Lipid-Lowering Efficacy of Ezetimibe in Patients with Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analyses

Patients with atherosclerotic cardiovascular disease (ASCVD), especially those with recent (< 1 year) acute coronary syndrome (ACS), are at high risk for recurrent cardiovascular events. This risk can be reduced by lowering low-density lipoprotein cholesterol (LDL-C) levels. A comprehensive meta-analysis on the LDL-C-lowering efficacy of ezetimibe is lacking. This study attempts to address this gap. A systematic literature review of randomized controlled trials evaluating the LDL-C-lowering efficacy of ezetimibe in the ASCVD population was conducted. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for publications from database inception to August 2018 and for conference abstracts from 2015 to August 2018. Meta-analyses were conducted to evaluate the LDL-C-lowering efficacy of ezetimibe in the ASCVD population and the recent ACS subgroup. In total, 12 studies were eligible for the meta-analyses. Treatment with combination ezetimibe plus statin therapy showed greater absolute LDL-C reduction than statin monotherapy (mean difference − 21.86 mg/dL; 95% confidence interval [CI] − 26.56 to − 17.17; p < 0.0001) after 6 months of treatment (or at a timepoint closest to 6 months). Similarly, in patients with recent ACS, combination ezetimibe plus statin therapy was favorable compared with statin monotherapy (mean treatment difference − 19.19 mg/dL; 95% CI − 25.22 to − 13.16; p < 0.0001). Ezetimibe, when added to statin therapy, provided a modest additional reduction in LDL-C compared with statin monotherapy. However, this may not be sufficient for some patients with ASCVD who have especially high LDL-C levels despite optimal statin therapy.     

Physicians' perceptions and beliefs on the current dyslipidemia management practices within Saudi Arabia

BackgroundLimited reports addressing physicians’ understanding of the various low-density lipoprotein cholesterol (LDL-C) targets/statin intensity required for treating the various dyslipidemia patient populations in Saudi Arabia are available. Therefore, the current study assessed the perceptions and beliefs of practicing clinicians in Saudi Arabia regarding the current practice for management of dyslipidemia and potential perceived barriers to adherence to lipid guidelines encountered in their regular clinical practice. Knowledge of different clinical practices and beliefs could have a positive impact on improving the quality of future care provided by physicians.MethodsA survey questionnaire was designed to assess physicians’ familiarity, usage, and adherence to seven different international guidelines and used to evaluate the management of dyslipidemia, practice of patient treatment, and perceived obstacles to adhering to lipid guidelines related to specific patients, doctors, and practice issues.ResultsA total of 467 physicians were recruited for the study: (1) 57.2% were primary care physicians (PCPs) and (2) 42.8% were specialists. About 90.8% of them followed lipid guidelines of which the most common set were based on those by the American College of Cardiology/American Heart Association. The most utilized risk assessment tool was the atherosclerotic cardiovascular disease (ASCVD) risk calculator. About 60% of the physicians set an LDL-C target for their patients based on a combination of patients’ risk factors and lipid profiles. In all, 42.1% of the physicians chose not to change existing therapy among patients with dyslipidemia to attain a non-high-density lipoprotein goal with controlled LDL-C level. Atorvastatin accounted for the greatest percentage of primary and secondary prevention choices (71.9% and 69.6%, respectively). Rosuvastatin was mostly preferred by physicians for patients with familial hypercholesterolemia. About two-thirds of the physicians (77.9%) prescribed statins to diabetic patients aged 40–75 years. Statin intolerance was encountered by 62.9% of the physicians in ≤ 10% of patients by 62.9%. Therapeutic strategies included switching to an alternative statin (40.1%) followed by reducing the statin dose (35.3%). Ezetimibe was prescribed by most physicians (77.9%) as an add-on to statin if the LDL-C target was not achieved. Fibrate was most preferred by physicians (62.7%) for hypertriglyceremia treatment followed by statins (28.7% of the physicians). Sixty-six percent reported not using proprotein convertase subtilisin/kexin type 9 serine protease inhibitors in their clinical practice due to unavailability at their institute (51.8%), high costs (26.3%), and/or lack of knowledge (20.6%). Perceived barriers to guideline adherence identified by physicians were lack of familiarity and knowledge of the guidelines, patient non-adherence, medication costs, and lack of timely follow-up appointments and educational tools. Multiple similarities and differences were observed after comparisons were made between specialists and PCPs in terms of guideline preference, clinical practice, and perceived barriers.ConclusionDifferent perceptions and attitudes among physicians in Saudi Arabia were found due to variable recommendations by international lipid guidelines. Perceived barriers that included the patient, physician, and practice were identified by physicians at multiple levels. Multiple challenges and different action gaps were observed when comparing specialists to PCPs. It is recommended that standardized practices be followed by clinicians in Saudi Arabia, and actions to address the outlined barriers are essential for optimizing health outcomes and ASCVD prevention.     

