Oral Antiplatelet Efficacy and Specificity of a Novel Nonpeptide Platelet GPIIb/IIIa Receptor Antagonist, DMP 802

Mousa, Shaker A.; Olson, R. E.; Bozarth, Jeffrey M.; Lorelli, William; Forsythe, Mark S.; Racanelli, Adrienne L.; Gibbs, Sandy; Schlingman, Karen; Bozarth, Tracy A.; Kapil, Ram P.; Wityak, John; Sielecki, Thais M.; Wexler, Ruth R.; Thoolen, Martin; Slee, Andrew M.; Reilly, Thomas M.; Anderson, Paul S.; Friedman, Paul A.

doi:10.1097/00005344-199808000-00001

Cited by 16 publications

(16 citation statements)

References 22 publications

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“…The difference in platelet dissociation rate appears to be responsible for the duration of in vivo antiplatelet efficacy. XR299 demonstrated sustained antiplatelet efficacy when given three times a day in canine platelets ( Mousa et al ., 1998d ), Roxifiban when given QD in baboon platelets ( Mousa et al ., 1998b ), and DMP802 when given once a week in baboon platelets ( Mousa et al ., 1998e ; Olson et al ., 1997 ). Roxifiban active form demonstrated high potency in inhibiting platelet aggregation.…”

Section: Discussionmentioning

confidence: 99%

“…Roxifiban (DMP 754), a methyl ester prodrug, has been shown to be 100% converted into its free acid active form (XV459) upon exposure to blood and liver esterases ( Mousa et al ., 1996 ). The active form of Roxifiban demonstrated potent antiplatelet efficacy and optimal antiplatelet duration as compared to other isoxazoline analogues ( Mousa & Wityak, 1998 ; Mousa et al ., 1998a , 1998b , 1998c , 1998d , 1998e ; 1999 ; 2000 ).…”

Section: Introductionmentioning

confidence: 99%

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Platelet GPIIb/IIIa binding characteristics of small molecule RGD mimetic: distinct binding profile for Roxifiban

Mousa

Bozarth

Naik

et al. 2001

British J Pharmacology

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A number of non‐peptide orally active RGD mimetic prodrug such as Orbofiban, Sibrafiban, SR121566, Roxifiban and others entered into the clinical evaluation stage. Some of these agents were terminated and some are still in clinical trials. The present study examined the platelet GPIIb/IIIa binding profiles for the active form of Roxifiban, Sibrafiban, SR121566 and Orbofiban using 3H‐Roxifiban active form (XV459), 3H‐DMP728, 125I‐Echistatin, and 125I‐Fibrinogen. Either DMP728, Orbofiban, Sibrafiban, SR121566 or Roxifiban active form as well as other RGD mimetic bind to the same binding site (s) on human platelets as evident from the competitive inhibition of binding of each other to human platelet. Additionally, Roxifiban active form competed with FITC labeled GPIIb/IIIa antagonist cyclic RGD peptidomimetic (XL086) as demonstrated using confocal microscopy technique. Roxifiban active form (XV459) demonstrated the highest potency in inhibiting 3H‐XV459, 3H‐DMP728, 125I‐Echistatin, and 125I‐Fibrinogen binding to human platelets as compared to the others. Structure activity relationship within the isoxazoline Roxifiban series showed that substituent at the α‐carbon next to the carboxy terminal represents an exosite for the affinity binding to human platelets leading to slow platelet dissociation rate. These data indicated a distinct binding profile for Roxifiban (high affinity to both activated and resting platelets associated with a relatively slow Koff) as compared to others. These differences might determine the pharmacodynamics and pharmackokinetics of the different GPIIb/IIIa antagonists. British Journal of Pharmacology (2001) 133, 331–336; doi:

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Platelet GPIIb/IIIa binding characteristics of small molecule RGD mimetic: distinct binding profile for Roxifiban

Mousa

Bozarth

Naik

et al. 2001

British J Pharmacology

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“…Two hundred microliter of platelet rich plasma was mixed with 20 ll of saline, DMP802 at 3 lM in saline or razaxaban at 1-10 lM in saline and incubated for 3 min at 37°C. DMP802 is a GPIIb/IIIa receptor antagonist (IC 50 = 29 nM against human platelet aggregation response to 10 lM ADP) [14] and was included as a positive control. Percentages of platelet aggregation were determined 4 min after the addition of 20 ll of the agonist (ADP at 10 lM, c-thrombin at 35 nM and collagen at 10 lg/ml, final concentration).…”

