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Biomedical subjects

Shaker A Mousa

Publications and source records attributed to Shaker A Mousa.

At least 19 recordsLinked to original sources
PubMed2007

Platelet GPIIb/IIIa antagonist, XV459, in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a serious, immune-related complication of heparin therapy. One of the most severe manifestations of HIT is the development of thromboembolic events, which is based on platelet activation and aggregation caused by HIT-associated antibodies. Therapeutic options for patients with HIT are limited despite advancement toward the development of alternative (nonheparin) anticoagulants, such as direct thrombin inhibitors and indirect anti-factor Xa agents. Platelet GPIIb/IIIa receptor antagonists have been shown to be the final common pathway for platelet aggregation regardless of the use of activator or anticoagulant. In this study, the ability of a novel platelet GPIIb/IIIa antagonist, a free acid form of roxifiban (XV459), to block platelet activation/aggregation in response to highly characterized heparin-PF4 antibody-positive plasma/heparin was examined using light transmittance aggregometry, serotonin release, and (125)I-fibrinogen binding assays to human platelets. XV459 at 20 nM maximally inhibited (P < 0.001) the platelet-activation/aggregation responses as mediated by the HIT antibody-positive plasma (in the presence of therapeutic heparin concentrations). Compared with controls, both HIT antibodies/heparin and TEAC (a mixture of thrombin [0.1 IU/ml], epinephrine [1 microg/ml], arachidonate [0.1 mM], and collagen [10 microml]) resulted in significantly higher levels of fibrinogen binding to human platelets (5-7-fold increase; P < 0.001). Concentration-dependent profiles of XV459 on the mean percent inhibition of (125)I-fibrinogen binding in the presence of HIT antibodies and TEAC were achieved ( approximately 50% inhibition at 10 nM XV459). The platelet GPIIb/IIIa receptor antagonist (XV459) might be of potential benefit in the management of thrombotic thrombocytopenia produced by heparin and/or related glycosaminoglycans.

Amino Acids↗
PubMed2007

In-vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists and thrombolytics on platelet/fibrin-mediated clot dynamics in human whole blood using thrombelastography.

Suppressing platelet activation improves efficacy of thrombolytic therapy for stroke and acute myocardial infarction. Combination treatment with recombinant tissue plasminogen activator (r-tPA) and glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor that binds with high affinity to platelets may therefore improve the efficacy of thrombolytic therapy. The effect of platelet GPIIb/IIIa antagonists and/or r-tPA on the dynamics of platelet/fibrin clot formation, strength, and lysis was determined using thrombelastography in human blood under thrombin or tissue factor stimulation. The study utilized platelet GPIIb/IIIa antagonists with high affinity and slow off-rate (Class I) from resting and activated platelets in comparison with Class II antagonists (lower affinity and fast off-rate from platelet GPIIb/IIIa receptors). The combination of the active form of roxifiban (XV459; Class I) or the active form of orbofiban (Class II) with a subeffective concentration of r-tPA resulted in a synergistic effect in clot lysis with roxifiban active form XV459 but not with that of orbofiban at therapeutically achievable concentrations that inhibit human platelet aggregation. These data indicate differential enhanced thrombolysis of low levels of r-tPA with high-affinity Class I but not with low-affinity Class II GPIIb/IIIa antagonists in the absence of anticoagulants.

Anticoagulants↗
PubMed2006

Pro-angiogenesis action of arsenic and its reversal by selenium-derived compounds.

