Subthreshold oscillations generated by TTX-sensitive sodium currents in dorsal cochlear nucleus pyramidal cells

During intracellular recordings in rodent brainstem slice preparations, dorsal cochlear nucleus (DCN) pyramidal cells (PCs) exhibit characteristic discharge patterns to depolarizing current injection that depend on the membrane potential from which the responses are evoked. When depolarized from hyperpolarized potentials, PCs can respond with a short-latency action potential followed by a long silent interval (pauser) or a train of action potentials with a long latency (buildup). During the silent intervals in a pauser or a buildup response, the membrane potential slowly depolarizes towards spike threshold, often exhibiting distinct voltage oscillations of 1–2 mV before the first spike. The subthreshold voltage oscillations were investigated using whole cell recordings from DCN PCs in rat pup (P10–14) brainstem slices. The oscillations were unaffected by excitatory and inhibitory neurotransmitter antagonists, and were not temporally locked to the onset of the depolarization. The oscillations typically became larger as spike threshold was approached, and had a characteristic frequency between 40 and 100 Hz. In the presence of tetrodotoxin (TTX, 500 nM), the oscillations were significantly suppressed, and could not be evoked at any voltage below or above spike threshold. The oscillations were not blocked by phenytoin or Cd²⁺, but they were affected by prior activity in the neuron for approximately 1 s. We conclude that voltage-gated Na⁺ channels are required to generate membrane oscillations during the buildup phase. We suggest that the subthreshold oscillations play a role in controlling spike timing in PCs when the membrane potential slowly approaches, or hovers near, spike threshold.     

氯化钾缓释片对充血性心力衰竭104例的保钾疗效

充血性心力衰竭患者１０４例（正在使用地高辛加排钾利尿剂）随机均分为氯化钾缓释片（Ｓｌｏｗ－Ｋ）及普通氯化钾片（ＲＫＣｌ）２组进行保钾治疗２ｗｋ,而后改换进入另１组作自身对照。结果：Ｓｌｏｗ－Ｋ组治疗１ｗｋ末血钾即显著增加,服药承受性较好;ＲＫＣｌ组治疗２ｗｋ末血钾才显著增加,且服药承受性较差,不良反应高达２６．９％。＊Ｐ＜０．０１。±２８９ｍｇ／ｄ）。在验证过程中所用利尿剂剂量不变。３观察项目服药前测血钾（Ｋ）、钠（Ｎａ）、氯（Ｃｌ）、肌酐（Ｃｒ）、尿素氮（ＢＵＮ）和心电图。服药后每１ｗｋ复查Ｋ,Ｎａ,Ｃｌ和心电图,每２ｗｋ加复查Ｃｒ和ＢＵＮ。结果Ｓｌｏｗ－Ｋ组１０４例患者全部完成研究。ＲＫＣｌ组在研究过程中共脱落１３例（其中坚持出院者３例,心衰严重救治无效而死亡３例,因胃肠道不良反应难以耐受而改服Ｓｌｏｗ－Ｋ导致研究中断者７例）,故能完成统计分析者为９１例。血清电解质治疗前后的变化２组治疗前的血Ｋ＋参数总体看来尚属正常范围,可能是由于在住院后短时间内测定血Ｋ＋,．所用排Ｋ＋利尿剂时间不长的关系。其中只有５例的血Ｋ＋在２－３ｍｍｏｌ／Ｌ的低水平。加服Ｓｌｏｗ－Ｋ片或ＲＫＣｌ片后,均能有效地使患者的血Ｋ＋提升?     

Preparation and evaluation of sodium diclofenac controlled-release tablets

The dissolution behaviour of a direct compression compact prepared with sodium diclofenac and dibasic calcium phosphate (DCP) in different weight ratios with or without Biosoluble polymer^® (acrylic-based resin) was investigated in distilled water and in a medium with changing pH. The results indicate that the amount of sodium diclofenac released from the compact was dependent on the amount of drug and DCP used in the compact, and was also controlled by the amount of Biosoluble polymer^® added. A chemical reaction forming diclofenac acid might occur on the surface of the sodium diclofenac compact during exposure to the acidic medium, which was confirmed by diffuse-reflectance spectroscopy. The tablet with a 12 weight ratio of sodium diclofenac to DCP exhibited a sustained-release behaviour, similar to commercial sustained-release products (Voltaren SR-100^® and Grofenac Retard^®), but a lower release rate was found as compared to the commercial products. The dissolution behaviour of the study tablet and the commercial products was found to be dependent on the dissolution medium and the rotating speeds. Glass beads were added to the dissolution assembly to simulate the influence of food, and the enhanced friction between tablet and glass beads might result in a higher dissolution rate of the tablet and the commercial products.     

