RP-HPLC法测定醋酸艾塞那肽的含量

目的建立测定醋酸艾塞那肽含量的方法。方法采用Global SP-120-5-C18-BIO(250mm×4.6mm,5μm)色谱柱;梯度洗脱;流动相A:乙腈-0.02mol·L-1磷酸二氢钠缓冲液(5∶95,含0.05%三乙胺,磷酸调pH2.5),流动相B:乙腈-0.02mol·L-1磷酸二氢钠缓冲液(70∶30含0.05%三乙胺,磷酸调pH2.5);检测波长为224nm;流速为1mL·min-1;柱温为30℃。结果艾塞那肽在0.475～2.375g·L-1范围内线性良好(r=0.9998);重现性RSD为0.74%;平均回收率为100.2%,RSD为0.5%(n=5);定量限为4.52ng。结论该方法准确、可靠,专属性强,可用于测定醋酸艾塞那肽的含量。     

重组艾塞那肽RP-HPLC法肽图分析

目的建立并验证胰蛋白酶裂解-反向高效液相色谱法进行重组艾塞那肽肽图分析研究。方法将重组艾塞那肽样品用胰蛋白酶水解,酶解所得的肽段通过反相高效液相色谱法进行分析,采用C_8色谱柱,以0.1%三氟乙酸(TFA)的水溶液为流动相A,以0.1%TFA的乙腈溶液为流动相B,梯度洗脱70min,得到重组艾塞那肽肽图,以此进行方法的专属性、重现性、定量限、批间同一性研究。结果本实验室制备的重组艾塞那肽可以通过胰蛋白酶裂解-RP-HPLC法进行肽图分析,专属性、重现性均满足要求,定量限为0.125mg/m L,三个批次间的肽图谱也完全一致。结论表明此方法简便可靠、准确度高、重复性好,验证研究可行,可用于重组艾塞那肽的质量控制。     

醋酸艾塞那肽在Wistar大鼠体内的药物代谢动力学研究

研究醋酸艾塞那肽（exendin-4）在Wistar大鼠体内的药物代谢动力学，组织分布以及排泄特征。IODOGEN（四氯二苯基苷脲）法制备^125I-exendin-4，大鼠皮下或静脉注射，^125I-exendin-4，以放射性核素示踪动力法检测血液中的药物浓度，由非房室模型评价药物动力学参数。同时研究了大鼠皮下注射^125I-exendin-4后的组织分布和排泄。大鼠皮下注射^125I-exendin-4后Tmax和t1/2分别是（0．25±0．02）h和（1．28±0．14）h，绝对生物利用度为（65．5±10．2）％；^125I-exendin-4的分布快速而广泛，其中以肾脏中最高，而在脑组织中只有微量^125I-exendin-4；^125I-exendin-4主要随尿液排泄。实验结果与国外公布的实验数据基本一致。醋酸艾塞那肽在大鼠中的药物代谢动力学参数为临床试验提供了科学依据。     

醋酸艾塞那肽在大鼠体内的代谢分布(英文)

目的研究醋酸艾塞那肽(exendin-4)在大鼠体内的组织分布。方法Iodo-GenTM法制备[125I]exendin-4,大鼠皮下注射[125I]exendin-4后,分别测定血浆或组织中的总放射性含量和酸沉淀放射性含量。结果[125I]exendin-4的酸沉淀放射性分布从高到低的顺序为肾脏>肺>膀胱>胰腺>肠>血浆>肾上腺>空肠>淋巴结>肝>脾>心脏>骨髓>胸腺>睾丸>脑>肌肉>脂肪。结论[125I]ex-endin-4的分布快速而广泛,其中以肾脏中最高,而在脑组织只发现微量的[125I]exendin-4。     