Inorganic arsenic (arsenite and arsenate) in drinking water has been associated with skin cancers and increased incidence of cardiovascular diseases. Additionally, studies have demonstrated the pro-angiogenic effect of arsenite and its potential promotion of tumor angiogenesis and tumor progression. Furthermore, recent reports demonstrated reversal of skin co-carcinogenesis by an organoselenium compound. The present study was undertaken to determine the effect and mechanism on angiogenesis of arsenite at low level and its potential reversal by various selenium-derived compounds. The pro-angiogenesis effects and mechanisms of sodium arsenite were determined using the chick chorioallantoic membrane (CAM) model over 3 days and compared with standard pro-angiogenesis factors, such as basic fibroblast growth factor (b-FGF). Additionally, the potential effect of various selenium-derived compounds--such as dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine--in reversing the pro-angiogenesis effect of arsenite or b-FGF was also determined in the CAM model. The pro-angiogenesis effect of arsenite or b-FGF was significantly (P < 0.01) blocked by dimethyl selenone, diphenyl selenone, sodium selenite or Se-methyl selenocysteine. The pro-angiogenesis effect of either sodium arsenite at 33 nM or b-FGF was blocked (P < 0.01) by the extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation inhibitor, PD 98059. Additionally, the pro-angiogenic effect of arsenic or b-FGF was blocked as well (P < 0.01) by the alphavbeta3 antagonist, XT199. These data suggest that the pro-angiogenesis effect of arsenic is initiated at the plasma membrane integrin alphavbeta3, involves activation of the ERK1/2 pathway and is effectively reversed by various selenium-derived compounds.

Angiogenesis Inducing Agents↗
PubMed2006

Role of current and emerging antithrombotics in thrombosis and cancer.

In the nearly 130 years since Trousseau first described migratory thrombophlebitis in cancer patients, thromboembolism has become a well-established presenting sign and complication of cancer. The coagulation system is activated in cancer and is further amplified by treatment with chemotherapy, radiation or surgery. Hypercoagulation is documented in virtually all cancer types, albeit at different rates, and is the second leading cause of death in cancer patients. The relationship between clotting activation and carcinogenesis supports the view of cancer as a hypercoagulable state and holds implications for the development of thrombosis, enhancement of tumor growth and risk of poor clinical outcomes. Although it is well recognized that cancer can activate the coagulation cascade, it is less well known that activation of the coagulation system may also support tumor progression. Additionally, platelet activation in cancer patients and its impact on tumor progression and metastasis further expand the role of the hemostatic system in malignancy. The problem of thrombosis in patients with metastatic diseases is a serious concern for clinicians. This review explores the mechanisms and clinical implications of coagulation and platelet activation in cancer. The prevention and treatment of venous thromboembolism in cancer will also be discussed by reviewing data from key clinical investigations. Finally, the emerging role of low-molecular-weight heparin as an antineoplastic agent will be explored. Warfarin and unfractionated heparin have been in clinical use for more than 50 years. Both are effective anticoagulants, but their use is associated with a number of impediments, including the need for intensive coagulation monitoring, wide variation in dose-response relationships, multiple drug interactions (in the case of warfarin), and serious immune-mediated thrombocytopenia (in the case of heparin). The introduction of low-molecular weight heparin advanced anticoagulation therapy by enhancing efficacy and eliminating the need for intensive coagulation monitoring. Fondaparinux, the first selective factor Xa inhibitor, represents yet another improvement in anticoagulation therapy. By binding rapidly and strongly to antithrombin, its sole physiologic target in plasma, fondaparinux catalyzes specifically the inhibition of factor Xa, which results in effective and linear dose-dependent inhibition of thrombin generation. Additionally, efficient inhibition of factor Xa activity impairs the activation of tissue factor/factor VIIa complex leading to downregulation of procoagulant state, pro-angiogenesis, and proinflammatory factors induced by tissue factor/factor VIIa. Furthermore, a number of orally active direct antithrombin and anti-factor Xa are in advanced clinical development for various thromboembolic disorders.

Journal Article↗
PubMed2006

Acting via a cell surface receptor, thyroid hormone is a growth factor for glioma cells.

