Paclitaxel exerts antiplatelet and antithrombotic activities: Additional benefit from use of paclitaxel-coated balloons and -eluting stents in coronary revascularization and prevention of in-stent restenosis.

INTRODUCTION: Paclitaxel is a microtubule-stabilizing drug used to treat several types of cancer, including ovarian and breast cancer. Because of its antiproliferative effect on vascular smooth muscle cells, balloons and stents are coated with paclitaxel for use in coronary revascularization and prevention of in-stent restenosis (ISR). However, mechanisms underlying ISR are complicated. Platelet activation is one of the major causes of ISR after percutaneous coronary intervention. Although the antiplatelet activity of paclitaxel was noted in rabbit platelets, the effect of paclitaxel on platelets remains unclear. This study investigated whether paclitaxel exhibits antiplatelet activity in human platelets. METHODS AND RESULTS: Paclitaxel inhibited platelet aggregation induced by collagen but not that induced by thrombin, arachidonic acid, or U46619, suggesting that paclitaxel is more sensitive to the inhibition of collagen-induced platelet activation. Moreover, paclitaxel blocked collagen receptor glycoprotein (GP) VI downstream signaling molecules, including Lyn, Fyn, PLCγ2, PKC, Akt, and MAPKs. However, paclitaxel did not directly bind to GPVI and cause GPVI shedding, as detected by surface plasmon resonance and flow cytometry, respectively, indicating that paclitaxel may interfere with GPVI downstream signaling molecules, such as Lyn and Fyn. Paclitaxel also prevented granule release and GPIIbIIIa activation induced by collagen and low convulxin doses. Moreover, paclitaxel attenuated pulmonary thrombosis and delayed platelet thrombus formation in mesenteric microvessels without significantly affecting hemostasis. CONCLUSION: Paclitaxel exerts antiplatelet and antithrombotic effects. Thus, paclitaxel may provide additional benefits beyond its antiproliferative effect when used in drug-coated balloons and drug-eluting stents for coronary revascularization and prevention of ISR.

Evolution of the inclusion/exclusion criteria and primary endpoints in pivotal trials of biologics and small oral molecules for the treatment of psoriasis.

Introduction: Primary endpoints and inclusion/exclusion criteria of biologics and small oral molecules for psoriasis treatment have been evolving due to a better understanding of the pathogenesis and potential risks.Areas covered: We analyzed the designs of key phase 3 pivotal trials of all biologics and small oral molecules approved for moderate to severe plaque psoriasis from published data on the ClinicalTrials.gov website and literature in the PubMed database. Alefacept, efalizumab, anti-tumor necrosis factors, anti-interleukin (IL)-12/IL-23, anti-IL-17 and anti-IL-23 inhibitors were discussed chronologically. Small oral molecules including tofacitinib and apremilast were also reviewed.Expert opinion: The primary endpoints of trials of biologics have been raised progressively and psoriasis area and severity index (PASI) 100 can now be readily achievable by the recent biologics. For safety, 5-year observation periods have become a gold standard after the report of progressive multifocal leukoencephalopathy after efalizumab. Also, the need for tuberculosis (TB) prophylaxis has also been relaxed in one trial of risankizumab. Small oral molecules are the future of affordable effective treatment for psoriasis, but the safety concerns must be overcome as reflected by their more stringent exclusion criteria. More biologic switch data and inclusion of patients previously excluded, e.g. viral hepatitis, are still needed.