Protective Effect of Coenzyme Q10-loaded Liposomes on the Myocardium in Rabbits with an Acute Experimental Myocardial Infarction

Purpose We assessed whether the infusion of Coenzyme Q10-loaded liposomes (CoQ10-L) in rabbits with an experimental myocardial infarction can result in increased intracellular delivery of CoQ10 and thus limit the fraction of the irreversibly damaged myocardium. Methods CoQ10-L, empty liposomes (EL), or Krebs–Henseleit (KH) buffer were administered by intracoronary infusion, followed by 30 min of occlusion and 3 h of reperfusion. Unisperse Blue dye was used to demarcate the net size of the occlusion-induced ischemic zone (“area at risk”) while nitroblue tetrazolium staining was used to detect the final fraction of the irreversibly damaged myocardium within the total area at risk. Results The total size of the area at risk in all experimental animals was approx. 20% wt. of the left ventricle (LV). The final irreversible damage in CoQ10-L-treated animals was only ca. 30% of the total area at risk as compared with ca. 60% in the group treated with EL (p < 0.006) and ca. 70% in the KH buffer-treated group (p < 0.001). Conclusions CoQ10-L effectively protected the ischemic heart muscle by enhancing the intracellular delivery of CoQ10 in hypoxic cardiocytes in rabbits with an experimental myocardial infarction as evidenced by a significantly decreased fraction of the irreversibly damaged heart within the total area at risk. CoQ10-L may provide an effective exogenous source of the CoQ10 in vivo to protect ischemic cells     

Clinical implications of the IMPROVE-IT trial in the light of current and future lipid-lowering treatment options

Introduction: A residual risk of morbidity and mortality from cardiovascular (CV) disease remains despite statin therapy. This situation has generated an interest in finding novel approaches of combining statins with other lipid-lowering agents, or finding new lipid and non-lipid targets, such as triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, cholesterol ester transfer protein (CETP), lipoprotein (a), fibrinogen or C-reactive protein. Areas covered: The recent results from the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated an incremental clinical benefit when ezetimibe, a non-statin agent, was added to simvastatin therapy. Expert opinion: The results from IMPROVE-IT revalidated the concept that low-density lipoprotein cholesterol (LDL-C) levels are a clinically relevant treatment goal. This trial also suggested that further decrease of LDL-C levels (53 vs. 70 mg/dl; 1.4 vs. 1.8 mmol/l) was more beneficial in lowering CV events. This “even lower is even better” evidence for LDL-C levels may influence future guidelines and the use of new drugs. Furthermore, these findings make ezetimibe a more realistic option to treat patients with statin intolerance or those who cannot achieve LDL-C targets with statin monotherapy.     