Recent evidence suggests that the thyroid hormone L-thyroxine (T4) stimulates growth of cancer cells via a plasma membrane receptor on integrin alphaVbeta3. The contribution of this recently described receptor for thyroid hormone and receptor-based stimulation of cellular mitogen-activated protein kinase [MAPK; extracellular signal-regulated kinase 1/2 (ERK1/2)] activity, to enhancement of cell proliferation by thyroid hormone was quantitated functionally and by immunologic means in three glioma cell lines exposed to T4. At concentrations of 1 to 100 nmol/L, T4 caused proliferation of C6, F98, and GL261 cells, measured by accumulation of proliferating cell nuclear antigen (PCNA) and radiolabeled thymidine incorporation. This effect was inhibited by the T4 analogue, tetraiodothyroacetic acid, and by an alphaVbeta3 RGD recognition site peptide, both of which block T4 binding to integrin alphaVbeta3 but are not agonists. Activation of MAPK by T4 was similarly inhibited by tetraiodothyroacetic acid and the RGD peptide. The thyroid hormone 3,5,3'-triiodo-L-thyronine (T3) and T4 were equipotent stimulators of PCNA accumulation in C6, F98, and GL261 cells, but physiologic concentrations of T3 are 50-fold lower than those of T4. In conclusion, our studies suggest that glioblastoma cells are thyroid hormone dependent and provide a molecular basis for recent clinical observations that induction of mild hypothyroidism may improve duration of survival in glioblastoma patients. The present experiments infer a novel cell membrane receptor-mediated basis for the growth-promoting activity of thyroid hormone in such tumors and suggest new therapeutic approaches to the treatment of patients with glioblastoma.

Animals↗
PubMed2006

Cellular and molecular mechanisms of nicotine's pro-angiogenesis activity and its potential impact on cancer.

The present study examined the mechanisms of nicotine's effect on angiogenesis and its impact on tumor growth. Nicotine demonstrated significant (P<0.01) stimulation of the release of endothelial cell growth factor, basic fibroblast growth factor (b-FGF) but not vascular endothelial growth factor (VEGF). In a concentration-dependent manner, nicotine induced endothelial cell tube formation. Additionally, in the chick chorioallantoic membrane (CAM) model of angiogenesis, nicotine effectively induced the generation of new blood vessels (P<0.01), an effect that is mediated via b-FGF. The pro-angiogenesis effect of nicotine in the CAM model was maximally blocked by either anti-integrin alphavbeta3 or inhibitor of mitogen activated protein kinase (MAPK, ERK 1/2). In the CAM tumor implant model, nicotine doubled (P<0.01) the growth rate of breast, colon, and lung cancer. These data indicated that the pro-angiogenesis effect is mediated via b-FGF and induced through the nicotinic receptor, alphavbeta3 integrin, and MAPK.

Cell Line, Tumor↗
PubMed2006

Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standard low-molecular-weight heparin, enoxaparin.

Low-molecular-weight heparins (LMWH) exhibit potent anticoagulant efficacy via their plasmatic effects on thrombin and factor Xa. These agents are also effective in releasing endothelial tissue factor pathway inhibitor (TFPI), the natural inhibitor of tissue factor, and exhibit significant anti-metastatic effects in experimental animal models. However, the potential for bleeding complications has slowed down the more widespread adoption of LMWH therapy in cancer patients. In this study, the effect of a non-anticoagulant form of LMWH (NA-LMWH) on experimental lung metastasis and tumor cell-induced platelet aggregation in vivo was compared to the LMWH enoxaparin. Using the B16 melanoma mouse model of metastasis, subcutaneous (s.c.) injection of NA-LMWH or enoxaparin (10 mg/kg), three hours before intravenous (i.v.) injection of metastatic melanoma cells, followed by daily doses for 14 days, reduced lung tumor formation by 70% (P < 0.001). I.v. injection of tumor cells resulted in a significant (50-62%, P < 0.01) fall in platelet counts. Pre-injection (i.v.) of enoxaparin completely abolished the tumor cell-induced thrombocytopenia, whereas NA-LMWH had no effect. Four hours after a single s.c. dose, enoxaparin but not NA-LMWH prolonged the clotting time three-fold and delayed the time to clot initiation more than 10-fold as measured by a Sonoclot analyzer and by thromboelastography, respectively. Enoxaparin but not NA-LMWH demonstrated a significant anticoagulant effect in mice. Both NA-LMWH and enoxaparin caused similar TFPI release from endothelial cells in vitro. These data provide evidence to support the potential of NA-LMWH as an anti-metastatic agent without any significant impact on coagulation.

Animals↗
PubMed2006

Role of current and emerging antithrombotics in thrombosis and cancer.

