Clinical implementation of rapid CYP2C19 genotyping to guide antiplatelet therapy after percutaneous coronary intervention

© 2018 The Author(s). Background: The CYP2C19 nonfunctional genotype reduces clopidogrel effectiveness after percutaneous coronary intervention (PCI). Following clinical implementation of CYP2C19 genotyping at University Florida (UF) Health Shands Hospital in 2012, where genotype results are available approximately 3 days after PCI, testing was expanded to UF Health Jacksonville in 2016 utilizing a rapid genotyping approach. We describe metrics with this latter implementation. Methods: Patients at UF Health Jacksonville undergoing left heart catheterization with intent to undergo PCI were targeted for genotyping using the Spartan RX™ system. Testing metrics and provider acceptance of testing and response to genotype results were examined, as was antiplatelet therapy over the 6 months following genotyping. Results: In the first year, 931 patients, including 392/505 (78%) total patients undergoing PCI, were genotyped. The median genotype test turnaround time was 96 min. Genotype results were available for 388 (99%) PCI patients prior to discharge. Of 336 genotyped PCI patients alive at discharge and not enrolled in an antiplatelet therapy trial, 1/6 (17%) poor metabolizers (PMs, with two nonfunctional alleles), 38/93 (41%) intermediate metabolizers (IMs, with one nonfunctional allele), and 119/237 (50%) patients without a nonfunctional allele were prescribed clopidogrel (p = 0.110). Clopidogrel use was higher among non-ACS versus ACS patients (78.6% vs. 42.2%, p < 0.001). Six months later, among patients with follow-up data, clopidogrel was prescribed in 0/4 (0%) PMs, 33/65 (51%) IMs, and 115/182 (63%) patients without a nonfunctional allele (p = 0.008 across groups; p = 0.020 for PMs versus those without a nonfunctional allele). Conclusion: These data demonstrate that rapid genotyping is clinically feasible at a high volume cardiac catheterization facility and allows informed chronic antiplatelet prescribing, with lower clopidogrel use in PMs at 6 months

Peri-Procedural Platelet Reactivity in Percutaneous Coronary Intervention

Platelet activation and aggregation play a pivotal role in thrombotic complications occurring during percutaneous coronary intervention (PCI), and peri-PCI anti-platelet therapy represents a standard of care. High platelet reactivity prior to PCI has been correlated with an increased incidence of peri-procedural myonecrosis. Pre-PCI platelet reactivity predicts post-PCI platelet reactivity and has a prognostic impact on subsequent ischaemic and bleeding events, so as the platelet inhibition measured post-PCI. Many anti-platelet treatment strategies, including aspirin, glycoprotein IIb/IIIa inhibitors, P2Y 12 receptor blockers and vorapaxar, are being used in the routine clinical practice to modify platelet reactivity at each stage, e.g. pre-, during and post-PCI. Anti-platelet strategies with a &apos;stronger and faster&apos; pharmacodynamic effect than clopidogrel have been mostly adopted in patients with acute coronary syndromes. However, several issues regarding the anti-platelet treatment such as benefits/risks of anti-platelet therapy pre-treatment and duration, and definite association between speed and potency of various anti-platelet agents and clinical outcomes remain controversial. We believe that a better understanding of peri-PCI platelet reactivity and its relations to outcomes may lead to the development of more effective and safe treatment strategies. © 2018 Georg Thieme Verlag KG

Non-bonded interactions in 2,2,4,4-tetramethyl-1,3-cyclobutanedithione and 2,2,4,4-tetramethyl-3-thio-1,3-cyclobutanedione

Electronic absorption and emission spectra as well as He(I) photoelectron spectra of 2,2,4,4-tetramethyl-,3-cyclobutanedithione and 2,2,4,4-tetramethyl-1-3-thio-1,3-cyclobutanedione have been interpreted on the basis of molecular orbital calculations. The results show that the non-bonded orbital of the dithione is split owing to through-bond interaction, the magnitude of splitting being 0.4 eV. The π* orbital of the dithione appears to be split by about 0.2 eV. Electronic absorption spectra show evidence for the existence of four n—π* transitions, arising out of the splitting of the orbitals referred to above, just as in the case of 2,2,4,4-tetramethyl-1,3-cyclobutanedione. Electronic and photoelectron spectra of the thio-dione show evidence for weak interaction between the C=S and C&.zdbnd;O groups, probably via π* orbitals. Infrared spectra of both the dithione and the thio-dione are consistent with the planar cyclobutane ring; the ring-puckering frequency responsible for non-bonded interactions is around 67 cm−1 in both the dithione and the thio-dione, the value not being very different from that in the dione. The 1,3-transannular distance is also similar in the three molecules

Effect of double reinforcements on elevated-temperature strength and toughness of molybdenum disilicide

Flexural strength and fracture toughness of molybdenum disilicide and its composites with 10 wt% TiB2 and 10 wt% TiB2 + 10 wt% SiC, synthesized by the hot-pressing technique, were evaluated as a function of temperature, ranging from ambient temperature to 1600xB0;C. Results show that the composites have higher strength and slightly lower toughness as compared with monolithic MoSi2 at room temperature. At high temperatures, the composites exhibit higher strength as well as higher toughness vis-xE0;-vis monolithic MoSi2. Among the composites, the double reinforcement of SiC and TiB2 was found to be more effective in improving the mechanical properties. A transition from brittle to ductile behavior was observed at temperatures greater than 1300xB0;C for all materials tested. The high-temperature mechanical behavior was found to be significantly influenced by the flow of an integranular glassy phase and the attendant cavity nucleation and growth along the grain boundaries. Micromechanisms responsible for the ambient as well as the elevated-temperature property improvement in composites are discussed with the aid of fractography

Non-bonded interactions in 2,2,4,4-tetramethyl-1,3-cyclobutanedithione and 2,2,4,4-tetramethyl-3-thio-1,3-cyclobutanedione

Electronic absorption and emission spectra as well as He(I) photoelectron spectra of 2,2,4,4-tetramethyl-1,3-cyclobutanedithione and 2,2,4,4-tetramethyl-1-3-thio-1,3-cyclobutanedione have been interpreted on the basis of molecular orbital calculations. The results show that the non-bonded orbital of the dithione is split owing to through-bond interaction, the magnitude of splitting being 0.4 eV. The π∗ orbital of the dithione appears to be split by about 0.2 eV. Electronic absorption spectra show evidence for the existence of four n-π∗ transitions, arising out of the splitting of the orbitals referred to above, just as in the case of 2,2,4,4-tetramethyl-1,3-cyclobutanedione. Electronic and photoelectron spectra of the thio-dione show evidence for weak interaction between the C=S and C&amp;.zdbnd;O groups, probably via π∗ orbitals. Infrared spectra of both the dithione and the thio-dione are consistent with the planar cyclobutane ring; the ring-puckering frequency responsible for non-bonded interactions is around 67 cm−1 in both the dithione and the thio-dione, the value not being very different from that in the dione. The 1,3-transannular distance is also similar in the three molecules

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