The Use of BDDCS in Classifying the Permeability of Marketed Drugs

We recommend that regulatory agencies add the extent of drug metabolism (i.e., ≥ 90% metabolized) as an alternate method in defining Class 1 marketed drugs suitable for a waiver of in vivo studies of bioequivalence. That is, ≥ 90% metabolized is an additional methodology that may be substituted for ≥ 90% absorbed. We propose that the following criteria be used to define ≥ 90% metabolized for marketed drugs: Following a single oral dose to humans, administered at the highest dose strength, mass balance of the Phase 1 oxidative and Phase 2 conjugative drug metabolites in the urine and feces, measured either as unlabeled, radioactive labeled or nonradioactive labeled substances, account for ≥ 90% of the drug dosed. This is the strictest definition for a waiver based on metabolism. For an orally administered drug to be ≥ 90% metabolized by Phase 1 oxidative and Phase 2 conjugative processes, it is obvious that the drug must be absorbed. This proposal, which strictly conforms to the present ≥ 90% criteria, is a suggested modification to facilitate a number of marketed drugs being appropriately assigned to Class 1. Opinions expressed in this report are those of the authors. For those authors affiliated with regulatory agencies (DMB & LXY) the opinions do not necessarily reflect the views or policies of the regulatory agencies.     

Effect of Atorvastatin Versus Rosuvastatin on Levels of Serum Lipids,Inflammatory Markers and Adiponectin in Patients with Hypercholesterolemia

Purpose  To compare the short-term effect of treatment with atorvastatin and rosuvastatin on levels of serum lipids, inflammatory markers and adiponectin in patients with hypercholesterolemia. Methods  Sixty-nine patients with hypercholesterolemia were randomly assigned to receive 10 mg/day of atorvastatin or rosuvastatin for 12 weeks. Inflammatory biomarkers, including highsensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-alpha, matrix metalloproteinase-9 (MMP-9), and endothelin (ET-1), plasminogen activator inhibitor type 1 (PAI-1) and plasma tissue plasminogen activator (tPA), adiponectin, and lipid profiles were measured before and after statin therapy. Results  Atorvastatin and rosuvastatin both lowered levels of hs-CRP, MMP-9, PAI-1, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) from baseline values, with rosuvastatin lowering TC and LDL-C to a greater extent than atorvastatin (P < 0.05). Adiponectin level increase was 15% higher than that at baseline with atorvastatin (P > 0.05) but 67% higher with rosuvastatin (P < 0.05). Conclusions  Therapy with both statins not only significantly improved lipid profiles but also decreased levels of vascular biomarkers hs-CRP, MMP-9, and PAI-1; however, only rosuvastatin increased serum adiponectin levels significantly in patients with hypercholesterolemia, which could imply a beneficial effect in coronary artery disease.     

Effect of verapamil on tachycardia-induced early cellular electrical remodeling in rabbit atrium

We investigated the effects of a 7-day verapamil pretreatment (VPT, 7.5 mg/kg bodyweight subcutaneously every 12 h) on ionic currents and molecular mechanisms underlying tachycardia-induced early electrical remodeling after 24-h rapid atrial pacing (RAP, 600 bpm) in rabbit atrium. Animals were divided into four groups (n = 6 each group): control (not paced, no verapamil), paced only, verapamil only and verapamil and paced, respectively. VPT doubled ICa,L [7.0 ± 0.7 pA/pF (control) vs 14.2 ± 0.6 pA/pF (verapamil only)]. RAP reduced ICa,L by 48% to 3.6 ± 0.7 pA/pF (paced only). RAP did not affect ICa,L in verapamil-treated animals and averaged 15.3 ± 0.2 pA/pF (paced and verapamil). RAP resulted in a significant decrease of the expression of the α1c subunit (−24.7%) and the β2A subunit (−13.3%), respectively. VPT led to a similar alteration of subunit expression as RAP [“control” vs “verapamil only”, decrease of α1c subunit (−25.4%), but no significant change in β2A subunit expression]. However, after VPT, further diminishment of α1c and β2A subunit expression after rapid atrial pacing was absent. (“verapamil” vs “verapamil and paced”, n = 6 both groups). RAP decreased Ito [−45%, 51.5 ± 3.9 pA/pF (control) vs 26.8 ± 1.5 pA/pF (paced only)] and was not influenceable by VPT. IK1 was neither affected by RAP nor verapamil pretreatment. Downregulation of α1c and β2A subunit expression and the resulting decay of ICa,L current densities were prevented by verapamil. However, these effects are abolished by multiple other adverse effects of verapamil on atrial electrophysiology.     

