苦参碱醇质体的制备☆

背景：醇质体是一种新型脂质体，具有高变形性、高包封率的优点，能完整地透过皮肤，尤其适合作为外用给药和透皮给药载体。 目的：制备苦参碱醇质体并评价其在大鼠皮肤中的在体抗炎活性。 设计、时间及地点：随机对照动物实验，于2007-08/2008-03在中南大学卫生部肝胆肠外科研究中心实验室完成。 材料：采用乙醇注入法与超声法结合制备苦参碱醇质体。 方法：采用激光动态散射仪检测醇质体粒径；超速离心法检测包封率；采用反射分光光度仪检测苦参碱制剂在体抗炎活性。 主要观察指标：苦参碱醇质体的粒径、包封率及大鼠在体皮肤的红斑指数变化。 结果：苦参碱醇质体平均粒径为50~200 nm，粒径分布窄，包封率为40%~90%。空白醇质体的红斑指数变化与生理盐水溶液比较没有显著差异（P > 0.05），而水-乙醇溶液与空白醇质体或生理盐水溶液相比有显著性差异(P < 0.01)。苦参碱醇质体与苦参碱非醇质体制剂相比能更快地消退红斑；空白醇质体既没有诱发红斑作用也没有抗炎活性。 结论：苦参碱醇质体的平均粒径依赖于其组成，随乙醇体积分数增加而减小，随磷脂质量浓度增加而增加；而包封率随乙醇和磷脂水平增加而增加。空白醇质体作为皮肤传递载体在大鼠皮肤显示有良好的耐受性；苦参碱醇质体能增强苦参碱对在体大鼠皮肤诱发红斑的抗炎活性。     

吲哚美辛柔性纳米脂质体与普通纳米脂质体体外透皮速率的比较*◆

背景：吲哚美辛口服副作用大,将其制成软膏局部应用,透皮扩散速率较慢,影响吸收。柔性纳米脂质体是一种新型的经皮给药载体,对药物的皮肤渗透有显著的促进作用。 目的：制备吲哚美辛柔性纳米脂质体并观察柔性纳米脂质体对吲哚美辛离体透皮扩散速率的影响。 设计、时间及地点：体外对照观察,于2008-07/2009-01在中南大学卫生部纳米生物技术重点实验室完成。 材料：用薄膜超声法制备吲哚美辛纳米柔性脂质体。 方法：采用小鼠体外皮肤的Franz扩散池作为渗透屏障进行体外透皮吸收实验,对比柔性纳米脂质体和普通脂质体的药物渗透速率。 主要观察指标：粒径、回收率、包封率、药物累积渗透速率。 结果：纳米脂质体作为载体粒径小,包封率高,具有可变形性,能顺利携带药物透过皮肤,提高吲哚美辛的透皮速率;与普通纳米脂质体相比,柔性纳米脂质体透皮速率更高。 结论：柔性纳米脂质体可显著地促进吲哚美辛的透皮吸收。     

低相对分子质量透明质酸脂质体的制备及透皮性能★

摘要 背景：透明质酸是一种用途广泛的高分子材料，在实际应用中，由于其相对分子质量较大，透皮吸收效果不理想，利用脂质体作为其载体可以改善其传输效果，具有较好的应用前景。 目的：观察包裹低相对分子质量透明质酸脂质体的透皮性能。 方法：采用薄膜法制备低相对分子质量透明质酸脂质体，设计正交实验，采用蛇蜕研究其透皮吸收性能。 结果与结论: 温度35 ℃、胆固醇与卵磷脂的比例为0.15∶1，透明质酸与卵磷脂的比例为0.03∶1、水合介质PBS的pH值为7.5，可制备包封率较高的低相对分子质量透明质酸脂质体；脂质体包裹低相对分子质量透明质酸，能有效得提高透明质酸透过蛇蜕的能力，达到了提高透明质酸透皮吸收率的作用。 关键词：低相对分子质量；透明质酸；脂质体；透皮吸收；包封率 doi:10.3969/j.issn.1673-8225.2011.03.021     

