The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Fadi T Khasawneh - One of the best experts on this subject based on the ideXlab platform.

  • The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin- Enhanced Platelet Function
    2016
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and Pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and Pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, Pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and Pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and Pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EM

  • the antidepressant 5 ht2a receptor antagonists Pizotifen and cyproheptadine inhibit serotonin enhanced platelet function
    PLOS ONE, 2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma Paez V Espinosa, Fadi T Khasawneh
    Abstract:

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and Pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and Pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, Pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and Pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and Pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and Pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their use may interfere with normal hemostasis.

  • Combination of Cyproheptadine and Pizotifen inhibits serotonin-enhanced ADP-induced human platelet aggregation in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human PRP was treated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) in the absence of agonists. (B) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with serotonin (15 µM). (C) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM). (D) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM) and serotonin (15 µM). Each experiment was repeated at least 3 times, with blood obtained from three separate donors.

  • Cyproheptadine and Pizotifen inhibit serotonin-enhanced ADP-induced human platelet aggregation in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human PRP was stimulated with submaximal concentration of ADP (1 µM) in the presence or absence of serotonin (15 µM). (B) Human PRP was pre-incubated with increasing doses of cyproheptadine (0.1–10 nM) for 1 min and activated with ADP (1 µM) and serotonin (15 µM). (C) Human PRP was pre-incubated with increasing doses of Pizotifen (0.01–1 nM) for 1 min and activated with ADP and serotonin. (D) Human PRP was pre-incubated with increasing doses of EMD 281014 (10–40 nM) for 1 min and activated with ADP and serotonin. (E) Human PRP was treated with the highest concentrations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) used in previous experiments, in the absence of agonists. (F) Human PRP was pre-incubated for 1 min with cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with serotonin (15 µM). (G) Human PRP was pre-incubated with cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM). Inset shows quantification of the data. Each experiment was repeated at least 3 times, with blood obtained from three separate donors.

  • Cyproheptadine and Pizotifen prolong occlusion times and tail bleeding times in mice.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    Each point represents the occlusion time or tail bleeding time of a single animal. Mice were treated IP with vehicle, 6/kg clopidogrel, 1 mg/kg cyproheptadine, 3 mg/kg Pizotifen, or 5 mg/kg EMD 281014 once daily for 5 days before experiments. (A) Mean occlusion times for mice treated with: vehicle = 375.3±31.89 sec (n = 11), clopidogrel = 987.6±196.5 sec (n = 8), cyproheptadine = 787.4±84.08 sec (n = 8), Pizotifen = 1199±253.1 sec (n = 8), and EMD 281014 = 879.9±270.0 sec (n = 8). **p

Olivia A Lin - One of the best experts on this subject based on the ideXlab platform.

  • The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin- Enhanced Platelet Function
    2016
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and Pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and Pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, Pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and Pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and Pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EM

  • the antidepressant 5 ht2a receptor antagonists Pizotifen and cyproheptadine inhibit serotonin enhanced platelet function
    PLOS ONE, 2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma Paez V Espinosa, Fadi T Khasawneh
    Abstract:

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and Pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and Pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, Pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and Pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and Pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and Pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their use may interfere with normal hemostasis.

  • Combination of Cyproheptadine and Pizotifen inhibits serotonin-enhanced ADP-induced human platelet aggregation in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human PRP was treated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) in the absence of agonists. (B) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with serotonin (15 µM). (C) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM). (D) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM) and serotonin (15 µM). Each experiment was repeated at least 3 times, with blood obtained from three separate donors.

  • Cyproheptadine and Pizotifen inhibit serotonin-enhanced ADP-induced human platelet aggregation in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human PRP was stimulated with submaximal concentration of ADP (1 µM) in the presence or absence of serotonin (15 µM). (B) Human PRP was pre-incubated with increasing doses of cyproheptadine (0.1–10 nM) for 1 min and activated with ADP (1 µM) and serotonin (15 µM). (C) Human PRP was pre-incubated with increasing doses of Pizotifen (0.01–1 nM) for 1 min and activated with ADP and serotonin. (D) Human PRP was pre-incubated with increasing doses of EMD 281014 (10–40 nM) for 1 min and activated with ADP and serotonin. (E) Human PRP was treated with the highest concentrations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) used in previous experiments, in the absence of agonists. (F) Human PRP was pre-incubated for 1 min with cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with serotonin (15 µM). (G) Human PRP was pre-incubated with cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM). Inset shows quantification of the data. Each experiment was repeated at least 3 times, with blood obtained from three separate donors.