Section: In Vitro Platelet Aggregationmentioning

confidence: 99%

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Wong

Crain

Watson

et al. 2007

J Thromb Thrombolysis

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Coactivation of platelets and the blood coagulation cascade contributes to the pathophysiology of arterial thrombosis. Combination therapy with antiplatelet and anticoagulant drugs may be needed for maximizing the prevention and treatment of arterial thrombosis. Few studies have thoroughly investigated the combined antithrombotic and bleeding effects of these antithrombotic agents. We, therefore, evaluated the antithrombotic and bleeding profiles of dual and triple therapy with razaxaban, a direct factor Xa inhibitor, plus aspirin and/or clopidogrel in rabbit models of electrolytic injury-induced carotid artery thrombosis and cuticle bleeding time, respectively. Compounds were infused either IV or into the portal vein from 1 h before arterial injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. We first evaluated the antithrombotic potency of razaxaban, and examined its ex vivo effects on coagulation parameters to confirm its selectivity. Antithrombotic ED(50) of razaxaban averaged 0.22 +/- 0.05 mg/kg/h (n = 6). Razaxaban at 3 mg/kg/h IV produced full antithrombotic efficacy, increased significantly ex vivo activated partial thromboplastin time and prothrombin time by 2.2 +/- 0.1- and 2.3 +/- 0.1-fold, respectively, and inhibited ex vivo factor Xa activity significantly by 91 +/- 5% (n = 6, P < 0.05) without affecting ex vivo thrombin activity. Razaxaban at concentrations up to 10 muM did not alter in vitro platelet aggregation responses to ADP, gamma-thrombin or collagen. To identify additive or synergistic antithrombotic effects of the various combination therapies, we purposefully used marginally effective doses of razaxaban at 0.1 mg/kg/h, aspirin at 0.3 mg/kg/h and clopidogrel at 1 mg/kg/h. Dual combination of threshold doses of razaxaban and aspirin or clopidogrel produced an enhanced antithrombotic effect without further increases in bleeding time. When compared with dual therapy with aspirin and clopidogrel (38 +/- 5% increase in blood flow), addition of razaxaban increased blood flow to 75 +/- 5% without additional bleeding time effects (n = 6/group, P < 0.05). In summary, razaxaban was an effective antithrombotic agent in a rabbit model of arterial thrombosis. Low-dose razaxaban was useful in combination with sub-optimal doses of aspirin and/or clopidogrel for the prevention of occlusive arterial thrombosis without excessive bleeding.

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“…with unactivated human platelets. This distinguishes these agents from most of the others currently under study in clinical trials (30).…”

Section: Xv459/dmp 754mentioning

confidence: 99%

“…Oral administration of DMP 802 at 0.1 mgkg in a canine model induced a significant (>50%) inhibition of ex vivo ADP-(100 mM) mediated platelet aggregation that was maintained for 24 h. Oral antiplatelet efficacy of DMP 802 was examined after single oral (0.05 to 0.20 mgkg) or repeated oral dosing at 0.05 mgkg daily for 5 d in mongrel dogs (30). Dose-dependent antiplatelet efficacy with an extended duration of action was demonstrated based on ex vivo inhibition of platelet aggregation induced by 100 pM ADP.…”

Section: Dmp 802mentioning

confidence: 99%

Orally Active Isoxazoline GPIIb/IIIa Antagonists

Mousa¹,

Wityak²

1998

Cardiovascular Drug Reviews

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Oral Antiplatelet Efficacy and Specificity of a Novel Nonpeptide Platelet GPIIb/IIIa Receptor Antagonist, DMP 802

Cited by 16 publications

References 22 publications

Platelet GPIIb/IIIa binding characteristics of small molecule RGD mimetic: distinct binding profile for Roxifiban

Platelet GPIIb/IIIa binding characteristics of small molecule RGD mimetic: distinct binding profile for Roxifiban

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Orally Active Isoxazoline GPIIb/IIIa Antagonists

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