聚乙二醇洛塞那肽联合达格列净治疗肥胖2型糖尿病患者的疗效及安全性研究

目的：探讨聚乙二醇洛塞那肽联合达格列净治疗肥胖2型糖尿病的临床疗效及安全性。方法：收集肥胖2型糖尿病患者98例,分为对照组和观察组,各49例。观察组予胰岛素泵治疗14 d后改用胰岛素治疗,对照组予聚乙二醇洛塞那肽联合达格列净治疗。比较2组治疗3个月前后血糖、糖化血红蛋白、空腹胰岛素及C肽水平、胰岛功能指标、血脂、血压水平及体质量改变。结果：观察组治疗前后体质量（W）、收缩压（DBP）、舒张压（SBP）无明显改善,而治疗组均有下降,2组治疗后空腹血糖（FPG）及餐后血糖（2hPG）、糖化血红蛋白（HbAlc）、总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白（LDL）低于治疗前,高密度脂蛋白（HDL）、空腹C肽水平（FCp）、β细胞功能指数F （HOMA-βF）高于治疗前,差异有统计学意义（P<0.05）,但治疗组改善更明显,2组间差异有统计学意义。治疗组低血糖发生率较观察组更低。结论：聚乙二醇洛塞那肽联合达格列净治疗肥胖2型糖尿病较胰岛素更具有临床疗效,且安全性好。     

杜仲叶绿原酸提取物对大鼠的减肥作用机制

目的研究杜仲叶绿原酸提取物(CAEF)减肥作用的可能机制。方法SD大鼠40只禁食不禁水,用高脂乳剂分别与CAEF(含量20.0%,42.4%)或奥利司他灌胃3天,收集粪便,测定其中所含的总脂量、胆固醇和胆汁酸排出量,据其值评价各药物对肠道吸收脂肪及对肠道酯酶抑制的影响。结果 42.4%CAEF可显著升高粪便中总脂质、胆固醇和胆汁酸含量,且强于奥利司他(P<0.05)。结论 CAEF通过抑制胰脂肪酶活性抑制脂肪吸收,促进胆固醇和胆汁酸的排出,这可能是其减肥的作用机制。     

聚乙二醇洛塞那肽治疗2型糖尿病的有效性和安全性系统评价

目的：系统评估聚乙二醇洛塞那肽（PEX168）在中国2型糖尿病（T2DM）患者中的疗效和安全性,为临床用药提供循证学依据。方法：计算机检索从建库至2021年3月31日的Cochrane Library、ClinicalTrails、Embase、Medline、PubMed、CNKI、万方、维普等数据库,检索聚PEX168治疗2型糖尿病的随机对照试验,对符合纳入标准的研究进行资料提取和质量评价,采用R软件的META程序包进行统计分析。结果：共纳入3项RCT共1 012名患者,背景治疗药物均为二甲双胍,Meta分析结果提示PEX168 100 μg与200 μg组降低糖化血红蛋白MD分别为（－0.83,95％CI：－0.87~0.79,P<0.01）和（－1.08,95% CI：－1.41~－0.75,P<0.01）,显著优于安慰剂组;不良反应中恶心、呕吐发生率高于对照组,差异有统计学意义（P<0.01,P=0.000 3）。结论：每周一次皮下注射PEX168 100 μg或200 μg与二甲双胍联用可显著改善血糖相关变量,而不会增加低血糖的风险,且具有良好的耐受性和安全性。     

聚乙二醇洛塞那肽治疗肥胖型2型糖尿病患者轴状胃切除术患者的临床研究

目的 观察聚乙二醇洛塞那肽注射液联合二甲双胍片对肥胖型2型糖尿病(T2DM)患者轴状胃切除术后血清代谢、血脂水平及肠道菌群的影响。方法 将接受轴状胃切除术的肥胖型T2DM患者按队列法分为试验组和对照组。对照组口服盐酸二甲双胍片0.5 g,tid。试验组在对照组治疗的基础上,联合聚乙二醇洛塞那肽注射液0.2 mg皮下注射,每周1次。2组患者均连续治疗3个月。比较2组患者的体质量指数(BMI)、血清代谢指标、血脂水平、血糖水平、肠道菌群及药物不良反应发生情况。结果 本研究试验组共纳入70例,对照组共纳入50例。治疗3个月后,试验组与对照组的BMI分别为(26.35±2.36)和(29.34±3.59)kg·m^-2,谷胱甘肽过氧化物酶分别为(192.42±13.18)和(134.27±12.86)U,白细胞介素-6分别为(6.14±1.78)和(7.65±2.09)μg·L^-1,空腹血糖分别为(5.36±0.41)和(7.43±0.78)mmol·L^-1,血浆总胆固醇分别为(2.55±0.67)和(3.47±0.79)mmol...     

