环孢素A壳聚糖眼用凝胶的制备及质量控制

目的:制备环孢素A壳聚糖眼用凝胶并建立其质量控制方法。方法:采用脱乙酰度90%的壳聚糖为凝胶基质、丙三醇为助溶剂和助悬剂制备眼用凝胶;采用高效液相色谱(HPLC)法测定其中主药的含量;并考察该制剂的稳定性;同时进行家兔刺激性及眼角膜滞留实验。结果:所制制剂为淡乳白色半透明凝胶,鉴别等符合2005年版《中国药典》中的相关规定;环孢素A检测浓度的线性范围为40～900mg·mL-1(r=0.9994),平均回收率为99.20%(RSD=0.61%,n=9);该制剂经冷冻、离心后未见分层和变色现象;对兔眼未见刺激性发生,在眼角膜滞留时间约为10～20min。结论:该制剂制备工艺简便可行,质量稳定可控。     

利福平滴眼液制备方法的改进

目的 :建立一种简易、准确地制备利福平滴眼液的方法。方法 :以计算量的盐酸溶解利福平 ,然后用等摩尔量的氢氧化钾中和 ,生成处方量的氯化钾。结果 :利用酸碱中和反应不但解决了利福平溶解困难和滴眼液的渗透压问题 ,还可避免以乙醇为溶剂而产生对眼睛的刺激性。结论 :本方法设计巧妙 ,制备简单 ,质量可控。     

Cryoprotective Effects of Saccharides on the Freeze-Drying of Sonicated Vesicles of the Novel Lipid A Analog,E5531

A sonicated dispersion of the novel lipid A analog, E5531, was feeze-dried in the presence of various additives such as saccharides and polyalcohols, and their cryoprotective effects were investigated. Fusion of the vesicles was examined by measuring fluorescence energy transfer and size distribution. Cryoprotective ability differed among the addtive species. The addition of polyalcohols led to considerable fusion. Although monosaccharides, similar to disaccharides, completely prevented the fusion of the vesicles during lyophilization, they showed far less ability to retain the entrapped calcein in the vesicles compared to disaccharides. Differential scanning calorimetry heating profiles of vesicles that had been lyophilized with various additives were obtained. Disaccharides and monosaccharides again resulted in markedly different thermal properties of the vesicles. This variety in cryoprotective ability of saccharide species can be attributed to differences in their interaction with the E5531 head group.     

Effects of acute and chronic administration of MCI-225, a new selective noradrenaline reuptake inhibitor with 5-HT3 receptor blocking action, on extracellular noradrenaline levels in the hypothalamus of stressed rats

In the present study, we investigated the effects of acute and chronic systemic administration of MCI-225 (4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine monohydrate hydrochloride), a newly-developed selective noradrenaline (NA) reuptake inhibitor with 5-HT3-receptor-blocking action, on extracellular NA levels in the hypothalamus of stressed and non-stressed rats by utilizing intracerebral microdialysis. Acute administration of MCI-225 (3 and 10 mg/kg, p.o.) significantly and dose-dependently increased extracellular NA levels in the hypothalamus in non-stressed rats. Footshock for 20 min also significantly increased NA levels in the hypothalamus of both groups of rats pretreated with vehicle and MCI-225. Although chronic administration of MCI-225 (3 or 10 mg/kg, p.o. for 14 days) did not alter the basal extracellular NA levels in the hypothalamus, the stress-induced increases in extracellular NA levels were significantly lower in rats chronically treated with MCI-225 (10 mg/kg) than those of rats pretreated with vehicle for the same period. The increase in extracellular NA levels induced by MCI-225 challenge (3 or 10 mg/kg, p.o.) were not different between rats chronically treated with MCI-225 or vehicle. These results suggest that MCI-225 enhances extracellular NA levels in the hypothalamus in both non-stressed and stressed rats by inhibiting NA uptake and that chronic systemic administration of MCI-225 did not alter basal extracellular NA levels, but reduced the increase in NA release caused by footshock stress. These data suggest the possibility that MCI-225 might possess anxiolytic and/or antidepressant properties.     

A Novel Suspension Formulation Enhances Intestinal Absorption of Macromolecules Via Transient and Reversible Transport Mechanisms

Purpose

Medium chain fatty acid salts promote absorption by increasing paracellular permeability of the intestinal epithelium. Novel oily suspension (OS) formulation disperses a powder containing sodium caprylate and macromolecules such as octreotide or fluorescent dextran (FD). Formulation safety, macromolecule absorption and pharmacokinetic (PK)/pharmacodynamic (PD) were evaluated.