医疗机构中药制剂创新和持续发展能力评价研究

目的 对医疗机构中药制剂创新和持续发展能力进行综合评价,为行政管理部门决策及各医院中药制剂可持续发展提供参考。方法 以浙江省133家医疗机构中药制剂调研数据为对象,利用层次分析法构建医疗机构中药制剂创新和持续发展能力评价体系,通过反向传播神经网络构建中药制剂室/中心评价体系预测模型。结果 构建的医疗机构中药制剂创新和持续发展能力评价指标体系包含4项二级指标以及19项三级指标,其中研发品种数、超百万品种数、注册品种数、研发方式、制剂室面积指标的权重值较高,分别为 0.15758、0.12928、0.09343、0.07879和0.07458。熵权法结合层次分析法的指标权重构建反向传播神经网络,Levenberg-Marquardt算法和Scaled Conjugate Gradient算法训练模型总体相关系数分别为0.98983和0.9348。结论 本研究构建了一个科学有效的医疗机构中药制剂创新和持续发展能力综合评价体系,可实现对医疗机构中药制剂综合能力的预测评价。     

维拉帕米脉冲控释片的设计和制备

目的：针对高血压、心绞痛常在凌晨发作的特点,研制夜间服药、凌晨释放的维拉帕米(VR)脉冲控释片。方法：全面考察影响药物释放滞后时间的因素。选用3种强崩解剂的不同用量,考察片芯崩解剂对时滞的影响。通过均匀设计实验考察外层包衣的组成和片剂的硬度,多元回归筛选最优处方,并考察不同溶出条件对控释效果的影响。结果：片芯所用的3种崩解剂以羧甲基淀粉钠的崩解性能较好,用量设计在25％左右。外层包衣处方中PEG 6000增加,氢化蓖麻油(HCO)、乙烯-醋酸乙烯共聚物(EVA)用量减少,硬度减小,释放滞后时间减少。由此确定释放滞后时间为3和5h的两个基本处方。结论：VR压制包衣片在体外溶出实验中能实现脉冲释药,并能通过调节辅料用量实现不同控释效果。     

外用药物制剂药品生产质量管理规范实施现状分析与研究

本文从外用药物制剂实施现状出发,通过在数据调研和大量文献收集的基础上,对从药品生产质量管理规范(GMP)的发展及其在我国的推行历史角度,分析并阐述了现阶段外用药物制剂GMP的实施状况,并对某制药集团属下25家药企实施2010版GMP的现状进行调查分析。由于历史发展的原因促使药品管理尚未完全规范以外,GMP标准的过时性和落后性影响了我国GMP工作的深入实施。只有保证了日常的GMP实施,才能有效地保证药品生产的高质量、低风险,有效地促进药品生产的质量保障,使药品真正达到国际水平,走向现代化、国际化。     

Pragmatic clinical trials in the context of regulation of medicines

Abstract

The pragmatic clinical trial addresses scientific questions in a setting close to routine clinical practice and sometimes using routinely collected data. From a regulatory perspective, when evaluating a new medicine before approving marketing authorization, there will never be enough patients studied in all subgroups that may potentially be at higher risk for adverse outcomes, or sufficient patients to detect rare adverse events, or sufficient follow-up time to detect late adverse events that require long exposure times to develop. It may therefore be relevant that post-marketing trials sometimes have more pragmatic characteristics, if there is a need for further efficacy and safety information. A pragmatic study design may reflect a situation close to clinical practice, but may also have greater potential methodological concerns, e.g. regarding the validity and completeness of data when using routinely collected information from registries and health records, the handling of intercurrent events, and misclassification of outcomes. In a regulatory evaluation it is important to be able to isolate the effect of a specific product or substance, and to have a defined population that the results can be referred to. A study feature such as having a wide and permissive inclusion of patients might therefore actually hamper the utility of the results for regulatory purposes. Randomization in a registry-based setting addresses confounding that could otherwise complicate a corresponding non-interventional design, but not any other methodological issues. Attention to methodological basics can help generate reliable study results, and is more important than labelling studies as ‘pragmatic’.     