包载雷帕霉素聚乳酸-聚乙醇酸纳米粒子的制备、表征及体外释放试验**☆

背景：新型可生物降解多聚物纳米控释载药制剂能显著改善药物穿透组织能力、再分布时程和滞留时间，可能克服载药基质对血管修复的负性影响，有望避免药物洗脱支架晚期支架内血栓。 目的：制备雷帕霉素-聚乳酸-聚乙醇酸纳米粒子（rapamycin poly(lactic-co-glycolic) acid nanoparticles, RPM-PLGA-NPs）并观察其表征及体外控释性能。 设计、时间及地点：单一样本实验于2003-03/09在中国医学科学院,中国协和医科大学,生物医学工程研究所生物医学材料重点实验室完成。 材料：聚乳酸-聚乙烯醇酸共聚物50∶50由美国Birmingham Polymers 公司提供。 方法：以可生物降解高分子材料聚乳酸-聚乙醇酸共聚物作载药基质，超声乳化-溶剂挥发法制备RPM-PLGA-NPs，采用双室扩散池行体外药物释放试验。 主要观察指标：测定平均载药量、平均包封率；激光光散射实验测定纳米粒子的粒径及分布；扫描电镜观察纳米粒子的表面形态；高效液相色谱法计算体外药物释放量、绘制累积释放曲线。 结果：成功制备了平均粒径为246.8 nm的RPM-PLGA-NPs，平均粒径246.8 nm，粒径分布集中在208~294 nm，呈窄分布；包封率大于77%,平均载药量为19.42%。体外释放近似于零级过程，至2周释放75％的药物。 结论：超声乳化-溶剂挥发法制备RPM-PLGA-NPs稳定可靠，包封效率高，载药量控制稳定，粒径小、范围窄，体外释放药物恒定、具有良好的控释效能。     

布洛芬磁性固体脂质纳米粒的制备

背景：布洛芬因溶解度和溶血问题,目前仍无注射给药剂型上市。 目的：将自制的磁流体载入固体脂质纳米粒中,制备布洛芬磁性固体脂质纳米粒。 方法：以包封率为指标,用正交设计确定布洛芬固体脂质纳米粒的最优处方。以共沉淀法制备Fe3O4磁流体作为磁性材料,采用乳化分散-超声法,按照最优处方制备布洛芬磁性固体脂质纳米粒。观察其表面形态、粒径大小、分布和Zeta电位、饱和磁化强度、包封率及体外释放特征。 结果与结论：通过正交实验得最优处方为布洛芬0.05 g、F-68 0.2 g、吐温80 0.05 g、卵磷脂0.1 g、单硬脂酸甘油酯0.05 g、磁流体2.5 mL。用该工艺和处方制备的布洛芬磁性固体脂质纳米粒粒子呈均匀球形;平均粒径、zeta电位为(122±16) nm和(-13.3±6.94) mV;药物包封率和Fe3O4铁包封率分别为84.15%和83.19%;布洛芬在给定介质中36 h释放较完全,符合制剂学性质要求。     

聚乳酸-羟基乙酸包载眼镜蛇毒细胞毒素缓释微球的表征及体外释放行为

背景：眼镜蛇毒细胞毒素具有强烈的细胞毒活性,但缺乏特异性,全身用药可导致严重毒副作用,而采用缓释载体包载进行间质化疗可达到提高肿瘤局部治疗效应,并且减轻全身毒性。 目的：制备眼镜蛇毒细胞毒素-聚乳酸-羟基乙酸微球,观察其一般性质和体外释药特性。 设计、时间及地点：观察性实验,于2007-12/2008-05在福建医科大学医药生物工程中心完成。 材料：聚乳酸-羟基乙酸、聚乙烯醇由中国科学院成都有机化学有限公司提供,广东产中华眼镜蛇毒。 方法：采用分子筛、离子交换分离,反相疏水高效液相色谱方法纯化细胞毒素,MTT法检测细胞毒活性,复乳-溶剂挥发法制备载药微球。 主要观察指标：扫描电镜观察载药微球的表面形态,激光粒径仪测微球粒径,计算包封率、载药量、体外释放周期。 结果：纯化的眼镜蛇细胞毒素具有明显的细胞毒作用,对HepG2细胞12,24 h的IC50分别为1.43,1.12 mg/L。复乳法制备微球表面光滑圆整,粒径2~8 μm,包封率和载药率分别为(74.10±9.92)%和(0.72±0.09)%,21 d药物累积释放63.3％,释放细胞毒素保持较好的生物学活性。 结论：采用复乳-溶剂挥发法可制备具有较高包封率、良好缓释效果、保持完整生物学活性的眼镜蛇毒细胞毒素-聚乳酸-羟基乙酸微球。     

