An experimental model to study isolated effects of thrombin in vivo.

Contains fulltext : 88126.pdf (publisher's version ) (Closed access)BACKGROUND: In addition to a recognized role in the coagulation cascade and haemostasis, thrombin is known to have multiple functions. We hypothesized that protracted intravenous infusion of thrombin at steady state will allow to study isolated thrombin effects in vivo. METHODS: Thrombin (0.05-0.9U/kg/min) was continuously infused in Sprague Dawley rats over five hours (n=38). The study consisted of three parts: dose escalation (n=21), dose verification (n=5) and a parallel group study to investigate whether thrombin effects can be antagonised by concomitant infusion of lepirudin (n=12). RESULTS: A thrombin dose of 0.9U/kg/min decreased platelet counts by 70% compared to the control group (median 230x10^9/L vs. 752x10^9/L; p=0.041). In accordance, infusion of 0.9U/kg/min of thrombin decreased fibrinogen level by 75% compared to the control group (56mg/dl vs. 220mg/dl; p=0.046). Cumulative thrombin doses of >/=0.1U/kg/min caused bleedings but not thromboembolic events. Thrombin at doses >/=0.15U/kg/min was lethal in four cases (30%). Platelet counts and fibrinogen levels after thrombin infusion correlated with bleeding events and mortality. Administration of thrombin at cumulative doses of 0.3-0.9U/kg/min was associated with a 3 to 6.5 -fold increase in IL-6 levels (139-306pg/ml vs. 47pg/ml, p<0.05). In contrast, thrombin infusion did not alter other markers of inflammation (IL-10, MCP-1 or TNF-alpha). In addition, lepirudin prevented thrombin- induced thrombocytopenia. CONCLUSION: Protracted intravenous infusion of thrombin offers a new experimental model, where consumption of fibrinogen and platelets correlates with bleedings and mortality. Infusion of thrombin increased only IL-6 levels but not other cytokines.1 november 201

The method of physick : containing the causes, signes, and cures of inward diseases in mans body from the head to the foote: whereunto is added the forme and rule of making remedies and medicines, which our physitions commonly use at this day, with the proportion, quantity, and names of each medicine, by Philip Barrough.

OBJECTIVES: To perform a systematic up-to-date review and critical discussion of potential clinical applications of cangrelor based on its pharmacologic properties and the main findings from randomized clinical studies. METHODS: A database search (PubMed, CENTRAL and Google Scholar) by two independent investigators, including proceedings from scientific sessions of ACC, AHA, ESC, TCT and EuroPCR, from January 1998 through December 2013. RESULTS: Cangrelor is a potent, intravenous, direct-acting P2Y12 antagonist with rapid onset and quickly reversible action. In contrast to ticagrelor, cangrelor's interaction with thienopiridines requires termination of cangrelor infusion before switching to clopidogrel or prasugrel. According to randomized trials, a cangrelor-clopidogrel combination is relatively safe and more effective than the standard clopidogrel regimen in both urgent and elective percutaneous coronary intervention (PCI) settings, with the advantage of this drug combination fully evident when the universal definition of myocardial infarction is applied. In contrast to available antiplatelet drugs with delayed onset and offset of action, its favorable properties make cangrelor a desirable agent for ad hoc elective PCI, high risk acute coronary syndromes treated with immediate coronary stenting and for bridging those surgery patients who require periprocedural P2Y12 inhibition. Current evidence on cangrelor therapy is limited by the lack of adequately powered studies assessing cangrelor co-administration either with prasugrel or ticagrelor, suboptimal design of some of the trials favoring cangrelor, potentially attenuated benefits with modern stent design, and finally, by the lack of survival advantage. CONCLUSIONS: With its pharmacokinetic and pharmacodynamic advantages, allowing consistent and strong P2Y12 inhibition, and with its rapid onset and swift reversal of action devoid of need for an antidote, cangrelor might improve clinical outcomes in clopidogrel-treated patients by reducing ischemic events, while maintaining a favorable safety profile. However, further studies, addressing the safety and efficacy of cangrelor on top of novel oral P2Y12 inhibitors, are warranted