Methods

Octreotide/OS toxicity was evaluated in monkeys following 9 months of daily oral enteric-coated capsule administration. The OS permeation effect was also assessed in rats, using FD/OS and octreotide/OS preparations. Octreotide/OS effects on circulating growth hormone (GH) levels were also measured.

Results

Safety assessment of octreotide/OS in monkeys after 9 months showed minor drug-related findings, comparable to the injectable octreotide. Octreotide exposure levels were similar across the treatment periods. In rats, OS facilitated FD permeation up to 70 kDa in a reversible, spatial and dose-dependent manner, independent of the intestinal dosing site. Following OS administration, the staining pattern of the tight-junction protein, ZO-1, changed transiently, and a paracellular penetration marker, LC-biotin, permeated between adjacent epithelial cells. Enteral octreotide/OS absorption was dose-dependent and suppressed rat GH levels.

Conclusions

Oral octreotide/OS dosing was shown to be safe in monkeys. OS enhances intestinal absorption of active octreotide, likely by transient alteration of the tight junction protein complex.     

重组人甲状旁腺素相关肽Pro-Pro-[Arg11]-hPTH(1-34)-Pro-Pro的制备工艺及活性研究

该研究优化了工程菌pED-4P-[Arg11]hPTH(1-34)/BL21的表达条件,目的蛋白表达量可达50%以上;运用正交设计法,确定包涵体溶解及融合蛋白乙醇沉淀的最佳条件,融合蛋白经酸水解后进行阳离子交换柱层析,最后采用阶段洗脱,回收率约为11 mg/L发酵液.卵巢摘除大鼠模型验证了其药效学活性.该工艺稳定,简便,易于控制,为后期中试及大规模生产提供了思路.     

MCI-154, a Ca2+ sensitizer, increases survival in cardiomyopathic hamsters.

To assess the long-term efficacy of a Ca2+ sensitizer MCI-154, 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate, on chronic heart failure, we studied the effects of the agent on the life span of cardiomyopathic hamsters of the BIO-14.6 strain. At approximately 150 days of age, 210 male hamsters were randomly divided into three groups: MCI-154 0.1 mg kg(-1), day(-1)(MCI-154-low), MCI-154 1 mg kg(-1) day(-1) (MCI-154-high), and control group. The median survival time in control, MCI-154-low and MCI-154-high groups was 227, 243 and 260 days after the start of treatment, respectively. Final survival rate at 284 days in control, MCI-154-low and MCI-154-high groups was 0, 17.1 and 38.6%, respectively. The cumulative survival times in the two MCI-154 treated groups were significantly prolonged in comparison with that in the control group (P < 0.0001). Thus, the present study clearly showed that MCI-154 prolonged the life span of cardiomyopathic hamsters, suggesting that long-term therapy with MCI-154 would be promising in the treatment of congestive heart failure.     

双氯芬酸钠眼用即型凝胶的研制

目的：探讨双氯芬酸钠眼用即型凝胶的制备及质量控制方法。方法：以卡波姆-940为基质制备凝胶,采用高效液相色谱法测定双氟芬酸钠的含量。结果：本法线性关系良好,平均加样回收率为97．66％,RSD为0．62％。结论：本方法处方设计合理,制备方法简便,含量测定方法适用于本品质量控制。     

富马酸酮替芬眼用即型凝胶的研制

目的探讨富马酸酮替芬眼用即型凝胶的制备及质量控制方法.方法以卡波姆为基质制备凝胶,采用紫外分光度法测定含量.结果富马酸酮替芬浓度在1.42～11.42μg·ml-1范围内线性关系良好,平均回收率为99.54%.结论本方法处方设计合理,制备方法简便,含量测定方法适用于本品质量控制.     

Attentional bias in active smokers, abstinent smokers, and nonsmokers

Attentional bias was studied with a modified version of the Stroop test in active smokers, abstinent smokers, and nonsmokers. The task was color-naming of incongruent color-words, smoking-related words, and neutral words. The results showed that the active smokers used longer verbal reaction time (VRT) to smoking-related words compared to abstinent smokers i.e., indicating stronger attentional bias in the active smokers. Furthermore, longer VRTs to the Stroop words compared to the smoking words and the neutral words were found only in nonsmokers and abstinent smokers. Finally, a significant negative correlation was found between attitudes against smoking and VRTs to the smoking-related words. Taken together the main finding was that the active smokers showed no differential response to the stimuli. This could be caused by a lack of ability to modulate attentional processes in active smokers.     