盐酸哌唑嗪缓释贴片的释药行为及其生物相容性评价

背景：盐酸哌唑嗪半衰期短,首剂效应明显,国内仅有普通片上市。 目的：研制以聚乙烯醇和明胶为骨架材料的盐酸哌唑嗪缓释贴片,并考察其释药行为和生物相容性。 设计、时间及地点：随机设计,动物对照实验,于2007-01/08在重庆医科大学药学院实验室进行。 材料：采用水性分散体法,以聚乙烯醇、明胶为骨架材料制备盐酸哌唑嗪亲水性凝胶骨架缓释贴片。 方法：①随机选用新西兰大白兔6只,取腹部皮肤进行体外透皮实验,以氮酮、丙二醇、骨架材料配比、载药量为影响因素,稳态透皮速率、时滞为指标,采用正交设计筛选最佳处方。②验证最佳处方,考察贴片物理特性、黏性及透皮行为,并采用差示扫描量热法对其进行差热分析。③随机选用新西兰大白兔12只,通过皮肤刺激性实验,考察贴片的生物相容性。 主要观察指标：①贴片最佳处方筛选及验证。②贴片的物理特性评价。③贴片的差热分析。④皮肤刺激性反应。 结果：①正交实验筛选的最佳处方为氮酮2%,丙二醇15%,骨架材料配比为5∶4,载药量1.0%。②按最佳处方制备的贴片外观、黏性良好;其稳态透皮速率、时滞和综合评分分别为(8.92±0.58)μg/(cm2•h),(3.38±1.17) h,81.58±8.42,其体外72 h内释药行为符合Higuchi方程模式(r=0.995 7),并趋近于零级释药模式(r=0.987 3),经皮渗透曲线重现性良好(P > 0.05);差热分析表明,盐酸哌唑嗪在骨架材料中以分子或无定形存在。③贴片生物相容性良好,对兔皮肤无刺激性。 结论：制备的亲水性凝胶骨架盐酸哌唑嗪缓释贴片生物相容性良好,具有持续平稳释药的特性。     

口服胰岛素缓释微球的制备

背景：口服胰岛素易被胃酸及胃肠道内的各种酶降解，难以透过胃肠道上皮细胞膜。针剂形式注射胰岛素也需要至少间隔36 h注射1次。 目的：制备口服胰岛素缓释微球。 设计、时间及地点：对比观察实验，于2003- 09/2004-12在南京信息工程大学药物化学实验室完成。 材料：胰岛素由南京生化制药厂提供。 方法：采用液中干燥法制备微球，利用在一定pH值条件下能溶解的丙烯酸树脂作为药物载体，得到包封胰岛素的丙烯酸树脂微球。 主要观察指标：扫描电镜观察口服胰岛素微球形态及粒径的大小。紫外分光光度法测定胰岛素的含量，考察内相聚合物浓度和搅拌速度对微球粒径和药物包封率的影响。 结果：扫描电镜下微球较圆整，表面较粗糙，球表面有许多小孔。随着搅拌速度的增加和内相聚合物浓度的减小，微球粒径减小，药物包封率有所增加。随着起始投药量的增加，微球中的含药量也相应增加，但投药量的高低对药物的包封率无显著影响。 结论：液中干燥法能较好地制备口服胰岛素缓释微球。     

硫酸庆大霉素-壳聚糖纳米粒的制备及性能评价

背景：庆大霉素珠链是较早用于治疗慢性骨髓炎的局部释药系统，但是由于其不能在体内降解吸收，须二次取出，因而限制了其的应用。因此国内外学者一直致力于可吸收材料负载抗生素装置的研究。 目的：制备负载庆大霉素的壳聚糖纳米粒，评价其性能，观察其体外释药行为及体外抗金黄色葡萄球菌的作用。 方法：以壳聚糖为药用载体，硫酸庆大霉素为模型药物，三聚磷酸钠为离子交联剂，采用离子交联法制备庆大霉素-壳聚糖纳米粒，在MH平板上进行抑菌实验，观察及评价其抑制金黄色葡萄球菌的作用。 结果与结论：制备的纳米粒形态为类圆形，粒径为40~70 nm，包封率及载药量分别为31.3%和15.4%，体外释药可持续14 d左右，对金黄色葡萄球菌的体外抑菌效果可持续25 d，在第5天纳米粒的抑菌作用达到最大，随着时间的推移，抑菌圈逐渐缩小。     