Fake photographs : making truths in photography

BACKGROUND: The aim of this study was to assess antiplatelet effect of prasugrel in acute coronary syndrome (ACS) patients with high on-treatment platelet reactivity (HTPR) on clopidogrel, undergoing percutaneous coronary intervention (PCI). METHODS: A prospective, platelet reactivity-guided, parallel-group, open-label study including 71 patients pretreated with clopidogrel 600 mg and assigned either to prasugrel (30 mg loading dose, 10 mg maintenance dose; n = 46) or clopidogrel (150 mg maintenance dose for 6 days and thereafter 75 mg maintenance dose; n = 25) regimen, based on vasodilator-stimulated phosphoprotein (VASP)-assessed platelet reactivity index (PRI; > 50% vs. </= 50%) measured next morning post-PCI. RESULTS: Median PRI value after switch to prasugrel sharply declined at 24 h (70.0 [61.3-75.6] vs. 11.9 [6.8-25.7]%; p < 0.000001) and slightly but significantly rose between 24 h and 30 days (27.9 [15.5-46.8]%; p < 0.0006). In contrast, median PRI values in the clopidogrel group were similar at baseline and at 24 h (25.1 [13.7-40.2] vs. 22.0 [18.4-36.8]%; p = NS) and then modestly rose at 30 days (30.3 [20.4-45.7]%; p < 0.03). The prevalence of HTPR decreased in the prasugrel group between baseline and 24 h measurements (100.0 vs. 4.3%; p < 0.0001). Rates of patients with HTPR at 24 h and 30 days were similar in both groups, so were the tendencies in patterns of platelet inhibition evaluated with multiple electrode aggregometry as compared with the VASP assay. CONCLUSIONS: Our study indicates that prasugrel overcomes HTPR on clopidogrel in the acute phase of interventionally treated ACS and maintains its antiplatelet potency in 30-day follow-up. Potential clinical benefits of personalized antiplatelet prasugrel-based therapy warrant further investigation in clinical ACS trials

Prolonged antithrombotic therapy in patients after acute coronary syndrome: A critical appraisal of current European society of cardiology guidelines

The increased risk of non-cardiovascular death in patients receiving clopidogrel or prasugrel in comparison with the placebo group in the Dual Antiplatelet Therapy (DAPT) trial in contrast to the decreased risk of cardiovascular death and all-cause death seen in patients treated with low-dose ticagrelor in the EU label population of the PEGASUS-TIMI 54 trial, resulted in inclusion in the 2020 ESC NSTE-ACS guidelines the recommendation for use of clopidogrel or prasugrel only if the patient is not eligible for treatment with ticagrelor. The prevalence of the primary outcome composed of cardiovascular death, stroke, or myocardial infarction was lower in the low-dose rivaroxaban and acetylsalicylic acid (ASA) group than in the ASA-alone group in the COMPASS trial. Moreover, all-cause mortality and cardiovascular mortality rates were lower in the rivaroxaban-plus-ASA group. Comparison of the PEGASUS-TIMI 54 and COMPASS trial patient characteristics clearly shows that each of these treatment strategies should be addressed at different groups of patients. A greater benefit in post-acute coronary syndrome (ACS) patients with a high risk of ischemic events and without high bleeding risk may be expected with ASA and ticagrelor 60 mg b.i.d. when the therapy is continued without interruption or with short interruption only after ACS. On the other hand, ASA and rivaroxaban 2.5 mg b.i.d. seems to be a better option when indications for dual antithrombotic therapy (DATT) appear after a longer time from ACS (more than 2 years) and/or from cessation of DAPT (more than 1 year) and in patients with multiple vascular bed atherosclerosis. Thus, both options of DATTs com-plement each other rather than compete, as can be presumed from the recommendations. However, a direct comparison between these strategies should be tested in future clinical trials. (Cardiol J 2020; 27, 6: 661–676). © 2020 Via Medica