Chemical approaches to sphingolipid research

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/6743

Stereoselective preparation of quaternary 2-vinyl sphingosines and ceramides and their effect on basal sphingolipid metabolism

The dicyclohexylborane-mediated addition of allene 1 to (E)-2-tridecenal affords a quaternary protected 2-amino-2-vinyl-1,3-diol in good yield as a single diastereomer. This compound is readily transformed into the four stereoisomers of the quaternary (E)-2-vinyl analogs of sphingosine. The metabolic fate and the effect of these compounds on the basal sphingolipid metabolism in human A549 lung adenocarcinoma cells has been studied, together with the ceramide analog of the most relevant vinylsphingosine derivative

Chemical approaches to sphingolipid research

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/6743

Chemical approaches to sphingolipid research

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/6743

CYP2C19 defines clopidogrel response in patients undergoing percutaneous neurointervention procedure

Resumen del trabajo presentado al 5th Symposium on Biomedical Research: "Advances and Perspectives In Pharmacology, Drug Toxicity and Pharmacogenetics", celebrado en Madrid del 15 al 16 de marzo de 2018.[Introduction]: Clopidogrel is a widely prescribed thienopyridine prodrug which inhibits platelet aggregation. It is prescribed to prevent atherothrombotic and thromboembolic events in patients who are given a stent implant in carotid, vertebral or cranial arteries. CYP2C19 is the most studied enzyme involved in clopidogrel metabolism. The most common CYP2C19 no function polymorphisms (*2 and *3) have been associated with hyporesponse to clopidogrel, showing lower levels of the active metabolite. On the contrary, the presence of the increased function allele (*17) has demonstrated enhanced platelet inhibition and clopidogrel hyperresponse.[Methods]: This observational retrospective study assessed antiplatelet response and clinical events after clopidogrel treatment in patients who underwent percutaneous neurointervention, related to CYP2C19 metabolizer status (normal (NM), intermediate/poor (IM-PM) and ultra-rapid (UM); inferred from *2, *3 and *17 allele determination by real-time PCR).[Results]: One hundred twenty-three patients were analysed, of which 83% had cardiovascular risk factors. The most common type of intervention was angioplasty with stent. According to the aggregation value, 58.7% of the patients were responders to clopidogrel; moreover, 4.1% required dose reduction and 12.2% change of treatment. CYP2C19 IM-PM had higher aggregation value (201.1 vs 137.6 NM, 149.4 UM, p<0.05) and lower response rate (37.5% vs. 69.8% NM, 61.1% UM), along with higher treatment change rate (25% vs. 5.7% NM, 10.5% UM). Moreover, 20% of the patients suffered from a subsequent clinical event. The highest ischemic events incidence occurred in NM (11.3% vs. 6.3% IM, 10.5% UM; p=0.358) and haemorrhagic events in UM (13.2% vs. 0% IM and 3.8% NM; p=0.041). No differences found regarding ischemic events’ onset time, while haemorrhagic events’ frequency in UM was higher with shorter onset time (p=0.047). Additionally, 53% of the patients were receiving concomitant treatment with proton-pump inhibitors (PPIs), which showed significantly higher aggregation value when compared to those not receiving PPI concomitant treatment (178.1 vs. 134.4; p=0.009).[Conclusion]: CYP2C19 no function and increased function alleles defined clopidogrel response. CYP2C19 genotyping and platelet reactivity quantification help to determine whether a patient could be at risk of ischemic or haemorrhagic event. CYP2C19 UM patients have increased bleeding risk after percutaneous neurointervention. Therapeutic recommendations should include an alternative therapeutic option in IM-PM or UM patients.M. Saiz-Rodriguez was co-financed by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social Europeo. D. Koller is co-financed by the H2020 Marie Sklodowska-Curie Innovative Training Network 721236 grant.Peer reviewe

Influence of CYP450 enzymes, CES1, PON1, ABCB1, and P2RY12 polymorphisms on clopidogrel response in patients subjected to a percutaneous neurointervention