负载紫杉醇壳聚糖纳米粒的制备、表征与释药性能

背景：紫杉醇是一种天然抗肿瘤药物,但其水溶性极低。壳聚糖经接枝改性，生成的共聚物可在液相中生成纳米粒，可用于药物的缓释和控释。 目的：对制备的负载紫杉醇的壳聚糖纳米粒进行表征，分析其体外药物释放能力。 设计、时间及地点：重复测量设计，于2008-01/07在华北煤炭医学院医学系实验室完成。 材料：壳聚糖，平均相对分子质量为2.0×105，脱乙酰度为92%，为浙江省玉环海洋生物化学有限公司产品。紫杉醇，批号082329802，为中国药品生物制品检定所产品。 方法：采用引发接枝效率高、引发反应条件温和的二羟基二过碘酸合镍钾为引发剂，在壳聚糖上接枝醋酸乙烯酯，该聚合物在水溶液中直接生成具有疏水核心、亲水表面的纳米粒，即壳聚糖纳米粒，再利用超声振荡技术将0.5~5.0 mg紫杉醇与上述纳米粒混合制成负载紫杉醇的壳聚糖纳米粒。 主要观察指标：激光粒度分析仪测定纳米颗粒的粒径大小、粒径分布及Zeta电位，透射电镜观察纳米颗粒的外观形态，高效液相色谱法分析负载紫杉醇的壳聚糖纳米粒的包封率、载药量和释药性能。 结果：壳聚糖纳米粒和负载紫杉醇的壳聚糖纳米粒，其粒径分别为196.2 nm和320.8 nm，粒径分布较窄，纳米粒表面均带正电荷，Zeta电位比较差异无显著性意义（F=0.818，F=3.38，P均>0.05）。稳定的纳米粒呈球形，粒径均匀。紫杉醇的加入量可影响纳米粒的包封率，紫杉醇的加入量为纳米粒的量2%时，达到最大包封率93.6%。体外模拟释药结果表明药物释放曲线分为两个阶段，突释阶段微球释药量在24 h内达48.3%，缓释阶段微球释药持续时间长，在175 h时释药量达75.9%，载药纳米粒的药物释放速率持续稳定。 结论：接枝共聚法制备壳聚糖纳米粒简便可靠，负载紫杉醇后纳米粒径明显变大，表面带有正电荷，且纳米粒对紫杉醇有很高的包封率，体外释药具有明显的缓释作用。     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Neonatal Seizures: Problems in Diagnosis and Classification

Summary: The clinical identification of neonatal seizures is critical for the recognition of brain dysfunction; however, diagnosis is often difficult because of the poorly organized and varied nature of these behaviors. Current classification systems are limited in their ability to communicate motor, autonomic, and electroencephalo-graphic features of seizures precisely and to provide a basis for uniform effective diagnosis, therapy, and determination of prognosis. Recent investigations of neonates, utilizing bedside electroencephalographic/polygraphic/ video monitoring techniques, have provided the basis for improved diagnosis and classification of seizures in the newborn. These studies have demonstrated that not all clinical phenomena currently considered to be seizures require electrocortical epileptiform activity for their initiation or elaboration. In addition, the specific clinical character of the phenomena considered to be seizures, the clinical state of the infant, and the character of the EEG indicate the probable pathophysiological mechanisms involved and suggest probable etiologies, prognosis, and therapy. Similarities between animal models that demonstrate reflex physiology and neonates with motor automatisms and tonic posturing suggest that these clinical behaviors may not be epileptic in origin but, rather, primitive movements of progression and posture mediated by brainstem mechanisms. Although not all clinical behaviors currently considered to be neonatal seizures may have similar pathophysiological mechanisms, they are clinically significant because they all indicate brain dysfunction.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Un nouveau cadre conceptuel de travail pour la psychiatrie

In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.     

Special Pharmacokinetic Considerations in Children

Summary: Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.