阿立哌唑自乳化释药系统的制备与质量评价

目的 制备阿立哌唑自乳化释药系统（ARP-SEDDSs）以提高药物的口服生物利用度。方法 HPLC法检测ARP在不同的油、表面活性剂和助表面活性剂中的溶解度,根据溶解度确定处方组成;采用伪三元相图筛选SEDDSs的处方比例;通过动态光散射、透射电镜、稀释稳定性和体外溶出对ARP-SEDDSs进行表征;大鼠分别ig给予自制ARP-SEDDSs和ARP混悬液（20 mg·kg^-1）后,HPLC法进行药动学研究,考察大鼠ig ARP-SEDDSs的生物利用度。结果 以油酸作为油相,以聚乙二醇15-羟基硬脂酸酯和异丙醇作为表面活性剂和助表面活性剂,优化得到ARP-SEDDSs处方为油酸-聚乙二醇15-羟基硬脂酸酯-异丙醇为2.0∶5.6∶2.4,载药量为10 mg·g^-1;ARP-SEDDSs经水稀释后可快速形成微乳,在透射电镜下可观察到微乳呈类球形,经动态光散射仪检测其平均粒径为（54.6±2.3）nm,聚合物分散性指数（PDI）为0.201±0.011,Zeta电位（-13.5±0.4）mV;ARP-SEDDSs在pH 6.8磷酸盐缓冲液中10 min的药物溶出度接近100%,远高于阿立哌唑口崩片（约10%）。大鼠体内药动学研究表明,与ARP混悬液相比,ARP-SEDDSs相对生物利用度为248.8%。结论 将ARP制备成自乳化释药系统,有助于药物快速溶出,显著提高了ARP的口服生物利用度。     

Population pharmacokinetic modelling of aripiprazole and its active metabolite,dehydroaripiprazole, in psychiatric patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Almost all reported studies have investigated the pharmacokinetics of aripiprazole in healthy volunteers.
• The pharmacokinetics of dehydroaripiprazole have not been identified in a combined model with aripiprazole.

WHAT THIS STUDY ADDS

• The data on aripiprazole and dehydroaripiprazole in psychiatric patients were modelled jointly using a population approach.
• The apparent clearance of aripiprazole in cytochrome P450 (CYP) 2D6 intermediate metabolizers (IM) was approximately 60% of that in CYP2D6 extensive metabolizers (EM) having two functional alleles, but the exposure to dehydroaripiprazole in CYP2D6 IM was similar to that in EM.

AIMS

The aims of this study were to develop a combined population pharmacokinetic model for both aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients and to identify to what extent the genetic polymorphisms of cytochrome P450 (CYP) enzymes contribute to the variability in pharmacokinetics (PK).

METHODS

A population pharmacokinetic analysis was performed using NONMEM software based on 141 plasma concentrations at steady state from 80 patients receiving multiple oral doses of aripiprazole (10–30 mg day¹).

RESULTS

A one-compartment model with first-order kinetics for aripiprazole and dehydroaripiprazole each was developed to describe simultaneously the concentration data. The absorption rate constant was fixed to 1.06 h¹. The typical value of apparent distribution volume of aripiprazole was estimated to be 192 l. Covariate analysis showed that CYP2D6 genetic polymorphisms significantly influenced the apparent clearance of aripiprazole (CL/F), reducing the interindividual variability on CL/F from 37.8% CV (coefficient of variation) to 30.5%. The CL/F in the CYP2D6 IMs was approximately 60% of that in CYP2D6 EMs having two functional alleles. Based on the CYP2D6 genotype, the metabolic ratios were calculated at 0.20–0.34. However, the plasma concentration : dose ratios of dehydroaripiprazole were not different across the CYP2D6 genotype.

CONCLUSIONS

This population pharmacokinetic model provided an adequate fit to the data for both aripiprazole and dehydroaripiprazole in psychiatric patients. The usefulness of CYP genotyping as an aid to select the starting dose should be further investigated.     