In the nearly 130 years since Trousseau first described migratory thrombophlebitis in cancer patients, thromboembolism has become a well-established presenting sign and complication of cancer. The coagulation system is activated in cancer and is further amplified by treatment with chemotherapy, radiation or surgery. Hypercoagulation is documented in virtually all cancer types, albeit at different rates, and is the second leading cause of death in cancer patients. The relationship between clotting activation and carcinogenesis supports the view of cancer as a hypercoagulable state and holds implications for the development of thrombosis, enhancement of tumor growth and risk of poor clinical outcomes. Although it is well recognized that cancer can activate the coagulation cascade, it is less well known that activation of the coagulation system may also support tumor progression. Additionally, platelet activation in cancer patients and its impact on tumor progression and metastasis further expand the role of the hemostatic system in malignancy. The problem of thrombosis in patients with metastatic diseases is a serious concern for clinicians. This review explores the mechanisms and clinical implications of coagulation and platelet activation in cancer. The prevention and treatment of venous thromboembolism in cancer will also be discussed by reviewing data from key clinical investigations. Finally, the emerging role of low-molecular-weight heparin as an antineoplastic agent will be explored. Warfarin and unfractionated heparin have been in clinical use for more than 50 years. Both are effective anticoagulants, but their use is associated with a number of impediments, including the need for intensive coagulation monitoring, wide variation in dose-response relationships, multiple drug interactions (in the case of warfarin), and serious immune-mediated thrombocytopenia (in the case of heparin). The introduction of low-molecular weight heparin advanced anticoagulation therapy by enhancing efficacy and eliminating the need for intensive coagulation monitoring. Fondaparinux, the first selective factor Xa inhibitor, represents yet another improvement in anticoagulation therapy. By binding rapidly and strongly to antithrombin, its sole physiologic target in plasma, fondaparinux catalyzes specifically the inhibition of factor Xa, which results in effective and linear dose-dependent inhibition of thrombin generation. Additionally, efficient inhibition of factor Xa activity impairs the activation of tissue factor/factor VIIa complex leading to downregulation of procoagulant state, pro-angiogenesis, and proinflammatory factors induced by tissue factor/factor VIIa. Furthermore, a number of orally active direct antithrombin and anti-factor Xa are in advanced clinical development for various thromboembolic disorders.

Administration, Oral↗
PubMed2005

Proangiogenesis action of the thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) is initiated at the cell surface and is integrin mediated.

We have recently described the proangiogenesis effects of thyroid hormone in the chick chorioallantoic membrane (CAM) model. Generation of new blood vessels from existing vessels was promoted 2- to 3-fold by either T(4) or T(3) at 10(-8)-10(-7) M total hormone concentrations. In the present studies, nanomolar concentrations of 3,5-diiodothyropropionic acid (DITPA), a thyroid hormone analog with inotropic but not chronotropic properties, exhibited potent proangiogenic activity that was comparable to that obtained with T(3) and T(4) in both the CAM model and in an in vitro three-dimensional human microvascular endothelial sprouting assay. The proangiogenesis effect of DITPA was inhibited by tetraiodothyroacetic acid, a thyroid hormone analog that competes with T(4) and T(3) for a novel cell surface hormone receptor site on integrin alphavbeta3. The thyroid hormone analogs DITPA, T(4), and T(4)-agarose, as well as basic fibroblast growth factor (b-FGF) and vascular endothelial cell growth factor, demonstrated comparable proangiogenic effects in the CAM model and in the three-dimensional human microvascular endothelial sprouting model. The proangiogenesis effect of either DITPA or b-FGF was blocked by PD 98059, an inhibitor of the ERK1/2 signal transduction cascade. Additionally, a specific integrin alphavbeta3 small molecule antagonist, XT199, effectively inhibited the proangiogenesis effect of DITPA and b-FGF. Thus, the proangiogenesis actions of thyroid hormone and its analog DITPA are initiated at the plasma membrane, apparently at integrin alphavbeta3, and are MAPK dependent.

Animals↗
PubMed2005

Novel in vitro perfusion model to study the interaction between coagulation and blood-borne metastasis.

