Drug self-assembly: A phenomenon at the nanometer scale with major impact in the structure–biological properties relationship and the treatment of disease

Under water-rich conditions, small amphiphilic and hydrophobic drug molecules self-assemble into supramolecular nanostructures. Thus, substantial modifications in their interaction with cellular structures and the ability to reach intracellular targets could happen. Additionally, drug aggregates could be more toxic than the non-aggregated counterparts, or vice versa. Moreover, since self-aggregation reduces the number of effective “monomeric” molecules that interact with the target, the drug potency could be underestimated. In other cases, the activity could be ascribed to the non-aggregated molecule while it stems from its aggregates. Thus, drug self-assembly could mislead from drug throughput screening assays to advanced preclinical and clinical trials. Finally, aggregates could serve as crystallization nuclei. The impact that this phenomenon has on the biological performance of active compounds, the inconsistent and often controversial nature of the published data and the need for recommendations/guidelines as preamble of more harmonized research protocols to characterize drug self-aggregation were main motivations for this review. First, the key molecular and environmental parameters governing drug self-aggregation, the main drug families for which this phenomenon and the methods used for its characterization are described. Then, promising nanotechnology platforms investigated to prevent/control it towards a more efficient drug development process are briefly discussed.     

新辅助化疗对胃癌手术患者罗库溴铵药效学影响

目的:观察新辅助化疗对胃癌手术患者罗库溴铵药效学影响。方法:50例择期行开放胃癌根治术患者,ASA分级Ⅰ或Ⅱ,性别不限,年龄40～68岁,体质量56～79 kg,25例术前未做化疗（N组）,25例术前行新辅助化疗（C组）。静脉诱导患者入睡后,给予罗库溴铵0.9 mg/kg,当4次成串刺激（TOF）为0时插入气管导管,T1恢复至对照值25%时追加罗库溴铵0.15 mg/kg。记录罗库溴铵起效时间（给药至T1为0时间,t1）、首剂作用时间（首次给药至T1达25%时间,t2）、临床肌松时间（T1从0恢复至25%时间,t3）、恢复指数（T1从25%恢复至75%所需时间,RI）和拔管时间（停用肌松药至T4/T1恢复至90%时间,t4）和罗库溴铵的总用量。结果:与N组相比,C组肌松药首次作用时间延长,临床肌松时间延长,术中总用量减少,恢复指数和拔管时间延长（P<0.05）。两组患者起效时间无统计学差异（P>0.05）。结论:新辅助化疗可减少术中肌松药的使用量。     

TCDCANa的合成及与CDCANa的药效对比

以鹅去氧胆酸和牛磺酸为基本原料制备了牛磺鹅去氧胆酸钠,收率63.4%,纯度≥92%,以TLC和IR法确定其结构.并将牛磺鹅去氧胆酸钠与鹅去氧胆酸钠进行平喘、抗炎和解热对比实验.药理实验结果为:牛磺鹅去氧胆酸钠和鹅去氧胆酸钠的平喘作用解痉率分别为(80.2±23.4)%和(73.3±22.7)%,抗炎作用抑制率分别为45.6%和36.8%,解热作用发热后90min时ΔT分别为(0.54±0.5)和(0.60±0.4)℃,牛磺鹅去氧胆酸钠与鹅去氧胆酸钠间存在显著性差异.药理实验表明牛磺鹅去氧胆酸钠具明显的平喘、抗炎和解热作用,其作用强于鹅去氧胆酸钠.     

Inhaled PYY(3–36) dry-powder formulation for appetite suppression

Objective: Peptide YY3–36 [PYY(3–36)] has shown efficacy in appetite suppression when dosed by injection modalities (intraperitoneal (IP)/subcutaneous). Transitioning to needle-free delivery, towards inhalation, often utilizes systemic pharmacokinetics as a key endpoint to compare different delivery methods and doses. Systemic pharmacokinetics were evaluated for PYY3–36 when delivered by IP, subcutaneous, and inhalation, the systemic pharmacokinetics were then used to select doses in an appetite suppression pharmacodynamic study.

Methods: Dry-powder formulations were manufactured by spray drying and delivered to mice via nose only inhalation. The systemic plasma, lung tissue, and bronchoalveolar lavage fluid pharmacokinetics of different inhalation doses of PYY(3–36) were compared to IP and subcutaneous efficacious doses. Based on these pharmacokinetic data, inhalation doses of 70:30 PYY(3–36):Dextran T10 were evaluated in a mouse model of appetite suppression and compared to IP and subcutaneous data.

Results: Inhalation pharmacokinetic studies showed that plasma exposure was similar for a 2?×?higher inhalation dose when compared to subcutaneous and IP delivery. Inhalation doses of 0.22 and 0.65?mg/kg were for efficacy studies. The results showed a dose-dependent (not dose proportional) decrease in food consumption over 4?h, which is similar to IP and subcutaneous delivery routes.

Conclusions: The pharmacokinetic and pharmacodynamics results substantiate the ability of pharmacokinetic data to inform pharmacodynamics dose selection for inhalation delivery of the peptide PYY(3–36). Additionally, engineered PYY(3–36):Dextran T10 particles delivered to the respiratory tract show promise as a non-invasive therapeutic for appetite suppression.     