从传统他汀及其联合治疗看调脂治疗的临床获益

摘要： 动脉粥样硬化性心血管疾病 （ASCVD） 是全球范围内主要的疾病负担, 亦是患者死亡的主要原因。既往大量关于他汀类药物调脂治疗的临床试验证实, 他汀类药物可有效降低 ASCVD 患者低密度脂蛋白胆固醇 （LDL-C） 水平、 全因死亡率和心血管病死亡率, 无 ASCVD 的患者亦可获益。然而, 目前无论是 ASCVD 高危患者还是无 ASCVD 的人群, 并未广泛应用降脂治疗。因此, 本文阐述了他汀类及其联合用药所带来的临床获益, 旨在增大受益人群, 改善预后。     

Sequential screening for diabetes—evaluation of a campaign in Swiss community pharmacies

Objective For early detection of persons at risk for type 2 diabetes, a combination of risk factor assessment and glucose measurement could be a promising approach and an opportunity for health promotion. The object of this study was to develop a sequential screening concept and to evaluate it in a national pharmacy based screening campaign.Method Community pharmacies of the German speaking part of Switzerland participating in the national Self Care campaign “Stop diabetes-test now” offered a free of charge “sequential screening” with (a) diabetes risk assessment, (b) consecutive capillary blood glucose measurement and (c) assessment of the motivation for lifestyle change based on the Transtheoretical Model (TTM) of behaviour change. A 35 items data sheet served as a structured screening protocol and enabled quick and reliable documentation of all relevant data. Outcomes measures were: age, sex, cigarette smoking, total score of the ADA diabetes risk-factor questionnaire, family history of diabetes, body mass index, insufficient physical activity, blood pressure, capillary blood glucose, motivation for lifestyle change, counselling activities and triage decisions of the pharmacy team.Results During the 5 weeks of spring 2002, 530 pharmacies screened a total of 93,258 persons (33.1% male, mean age 60.9 years ± 14.1 (SD)). Risk profile: family history of diabetes 26.4%; BMI ≥ 25 kg/m² 49.3%; low physical activity 27.2%; elevated blood pressure 45.7%. Stratification into risk groups: < 2 risk factors 21.6%; ≥ 2 risk factors 71.5%; borderline glycaemia (FG 5.3–6.1 mmol/l, confirmed in a second measurement) 2.5% and hyperglycaemia (FG ≥ 6.1 mmol/1 or NFG ≥ 11.1 mmol/1) 4.4%.Of all persons screened, 6.4% were referred to a physician and 73.7% got targeted advice with respect to physical activity and/or nutrition based on their specific risk profile.Conclusion The screening campaign attracted an important part of Swiss German speaking adults (2.4%). The sequential screening could successfully be implemented into pharmacy practice. Of the generally elderly persons screened, 6.9% were detected with suspicion for diabetes type 2 and 71.5% had at least two risk factors. This provided an opportunity to initiate targeted counselling regarding therapeutic lifestyle change.     

The Role of Cohort Studies in Drug Development: Clinical Evidence of Antiviral Activity of Serotonin Reuptake Inhibitors and HMG-CoA Reductase Inhibitors in the Central Nervous System