The association between cancer and hemostasis has long been studied in cell culture, animal models, and cancer patients developing thrombosis. The variety of biologic mechanisms involved in malignancy and metastasis makes the understanding of the relative importance of each mechanism difficult. We have developed a novel in vitro perfusion model that allows for the isolated study of the interactions between tumor cells and components of the hemostatic system under normal physiologic conditions. Segments of denuded umbilical cord or saphenous vein are cut longitudinally and mounted in a perfusion chamber under sterile conditions. Human breast cancer cells are perfused for 24 h under venous flow conditions with either whole blood (WB), platelet-rich plasma (PRP), platelet-poor plasma (PPP), or serum. Tissue samples are fixed and stained with hematoxylin and eosin as well as with pan-cytokeratin. Morphometric analysis is performed to quantify cancer cell adhesion. With PRP, this model maintains normal human physiologic conditions for the duration of the experiment. It differentiates between previously characterized high and low metastatic breast cancer cell lines. In addition, different vein tissue types do not alter tumor cell attachment. This model appears to be an accurate representation of the pathophysiology of in vivo metastasis. This model may serve as a useful bridge between cell culture studies and animal models. It may be a useful tool to elucidate the role of selected hemostatic systems in blood-borne metastasis and may potentially serve as a screening tool for the development of antimetastatic pharmaceutical agents.

Blood Circulation↗
PubMed2005

Effect of low molecular weight heparin and different heparin molecular weight fractions on the activity of the matrix-degrading enzyme aggrecanase: structure-function relationship.

The matrix-degrading enzyme aggrecanase has been identified in cartilage and is largely responsible for cartilage breakdown. The present study determined the efficacy of different heparin molecular weight fractions (HMWFs) and low molecular weight heparins (LMWHs) on aggrecanase activity. Aggrecanase activity was determined using biotinylated peptide substrate, which was immobilized onto streptavidin-coated 96-well plates; aggrecanase enzyme was then added. Proteolysis of the substrate at the specific amide bond was detected using specific antibody for the neoepitope generated. HMWFs ranging from 1,700 to 12,000 Da demonstrated a concentration-dependent inhibitory efficacy of aggrecanase activity, with a Ki ranging from 5,000 nM down to 1 nM as a function of the molecular weight. The higher the molecular weight distribution, the greater the inhibitory efficacy of the heparin fragments toward aggrecanase activity. The absence or presence of antithrombin did not alter the affinity of heparin in inhibiting aggrecanase. Additionally, tissue factor pathway inhibitor at various levels did not alter the activity of aggrecanase. LMWHs demonstrated different levels of potency in inhibiting aggrecanase activity as a function of their average molecular weight distribution. Tinzaparin (average molecular weight = 6,500 Da) and enoxaparin (average molecular weight = 4,500 Da) demonstrated a Ki of 20 and 80 nM, respectively. The aggrecanase inhibitory effect of LMWH might contribute to blocking inflammation and tumor invasion by inhibiting aggrecanase activity and maintaining an intact extracellular matrix barrier.

Animals↗
PubMed2005

Effects of including soy protein in a blood cholesterol-lowering diet on markers of cardiac risk in men and in postmenopausal women with and without hormone replacement therapy.

BACKGROUND: Increased consumption of soy foods has been associated with reduction in low density lipoprotein cholesterol (LDL-C) in both clinical and observational studies. However, it is not clear whether adding soy to a low-fat diet has additional lipid-lowering benefits, and few previous studies have examined these effects in women using hormone replacement therapy (HRT+). METHODS: We tested whether adding soy protein to a low-fat, high-fiber, Step I diet improved cardiac risk markers in 18 postmenopausal women and 14 men with hypercholesterolemia and examined whether concurrent use of HRT altered diet responsiveness. Diets were matched for macronutrient content, and all food was provided. After 3 weeks on the Step I diet, subjects were randomized to diets (6 weeks) containing 25 g/day protein isolate from soy or cow's milk, with crossover. The soy treatment contained 90 mg/day isoflavones. Lipids, vascular cell adhesion molecule-1 (VCAM-1), p-selectin, and urinary isoflavonoids were measured at the end of each diet. RESULTS: In men and HRT- women only, there were significant reductions in LDL-C (-17.3%), high-density lipoprotein cholesterol (HDL-C) (-15.3%), and triglycerides (-11.5%) during the Step I diet, and soy had no additional effects. At study entry, HRT+ women had lower LDL-C and higher triglycerides than men. Their LDL-C was unchanged, and triglycerides were significantly reduced (-15.1%) by the Step I diets. Isoflavonoid excretion was unrelated to diet response or HRT status. CONCLUSIONS: In men and HRT- women, the diets significantly lowered LDL-C, independent of soy intake. In HRT+ women, the diets improved triglycerides without lowering HDL-C.

