Transdermal delivery of 4-aminopyridine accelerates motor functional recovery and improves nerve morphology following sciatic nerve crush injury in mice

Oral 4-aminopyridine(4-AP)is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral nerve injury including the promotion of re-myelination,improvement of nerve conductivity,and acceleration of functional recovery.We hypothesized that,instead of oral or injection administration,transdermal 4-AP(TD-4-AP)could also improve functional recovery after traumatic peripheral nerve injury.Mice with surgical traumatic peripheral nerve injury received TD-4AP or vehicle alone and were examined for skin permeability,pharmacokinetics,functional,electrophysiological,and nerve morphological properties.4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to TD-4-AP dose.While a single dose of TD-4-AP administration demonstrated rapid transient improvement in motor function,chronic TD-4-AP treatment significantly improved motor function and nerve conduction and these effects were associated with fewer degenerating axons and thicker myelin sheaths than those from vehicle controls.These findings provide direct evidence for the potential transdermal applicability of 4-AP and demonstrate that 4-AP delivered through the skin can enhance in-vivo functional recovery and nerve conduction while decreasing axonal degeneration.The animal experiments were approved by the University Committee on Animal Research(UCAR)at the University of Rochester(UCAR-2009-019)on March 31,2017.     

新型冠状病毒肺炎流行期间四川省德阳市民众行为及心理调查

目的 了解新型冠状病毒肺炎流行期间德阳市民众掌握相关知识的情况、行为变化及心理状态,为政府和个体采取有效的措施提供科学依据。方法 采用网上问卷的方式调查德阳地区民众1 380人,利用SPSS 23.0软件进行统计分析。结果 人们由传统的电视、广播、报纸等途径获得相关知识发展为以电视、网络、微信、抖音等获得;除了通风及抢购口罩和消毒液以外,普遍大众都持积极行为表现,尤其是大专及以上文化程度者明显高于高中及以下文化程度者,差异有统计学意义（P<0.01）;人们心理状态方面：感到恐惧和悲观失望者大专及以上学历低于高中及以下学历;担心传染、担心家人健康、心情压抑、易怒发脾气者大专及以上学历均高于高中及以下学历,差异有统计学意义（P<0.05）;居民产生恐惧心理的主要原因有7项,其中传染性强、潜伏期长且具传染性、疑似病例增多、药品及防护物质缺乏等项目上大专及以上学历者所占比例均高于高中及以下学历者,差异有统计学意义（P<0.05）。结论 疫情期间,德阳民众普遍存在恐慌、焦虑、悲观等心理状态,应采取有针对性的健康教育策略和措施,对有效预防控制疾病传播非常重要,同时还要注重防止因疫情引起的心理疾病发生。     

Comportements d’attachement d’enfants d’âge préscolaire consultant en pédopsychiatrie : lien avec des caractéristiques psychologiques maternelles

ObjectivesThe aim of this study was to examine whether variables related to mothers’ psychological functioning could be associated with mother-child attachment insecurity in children referred to an outpatient mental health clinic.MethodTwenty-nine children (23–71 months) and their mothers participated in this study. According to child age, mother-child attachment was assessed using the Strange Situation or the Separation-Reunion Procedure. Mothers’ symptoms of depression, anxiety and parental stress were assessed using self-report inventories.ResultsAvoidant attachment was marginally related to maternal depression and significantly associated with maternal anxiety. Greater parental stress was related to more disorganized and less secure attachment behaviors. A marginal association was also found between maternal stress and ambivalent attachment behaviors.ConclusionThese results support the importance of pursuing research on possible links between maternal psychological determinants and mother-child attachment in children referred to outpatient mental health clinics.     

Phase 1 study of crisaborole in Japanese healthy volunteers and patients with atopic dermatitis

Crisaborole ointment, 2%, is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD). This parallel-cohort, phase 1 study was conducted to investigate skin irritation potential and safety of crisaborole in healthy Japanese adults (cohort 1) and the safety and pharmacokinetic profile of crisaborole and metabolites AN7602 and AN8323 in Japanese adults with mild to moderate AD (cohort 2). In cohort 1, 20 healthy volunteers received single applications of crisaborole and vehicle simultaneously on separate locations under 48-h occlusion. In cohort 2, 12 patients with mild to moderate AD received crisaborole (n = 10) or vehicle (n = 2) twice daily for 8 days. Skin irritation and safety were assessed in cohort 1. Pharmacokinetics and safety were assessed in cohort 2. Skin irritation index (scale 0–400) was 40.0 for crisaborole and 5.0 for vehicle. No treatment-emergent adverse events (TEAE) were reported in cohort 1. The most common TEAE in the crisaborole group in cohort 2 were application site irritation (n = 7) and application site pain (n = 4). Crisaborole was rapidly absorbed, with limited systemic exposure between days 1 and 8 that was comparable with that seen in US-based participants in previous trials. Crisaborole had higher skin irritation than vehicle under occlusion in healthy Japanese adults and had an acceptable safety profile in Japanese adults with mild to moderate AD.     

吸入制剂人体药动学研究中关于给药的探讨

给药是药物临床试验中的关键环节，也是吸入制剂人体药动学研究中的难点之一。对吸入制剂给药环节中一些细节的把握可能直接影响制剂间生物等效性的建立，包括给药前准备、吸入技术培训、给药中及给药后处理等。本文将结合临床实践经验，针对吸入制剂人体药动学研究中的给药环节进行探讨并总结。     

Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration

Objectives: To establish the first plasma and cerebrospinal fluid (CSF) oxycodone population pharmacokinetic (PopPK) model after epidural (EPI) and intravenous (IV) oxycodone administration.

Methods: The study was conducted with 30 female subjects undergoing elective gynecological surgery with epidural analgesia. A parallel single dose of EPI oxycodone with IV placebo (EPI group; n = 18) or IV oxycodone with EPI placebo (IV group; n = 12) was administered. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for CSF sampling at L3/4. Plasma and CSF for oxycodone analysis were frequently collected. A PopPK model was built using the NONMEM software package.

Results: Plasma and CSF oxycodone concentrations were evaluated using separate central plasma and CSF compartments and separate peripheral plasma and CSF compartments. Epidural space served as a depot compartment with transfer to both the plasma and CSF central compartments. The population parameters for plasma clearance and apparent distribution volumes for central and peripheral compartments for plasma and CSF were 37.4 L/h, 90.2 L, 68.9 L, 0.035 L (fixed based on literature), and 0.039 L, respectively.

Conclusion: A PopPK model was developed and found to precisely and accurately describe oxycodone time-concentration data in plasma and CSF.     

Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy

In recent years, pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose. Indeed, pharmacogenetics may exert its action on immunosuppressant drugs at three levels. Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation. Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants. Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways. Of course, not all genes have been discovered and studied, but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined. Other genes on the basis of relevant studies have been proposed as good candidates for future studies. Unfortunately, to date, clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney, heart and lung transplantation is recommended. The conclusions of the studies on the recommended candidate genes, together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.