Tanshinol sustained-release pellets with absorption enhancer: optimization,characterization, pharmacokinetics and pharmacodynamics

The objective of this study was to develop tanshinol sustained-release pellets (TS–SRPs) for the treatment of angina. Considering the poor intestinal absorption of TS, sodium caprate (SC) was used as an absorption enhancer for bioavailability improvement. Single-pass intestinal perfusion in rats demonstrated that the permeability of TS was remarkably enhanced, when the weight ratio of TS to SC was 1:3. Then, the cores were prepared with TS, SC and MCC at a weight ratio of 1:3:16 via extrusion–spheronization, followed by coating with Eudragit^® RS30D/RL30D dispersion (9:1, w/w). In vitro release studies revealed that release methods and rotation rates had no significant effects on the drug release of optimized TS–SC–SRPs except for the dissolution media. The release behavior was characterized as non-Fick diffusion mechanism. The pellets possessed a dispersion-layered spherical structure and were stable during three months of storage at 40?°C/75% RH. Compared with TS immediate-release pellets, the AUC_0–24 in healthy rabbits was increased by 1.97-fold with prolonged MRT (p?相似文献   

A single subcutaneous administration of a sustained-release ivermectin suspension eliminates Psoroptes cuniculi infection in a rabbit farm

Abstract

Background: Psoroptes cuniculi mites are the most common ear parasites infesting breeding female rabbits. The suffering rabbits show cutaneous signs of the infestation in the ears and are prone to secondary infections.

Objectives: This trial was conducted to eliminate P. cuniculi in farm rabbits with a sustained-release ivermectin-loaded solid dispersion suspension (IVM-SD) suspension, and studied the stability of the formulation.

Animals: There were 986 breeding female Hyplus rabbits naturally infected with P. cuniculi.

Methods: All rabbits infected with P. cuniculi were subcutaneously administered with a single dose of IVM-SD suspension at 2?mg/kg body weight. Twenty-seven rabbits with severe infections were observed daily and examined on days 0 and 14 to score the lesions and count mites in crusts.

Results: Fourteen days after the treatment no live mites were detected, demonstrating 100% therapeutic efficacy. The mean lesion scores decreased from 4.33 to 0.11 in the left ears and from 4.22 to 0.22 in the right ears. No reinfection occurred within 60?days of treatment.

Conclusions: A single subcutaneous administration of the IVM-SD suspension at 2?mg/kg was effective in eliminating P. cuniculi infection in the rabbit farm.     

Formulation and evaluation of novel coated floating tablets of bergenin and cetirizine dihydrochloride for gastric delivery

A novel coated gastric floating drug-delivery system (GFDDS) of bergenin (BN) and cetirizine dihydrochloride (CET) was developed. First, the pharmacodynamic studies were performed and the results revealed that the new compounds of bergenin/cetirizine dihydrochloride had comparative efficacy as commercial products (bergenin/chlorphenamine maleate) but with fewer side effects on central nervous system (CNS). Subsequently, bergenin was formulated as an extended-release core tablet while cetirizine dihydrochloride was incorporated into the gastric coating film for immediate release. The formulation of GFDDS was optimized by CET content uniformity test, in vitro buoyancy and drug release. Herein, the effects of sodium bicarbonate (effervescent), hydroxypropyl methylcellulose (HPMC, matrix polymer) and coating weight gain were investigated respectively. The optimized GFDDS exhibited good floating properties (buoyancy lag time < 2?min; floating duration > 10?h) and satisfactory drug-release profiles (immediate release of CET in 10?min and sustained release of BN for 12?h). In vivo gamma scintigraphy proved that the optimized GFDDS could retain in the stomach with a prolonged gastric retention time (GRT) of 5?h, and the coating layer showed no side effect for gastric retention. The novel coated gastric floating drug-delivery system offers a new approach to enhance BN’s absorption at its absorption site and the efficacy of both CET and BN.     

生物活性测定法评价银黄注射液解热质量的实验研究

目的建立银黄注射液生物活性测定法的质量标准。方法用内毒素造成家兔发热模型,观察银黄注射液的解热作用,以采用生物活性测定法评价药品质量。结果静脉注射细菌内毒素可引起家兔稳定的发热,银黄注射液对细菌内毒素所致家兔体温升高有明显抑制作用。结论可以采用药物对细菌内毒素所致家兔发热模型的影响评价银黄注射液的生物活性。     

基层医院呼吸系统临床抗菌药物的给药分析

目的 调查基层医院呼吸科住院患者抗菌药物的应用情况,分析药效、药动学对制定、优化给药方案的指导意义,为临床合理用药提供依据。方法 随机抽查和统计2004年1月至12月无锡市锡山人民医院呼吸科住院患者的病历,了解常用抗菌药物及其用法、用量和临床应用以及病原菌检查,并调查临床医师依据药效、药动学制定、优化给药方案的情况,结合特征患者的病案资料进行分析。结果 呼吸科抗菌药物以喹诺酮类和头孢菌素类使用频率较高,在抗菌药物的给药方案上根据病原菌检查选择药物,依据PD/PK制定给药方案较为合理。结论 使用抗菌药物前送检标本、依据抗菌药物PD/PK对制定给药方案有重要意义。     

乌司他丁治疗急性胰腺炎的临床疗效评价

目的: 观察乌司他丁(UTI)治疗各型急性胰腺炎(AP)的临床疗效。方法: 将102 例急性胰腺炎患者随机分成2 组,对照组51 例(轻症38 例、重症I 型13 例);治疗组51 例(轻症38 例、重症I 型13 例)。对照组采用综合基础治疗,治疗组在综合基础治疗的基础上加用乌司他丁。按痊愈、显效、有效和无效四级评定疗效。结果: 治疗组轻症有效率为92.1 %,重症I 型为84.6 %;对照组轻症有效率为71.1 %,重症I 型为38.5 %,两组有显著差异性(P<0.05),治疗组对腹痛、血尿淀粉酶、白细胞和TB等的恢复明显优于对照组(P<0.05)。结论: 乌司他丁用于治疗急性水肿型胰腺炎和重症I型均有较好疗效,不良反应较少。