Apolipoproteins↗
PubMed2005

Human alphavbeta3 integrin potency and specificity of TA138 and its DOTA conjugated form (89)Y-TA138.

The present study was undertaken to define the alphavbeta3-binding potency and specificity of TA138, a nonpeptide integrin antagonist, and its conjugated form, 89Y-TA138. Various integrin-specific binding and functional assays as well as cell-adhesion assays were used to determine the potency and integrin specificity for TA138 and 89Y-TA138. Both TA138 and 89Y-TA138 inhibited alphavbeta3-mediated [125I]echistatin binding to 293-beta3-transfected cells, with IC50 values of 0.046 and 0.059 microM, respectively, and IC50 values of 0.012 and 0.018 microM, respectively, in inhibiting an alphavbeta3 integrin-mediated 293-beta3-transfected cell adhesion to fibrinogen. TA138 inhibited human umbilical vein endothelial cell adhesion to fibrinogen, with an IC50 value of 0.052 +/- 0.006 microM. Both TA138 and 89Y-TA138 demonstrated a relatively high degree of specificity for human alphavbeta3 integrin as compared with other human integrins, including alphavbeta5, alphaIIbbeta3, and alpha5beta1 (IC50 > 10 microM). Both 89Y-TA138 and TA138 demonstrated comparable alphavbeta3 affinity and specificity as compared with other closely related human integrins such as alphavbeta5, alphaIIbbeta3, or alpha5beta1.

Cell Adhesion↗
PubMed2005

Alpha v integrin affinity/specificity and antiangiogenesis effect of a novel tetraaza cyclic peptide derivative, SU015, in various species.

The present study was undertaken to define the alpha v beta3 and alpha v beta5 binding potency and specificity of SU015, an integrin antagonist. SU015 inhibited alpha v beta3-mediated human umbilical vein endothelial cell or 293/beta3-transfected CHO cell adhesion to fibrinogen, with IC50 values of 0.21 +/- 0.11 muM and 0.32 +/- 0.02 microM. SU015 demonstrated comparable affinity to alpha v beta5 as compared with alpha v beta3 affinity, as well as a relatively high degree of specificity for human alpha v beta3- and alpha v beta5-mediated functions, as compared with other human integrins, including alphaIIbbeta3 (IC50 >100 microM), alpha5/beta1 (IC50 >100 microM), and alpha4/beta1 (IC50 >100 microM). SU015 demonstrated different degrees of species specificity in blocking alpha v beta3-mediated cellular adhesion, with relatively higher affinity to monkey (IC50 = 0.10 microM) and dog (IC50 = 1.30 microM) endothelial or smooth muscle cell alpha v beta3-mediated adhesion. Additionally, SU015 demonstrated a high degree of alpha v beta3 and alpha v beta5 specificity as compared with alpha4beta1-, alpha5beta1-, or alpha IIb beta3-mediated binding in the above species. In conclusion, SU015 is an alpha v beta3 and alpha v beta5 antagonist with relatively higher potency and specificity as compared with alpha IIb beta3, alpha5beta1, or alpha4beta1 integrins. Additionally, comparable alpha v beta3 and alpha v beta5 affinity for SU015 was demonstrated with human and monkey endothelial cells. These data also suggest that this bicyclic RGD analogue linked to a linker at the bottom leaves the RGD at the top available for binding and allows for conjugation with radioisotope for imaging and radiotherapy.

Animals↗
PubMed2005

The proangiogenic action of thyroid hormone analogue GC-1 is initiated at an integrin.