Background Effective antiretroviral therapy (ART) has reduced the incidence of HIV-associated neurocognitive impairment (HNCI) but its prevalence remains high. Clinical trials have yet to identify a consistently effective treatment for HNCI, other than ART, but in vitro data support that some drugs approved by the Food and Drug Administration (FDA) for other indications might benefit individuals with HNCI. Some of these drugs, such as serotonin reuptake inhibitors (SRIs) and HMG-CoA reductase inhibitors (statins), may do so by reducing HIV replication in the CNS and are already widely used by HIV-infected individuals. Methods Six-hundred fifty-eight HIV-infected participants of the CHARTER cohort had a baseline assessment, which included comprehensive neuropsychological (NP) testing and HIV RNA measurements in plasma and cerebrospinal fluid (CSF). Four-hundred sixty-seven (71%) subjects used ART, 195 (30%) used SRIs, and 63 (10%) used statins. Results SRI users were less likely to have HIV RNA levels in CSF above 50 copies (c)/mL (29 vs. 37% in non-SRI users, OR 0.69, p = 0.05). This association was most evident for three of the seven SRIs (citalopram, sertraline, and trazodone, or “antiviral” SRIs, combined 25 vs. 38% in non-SRI users, OR 0.56, p = 0.01) and was strongest in those not taking concomitant ART (61 vs. 83%, OR 0.31, p = 0.01). “Antiviral” SRI users also performed better on NP tests (median global deficit score 0.37 vs. 0.47, p = 0.04). Statin users were also less likely to have HIV RNA levels in CSF above 50 c/mL (16 vs. 37%, p < 0.001) but, in contrast to SRIs, the association was strongest in those taking ART (2 vs. 18%, p < 0.001). Statin use was not associated with better NP performance. Multivariate analyses indicated that the use of “antiviral” SRIs—but not statins—was associated with undetectable HIV RNA levels in CSF and better NP performance. Conclusions SRIs may reduce HIV replication in CSF and improve NP performance. This was particularly true for three SRIs—supporting differences in antiviral efficacy between drugs—in individuals who were not taking ART. In contrast, statins were not associated with lower HIV replication in CSF in multivariate analyses and were not associated with better NP performance. These analyses support the value of large observational cohort studies in identifying FDA-approved drugs that may be worth further investigation.     

Patterns of practice for acute myocardial infarction in a population from ten countries

Background: There is conclusive evidence from large scale randomized clinical trials (RCTs) that several treatments administered in the acute phase of a myocardial infarction (AMI) reduce mortality. However, only a minority of patients admitted with AMI receives at the appropriate treatments. Objectives: This study aims at (1) describe the utilization patterns for AMI; (2) determine the appropriateness of prescribing, measured as adherence to the ACC/AHA guidelines; and (3) determine which factors are associated with the administration of thrombolytic agents. Methods: The study was a multi-center survey carried out in ten countries (nine European and one Canadian province) over a 3-month period. Data were prospectively collected by clinical pharmacists. All consecutive patients admitted to the participating hospitals during the study period with a diagnosis of suspected AMI were included in the study. Rates of use were calculated as “overall utilization” and “adjusted utilization” (e.g., accounting for eligibility). Results: Data were available on 1976 patients from 56 participating centers. The mean age of the patients was 65 years (range 25–95, SD = 12.6) and 29.7% were women. Adjusted utilization rates were 63.7% for thrombolysis, 88% for aspirin, and 65.9% for β-adrenergic blocking agents. The most utilized thrombolytic agent was streptokinase (65.9%). The main reasons given by physicians for not administering thrombolysis was the delay from chest pain onset to admission. Patients admitted to teaching hospitals were less likely to receive aspirin than patients admitted to general hospitals (adjusted rate 90.1% vs 86%, P = 0.007), but they were more likely to undergo a primary invasive procedure (11.0% vs 2.5% P = 0.001). Multivariate analysis showed that age greater than 74 years, delay, prior myocardial infarction, and Killip scale were correlated with the non-utilization of thrombolysis. Conclusion: Recommended treatments are still underutilized in patients with AMI. Increased utilization is required, particularly for elderly people. There is a wide variability among hospitals with different affiliations (teaching vs non teaching), demonstrating the different patterns of practice in various settings. Received: 2 February 1998 / Accepted in revised form: 8 August 1998     

Quetiapine augmentation of paroxetine CR for the treatment of refractory generalized anxiety disorder: preliminary findings