  • Cyproheptadine and Pizotifen prolong occlusion times and tail bleeding times in mice.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    Each point represents the occlusion time or tail bleeding time of a single animal. Mice were treated IP with vehicle, 6/kg clopidogrel, 1 mg/kg cyproheptadine, 3 mg/kg Pizotifen, or 5 mg/kg EMD 281014 once daily for 5 days before experiments. (A) Mean occlusion times for mice treated with: vehicle = 375.3±31.89 sec (n = 11), clopidogrel = 987.6±196.5 sec (n = 8), cyproheptadine = 787.4±84.08 sec (n = 8), Pizotifen = 1199±253.1 sec (n = 8), and EMD 281014 = 879.9±270.0 sec (n = 8). **p

Hari Priya Vemana - One of the best experts on this subject based on the ideXlab platform.

  • The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin- Enhanced Platelet Function
    2016
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and Pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and Pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, Pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and Pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and Pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EM

  • the antidepressant 5 ht2a receptor antagonists Pizotifen and cyproheptadine inhibit serotonin enhanced platelet function
    PLOS ONE, 2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma Paez V Espinosa, Fadi T Khasawneh
    Abstract:

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and Pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and Pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, Pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and Pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and Pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and Pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their use may interfere with normal hemostasis.

  • Combination of Cyproheptadine and Pizotifen inhibits serotonin-enhanced ADP-induced human platelet aggregation in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human PRP was treated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) in the absence of agonists. (B) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with serotonin (15 µM). (C) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM). (D) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM) and serotonin (15 µM). Each experiment was repeated at least 3 times, with blood obtained from three separate donors.

  • Cyproheptadine and Pizotifen inhibit serotonin-enhanced ADP-induced human platelet aggregation in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human PRP was stimulated with submaximal concentration of ADP (1 µM) in the presence or absence of serotonin (15 µM). (B) Human PRP was pre-incubated with increasing doses of cyproheptadine (0.1–10 nM) for 1 min and activated with ADP (1 µM) and serotonin (15 µM). (C) Human PRP was pre-incubated with increasing doses of Pizotifen (0.01–1 nM) for 1 min and activated with ADP and serotonin. (D) Human PRP was pre-incubated with increasing doses of EMD 281014 (10–40 nM) for 1 min and activated with ADP and serotonin. (E) Human PRP was treated with the highest concentrations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) used in previous experiments, in the absence of agonists. (F) Human PRP was pre-incubated for 1 min with cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with serotonin (15 µM). (G) Human PRP was pre-incubated with cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM). Inset shows quantification of the data. Each experiment was repeated at least 3 times, with blood obtained from three separate donors.

  • Cyproheptadine and Pizotifen prolong occlusion times and tail bleeding times in mice.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    Each point represents the occlusion time or tail bleeding time of a single animal. Mice were treated IP with vehicle, 6/kg clopidogrel, 1 mg/kg cyproheptadine, 3 mg/kg Pizotifen, or 5 mg/kg EMD 281014 once daily for 5 days before experiments. (A) Mean occlusion times for mice treated with: vehicle = 375.3±31.89 sec (n = 11), clopidogrel = 987.6±196.5 sec (n = 8), cyproheptadine = 787.4±84.08 sec (n = 8), Pizotifen = 1199±253.1 sec (n = 8), and EMD 281014 = 879.9±270.0 sec (n = 8). **p

Zubair A Karim - One of the best experts on this subject based on the ideXlab platform.

  • The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin- Enhanced Platelet Function
    2016
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and Pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and Pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, Pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and Pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and Pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EM

  • the antidepressant 5 ht2a receptor antagonists Pizotifen and cyproheptadine inhibit serotonin enhanced platelet function
    PLOS ONE, 2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma Paez V Espinosa, Fadi T Khasawneh
    Abstract:

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and Pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and Pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, Pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and Pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and Pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and Pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their use may interfere with normal hemostasis.

  • Combination of Cyproheptadine and Pizotifen inhibits serotonin-enhanced ADP-induced human platelet aggregation in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human PRP was treated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) in the absence of agonists. (B) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with serotonin (15 µM). (C) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM). (D) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM) and serotonin (15 µM). Each experiment was repeated at least 3 times, with blood obtained from three separate donors.

  • Cyproheptadine and Pizotifen inhibit serotonin-enhanced ADP-induced human platelet aggregation in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human PRP was stimulated with submaximal concentration of ADP (1 µM) in the presence or absence of serotonin (15 µM). (B) Human PRP was pre-incubated with increasing doses of cyproheptadine (0.1–10 nM) for 1 min and activated with ADP (1 µM) and serotonin (15 µM). (C) Human PRP was pre-incubated with increasing doses of Pizotifen (0.01–1 nM) for 1 min and activated with ADP and serotonin. (D) Human PRP was pre-incubated with increasing doses of EMD 281014 (10–40 nM) for 1 min and activated with ADP and serotonin. (E) Human PRP was treated with the highest concentrations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) used in previous experiments, in the absence of agonists. (F) Human PRP was pre-incubated for 1 min with cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with serotonin (15 µM). (G) Human PRP was pre-incubated with cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM). Inset shows quantification of the data. Each experiment was repeated at least 3 times, with blood obtained from three separate donors.