Our early reported investigations have demonstrated potent proangiogenic effects of L-thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3) in the chick chorioallantoic membrane (CAM) model. Tetraiodothyroacetic acid (tetrac) blocks T4 binding to plasma membranes and its pro-angiogenic effect. T4/T3 stimulates expression of fibroblast growth factor 2 (FGF2) in endothelial cells. Thyroid hormone (T4/T3) is principally responsible for transcriptional activation mediated by nuclear thyroid hormone receptors TRbeta and TRalpha. In contrast, the hormone analogue GC-1 also stimulates transcriptional activation via TRbeta1. In the present study, we have defined the effect of GC-1, compared with T4 and T4-agarose, on angiogenesis in the CAM assay. GC-1 demonstrated a proangiogenic effect similar to that of T4 and T4-agarose. Tetrac inhibited GC-1- and T4-induced angiogenesis, indicating dependence on T4 and GC-1 binding to plasma membranes. The effects of GC-1, T4-agarose, and FGF2 were blocked by PD 98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor. Additionally, the alphavbeta3 integrin antagonist XT199 inhibited angiogenesis induced by T4-agarose, GC-1, or FGF2. Thus, the proangiogenic effects of GC-1 and T4 are initiated at the plasma membrane, require interaction with alphavbeta3 integrin receptor, and are dependent on MAPK activation.

Acetates↗
PubMed2005

Using thrombelastography to determine the efficacy of the platelet glycoprotein IIb/IIIa antagonist, roxifiban, on platelet/fibrin-mediated clot dynamics in humans.

The effect of platelet glycoprotein IIb/IIIa antagonists on the dynamics of platelet/fibrin clot formation and strength was determined using thrombelastography (TEG) under conditions of recalcification or tissue factor addition. In the present investigation, the effect of roxifiban (class I) on ex vivo clot dynamics using recalcified blood was tested in normal, healthy volunteers (n = 7) dosed with 1 mg BID roxifiban for 9 days. Roxifiban inhibited platelet aggregation induced by 20 mumol/l adenosine diphosphate by 60-90% but did not significantly affect any of the TEG parameters either at peak, trough, or subtrough drug levels. Addition of 30 nmol/l roxifiban free acid (XV459; which is ineffective by itself to modify TEG parameters) to human blood obtained from roxifiban-treated subjects resulted in 45-60% (P < 0.01) inhibition of clot strength (maximum amplitude), 90-100% (P < 0.01) inhibition of initial kinetic of clot development (angle alpha), and 50-70% (P < 0.01) inhibition of early clot initiation (K). These data suggest that a subthreshold blood level of 40-50 nmol/l roxifiban active form was achieved in those subjects, as estimated from an in vitro calibration with XV459. These data indicate (not studied) that roxifiban, at a targeted clinical dosing regimen, failed to achieve sufficient exposure to modulate platelet-mediated clot retraction.

Amidines↗
PubMed2005

Ximelagatran, the new oral anticoagulant: would warfarin survive the challenge?

The last decade witnessed major advances in the prevention and treatment of venous as well as of arterial thrombosis. Limitations of existing anticoagulants led to the development of novel therapeutic approaches. Ximelagatran is a new direct thrombin inhibitor (DTI) that is given orally, without the need for close monitoring. This compound was tried in the treatment of active venous thromboembolism, and the results were encouraging. Randomized trials suggest that ximelagatran is not inferior to warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Multiple controlled, prospective trials compared ximelagatran with low molecular weight heparin or warfarin in prevention of venous thromboembolism in patients undergoing major orthopedic procedures. The results of these clinical trials are reviewed in this article. Because of certain safety concerns (increased liver enzymes, potential hepatonecrosis, and increased coronary events) ximelagatran has not yet been approved by the FDA. Additional studies may be required to address these concerns. Ximelagatran has been approved, however, by the European regulatory authorities for short-term thromboprophylaxis. The success of ximelagatran or other oral antithrombin agents would provide significant proof of the concept for the long-term use of oral antithrombins in the prevention and treatment of both arterial and venous thrombosis.

Animals↗