Rationale More data are needed to guide “next step” strategies for patients with generalized anxiety disorder (GAD) remaining symptomatic despite initial pharmacotherapy. Objective This study prospectively examined the relative efficacy of quetiapine versus placebo augmentation for individuals with GAD remaining symptomatic with initial paroxetine CR pharmacotherapy. Materials and methods Adult outpatients with GAD were recruited from 2004 to 2007 at two academic centers. Phase 1 consisted of 10 weeks of open-label paroxetine CR flexibly dosed to a maximum of 62.5 mg/day. Those remaining symptomatic (Hamilton Anxiety Scale [HAM-A] ≥ 7) at week 10 were randomized to quetiapine or placebo augmentation flexibly dosed from 25 to 400 mg/day. Results For participants receiving paroxetine CR (n = 50), there was a significant reduction in HAM-A scores (baseline mean ± SD = 22.4 ± 4.2 to endpoint mean ± SD = 11.2 ± 6.9; paired t = 12.1, df = 49, t < 0.0001) with 40% (n = 20) achieving remission. Counter to our hypothesis, we did not find significant benefit for quetiapine augmentation of continued paroxetine CR (HAM-A reduction mean ± SD = 2.6 ± 5.8 points quetiapine, 0.3 ± 5.5 points placebo; t = 0.98, df = 20, p = n.s.) in the randomized sample (n = 22) with relatively minimal additional improvement overall in phase 2. Conclusions Although conclusions are considered preliminary based on the relatively small sample size, our data do not support the addition of quetiapine to continued paroxetine CR for individuals with GAD who remain symptomatic after 10 weeks of prospective antidepressant pharmacotherapy and suggest that further research examining strategies for GAD refractory to antidepressants is needed.     

Baseline,delta, and achieved low-density lipoprotein cholesterol levels and cardiovascular risk in patients on statin therapy: A post-hoc resampling mediation analysis of treating new targets [TNT] trial

Clinical guidelines for monitoring low-density lipoprotein cholesterol (LDL-C) after statin therapy do not clearly define the clinical roles of baseline LDL-C, ΔLDL-C, and achieved LDL-C according to statin intensity. We performed post-hoc analysis of the Treating to New Target (TNT) study to evaluate individual LDL-C parameters after statin therapy. Primary outcome was the risk for total major adverse cardiovascular events (MACE). We use resampling multilevel mediation analysis to analyze complex relationships among LDL-C parameters based on similar statin intensities. Tertiles for resample A (matched baseline LDL-C; distinct achieved LDL), resample B (matched ΔLDL-C; distinct baseline LDL-C), and resample C (matched achieved LDL-C; distinct ΔLDL-C) were analyzed using Cox proportional hazard ratios. In original data analysis, the incidence of MACE was reduced in those with lower achieved LDL-C in total, low, and high intensity statin users (hazard ratios [HRs] = 0.990, 0.992, 0.992; respectively; all P-values < .001). In mediation analysis, resample A showed consistently high incidence for MACE in the middle tertile (HR = 1.237; 95% confidential interval [CI] = 1.008-1.517; P-value = .041) and highest tertile (HR = 1.275; 95% CI = 1.021-1.592; P-value = .032) compared to the lowest tertile. However, resamples B and C did not show consistent differences. Similarly, no consistent statistical difference in MACE according to statin intensity. Lower achieved LDL-C decreased MACE in participants with a similar baseline LDL-C after statin therapy. However, the change in absolute values of ΔLDL-C and achieved LDL-C should be interpreted in an individualized manner due to their complex collinearity, and statin intensity should also be taken into consideration.     

The efficacy of statin monotherapy uptitration versus switching to ezetimibe/simvastatin: results of the EASEGO study

ABSTRACT

Objective: To assess the incremental low-density lipoprotein-cholesterol (LDL-C) lowering efficacy of doubling the statin dose or switching to the ezetimibe/simvastatin 10/20?mg combination tablet (EZE/SIMVA) in patients on simvastatin 20?mg or atorvastatin 10?mg not at LDL-C target < 2.5?mmol/L.