  • Cyproheptadine and Pizotifen prolong occlusion times and tail bleeding times in mice.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    Each point represents the occlusion time or tail bleeding time of a single animal. Mice were treated IP with vehicle, 6/kg clopidogrel, 1 mg/kg cyproheptadine, 3 mg/kg Pizotifen, or 5 mg/kg EMD 281014 once daily for 5 days before experiments. (A) Mean occlusion times for mice treated with: vehicle = 375.3±31.89 sec (n = 11), clopidogrel = 987.6±196.5 sec (n = 8), cyproheptadine = 787.4±84.08 sec (n = 8), Pizotifen = 1199±253.1 sec (n = 8), and EMD 281014 = 879.9±270.0 sec (n = 8). **p

Enma V. P. Espinosa - One of the best experts on this subject based on the ideXlab platform.

  • The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin- Enhanced Platelet Function
    2016
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and Pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and Pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, Pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and Pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and Pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EM

  • Combination of Cyproheptadine and Pizotifen inhibits serotonin-enhanced ADP-induced human platelet aggregation in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human PRP was treated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) in the absence of agonists. (B) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with serotonin (15 µM). (C) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM). (D) Human PRP was pre-incubated with different combinations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM) and serotonin (15 µM). Each experiment was repeated at least 3 times, with blood obtained from three separate donors.

  • Cyproheptadine and Pizotifen inhibit serotonin-enhanced ADP-induced human platelet aggregation in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human PRP was stimulated with submaximal concentration of ADP (1 µM) in the presence or absence of serotonin (15 µM). (B) Human PRP was pre-incubated with increasing doses of cyproheptadine (0.1–10 nM) for 1 min and activated with ADP (1 µM) and serotonin (15 µM). (C) Human PRP was pre-incubated with increasing doses of Pizotifen (0.01–1 nM) for 1 min and activated with ADP and serotonin. (D) Human PRP was pre-incubated with increasing doses of EMD 281014 (10–40 nM) for 1 min and activated with ADP and serotonin. (E) Human PRP was treated with the highest concentrations of cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) used in previous experiments, in the absence of agonists. (F) Human PRP was pre-incubated for 1 min with cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with serotonin (15 µM). (G) Human PRP was pre-incubated with cyproheptadine (10 nM), Pizotifen (1 nM), and EMD 281014 (40 nM) for 1 min and activated with ADP (1 µM). Inset shows quantification of the data. Each experiment was repeated at least 3 times, with blood obtained from three separate donors.

  • Cyproheptadine and Pizotifen prolong occlusion times and tail bleeding times in mice.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    Each point represents the occlusion time or tail bleeding time of a single animal. Mice were treated IP with vehicle, 6/kg clopidogrel, 1 mg/kg cyproheptadine, 3 mg/kg Pizotifen, or 5 mg/kg EMD 281014 once daily for 5 days before experiments. (A) Mean occlusion times for mice treated with: vehicle = 375.3±31.89 sec (n = 11), clopidogrel = 987.6±196.5 sec (n = 8), cyproheptadine = 787.4±84.08 sec (n = 8), Pizotifen = 1199±253.1 sec (n = 8), and EMD 281014 = 879.9±270.0 sec (n = 8). **p

  • Cyproheptadine, and Pizotifen inhibit intracellular calcium elevation and Src activation in human platelets in vitro.
    2014
    Co-Authors: Olivia A Lin, Zubair A Karim, Hari Priya Vemana, Enma V. P. Espinosa, Fadi T Khasawneh
    Abstract:

    (A) Human platelets were loaded with Fura-2/AM to measure intracellular [Ca2+]i, in the presence or absence of Cyproheptadine (10 nM), Pizotifen (1 nM) or EMD 281014 (40 nM) and activated with ADP (1 µM), serotonin (15 µM) or ADP and serotonin together. (B) Human platelets were incubated in the presence or absence of Cyproheptadine (10 nM), Pizotifen (1 nM) or EMD 281014 (40 nM) for 5 minutes and then stimulated with ADP (1 µM), serotonin (15 µM) or ADP and serotonin together for 3 minutes, and subjected to immunoprecipitation followed by immunoblotting with anti-Src and anti-phosphotyrosine antibodies; upper panel shows quantification of the data using densitometry analysis. Each experiment was repeated at least 3 times, with blood obtained from three separate donors.