[Purpose]: Clopidogrel is a thienopyridine prodrug that inhibits platelet aggregation. It is prescribed to prevent atherothrombotic and thromboembolic events in patients receiving a stent implant in carotid, vertebral, or cranial arteries. The influence of cytochrome P-450 (CYP) 2C19 on the response to clopidogrel has been widely studied; however, the effect of other genes involved in clopidogrel absorption and metabolism has not been established in this cohort of patients.[Methods]: This observational retrospective study assessed the antiplatelet response and the prevalence of hemorrhagic or ischemic events after percutaneous neurointervention in clopidogrel-treated patients, related to 35 polymorphisms in the genes encoding the clopidogrel-metabolizing enzymes (CYP2C19, CYP1A2, CYP2B6, CYP2C9, CYP2C9, CYP3A4, CYP3A5, carboxylesterase-1 [CES1], and paraoxonase-1 [PON1]), P-glycoprotein transporter (ABCB1), and platelet receptor P2Y12. Polymorphisms were analyzed by quantitative real-time polymerase chain reaction and matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry. Antiplatelet response was documented with the VerifyNow system (Accriva, San Diego, California).[Findings]: We confirmed that CYP2C19 is the most important enzyme involved in clopidogrel response. The carriage of the CYP2C19*2 allele was strongly associated with hyporesponse to clopidogrel, while the CYP2C19*17 allele was a protective factor for the development of ischemic events (odds ratio = 0.149; P = 0.002) but a risk factor for bleeding (odds ratio = 3.60; P = 0.038). Patients carrying ABCB1 mutated alleles showed lower aggregation values, suggesting that clopidogrel absorption is influenced by P-glycoprotein. In fact, the percentage of responders was significantly higher in the group carrying the mutated haplotype compared to the wild type (80.8% vs 43.3%; P = 0.009). Patients with the CES1 G143E C/T genotype showed a considerably lower, aggregation value versus wild-type patients, although the difference was not significant likely due to the small sample size (59.0 [21.2] vs 165.2 [86.0] PRU; P = 0.084), which suggests an increased active metabolite formation. No relationship was found between polymorphisms in other CYP genes, PON1, or P2RY12 and response to clopidogrel in patients subjected to neurointervention procedures.[Implications]: Therapeutic guidelines recommend that CYP2C19 intermediate and poor metabolizers with acute coronary syndromes undergoing percutaneous coronary intervention receive an alternative antiplatelet therapy; however, genotype-guided therapy is not a standard recommendation for neurovascular conditions. This is the first study to carry out a joint analysis of CYP2C19 and other genes involved in clopidogrel treatment in patients receiving percutaneous neurointervention. Our findings support routine genotyping in clopidogrel-treated patients. Moreover, we encourage considering an alternative antiplatelet therapy in CYP2C19 intermediate, poor and ultrarapid metabolizers. Additionally, ABCB1 polymorphisms could be considered for a better pharmacogenetic approach.D. Koller has received research funding from H2020 Marie Sklodowska-Curie Innovative Training Network grant 721236. P. Zubiaur has received research funding from the Department of Education, Community Youth and Sports of Madrid and the European Social Fund. The MassArray genotyping service was carried out at CEGEN-PRB3-ISCIII, which is supported by PE I+D+i 2013–2016 grant PT17/0019, funded by Instituto de Salud Carlos III (ISCIII) and European Regional Development Fund (ERDF).Peer reviewe

Influence of CYP2C19 phenotype on the efect of clopidogrel in patients undergoing a percutaneous neurointervention procedure

This observational retrospective study assessed the antiplatelet response and clinical events after clopidogrel treatment in patients who underwent percutaneous neurointervention, related to CYP2C19 metabolizer status (normal (NM), intermediate/poor (IM‐PM), and ultrarapid (UM); inferred from *2, *3, and *17 allele determination). From 123 patients, IM‐PM had a higher aggregation value (201.1 vs. 137.6 NM, 149.4 UM, P < 0.05) and lower response rate (37.5% vs. 69.8% NM, 61.1% UM), along with higher treatment change rate (25% vs. 5.7% NM, 10.5% UM). The highest ischemic events incidence occurred in NM (11.3% vs. 6.3% IM, 10.5% UM) and hemorrhagic events in UM (13.2% vs. 0% IM and 3.8% NM). No differences were found regarding ischemic event onset time, while hemorrhagic event frequency in UM was higher with shorter onset time (P = 0.047). CYP2C19 no‐function and increased function alleles defined the clopidogrel response. UM patients had increased bleeding risk. Therapeutic recommendations should include dose reduction or treatment change in UM.M. Saiz-Rodriguez is co-financed by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social Europeo. D. Koller is co-financed by the H2020 Marie Sklodowska-Curie Innovative Training Network 721236 grant.Peer reviewe