Study design and methods: Patients with documented coronary heart disease (CHD) and/or type 2 diabetes (DM2) with LDL-C ≥ 2.5 and < 5.0?mmol/L despite treatment with atorvastatin 10?mg or simvastatin 20?mg were randomized to (1) double statin dose or (2) switch to ezetimibe/simvastatin 10/20, according to a PROBE study design. LDL-C, lipoprotein subfractions and safety data were assessed during the study.

Results: 119 of 178 (67%) patients in the EZE/SIMVA group and 49 of 189 (26%) in the doubling statin group reached target LDL-C < 2.5?mmol/L. The odds ratio of success for EZE/SIMVA versus doubling statin treatment in reaching the LDL-C target of < 2.5?mmol/L was 5.7 (95% CI: 3.7–9.0, p < 0.0001). A reduction in total cholesterol (TC), total/high density lipoprotein (HDL) cholesterol ratio and apolipoprotein B was observed in both groups, but this reduction was significantly more pronounced in the EZE/SIMVA group as compared with the doubling statin dose group. Treatment was well tolerated and no difference was observed between the two groups with regard to adverse effects.

Conclusions: In CHD/DM2 patients treated with simvastatin or atorvastatin with LDL-C persistently ≥ 2.5?mmol/L, switching to the EZE/SIMVA was more effective in attaining the LDL-C target of < 2.5?mmol/L than doubling the statin dose.     

Assessment of micafungin loading dosage regimens against Candida spp. in ICU patients by Monte Carlo simulations

To assess the efficacy of loading dose on micafungin by simulating different dosage regimens. A published study of micafungin in ICU patients was employed to simulate nine different dosage regimens which were sorted out three groups in terms of three maintenance doses. Using pharmacokinetic parameters and pharmacodynamic data, 5000-subject Monte Carlo simulations were conducted to simulate concentration-time profiles of micafungin, calculate probabilities of target attainment (PTAs), and cumulative fractions of response (CFRs) in terms of AUC/MIC targets. PTAs were calculated using AUC/MIC cut-offs: 285 (Candida parapsilosis), 3000 (all Candida spp.), and 5000 (non-parapsilosis Candida spp.). PTA or CFR > 90% was considered optimal for a dosage regimen. The concentration-time profiles of micafungin-simulated dosage regimens were obtained. PTA values were over 90% while applying the loading dose in each group of regimens: for Candida albicans and Candida glabrata (AUC/MIC = 5000), all regimens with loading dose provided PTAs of ≥ 90% for MIC ≤ 0.008 mg/L. The PTAs (AUC/MIC = 3000) were over 90% for MIC ≤ 0.008 mg/L in any regimen. However, for MIC inferior to 0.016 mg/L, only loading dosage regimens provided PTAs exceeding 90%. For C. parapsilosis (AUC/MIC = 285), the maximum MIC of achieving a PTA ≥ 90% was 0.25 mg/L both in the regimens of B (150 mg maintenance dose) and C (200 mg maintenance dose) with loading dose. In addition, CFR of any regimen with loading dose was ≥ 90% against C. albicans and C. glabrata. None of the dosage regimens achieved an expected CFR against C. parapsilosis. The dosage regimen of micafungin which had a loading dose of 1.5 times was more suitable for ICU patients infected by Candida spp.     

