 2 nM. SDS-PAGE showed that OTR4120 induced the formation of covalently linked complexes between antithrombin III or heparin cofactor II and thrombin. OTR4120 induced anticoagulant effects, and antithrombin activity was greatest 90 min after intraperitoneal injection. No bleeding or significant platelet count changes occurred with doses smaller than 55 mg/kg. Interestingly, orally administered OTR4120 crossed the gastrointestinal barrier and, in a dose of 70 mg/kg, induced significant ex vivo antithrombotic activity in the bloodstream.
Journal of Biomedical Materials Research Part A 01/2008; 83(4):1024-31. · 2.63 Impact Factor