他克莫司缓释胶囊与他克莫司胶囊的临床对照试验

目的 比较和评价首次肾移植受者使用他克莫司缓释胶囊和他克莫司胶囊治疗的安全性和有效性.方法 11家中心的241例肾移植受者随机分配为试验组(应用他克莫司缓释胶囊+吗替麦考酚酯+皮质激素)和对照组(应用他克莫司胶囊+吗替麦考酚酯+皮质激素),观察时间从移植当天至术后12周.试验组受试者每天上午一次性服用他克莫司缓释胶囊,对照组受试者每天早晚分2次服用他克莫司胶囊.两组试验药物的起始剂量均为0.1～0.15 mg·kg-1·d-1.分别在治疗前和治疗后第1、3、7、14、28、56和84 d各随访1次.对两组受者用药的有效性、安全性、依从性以及不良反应进行对比分析.结果 进入符合方案分析集者共223例,其中试验组111例,对照组112例.两组受者的平均年龄、性别、原发病的差异均无统计学意义,各有12例发生急性排斥反应.对照组和试验组分别有36例(32.1%)和37例(33.3%)发生与试验药物相关的不良反应.无受者连续3 d未按照方案服用药物.两组治疗后期较治疗前期的服药量均减少,且组内差异有统计学意义(P<0.05).治疗早期两组血他克莫司浓度较接近,从28 d开始,试验组血药浓度低于对照组,但差异无统计学意义.结论 从药物安全性、药物治疗的有效性、相关不良反应以及受者依从性各方面分析显示,每天1次的他可莫司缓释胶囊均非劣效于每天2次的他克莫司胶囊,在临床应用中,用他克莫司缓释胶囊代替他克莫司胶囊是切实可行的.

Abstract：

Objective To compare the efficacy and safety of twice-daily tacrolimus (Tacrolimus BID; Prograf) vs once-daily prolonged release tacrolimus (Tacrolimus QD; Advagraf), combined with steroids and mycophenolate mofetil in preventing acute rejection in De Novo renal transplantation patients. Methods 241 patients from 11 centers were randomized into two groups with 3 months observation period post-transplantation. Advagraf was administered as a single oral dose in the morning (initially 0. 1-0. 15 mg/kg every day) and Prograf was administered in two equal oral doses 12h apart (initially 0. 1-0. 15 mg/kg). Study visits were scheduled for days 1, 3, 7, 14, 28, 56, 84post-transplantion. The efficacy, safety, compliance and adverse effects were compared between two groups. Results Totally 223 patients completed the study. The two groups were comparable in age,gender and primary disease. There were 12 episodes of acute rejection in each group. There was no graft loss or patient death in both groups. The incidence of drug related adverse events was 32. 1 %and 33. 3% respectively in the control and experimental groups. Dosage was decreased in both groups and there was significant difference in each group. The trough level was similar at the initiate period.Twenty-eight days post-transplantation the trough level in the Advagraf group was lower than in the Prograf group. Conclusion Advagraf has the same efficacy, safety and drug related adverse effects as Prograf. It is practical and feasible for Advagraf substitute for Prograf in clinical practice.     

放射性核素示踪技术用于地尔硫(卓)缓释粘附材料的研究

目的　筛选口服缓释地尔硫的生物粘附材料。方法　通过测定可用于制药的粘附聚合物羟丙基甲基纤维素 (HPMC)类、卡波姆 (Cb)类、聚维酮 (PVP)K30和羧甲基纤维素钠 (CMCNa)与大鼠胃和肠黏膜的最大粘附力及其在大鼠胃和肠道的排空速度 ,筛选出最佳粘附材料 ,再用放射性核素体内示踪技术验证其在犬胃、肠的粘附能力。结果　Cb与大鼠肠黏膜的粘附力为 19.6～ 31.0g,显著大于其他材料 (4.0～ 2 4 .3g)。Cb934在大鼠胃内的排空半衰期为 7.4h,大于其他材料。含5 0 %Cb934的粘附颗粒能将其在犬胃内的排空半衰期延长 1倍 ;8h时犬小肠含Cb9345 0 %和 10 0 %的粘附颗粒滞留量分别为 2 9.6 %和 5 5 .1% ,而不含Cb934的粘附颗粒 6h时即为 0。结论　Cb934可作为口服缓释剂生物粘附材料。