他克林的合成

抗早老性痴呆药他克林可由苯胺为原料，经靛红、邻氨基苯甲腈制备。５步反应总收率４７％。     

他克林的合成研究

目的：合成抗早老性痴呆药他克林。方法：以邻氨基苯甲酸为原料,经缩合,氯化,氨化反应,制得他克林,结果：每步反庆均经改进,总收率达40．7％,所得产品熔点,IR,^1HNMR光谱数据,与文献报道值一致。结论：本工艺路线方法简单,原料易得,易工业化生产。     

盐酸他克林前体药物的合成

目的：增加盐酸他克林的脂溶性。方法：将他克林与不同的酸酐反应，合成系列不同的地克林前体药物。结果：所合成的化合物经紫外，红外，核磁，质谱等初步鉴定为目标化合物。结论：该法有助于他克林前体药物的研究。     

他克林衍生物及其类似物的研究进展

他克林是一个选择性较好但毒副作用明显的乙酷胆碱酯酶抑制剂。为了克服其不足，许多他克林衍生物和类似物都已被合成并进行了药理研究。从他克林的芳环、脂环和侧链氨基等3个方面对他克林衍生物及类似物的合成和药理研究进行综述。     

克林沙星合成路线图解

克林沙星合成路线图解ＧＲＡＰＨＩＣＡＬＳＹＮＴＨＥＴＩＣＲＯＵＴＥＳＯＦＣＬＩＮＡＦＬＯＸＡＣＩＮ刘明亮郭惠元＊（中国医学科学院、中国协和医科大学医药生物技术研究所，北京１０００５０）ＬＩＵＭｉｎｇ－Ｌｉａｎｇ，ＧＵＯＨｕｉ－Ｙｕａｎ＊（Ｉｎｓｔｉｔ...     

高效液相色谱法测定盐酸他克林的含量

HPLC法测定盐酸他克林的含量。采用十八烷基硅烷键合硅胶填充柱，流动相为0.2％磷酸三乙胺溶液－乙腈（80：20，v／v），检测波长为240nm，最低检测浓度为10ng／ml（S／N＝3），在0．5～3．0μg／ml范围内呈良好的线性关系，日内及日间相对标准差均小于2．0％。     

盐酸克林霉素合成工艺

盐酸克林霉素合成工艺ＳＹＮＴＨＥＴＩＣＰＲＯＣＥＳＳＯＦＣＬＩＮＤＡＭＹＣＩＮＨＹＤＲＯＣＨＬＯＲＩＤＥ吴为忠（苏州第四制药厂，江苏２１５００８）ＷＵＷｅｉ－Ｚｈｏｎｇ（ＳｕｚｈｏｕＮｏ．４ＰｈａｒｍａｃｅｕｔｉｃａｌＦａｃｔｏｒｙ，Ｊｉａｎｇｓｕ２...     

基于他克林的多靶点乙酰胆碱酯酶抑制剂的研究进展

乙酰胆碱酯酶(acetylcholinesterase,AChE)是目前治疗阿尔采末病(Alzheimer’s disease,AD)的一个重要靶点。其中基于他克林的二联体(dimeric)和杂合体(hybrid)的研究得到广泛重视。设计思路正由同时结合AChE双位点提高抑制活性和选择性转变为针对AD多靶点定向作用的开发。该文综述了基于他克林的二联体或杂合体的抗AD研究进展及对其展望。     

他克林治疗阿尔采末病:在中国的多中心双盲研究

目的：验证他克林治疗轻至中度阿尔采末病（ＡＤ）的疗效。方法：轻至中度ＡＤ病人６８例完成验证,其中３４例（男性１８例,女性１６例,年龄６７ａ±７ ａ）用他克林自 １０ ｍｇ,ｐｏ, ｑｉｄ起,另外 ３４例（男性 １８例,女性 １６例,年龄 ６７ ａ±９ ａ）用安慰剂（淀粉）自 １０ ｍｇ,ｐｏ, ｑｉｄ起。 ２组每 ６ Ｗｋ日量各增加 ４０ｍｇ,最高日量 ４０ ｍｇ,ｐｏ, ｑｉｄ。总疗程均为２４ ｗｋ。结果：他克林组在认知功能、日常生活及总体疗效方面改善率均显著高于安慰剂组（ Ｐ＜ ０． ０５或０．０１）,他克林副作用主要为胃肠道反应,包括ＡＬＴ升高（１４％）。结论：他克林治疗轻至中度ＡＤ病人有效。     

Quantitative Whole-Body Autoradiographic Determination of Tacrine Tissue Distribution in Rats Following Intravenous or Oral Dose

Tacrine (l,2,3,4-tetrahydro-9-acridinamine) has been employed in diverse clinical situations but has recently been of considerable interest for the treatment of cognitive deficits associated with senile dementia (Alzheimer's disease). The present studies examined tissue distribution of radiolabeled tacrine by quantitative whole-body autoradiography. Tacrine radioequivalents were widely distributed to tissue following iv or peroral dose, with an apparently prolonged absorption phase following po dose. The presence of high levels of activity in kidneys and ureters indicates a major role for urinary excretion, but there is also evidence for biliary excretion and direct secretion of compound or metabolites into the intestinal lumen. Tacrine was rapidly taken up into the brain and demonstrated regional localization to cortex, hippocampus, thalamus, and striatum. Although the inhibition of acetylcholinesterase by tacrine is well documented, regional uptake in brain did not correlate consistently with distribution of the enzyme, supporting suggestions by others that the alleged action of tacrine in treatment of senile dementia may be by mechanisms other than cholinesterase inhibition.     

