Single nucleotide polymorphisms in the cannabinoid CB2 receptor: Molecular pharmacology and disease associations.

Preclinical evidence implicating cannabinoid receptor 2 (CB2) in various diseases has led researchers to question whether CB2 genetics influence aetiology or progression. Associations between conditions and genetic loci are often studied via single nucleotide polymorphism (SNP) prevalence in case versus control populations. In the CNR2 coding exon, ~36 SNPs have high overall population prevalence (minor allele frequencies [MAF] ~37%), including non-synonymous SNP (ns-SNP) rs2501432 encoding CB2 63Q/R. Interspersed are ~27 lower frequency SNPs, four being ns-SNPs. CNR2 introns also harbour numerous SNPs. This review summarises CB2 ns-SNP molecular pharmacology and evaluates evidence from ~70 studies investigating CB2 genetic variants with proposed linkage to disease. Although CNR2 genetic variation has been associated with a wide variety of conditions, including osteoporosis, immune-related disorders, and mental illnesses, further work is required to robustly validate CNR2 disease links and clarify specific mechanisms linking CNR2 genetic variation to disease pathophysiology and potential drug responses.

Can a Single Measurement of Apixaban Levels Identify Patients at Risk of Overexposure? A Prospective Cohort Study.

Background Patients with atrial fibrillation (AF) are frequently treated with apixaban 2.5-mg twice daily (BID) off-label, presumably to reduce the bleeding risk. However, this approach has the potential to increase the risk of ischemic stroke. If a single measurement could reliably identify patients with high drug levels, the increased stroke risk may be mitigated by confining off-label dose reduction to such patients. Objectives This study aimed to determine whether a single high apixaban level is predictive of a similarly high level when the test is repeated in 2 months. Methods In this prospective cohort study of clinic patients receiving apixaban 5-mg BID for AF or venous thromboembolism, peak and trough apixaban levels were measured using the STA-Liquid anti-Xa assay at baseline and 2 months. We calculated the proportions of patients with levels that remained in the upper quintile. Results Of 100 enrolled patients, 82 came for a second visit, 55 of whom were treated with apixaban 5-mg BID. Seven (63.6%, 95% confidence interval [CI]: 35.4-84.8%) and nine (81.8%, 95% CI: 52.3-94.9%) of 11 patients with a baseline trough and peak level in the upper quintile, respectively, had a subsequent level that remained within this range. Only one (9.1%, 95% CI: 1.6-37.7%) patient had a subsequent level that fell just lower than the median. Conclusion The trough and peak levels of apixaban in patients who have a high level on a single occasion, usually remain high when the assay is repeated in 2 months. Accordingly, the finding of a high apixaban level in patients deemed to be at high risk of bleeding, allows physicians contemplating off-label use of the 2.5-mg BID dose to limit its use to selected patients who are less likely to be exposed to an increased risk of thrombosis.

Elevated High-Sensitivity Troponin I in the Stabilized Phase after an Acute Coronary Syndrome Predicts All-Cause and Cardiovascular Mortality in a Highly Admixed Population: A 7-Year Cohort / A Troponina I de Alta Sensibilidade Elevada na Fase Estabilizada após Síndrome Coronariana Aguda Prevê Mortalidade por Todas as Causas e Mortalidade Cardiovascular em uma População Altamente Miscigenada: Uma Coorte de 7 Anos

Abstract Background: High-sensitivity cardiac troponin I (hs-cTnI) has played an important role in the risk stratification of patients during the in-hospital phase of acute coronary syndrome (ACS), but few studies have determined its role as a long-term prognostic marker in the outpatient setting. Objective: To investigate the association between levels of hs-cTnI measured in the subacute phase after an ACS event and long-term prognosis in a highly admixed population. Methods: We measured levels of hs-cTnI in 525 patients 25 to 90 days after admission for an ACS event; these patients were then divided into tertiles according to hs-cTnI levels and followed for up to 7 years. We compared all-cause and cardiovascular mortality using Cox proportional hazards models and adopting a significance level of 5%. Results: After a median follow-up of 51 months, patients in the highest tertile had a greater hazard ratio (HR) for all-cause mortality after adjustment for age, sex, known cardiovascular risk factors, medication use, and demographic factors (HR: 3.84, 95% CI: 1.92-8.12). These findings persisted after further adjustment for estimated glomerular filtration rate < 60 ml/min/1.73 m2 and left ventricular ejection fraction < 0.40 (HR: 6.53, 95% CI: 2.12-20.14). Cardiovascular mortality was significantly higher in the highest tertile after adjustment for age and sex (HR: 5.65, 95% CI: 1.94-16.47) and both in the first (HR: 4.90, 95% CI: 1.35-17.82) and second models of multivariate adjustment (HR: 5.89, 95% CI: 1.08-32.27). Conclusions: Elevated hs-cTnI levels measured in the stabilized phase after an ACS event are independent predictors of all-cause and cardiovascular mortality in a highly admixed population.

Resumo Fundamento: A troponina cardíaca de alta sensibilidade I (TnI-as) tem desempenhado um papel importante na estratificação de risco dos pacientes durante a fase intra-hospitalar da síndrome coronariana aguda (SCA), mas poucos estudos determinaram seu papel como marcador prognóstico de longo prazo no ambiente ambulatorial. Objetivo: Investigar a associação entre os níveis de TnI-as medidos na fase subaguda após um evento de SCA e o prognóstico a longo prazo, em uma população altamente miscigenada. Métodos: Medimos os níveis de TnI-as em 525 pacientes em um período de 25 a 90 dias após a entrada em hospital por um evento de SCA; esses pacientes foram então divididos em tercis conforme os níveis de TnI-as, e acompanhados por até 7 anos. Comparamos as mortalidades por todas as causas e cardiovascular através de modelos de riscos proporcionais de Cox e adotando um nível de significância de 5%. Resultados: Após um acompanhamento médio de 51 meses, os pacientes no tercil mais alto apresentaram uma taxa de risco (HR) maior para mortalidade por todas as causas, após ajustes para idade, sexo, fatores de risco cardiovascular conhecidos, uso de medicação e fatores demográficos (HR: 3,84 IC 95%: 1,92-8,12). Esses achados persistiram após um ajuste adicional para uma taxa de filtração glomerular (TFG) estimada < 60 ml/min/1,73 m2 e uma fração de ejeção do ventrículo esquerdo < 0,40 (HR: 6,53; IC95%: 2,12-20,14). A mortalidade cardiovascular foi significativamente maior no tercil mais alto, após ajustes para idade e sexo (RR: 5,65; IC95%: 1,94-16,47) e tanto no primeiro modelo de ajuste multivariado (HR: 4,90; IC 95%: 1,35-17,82) quanto no segundo (HR: 5,89; IC95%: 1,08-32,27). Conclusões: Níveis elevados de TnI-as, medidos na fase estabilizada após um evento de SCA, são preditores independentes de mortalidade por todas as causas e de mortalidade cardiovascular em uma população altamente miscigenada.