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There are several previous studies on the association of vitamin E with prevention of stroke but the findings remain controversial. We have conducted a systematic review, meta-analysis together with trial sequential analysis of randomised controlled trials to evaluate the effect of vitamin E supplementation versus placebo/no vitamin E on the risk reduction of total, fatal, non-fatal, haemorrhagic and ischaemic stroke. Relevant studies were identified by searching online databases through Medline, PubMed and Cochrane Central Register of Controlled Trials. A total of 18 studies with 148 016 participants were included in the analysis. There was no significant difference in the prevention of total stroke (RR (relative risk)=0.98, 95% CI 0.92–1.04, p=0.57), fatal stroke (RR=0.96, 95% CI 0.77–1.20, p=0.73) and non-fatal stroke (RR=0.96, 95% CI 0.88–1.05, p=0.35). Subgroup analyses were performed under each category (total stroke, fatal stroke and non-fatal stroke) and included the following subgroups (types of prevention, source and dosage of vitamin E and vitamin E alone vs control). The findings in all subgroup analyses were statistically insignificant. In stroke subtypes analysis, vitamin E showed significant risk reduction in ischaemic stroke (RR=0.92, 95% CI 0.85–0.99, p=0.04) but not in haemorrhagic stroke (RR=1.17, 95% CI 0.98–1.39, p=0.08). However, the trial sequential analysis demonstrated that more studies were needed to control random errors. Limitations of this study include the following: trials design may not have provided sufficient power to detect a change in stroke outcomes, participants may have had different lifestyles or health issues, there were a limited number of studies available for subgroup analysis, studies were mostly done in developed countries, and the total sample size for all included studies was insufficient to obtain a meaningful result from meta-analysis. In conclusion, there is still a lack of statistically significant evidence of the effects of vitamin E on the risk reduction of stroke. Nevertheless, vitamin E may offer some benefits in the prevention of ischaemic stroke and additional well-designed randomised controlled trials are needed to arrive at a definitive finding. PROSPERO registration number: CRD42020167827.

2,4,6-trihydroxy-3-geranylacetophenone (tHGA) is a bioactive compound that shows excellent anti-inflammatory properties. However, its pharmacokinetics and metabolism have yet to be evaluated. In this study, a sensitive LC-HRMS method was developed and validated to quantify tHGA in rat plasma. The method showed good linearity (0.5–80 ng/mL). The accuracy and precision were within 10%. Pharmacokinetic investigations were performed on three groups of six rats. The first two groups were given oral administrations of unformulated and liposome-encapsulated tHGA, respectively, while the third group received intraperitoneal administration of liposome-encapsulated tHGA. The maximum concentration (Cmax), the time required to reach Cmax (tmax), elimination half-life (t1/2) and area under curve (AUC0–24) values for intraperitoneal administration were 54.6 ng/mL, 1.5 h, 6.7 h, and 193.9 ng/mL·h, respectively. For the oral administration of unformulated and formulated tHGA, Cmax values were 5.4 and 14.5 ng/mL, tmax values were 0.25 h for both, t1/2 values were 6.9 and 6.6 h, and AUC0–24 values were 17.6 and 40.7 ng/mL·h, respectively. The liposomal formulation improved the relative oral bioavailability of tHGA from 9.1% to 21.0% which was a 2.3-fold increment. Further, a total of 12 metabolites were detected and structurally characterized. The metabolites were mainly products of oxidation and glucuronide conjugation.

Background: Atrial fibrillation (AF) is common after cardiac surgery and has been associated with poor outcome and increased resource utilization. The main objective of this study is to determine the incidence of POAF in Malaysia and identify the predictors of developing POAF. The secondary outcome of this study would be to investigate the difference in mortality and morbidity rates and the duration of intensive care unit (ICU), high dependency unit (HDU) and hospital stay between the two. Methods: This is a retrospective single-center, cross sectional study conducted at the National Heart Institute, Malaysia. Medical records of 637 who underwent coronary artery bypass grafting (CABG) surgery in 2015 were accrued. Pre-operative, operative and post-operative information were subsequently collected on a pre-formulated data collection sheet. Data were then analyzed using IBM SPSS v23. Results: The incidence of POAF in our study stands at 28.7% with a mean onset of 45±33 hours post operatively. Variables with independent association with POAF include advancing age, Indian population, history of chronic kidney disease, left ventricular ejection fraction and beta-blocker treatment. The mortality rate is significantly higher statistically (p < 0.05), and similarly the incidence of stroke. The incidence of other post-operative complications was also significantly higher statistically. The duration of ICU, HDU and hospital stays were statistically longer (p < 0.001) with higher rates of ICU readmissions and reintubations seen. Conclusion: We conclude that the incidence of POAF in Malaysia is comparable to the figures in Western countries, making POAF one of the most commonly encountered condition after CABG with similar higher rates of mortality, poor outcomes and longer duration of stay, and therefore increased cost of care. Strategies to reduce the incidence of AF after cardiac surgery should favorably affect surgical outcomes and reduce utilization of resources and thus lower cost of care.

