Assessment of cytochrome P450‐mediated drug–drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation

Orteronel is a nonsteroidal, selective inhibitor of 17,20‐lyase that was recently in phase 3 clinical development as a treatment for castration‐resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC₅₀ values of 17.8, 27.7, 30.8 and 38.8 µm , respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC₅₀ > 100 µm ). Orteronel also does not exhibit time‐dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/K_i ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug–drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)‐warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration–time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a ‘non‐inhibitor’ and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. Copyright © 2014 John Wiley & Sons, Ltd.     

An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib

Aim/MethodsThis was a phase 1, open label, non-randomized study designed to assess the pharmacokinetics and safety/tolerability of 10 consecutive once daily 40 mg oral doses of darapladib in subjects with moderate hepatic impairment (n = 12) compared with matched healthy volunteers (n = 12).ResultsFor total darapladib, a small increase in total and peak exposure was observed in the subjects with moderate hepatic impairment compared with the subjects with normal hepatic function. The area under the plasma concentration−time curve during a dosing interval of duration τ (AUC(0,τ), geometric mean 223 ng ml⁻¹ h [90% CI 158, 316 ng ml⁻¹h], in moderate hepatic impaired subjects, vs. geometric mean 186 ng ml⁻¹h [90% CI 159, 217 ng ml⁻¹h], in healthy subjects) and maximum concentration (C_max) were 20% and 7% higher, respectively, in the subjects with moderate hepatic impairment than in the healthy control subjects and there was no change in time to maximum concentration (t_max). Protein binding was performed to measure the amount of unbound drug vs. bound. Steady-state was achieved by day 10 for darapladib and its metabolites (M4, M3 and M10). Darapladib was generally well tolerated, with adverse events (AEs) reported by seven subjects in the hepatic impairment group and three subjects in the healthy matched group (five and one of which were drug-related AEs, respectively). The most common AEs were gastrointestinal. These AEs were mostly mild to moderate and there were no deaths, serious AEs or withdrawals due to AEs.ConclusionsThe results of this phase 1 study show that darapladib (40 mg) is well tolerated and its pharmacokinetics remain relatively unchanged in patients with moderate hepatic impairment.     

家属参与个性化干预对轻度认知功能损害患者静脉输液安全的影响

目的探讨家属参与个性化护理干预对轻度认知功能损害患者静脉输液安全的影响。方法将2013年9月至12月在中心注射室进行静脉输液治疗的MCI患者39例为对照组,2014年1月至4月的MCI患者40例为观察组,对两组患者进行相同内容的护理干预,观察组患者家属参与护理干预的全过程。1个月后,比较两两组患者的蒙特利尔认知评估量表(MoCA)各认知域得分及总分、输液安全问题发生率及对输液过程满意度。结果干预后观察组MoCA各认知域得分及总分、输液安全问题发生率及对输液过程满意度均优于对照组,比较差异有统计学意义(P<0.05)。结论家属参与个性化护理干预不仅能改善MCI患者的认知功能,而且能有效减少患者输液安全问题的发生率,提高其对输液过程的满意度。     

Selective Effects of D- and L-Govadine in Preclinical Tests of Positive,Negative, and Cognitive Symptoms of Schizophrenia

There is a critical need to develop novel pharmacotherapeutics capable of addressing the positive, negative, and cognitive symptoms of schizophrenia. Building on recent studies with a racemic mixture of the synthetic tetrahydroprotoberberine, D,L-Govadine, we isolated the D- and L-stereoisomers and employed a battery of behavioral, neurochemical, and electrophysiological procedures to assess their individual therapeutic potential. Rodent models predictive of antipsychotic efficacy and those that model positive symptoms were employed and we found that L-Govadine, but not D-Govadine, improved these measures. Pretreatment with either stereoisomer during CS pre-exposure prevented the disruption of latent inhibition by amphetamine. Moreover, pretreatment with either stereoisomer also improved deficits in social interaction in the neonatal ventral hippocampal lesioned rat. Improved cognitive performance in two different prefrontal cortex-dependent tasks was observed with D-, but not L-Govadine, which strongly suggests that the D-steroisomer may be an effective cognitive enhancer. Alterations in dopamine efflux were also assessed and L-Govadine increased dopamine efflux in both the prefrontal cortex and nucleus accumbens. However, D-Govadine only increased dopamine efflux in the prefrontal cortex and not in the nucleus accumbens. Electrophysiological studies confirmed that L-Govadine is a DA-D2 antagonist, whereas D-Govadine shows no appreciable physiological effects at this receptor. Collectively these data show that L-Govadine performs well on measures predictive of antipsychotic efficacy and rodent models of positive symptoms through antagonism of DA-D2 receptors, whereas D-Govadine improves impairments in compromised memory function in delayed response tasks possibly through selective increases in DA efflux in the frontal cortex.     