A Novel Phase Inversion-Based Process for the Preparation of Lipid Nanocarriers

Purpose. To develop and subsequently evaluate a novel phase inversion-based method used to formulate lipidic nanocapsules. Methods. Mechanical properties of emulsions prepared by multi-inversion phase processes were investigated using a drop tensiometer. Based on the results obtained, a formulation process was developed and a new type of nanocarrier was prepared. These particulates were sized by photon correlation spectroscopy and were visualized by atomic force microscopy and transmission electronic microscopy. Differential scanning calorimetry was also performed. Results. The marginally cohesive but stable interfacial properties of the initial system led to the formulation of lipidic nanocapsules that were composed of a liquid core surrounded by a cohesive interface and were dispersed in an aqueous medium. These related suspensions were stable upon dilution for several months. The control of the formulation parameters allowed an adjustment of the particle mean diameter in the range of 25-100 nm with a monodisperse size distribution. Conclusions. A novel and convenient process for the preparation of lipidic nanocapsules is described. The structure of these particulates resembles a hybrid between polymeric nanocapsules and liposomes. Such nanocapsules display a strong potential for drug delivery.     

Effects of MCI-727, a new antiulcer agent, on various gastric and duodenal lesions in experimental animals

Effects of a new antiulcer drug, MCI-727, on gastric and duodenal lesions, gastric secretion and gastric motility were studied in comparison with cimetidine and teprenone. MCI-727 dose-dependently (3-100 mg/kg, p.o. or i.d.) inhibited the development of acute gastric or duodenal lesions such as pyrolus ligation-, water-immersion stress-, indomethacin-, HCl-, HCl-ethanol-induced gastric lesions and cysteamine-induced duodenal lesions in rats and histamine-induced duodenal lesions in guinea pigs. These antiulcer effects exceeded those of cimetidine or teprenone. Repeated administration of MCI-727 (0.3-3 mg/kg/day, p.o., for 10 days) significantly promoted the spontaneous healing of acetic acid-induced chronic gastric ulcers. Concerning gastric acid secretion, MCI-727 selectively inhibited tetragastrin-stimulated acid secretion without effecting basal acid secretion and acid secretion by other stimuli. Cimetidine and teprenone inhibited acid secretion in several cases. MCI-727 and teprenone had inhibitory effects on gastric motility, although cimetidine had no effect. These results suggest that MCI-727 has a wide spectrum of antiulcer activity, and its mode of antiulcer action is different from that of cimetidine or teprenone.     

钙增敏剂MCI-154对内毒素血症大鼠心肌收缩系统钙敏感性的影响(英文)

目的:研究MCI-154对内毒素血症大鼠心肌收缩系统钙敏感性的影响.方法:利用皂素500 mg/L制备内毒素血症大鼠蜕膜右心室乳头状肌标本,用不同钙浓度的含或不含强心药物的激活液进行顺序激活,记录Ca~(2 )激活张力.结果:同正常对照组相比,内毒素血症大鼠蜕膜乳头状肌钙最大激活张力(T_(max))降低,pCa_(50)值下降.甲腈吡酮50μmol/L对上述异常无明显的改善作用.内毒素血症大鼠蜕膜乳头状肌经含MCI-154 10 μmol/L的激活液处理后,T_(max)和pCa_(50)值明显增加,与假休克组类似,明显高于内毒素血症组和内毒素血症 甲腈吡酮组值.MCI-154的上述作用还具有剂量依赖性.结论:大鼠内毒素血症后,心肌收缩系统对Ca~(2 )敏感性降低,MCI-154可明显增加内毒素血症大鼠心肌收缩蛋白对钙的敏感性,增加心肌钙最大激活张力.     

离子敏感型吲哚美辛眼用原位凝胶的制备与质量控制

目的以海藻酸钠为凝胶基质,羟丙基甲基纤维素（hydroxypropyl methyl cellulose,HPMC）为增黏剂,制备吲哚美辛离子敏感型眼用原位凝胶,并进行质量标准研究及释放度测定。方法通过对海藻酸钠与HPMC的配比研究,筛选最佳凝胶基质,制备吲哚美辛离子敏感型眼用原位凝胶;采用紫外分光光度法测定含量,用透析袋法进行体外释药实验,研究体外释药特性与机制。结果与吲哚美辛溶液相比,吲哚美辛离子敏感型眼用原位凝胶释药时间延长至8 h, 释药量均＞93%,而且具有良好的缓释效果。结论以海藻酸钠与HPMC制备的吲哚美辛离子敏感型眼用原位凝胶质量稳定,对眼部无刺激,且具有缓释、长效作用。     

4-F-PCP,a Novel PCP Analog Ameliorates the Depressive-Like Behavior of Chronic Social Defeat Stress Mice via NMDA Receptor Antagonism

