The influence of body size on the pharmacodynamic and pharmacokinetic response to clopidogrel and prasugrel: A retrospective analysis of the FEATHER study

Introduction

Patients treated with clopidogrel who have higher body size exhibit greater platelet reactivity than patients with lower body size. In a retrospective analysis of the FEATHER trial, we examined the relationship between platelet response to thienopyridines clopidogrel 75 mg (Clop-75), prasugrel 5 mg (Pras-5), and prasugrel 10 mg (Pras-10) using 3 body size indices: body weight (BW), body mass index (BMI), and body surface area (BSA). Relationships were assessed as continuous variables and as 4 incremental body size groups.

Materials and Methods

Aspirin-treated patients with stable coronary artery disease (N = 72) and a BW range of 45-134 kg received Clop-75, Pras-5, and Pras-10 in a 3-period, blinded, cross-over study. Platelet assays included maximum platelet aggregation (MPA) to 20 μM ADP by light transmission aggregometry, VerifyNow-P2Y12 reaction units (PRU), and vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). Exposure to active metabolites (AMs) was also assessed.

Results

Body size was a determinant of AM exposure and residual platelet reactivity regardless of type and dose of thienopyridine. BW and BSA demonstrated marginally stronger correlations with platelet reactivity; VASP-PRI demonstrated a stronger correlation with the body size than the other tests. Correlation coefficients ranged from a high of 0.64 (BW vs. PRI on Pras-5) to a low of 0.34 (BMI vs. MPA on Pras-10), but all were statistically significant (p < 0.01).

Conclusions

Using a comprehensive selection of body size indices, AM exposures, platelet function tests, and thienopyridine doses, we demonstrated a consistent inverse relationship between body size and response to clopidogrel and prasugrel.     

A case series of LMWH use in pregnancy: Should trough anti-Xa levels guide dosing?

Introduction

Pregnancy is a thrombogenic state, increasing the risk for venous thromboembolism (VTE), and the risk of valve thrombosis amongst women with mechanical heart valves (MHV). While low molecular weight heparins (LMWH) are generally dosed based on weight (i.e., enoxaparin 1 mg/kg every 12 hours), data in pregnant women have shown that weight-based dosing does not consistently achieve target anti-Xa levels. In women with MHV, our practice includes titrating LMWH doses to target both trough and peak anti-Xa levels, while for those with VTE peak anti-Xa levels guide dosing.

Materials/Methods

This retrospective case series included pregnant women requiring LMWH treatment doses with at least 3 peak (+/− trough) anti-Xa levels. Our primary objective was to describe the actual LMWH dose required to achieve targeted anti-Xa levels relative to weight-based dosing in patients with MHV. Secondarily, we compared the same for VTE patients; compared actual dosing between those with MHV and VTE; and examined maternal and fetal outcomes.

Results/Conclusion

Women with MHV (N = 4) required greater than weight-based dosing of enoxaparin (1.35 mg/kg Q12H) to achieve targeted anti-Xa levels. Importantly, achieving target peak anti-Xa levels did not always ensure maintenance of minimum trough levels. VTE patients (N = 12) did not require more enoxaparin (0.96 mg/kg Q12H) than weight based dosing. MHV patients received more enoxaparin compared to VTE patients (P < 0.001). No bleeding or clotting complications were associated with LMWH administration. In pregnant women with MHV at high risk of thromboembolism, LMWH dosing guided by trough and peak anti-Xa levels should be considered.     

The effect of talking about psychological trauma with a significant other on heart rate reactivity in individuals with posttraumatic stress disorder

Individuals with posttraumatic stress disorder (PTSD) commonly make efforts to avoid trauma-oriented conversations with their significant others, which may interfere with the natural recovery process. Trauma-oriented conversations can be experienced as physiologically arousing, depending on the intensity of PTSD symptoms and perceptions of social support. In the current investigation, changes in heart rate responses to a trauma-oriented social interaction with a significant other were assessed. Perceived supportive and unsupportive or negative social interactions were examined as moderators of the association between heart rate changes to this context and intensity of PTSD symptoms. A total of 46 individuals with PTSD completed diagnostic interviews and self-report measures of symptoms and perceived supportive and negative social interactions during a trauma-oriented social interaction with a significant other. Heart rate was continuously measured during this interaction. Results showed that engagement in a trauma-oriented social interaction was predictive of elevations in heart rate that positively correlated with intensity of PTSD symptoms. The moderation hypothesis was partially supported. In addition, perceived negative social interactions positively correlated with elevations in heart rate. These findings can inform social intervention efforts for individuals with PTSD.     