左侧丘脑结节动脉梗死患者的认知功能障碍：1例病例报告及文献复习

血管性认知功能障碍目前正逐步成为脑卒中后临床关注的重点。多种机制介导的血管性认知功能障碍是一类异质性疾病,而作为与血管性事件直接相关的重要部位的梗死在其中起着重要作用。左侧丘脑结节动脉梗死所造成的急性认知功能障碍因病变部位较局限,易为临床医生忽略。本文报告1例左侧丘脑结节动脉梗死患者的诊治情况,并就此种重要部位梗死患者的认知功能障碍作一简要介绍。     

精神分裂症超高危人群、首发患者认知功能与精神病理症状的相关性及帕利哌酮的干预作用

目的：探讨精神分裂症患者各个阶段认知功能的特点及与精神病病理症状的相关性,并研究帕利哌酮的干预作用。方法运用持续操作测验（CPT）和 Stroop 色词测验对满足入组标准的超高危组、首发组及正常组人群进行认知功能评定,并运用阳性与阴性症状量表（PANSS）对各组的精神病性症状进行评估;评估认知功能与精神病症状的相关性。对首发组患者采用帕利哌酮进行治疗,观察治疗前后 CPT、Stroop 色词测验及 PANSS 评分。结果3组 CPT 和 Stroop 色词测验存在显著性差异（ P ﹤0.05）;PANSS 总分与 CPT 存在相关性。首发精神分裂症患者治疗后,CPT 和 Stroop 色词测验得分均明显升高,PANSS 评分显著下降,与治疗前相比,差异有统计学意义（ P ﹤0.05）。结论认知功能缺损可能对精神分裂症发病有一定的预测价值;而疾病的发作可能会进一步加重这一缺损;且精神病性症状愈严重,患者的认知功能下降愈明显。帕利哌酮对首发精神分裂症有良好的治疗作用,能显著改善患者的认知功能和精神病理症状。     

社区老年人轻度帕金森病样体征的调查研究

目的：调查社区老年人轻度帕金森病样体征的患病率,研究伴有轻度帕金森病样体征（MPS）与轻度认知功能损害（MCI）之间的关系。方法以492例≥60岁老年人为研究对象,使用帕金森病统一评分量表（the unified Parkinson’s disease rating scale, UPDRS）第3部分缩写版本评定MPS。将研究对象分为MPS组和无MPS组,比较MCI患病情况,分析MPS与MCI之间联系。结果 MPS组较无MPS组的年龄大,糖尿病比例、遗忘型MCI （MCI-amnestic, A-MCI）发病率高,差异有统计学意义（P〈0.05）。结论 MPS与MCI的发生关系密切,不同类型MPS对MCI影响不同。     

泪点栓治疗视频终端顽固性干眼症的临床效果研究

目的：探讨泪点栓治疗视频终端顽固性干眼症的临床效果。方法选取2013年2~5月本院收治的视频终端顽固性干眼症患者59例（118只眼）,按照治疗方法不同分为两组,观察A组30例（60只眼）和观察B组29例（58只眼）,观察A组采用上下泪小点植入永久性泪点栓治疗,观察B组采用上泪小点植入临时性自溶性泪点栓,下泪小点植入永久性泪点栓治疗。结果两组治疗后3个月的BUT、Schirmer-Ⅰ明显高于治疗前,FL及主观症状评分明显低于治疗前,差异有统计学意义（P〈0.05）。两组治疗后3个月的BUT、Schirmer-Ⅰ、FL及主观症状评分比较,差异无统计学意义（P〉0.05）。观察A组的并发症发生率高于观察B组（P〈0.05）。结论采用泪点栓可显著改善视频终端顽固性干眼症患者的临床症状,上泪小点植入临时性自溶性泪点栓,下泪小点植入永久性泪点栓治疗安全性更高。