Dual antiplatelet therapy of aspirin and clopidogrel is pivotal for patients undergoing percutaneous coronary intervention. However, the variable platelets reactivity response to clopidogrel may lead to outcome failure and recurrence of cardiovascular events. Although many genetic and nongenetic factors are known, great portion of clopidogrel variable platelets reactivity remain unexplained which challenges the personalization of clopidogrel therapy. Current methods for clopidogrel personalization include CYP2C19 genotyping, pharmacokinetics, and platelets function testing. However, these methods lack precise prediction of clopidogrel outcome, often leading to insufficient prediction. Pharmacometabolomics which is an approach to identify novel biomarkers of drug response or toxicity in biofluids has been investigated to predict drug response. The advantage of pharmacometabolomics is that it does not only predict the response but also provide extensive information on the metabolic pathways implicated with the response. Integrating pharmacogenetics with pharmacometabolomics can give insight on unknown genetic and nongenetic factors associated with the response. This review aimed to review the literature on factors associated with the variable platelets reactivity response to clopidogrel, as well as appraising current methods for the personalization of clopidogrel therapy. We also aimed to review the literature on using pharmacometabolomics approach to predict drug response, as well as discussing the plausibility of using it to predict clopidogrel outcome.

Background. The CYP2C19*2 allele may be associated with a reduced antiplatelet effect for clopidogrel. Here, we assessed whether CYP2C19*2 alleles correlate with clopidogrel responsiveness following the administration of clopidogrel in healthy Malaysian volunteers. Methods. Ninety volunteers were genotyped for CYP2C19*2 and CYP2C19*3 alleles. Forty-five of 90 volunteers were included in the clopidogrel response studies and triaged into three genotypes, namely, CYP2C19*1/*1 (n=17), CYP2C19*1/*2 (n=21), and CYP2C19*2/*2 (n=7). All subjects received 300 mg of clopidogrel, and platelet reactivity was assessed after a four-hour loading utilizing the VerifyNow-P2Y12 assay. Platelet activity was reported using P2Y12 reaction units (PRUs), and nonresponder status was prespecified at PRU ≥ 230. Results. Following clopidogrel intake, CYP2C19*2/*2 carriers had a significantly higher mean PRU compared to the CYP2C19*1/*2 and CYP2C19*1/*1 (291.0 ± 62.1 versus 232.5 ± 81.4 versus 147.4 ± 87.2 PRU, P

Background: One of the most common complications following coronary artery bypass grafting (CABG) surgery is atrial fibrillation (AF), which contributes towards increasing morbidity and mortality, length of hospital stay (LoHS) and reduced quality of life (QoL) of patients. Objectives: To determine whether the intake of Tocotrienol, a Vitamin E isomer derived from palm oil, before and immediately following CABG prevents AF, reduces LoHS, and improves the QoL of patients. Protocol: The study is registered with the National Medical Research Register with a trial number NMRR-17-1994-34963 and designed as a prospective, randomized controlled trial (RCT) with parallel groups. The experimental group will receive two 200mg Tocotrienol capsules each day, while the control group will receive two identical placebo (palm Super Olein) capsules per day. ECG readings will be used to detect AF post operatively, LoHS will be measured by checking the records from the National Heart Institute Hospital register, and the health-related Quality of Life (HRQoL) analysis (the Malay version of the Short Form 36 Questionnaire) will be used to analyse QoL. The sample size was calculated to be 140 in each arm of the RCT for a power of 0.8 and a significance level of 0.05. Funding: HOVID Berhad funds this research project. Expected outcomes: The primary endpoint is the development of postoperative AF, whilst the secondary endpoints are the LoHS and HRQoL of patients post CABG. Future implications: Prevention of AF and its complications such as cardiovascular or cerebrovascular events, especially stroke, is an important output. Malaysia is one of the biggest producers and exporters of palm oil and palm oil products. Thus, the possibility of marketing Tocotrienol, in reducing AF post CABG surgery, is a very important proposition indeed. Trial number: NMRR-17-1994-34963

Background: One of the most common complications following coronary artery bypass grafting (CABG) surgery is atrial fibrillation (AF), which contributes towards increasing morbidity and mortality, length of hospital stay (LoHS) and reduced quality of life (QoL) of patients. Objectives: To determine whether the intake of Tocotrienol, a Vitamin E isomer derived from palm oil, before and immediately following CABG prevents AF, reduces LoHS, and improves the QoL of patients. Protocol: The study is registered with the National Medical Research Register with a trial number NMRR-17-1994-34963 and designed as a prospective, randomized controlled trial (RCT) with parallel groups. The experimental group will receive two 200mg Tocotrienol capsules each day, while the control group will receive two identical placebo (palm Super Olein) capsules per day. ECG readings will be used to detect AF post operatively, LoHS will be measured by checking the records from the National Heart Institute Hospital register, and the health-related Quality of Life (HRQoL) analysis (the Malay version of the Short Form 36 Questionnaire) will be used to analyse QoL. The sample size was calculated to be 140 in each arm of the RCT for a power of 0.8 and a significance level of 0.05. Funding: HOVID Berhad funds this research project. Expected outcomes: The primary endpoint is the development of postoperative AF, whilst the secondary endpoints are the LoHS and HRQoL of patients post CABG. Future implications: Prevention of AF and its complications such as cardiovascular or cerebrovascular events, especially stroke, is an important output. Malaysia is one of the biggest producers and exporters of palm oil and palm oil products. Thus, the possibility of marketing Tocotrienol, in reducing AF post CABG surgery, is a very important proposition indeed. Trial number: NMRR-17-1994-34963