Efecto de la ortesis de tobillo pie en el control postural tras el accidente cerebrovascular: revisión sistemática

Introduction

Stroke is currently the main cause of permanent disability in adults. The impairments are a combination of sensory, motor, cognitive and emotional changes that result in restrictions on the ability to perform basic activities of daily living (BADL). Postural control is affected and causes problems with static and dynamic balance, thus increasing the risk of falls and secondary injuries. The purpose of this review was to compile the literature to date, and assess the impact of ankle-foot orthosis (AFO) on postural control and gait in individuals who have suffered a stroke.

Development

The review included randomised and controlled trials that examined the effects of AFO in stroke patients between 18 and 80 years old, with acute or chronic evolution. No search limits on the date of the studies were included, and the search lasted until April 2011. The following databases were used: Pubmed, Trip Database, Cochrane library, Embase, ISI Web Knowledge, CINHAL and PEDro. Intervention succeeded in improving some gait parameters, such as speed and cadence. However it is not clear if there was improvement in the symmetry, postural sway or balance.

Conclusions

Because of the limitations of this systematic review, due to the clinical diversity of the studies and the methodological limitations, 0these results should be considered with caution.     

State-related electroencephalographic deviances in attention deficit hyperactivity disorder

This study investigated the stability and state-related characteristics of electroencephalographic (EEG) deviances in attention-deficit/hyperactivity disorder (ADHD). Three minutes resting EEG with eyes closed and eyes open were compared between 21 children with ADHD and 29 typically developing children. Across resting conditions, children with ADHD exhibited divergent topographic distribution for theta, alpha and beta power compared to typically developing children. In addition, less alpha and theta suppression to eye opening was found in children with ADHD, but only in those without comorbid ODD/CD. Findings of the present study refer to a consistent divergence in topographic distribution in ADHD across resting state conditions, yet demonstrate that state-related factors and comorbidity may also contribute to resting EEG deviances in ADHD. The state-related findings are in accord with several theoretical accounts emphasizing the role of contextual and state factors defining deficits in ADHD.     

腰穿放液后脑血流变化预测正常压力脑积水分流效果的研究

【目的】通过腰穿放液前后脑血流变化预测正常压力脑积水(NPH)患者行分流手术的效果。【方法】回顾性分析26例NPH患者腰穿放液前后脑血流变化与脑室-腹腔(V-P)分流术后效果的相关性。【结果】分流术后2个月患者症状改善与腰穿放液前后脑血流的变化呈正相关,其中症状改善显效和有效患者腰穿后脑血流速度较前明显增加,而无效患者前后差异无统计学意义。【结论】腰穿放脑脊液前后脑血流的变化可作为预测NPH患者行分流手术疗效的指标。     

失血性休克大鼠血管平滑肌钙敏感性变化及其在休克双相血管反应性变化中的作用

目的观察失血性休克后血管平滑肌钙敏感性是否存在双相变化,以及钙敏感性的双相变化与血管反应性双相变化的关系。方法取失血性休克大鼠肠系膜上动脉(SMA),采用离体血管环张力测定技术,观察在失血性休克后不同时间点(休克即刻、休克30min、休克1h、休克2h)大鼠SMA血管环对梯度浓度去甲肾上腺素(NE)的收缩反应性,以及在去极化状态下(120mmol/LK+)血管环对梯度浓度钙的收缩反应性变化(钙敏感性),分析血管反应性变化与钙敏感性变化的关系;同时观察钙敏感性增强剂血管紧张素(Ang)和钙敏感性抑制剂胰岛素对血管反应性的影响。结果休克早期(即休克即刻和休克30min时)SMA对NE和钙的反应性明显升高,量效曲线明显左移,最大收缩力(Emax)明显升高(P均<0.05);随着休克时间的延长,血管环对NE和钙的反应性均逐渐下降,到休克2h均已明显降低,其量效曲线明显右移,E-max明显降低(P<0.05或P<0.01);休克后不同时间点血管反应性变化与钙敏感性变化呈显著正相关(r=0.9624,P<0.05)。具有钙敏感性增强作用的Ang(1×10-9mol/L)可明显升高休克2h血管环对NE和钙的反应性(P<0.05或P<0.01),而有钙敏感性抑制作用的胰岛素则可降低休克早期(休克即刻)血管环对NE和钙的反应性(P<0.05或P<0.01)。结论失血性休克血管平滑肌细胞存在钙敏感性的双相变化,血管平滑肌细胞钙敏感性双相变化在失血性休克血管反应性的双相变化中起重要作用。     

Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity

Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses (‘cue reactivity'') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT_2C receptor (5-HT_2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT_2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT_2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT_2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.     

脑卒中患者吞咽障碍的康复护理

吞咽障碍是脑卒中患者的常见并发症，若不及时处理，不仅会造成机体营养代谢失调，还会因进食不当引起吸入性肺炎，重者危及生命。2006年1月-2008年3月我院康复中心对30例脑卒中合并吞咽障碍的患者实施早期的康复护理，效果良好，现报告如下。