Major depressive disorder is a leading cause of disability in more than 280 million people worldwide. Monoamine-based antidepressants are currently used to treat depression, but delays in treatment effects and lack of responses are major reasons for the need to develop faster and more efficient antidepressants. Studies show that ketamine (KET), a PCP analog, produces antidepressant effects within a few hours of administration that lasts up to a week. However, the use of KET has raised concerns about side effects, as well as the risk of abuse. 4 -F-PCP analog is a novel PCP analog that is also an NMDA receptor antagonist, structurally similar to KET, and might potentially elicit similar antidepressant effects, however, there has been no study on this subject yet. Herein, we investigate whether 4-F-PCP displays antidepressant effects and explored their potential therapeutic mechanisms. 4-F-PCP at 3 and 10 mg/kg doses showed antidepressant-like effects and repeated treatments maintained its effects. Furthermore, treatment with 4-F-PCP rescued the decreased expression of proteins most likely involved in depression and synaptic plasticity. Changes in the excitatory amino acid transporters (EAAT2, EAAT3, EAAT4) were also seen following drug treatment. Lastly, we assessed the possible side effects of 4-F-PCP after long-term treatment (up to 21 days). Results show that 4-F-PCP at 3 mg/kg dose did not alter the cognitive function of mice. Overall, current findings provide significant implications for future research not only with PCP analogs but also on the next generation of different types of antidepressants.     

Ionotropically Gelled Novel Hydrogel Beads: Preparation, Characterization and In vitro Evaluation

Prolonged release drug delivery system of stavudine was made by ionotropic gelation and polyelectrolyte complexation technique. Cross-linking reinforced chitosan-gellan complex beads were prepared by gelation of anionic gellan gum, the primary polymer, with oppositely charged counter ion to form beads which were further complexed with chitosan as a polyelectrolyte. The effect of this polymer on release profile of drug was studied. Beads without chitosan complexation were also made. The reaction of chitosan-gellan complex dominates the formation of skin layer on the surface of beads. Stavudine an antiretroviral drug was selected as novel drug for the experiment. The final formulations were subjected to in vitro evaluation and several characterization studies. Batches with gellan gum shows Higuchi model, while chitosan-gellan shows zero order release. All the batches with copolymer showed sustained the drug release more than 12 h, whereas with gellan gum alone showed up to 10 h. Batches with chitosan showed maximum drug encapsulation efficiency.     

Improvement of pentobarbital-induced heart failure by MCI-154, a novel and potent cardiotonic agent, in the dog heart-lung preparation

The efficacy of MCI-154, a new pyridazinone cardiotonic agent, in improving heart failure was assessed in dog heart-lung preparations in which cardiac function had been severely depressed by pentobarbital. MCI-154 in doses of 10-100 micrograms improved the cardiac function curve and restored it to the control level at 100 micrograms. At this dose, MCI-154 neither produced an increase in heart rate beyond the control value nor induced arrhythmias. The effects of MCI-154 were not affected by atenolol, a cardioselective beta 1-blocker. These results indicate that MCI-154 would be of potential use in the treatment of heart failure.     

The Novel Cognitive Enhancer ST101 Enhances Acetylcholine Release in Mouse Dorsal Hippocampus Through T-type Voltage-Gated Calcium Channel Stimulation

We recently developed a novel cognitive enhancer, ST101 (spiro[imidazo[1,2-a] pyridine-3,2-indan]-2(3H)-one), that activates T-type voltage-gated calcium channels (VGCCs). Here, we address whether T-type VGCC activation with ST101 mediates its cognitive effects in vivo and the relevance of T-type VGCC activation to acetylcholine (ACh) release in the hippocampus. Acute intraperitoneal administration of ST101 (1 mg/kg, i.p.) improved memory-related behaviors in both olfactory bulbectomized (OBX) and scopolamine-treated mice. Effects of ST101 administration were abolished by both intraperitoneal and intracerebroventricular pre-administration of the T-type VGCC inhibitor mibefradil. Acute administration of ST101 enhanced basal and nicotine-induced ACh release in the dorsal hippocampus in both OBX and sham-treated mice. Enhanced ACh release was abolished by infusion with mibefradil (10 μM) but not with the L-type VGCC inhibitor nifedipine (10 μM). As expected, significantly reduced CaMKIIα, PKCα, and ERK phosphorylation was restored by acute ST101 administration in the OBX mouse hippocampal CA1 region. Enhancement of CaMKIIα and PKCα but not ERK phosphorylation was inhibited by mibefradil (20 mg/kg, i.p.) pre-administration. Increased CaMKIIα and PKCα phosphorylation was confirmed by increased phosphorylation of GluR1, synapsin I, and NR1. Taken together, stimulation of T-type VGCCs is critical for the enhanced hippocampal ACh release and improved cognitive function seen following ST101 administration.