贝派地酸在血脂异常和他汀类药物不耐受患者中的应用进展

血浆低密度脂蛋白胆固醇（low-density lipoprotein cholesterol,LDL-C）升高是公认的动脉粥样硬化性心血管疾病（atherosclerotic cardiovascular disease,ACSVD）的危险因素之一。目前用于治疗高LDL-C血症的主要药物为他汀类药物,其他可选药物包括依折麦布和前蛋白转化酶枯草杆菌蛋白酶9抑制剂（inhibitors of proprotein convertase subtilisin/kexin type 9,i-PSCK9）等。这些可选药物使众多因LDL-C升高而面临ACSVD风险的患者受益,但仍有约10%的ACSVD高危患者因对他汀类药物不耐受,血浆LDL-C水平无法最终达标而持续面临ACSVD风险。贝派地酸（ETC-1002）是一种以ATP柠檬酸裂解酶（ATP citrate lyase,ACL）为靶点的新型胆固醇合成抑制剂,目前研究表明其有中等强度的降低胆固醇作用。同时,该药只在肝脏中转化为活性形式,没有肌肉相关副作用,可以作为他汀类药物不耐受患者新的降脂治疗选择。本文讨论了贝派地酸在血脂异常和他汀类药物不耐受患者中的应用进展,主要从贝派地酸的作用机制、药动学、有效性、安全性以及耐受性等几个方面进行阐述。     

Association of MDR1 genotypes with susceptibility to colorectal cancer in older non-smokers

Objective The multidrug resistance gene 1 (MDR1) seems to play a role in the carcinogenesis of colorectal tumors. The importance of MDR1 SNPs 2677G > T/A in exon 21 and 3435C > T in exon 26 for cancer susceptibility, however, has not yet been clearly defined. Methods Two hundred and eighty-five colorectal cancer patients and 275 controls from five hospitals in the European part of Russia were genotyped for the polymorphisms −129T > C (rs3213619) in exon 1b, 2677G > T/A (rs2032582), and 3435C > T (rs1045642) in this population-based case-control study. Genotype-phenotype analysis was performed with simultaneous consideration of lifestyle risk factors. Results Our analysis confirmed the preponderate impact of smoking on colorectal cancer development. The risk of heavy smokers (≥60 pack years) to develop colorectal cancer by far exceeded that of lifelong non-smokers (OR = 3.9, 95% CI: 1.4 to 10.6). Smoking is a more potent risk factor than is the genetic influence of MDR1 in our study. However, a smoking and age-stratified analysis, revealed a statistically significant association between MDR1 genotypes and colorectal cancer in life-long non-smokers with an age ≥63 years (the median age in our sample). The association was stronger for rectal cancer than for colon cancer. Patients who carried the genotypes (−129TT; 2677GG; 3435CC) or (−129TT; 2677TT; 3435TT) developed more frequently colorectal cancer than others (OR = 3.9; 95% CI: 2.0 to 7.7). Conclusions Our results show that the interaction of genetic and lifestyle risk factors should be taken into account to elucidate the genetic influence of MDR1 variability on cancer susceptibility.     

Drug Delivery to the Skin From Sub-micron Polymeric Particle Formulations: Influence of Particle Size and Polymer Hydrophobicity

Purpose  To investigate the influence of particle size and polymer properties on the topical delivery of a lipophilic “active” species (Nile Red (NR)) from sub-micron polymeric particles. Methods  Three poly-(ε-caprolactone) (CAPA) formulations were examined to assess the impact of particle size. Three other formulations, based on cellulose acetate butyrate (CAB), CAPA and polystyrene were studied to address the role of polymer hydrophobicity. In vitro skin permeation, and confocal microscopy and stratum corneum (SC) tape-stripping were used to evaluate the cutaneous disposition of NR. Results  NR delivery into the SC was greater from the larger particles, the overall smaller surface area of which enhanced the “leaving tendency” of the lipophilic “active”. Skin uptake of NR (measured as “%payload released”) from polystyrene, CAPA and CAB particles increased with decreasing polymer hydrophobicity (polystyrene > CAPA > CAB) as expected. Confocal microscopy revealed that NR released from the particles accumulated in, and penetrated via, lipid domains between the SC corneocytes. The particles showed affinity for hairs, and concentrated on the skin surface at the follicular openings. Conclusions  Delivery of a model drug to the skin from sub-micron polymeric particle formulations is sensitive to the particle size and the relative hydrophobicity of the carrier.