Investigational drugs for treating agitation in persons with dementia

Introduction: Agitation is common and distressing in persons with dementia, but safe, effective treatments remain elusive. In this review, the authors describe investigational compounds in ongoing or recently completed clinical trials for this indication and provide an opinion on how they may meet current therapeutic needs.

Areas covered: Phase II and phase III clinical trials for agitation in persons with dementia were searched in US and EU clinical trial registries and in the medical literature for the period January 2013-February 2016

Expert opinion: The authors searches identified 24 recent clinical trials investigating new treatments for agitation in persons with dementia. Candidate drugs in phase III development included the antipsychotic brexpiprazole, the antidepressant citalopram, the novel compound AVP-786 (deuterated-dextromethorphan/quinidine combination) and the cannabinoid nabilone. Of the compounds in phase II clinical trials, ELND005 (scyllo-inositol) is intended to progress into phase III development, based on evidence from a subgroup analysis and biomarker data. After many years without an FDA/EMA (Food and Drug Administration/European Medicines Agency) approved medication to treat agitation in persons with dementia, we may see the arrival of the first approved drug in the near future.     

Safety and efficacy from a 6‐week double‐blind study and a 52‐week open‐label extension of aripiprazole in adolescents with schizophrenia in Japan

Aim

The purpose of this study was to evaluate the safety and efficacy of aripiprazole in adolescents with schizophrenia (SCZ) in Japan.

Methods

In a 6‐week, randomized, double‐blind, dose‐comparison study, adolescents (aged 13–17 years) with SCZ were randomized to receive aripiprazole 2, 6–12, or 24–30 mg/day. Patients who completed the 6‐week study participated in a 52‐week, flexible‐dose, open‐label extension (OLE) study of aripiprazole (initial dose: 2 mg/day, maintenance dose: 6–24 mg/day, maximum dose: 30 mg/day).

Results

In the 6‐week study, the percentage of patients completing treatment was: 77.1% (27/35) for 2 mg/day; 80.0% (24/30) for 6–12 mg/day; and 85.4% (35/41) for 24–30 mg/day. The least squares mean change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to endpoint (primary efficacy endpoint, last observation carried forward) was ?19.6 for 2 mg/day, ?16.5 for 6–12 mg/day, and ? 21.6 for 24–30 mg/day. The most common (≥20% patients in any group) treatment‐emergent adverse events (TEAE) were nausea, akathisia, insomnia, and somnolence. Most TEAE were mild or moderate in severity. There were no deaths. In the OLE, 60.3% (41/68) of patients completed treatment, and the PANSS total score decreased by ?7.9 from OLE baseline to week 52. The most common (≥20% patients) TEAE were nasopharyngitis and somnolence. Most TEAE were mild or moderate in severity. There were no deaths.

Conclusion

These study results suggest that aripiprazole would be safe and well tolerated in both short‐ and long‐term treatment for adolescents with SCZ in Japan.

     

Low‐dose aripiprazole resolved complex hallucinations in the left visual field after right occipital infarction (Charles Bonnet syndrome)

We reported a patient who suffered from complex visual hallucinations with left homonymous hemianopsia. Brain imaging showed an acute haemorrhage infarct at the right occipital lobe. Charles Bonnet syndrome (CBS) was suspected and aripiprazole was prescribed at 5 mg daily. After 3 weeks, the symptoms of hallucinations and anxiety were relieved. Although some CBS patients might be self‐limited without discomfort, low‐dose aripiprazole can be considered as a safe medication for significantly anxious patients with CBS.     

Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study

Marcus R, Khan A, Rollin L, Morris B, Timko K, Carson W, Sanchez R. Efficacy of aripiprazole adjunctive to lithium or valproate in the long‐term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double‐blind, randomized study.
Bipolar Disord 2011: 13: 133–144. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Listen to interview with article author Objectives: To evaluate the efficacy and safety of aripiprazole (ARI) adjunctive to lithium (Li) or valproate (Val) (ARI + Li / Val) compared with placebo (PLB) adjunctive to Li or Val (PLB + Li / Val) as maintenance therapy for patients with bipolar I disorder who had an inadequate response to Li or Val monotherapy. Methods: Patients with a current manic/mixed episode received Li or Val for at least 2 weeks. Those with an inadequate response [Young Mania Rating Scale (YMRS) total score ≥ 16 and ≤ 35% decrease from baseline at 2 weeks] received adjunctive single‐blind ARI plus mood stabilizer. Patients who achieved stability [YMRS and Montgomery–Åsberg Depression Rating Scale (MADRS) score ≤ 12] for 12 consecutive weeks were randomized to double‐blind ARI (10–30 mg/day) or PLB + Li / Val. Relapse was monitored for 52 weeks. Adverse events (AEs) were also evaluated. Results: A total of 337 patients were randomized to ARI + Li / Val (n = 168) or PLB + Li / Val (n = 169). The Kaplan–Meier relapse rate at 52 weeks was 17% with ARI + Li / Val and 29% with PLB + Li / Val. ARI + Li / Val significantly delayed time to any relapse compared with PLB + Li / Val; hazard ratio = 0.54 (95% confidence interval: 0.33–0.89; log‐rank p = 0.014). The most common AEs ≥ 5% (ARI + Li / Val versus PLB + Li / Val) were headache (13.2% versus 10.8%), weight increase (9.0% versus 6.6%), tremor (6.0% versus 2.4%), and insomnia (5.4% versus 9.6%). Conclusions: Continuation of ARI + Li / Val treatment increased the time to relapse to any mood episode compared with Li or Val monotherapy, and was relatively well tolerated during the one‐year study. These findings suggest that there is a long‐term benefit in continuing ARI adjunctive to a mood stabilizer after sustained remission is achieved.     

阿立哌唑治疗首发精神分裂症的随访对照研究

目的：探讨阿立哌唑与利培酮治疗首发精神分裂症的疗效和安全性。方法：将148例首发精神分裂症患者随机分为阿立哌唑组75例和利培酮组73例。以阳性与阴性症状量表（PANSS）减分率评定疗效同时评定社会功能缺陷筛选表（SDSS）和治疗中出现的症状量表（TESS）,以SDSS评定社会功能,用TESS评定不良反应。结果：阿立哌唑组与利培酮组在痊愈率、显效率、PANSS评分与SDSS评分差异无统计学意义（P均〉0.05）。阿立哌唑组在体质量增加、内分泌失调与锥体外系方面少于利培酮组,而在兴奋激越与恶心呕吐多于利培酮组,差异均具有统计学意义（P均〈0.05）。结论：阿立哌唑与利培酮治疗首发精神分裂症长期疗效均好,阿立哌唑不良反应较少,依从性高。     

阿立哌唑治疗抗精神病药所致闭经的精神分裂症对照研究

目的:探讨阿立哌唑对抗精神病药所致闭经的精神分裂症患者的影响.方法:69例抗精神病药引起闭经的女性精神分裂症患者,随机分为A组(单用阿立哌唑治疗)34例和B组(用其他抗精神病药联合中药血府逐瘀汤治疗)35例,观察疗程3个月.于治疗前、治疗后1、2、3个月测定血清催乳素浓度,并评定闭经的疗效.结果:治疗后两组血清催乳素浓...     

Rapid response to antipsychotic treatment on psychotic prodrome: Implications from a case series

The feasible intervention strategy at the prodromal state of psychosis is under debate. We report nine subjects clinically in a putative prodromal state of psychosis who responded to low‐dose aripiprazole within the first week of medication. We conjecture that the pathophysiological processes might be easier to modify by antipsychotics in the prodromal state and we believe a short‐term low‐dose trial of antipsychotic agents is a convenient option for subjects at ultra high risk of psychosis. We urge specific attention to monitor the dissolution of psychotic‐like symptoms carefully in order to have a better understanding of the pathogenesis and pharmacotherapy in the inception of psychosis.