Alzheimer's disease: Tacrine and tacrine metabolite concentrations in plasma and cognitive change

In a clinical trial of tacrine in patients with Alzheimer's disease, improvement, measured by changes on both total (ADAST) and the cognitive sub-component (ADASC) of the Alzheimer's Disease Assessment Scale (ADAS) over a 6-week period, correlated significantly with plasma levels of tacrine. Change on the ADAS (both total and the cognitive subcomponent) also correlated significantly with three monohydroxylated metabolites of tacrine 1, hydroxy-tacrine (1-OH-THA), 2, hydroxy-tacrine (2-OH-THA), and 4, hydroxy-tacrine (4-OH-THA). However, changes of the relatively small non-cognitive component of the ADAS were not significantly correlated with plasma levels of tacrine. Multiple correlational analysis revealed that the combined influences of these metabolites were no greater than the effects of tacrine alone in ameliorating the symptoms of Alzheimer's disease. An alternative measure of cognitive performance, the Mini Mental State Exam (MMSE) did not correlate significantly with plasma concentrations of tacrine or its metabolites. Tacrine and these metabolites are bound to plasma proteins. In 10 patients with Alzheimer's disease receiving tacrine, the percentage of tacrine, 1-OH-THA, 2-OH-THA, and 4-OH-THA, that was free in plasma was found to be 19.7 ± 3.3, 51.3 ± 7.7, 40.7 ± 6.9, and 42.4 ± 6.3 (mean ± SD), respectively. © Wiley-Liss, Inc.     

盐酸多奈哌齐的合成

4-哌啶甲酸甲酯经N-苄基取代、KBH4/ZnCl2还原、Swern氧化得到1-苄基-4-哌啶甲醛(5);3-(3,4-二甲氧基苯基)丙烯酸经催化氢化、闭环生成5,6-二甲氧基-1-茚酮(8).5和8再经Aldol缩合、催化氢化、成盐制得盐酸多奈哌齐,总收率33%(以4-哌啶甲酸甲酯计).     

富马酸奈拉西坦的合成

苄胺和衣康酸经缩合、氯化及酰胺化得到1-苄基-4-氨甲酰基-2-吡咯烷酮,再经脱水、高压氢化、成盐等反应制得富马酸奈拉西坦,总收率接近44%.     

占诺美林草酸盐的合成

以3-吡啶甲醛为起始原料，经加成、环合、亲核取代、甲基化、还原及成盐等反应合成了占诺美林草酸盐，改进了中间体的分离纯化，简化了操作，总收率14．1％。     

Response Surface Methodology to Investigate the Iontophoretic Delivery of Tacrine Hydrochloride

No HeadingPurpose. The objective of this work was to apply response surface approach to investigate the main and interaction effects of delivery parameters for iontophoretic delivery of tacrine HCl in vitro.Methods. Iontophoresis was used to deliver tacrine HCl across rat skin. Experiments were performed according to Box-Behnken design to evaluate effects of drug concentration (X₁), current density (X₂), and donor buffer molarity (X₃) on cumulative drug delivered in 24 h (Y₁), 6 h (Y₂), iontophoretic flux (Y₃), and post-iontophoretic flux (Y₄).Results. Mathematical model for Y₁ was Y₁ = 0.653 + 0.163 * X₁ + 0.456 * X₂ – 0.156 * X₃ + 0.190 * X₁X₂ + 0.139* X₃X₃. Response surface plot indicated that at low level of X₂ (0.1mA/cm²), X₁ had little effect on Y₁. However, at high level of X₂ (0.5 mA/cm²), Y₁ significantly increased from 0.75 mg/cm² to 1.46 mg/cm² when X₁ increased from 1% to 9%. Regression equations predicted responses for Y₁ to Y₄, for optimal formulation, which were in reasonably good agreement with experimental values.Conclusions. Experimental design methodology revealed an interaction between drug concentration and current density, which would have been difficult to predict from one factor at a time classic experimental approach.     

乙酰胆碱酯酶抑制剂他克林和多奈哌齐抗星形孢菌素致凋亡作用的比较

目的用星形孢菌素(STS)诱导NG108-15和HeLa细胞凋亡,观察他克林和多奈哌齐是否具有抗凋亡作用。方法MTT测定分析细胞损伤状况;相差显微镜和Hoechst 33342染色观察细胞及胞核形态;DNA提取及琼脂糖凝胶电泳观察凋亡特征性梯带;免疫印迹分析Bcl-2和Bax的表达水平。结果经0.1 mmol·L^-1他克林预处理后,由STS诱导的NG108-15细胞凋亡受到明显抑制。多奈哌齐预处理无保护作用。免疫印迹表明他克林可显著抑制Bax的表达,同时还可促进Bcl-2的表达。多奈哌齐和他克林预处理对STS诱导的HeLa细胞损伤无明显的保护作用。结论 他克林的抗凋亡作用与AChE抑制作用似乎没有明显关联。他克林对STS损伤的保护作用有细胞选择性。