Background: One of the most common complications following coronary artery bypass grafting (CABG) surgery is atrial fibrillation (AF), which contributes towards increasing morbidity and mortality, length of hospital stay (LoHS) and reduced quality of life (QoL) of patients. Objectives: To determine whether the intake of Tocotrienol, a Vitamin E isomer derived from palm oil, before and immediately following CABG prevents AF, reduces LoHS, and improves the QoL of patients. Protocol: The study is registered with the National Medical Research Register with a trial number NMRR-17-1994-34963 and designed as a prospective, randomized controlled trial (RCT) with parallel groups. The experimental group will receive two 200mg Tocotrienol capsules each day, while the control group will receive two identical placebo (palm Super Olein) capsules per day. ECG readings will be used to detect AF post operatively, LoHS will be measured by checking the records from the National Heart Institute Hospital register, and the health-related Quality of Life (HRQoL) analysis (the Malay version of the Short Form 36 Questionnaire) will be used to analyse QoL. The sample size was calculated to be 140 in each arm of the RCT for a power of 0.8 and a significance level of 0.05. Funding: HOVID Berhad funds this research project. Expected outcomes: The primary endpoint is the development of postoperative AF, whilst the secondary endpoints are the LoHS and HRQoL of patients post CABG. Future implications: Prevention of AF and its complications such as cardiovascular or cerebrovascular events, especially stroke, is an important output. Malaysia is one of the biggest producers and exporters of palm oil and palm oil products. Thus, the possibility of marketing Tocotrienol, in reducing AF post CABG surgery, is a very important proposition indeed. Trial number: NMRR-17-1994-34963

Background: Atrial fibrillation (AF) is common after cardiac surgery and has been associated with poor outcome and increased resource utilization. The main objective of this study is to determine the incidence of POAF in Malaysia and identify the predictors of developing POAF. The secondary outcome of this study would be to investigate the difference in mortality and morbidity rates and the duration of intensive care unit (ICU), high dependency unit (HDU) and hospital stay between the two. Methods: This is a retrospective single-center, cross sectional study conducted at the National Heart Institute, Malaysia. Medical records of 637 who underwent coronary artery bypass grafting (CABG) surgery in 2015 were accrued. Pre-operative, operative and post-operative information were subsequently collected on a pre-formulated data collection sheet. Data were then analyzed using IBM SPSS v23. Results: The incidence of POAF in our study stands at 28.7% with a mean onset of 45±33 hours post operatively. Variables with independent association with POAF include advancing age, Indian population, history of chronic kidney disease, left ventricular ejection fraction and beta-blocker treatment. The mortality rate is significantly higher statistically ( p < 0.05), and similarly the incidence of stroke. The incidence of other post-operative complications was also significantly higher statistically. The duration of ICU, HDU and hospital stays were statistically longer ( p < 0.001) with higher rates of ICU readmissions and reintubations seen. Conclusion: We conclude that the incidence of POAF in Malaysia is comparable to the figures in Western countries, making POAF one of the most commonly encountered condition after CABG with similar higher rates of mortality, poor outcomes and longer duration of stay, and therefore increased cost of care. Strategies to reduce the incidence of AF after cardiac surgery should favorably affect surgical outcomes and reduce utilization of resources and thus lower cost of care.

Aim: nlmixr offers first‐order conditional estimation (FOCE), FOCE with interaction (FOCEi) and stochastic approximation estimation‐maximisation (SAEM) to fit nonlinear mixed‐effect models (NLMEM). We modelled metformin's pharmacokinetic data using nlmixr and investigated SAEM and FOCEi's performance with respect to bias and precision of parameter estimates, and robustness to initial estimates. Method: Compartmental models were fitted. The final model was determined based on the objective function value and inspection of goodness‐of‐fit plots. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re‐estimated as the initial estimates were perturbed 100 times and resultant changes evaluated. Results: The absorption kinetics of metformin depend significantly on food status. Under the fasted state, the first‐order absorption into the central compartment was preceded by zero‐order infusion into the depot compartment, whereas for the fed state, the absorption into the depot was instantaneous followed by first‐order absorption from depot into the central compartment. The means of relative mean estimation error (rMEE) (MEESAEMMEEFOCEi) and rRMSE (RMSESAEMRMSEFOCEi) were 0.48 and 0.35, respectively. All parameter estimates given by SAEM appeared to be narrowly distributed and were close to the true value used for simulation. In contrast, the distribution of estimates from FOCEi were skewed and more biased. When initial estimates were perturbed, FOCEi estimates were more biased and imprecise. Discussion: nlmixr is reliable for NLMEM. SAEM was superior to FOCEi in terms of bias and precision, and more robust against initial estimate perturbations. [ABSTRACT FROM AUTHOR]