A novel protocol for studying food or drug seeking in rhesus monkeys

The purpose of this study was to determine if multiple aspects of drug and food-reinforced behavior could be measured in a single study. Drug or food seeking can be observed under four conditions: 1) internal drug or food cues and external stimulus cues present; self-administration, 2) only internal cues present; priming, 3) no internal or external stimulus cues present; abstinence, and 4) no internal cues, but external stimulus cues present; extinction. Six adult rhesus monkeys lived in three-chambered enclosures: fluid (0.26, 0.52 mg/kg per delivery cocaine hydrochloride, sweetened-vehicle, or water)- related cues and oral fluid self-administration were specific to one end chamber, food pellet-related cues and food self-administration were specific to the other end chamber, and no food cues or fluid cues were available in the middle chamber. Throughout the 10-h experimental day, monkeys experienced multiple food, fluid, and stimulus-cue test sessions. Adding cocaine to the vehicle initially increased fluid intake during training (condition 1), but vehicle intake did not return to baseline levels after cocaine was later removed (condition 4). Monkeys developed a location preference for the fluid chamber, even when fluid was not available, when responding was reinforced by cocaine, but not when responding was reinforced by vehicle (condition 3). Non-contingent food or fluid delivery did not increase responding in non-deprived animals (condition 2). The current protocol provides both self-administration and place-preference measures of the motivational effects of drugs. Given that human drug abusers spend much time thinking about and seeking drugs prior to actual self-administration, an animal model that uses multiple measures of drug seeking may be useful in the preclinical testing of pharmacological adjuncts for the treatment of drug abuse. Received: 9 September 1996 / Final version: 14 March 1997     

The ascending limb of the cocaine dose-response curve for reinforcing effect in rhesus monkeys

Rationale. To date, the literature on the intravenous self-administration of cocaine by laboratory animals lacks a compelling demonstration of an ascending limb to the dose-response function. It has been argued that previous demonstrations of an ascending limb are confounded by the extinction process. Objective. The objective was to examine the relationship between cocaine dose and intravenous self-injection frequency at the low end of the cocaine dose range (0.03–0.00075 mg/kg per injection). Methods. Three adult rhesus monkeys were given the opportunity to self-inject cocaine on a fixed-ratio 1 schedule of reinforcement with no timeouts between injections. Single cocaine doses were presented for between 13 and 27 consecutive 2-h sessions in the order of 0.03, 0.01, 0.003, 0.0015_a, 0.00075, and 0.0015_b mg/kg per injection. Results. An ascending limb of the cocaine dose-response curve was found to exist between the doses of 0.00075 and 0.003 mg/kg per injection. Conclusions. The fact that response rate increased from 0.00075 to 0.0015_b mg/kg per injection, and remained stable at this intermediate level, negates the possibility that responding at 0.0015_b mg/kg per injection is an artifact of experimental extinction. The finding that significantly less cocaine was taken at 0.0015_b mg/kg per injection than at higher doses demonstrates that satiety was not the mechanism by which cocaine intake was regulated on the ascending limb of the dose-response curve. Electronic Publication     

Drinking device for rhesus monkeys

A drinking device for rhesus monkeys is described which is simple, reliable, and permits intermittent scheduling of liquid availability. The device may be of particular use in oral drug self-administration experiments since the amount of fluid dispensed may be calibrated and spillage is minimal. The system has been successfully used for over 3 years with 9 unrestrained rhesus monkeys.     

Self-administration of cocaine: scopolamine combinations by rhesus monkeys

RATIONALE: Several halogenated analogs of benztropine (BZT) have previously been characterized as potent dopamine (DA) uptake inhibitors with diminished reinforcing effects relative to cocaine. In addition to their effects on DA uptake, these compounds are potent muscarinic cholinergic antagonists.OBJECTIVES: The present experiments were designed to examine the hypothesis that the anticholinergic action of the BZT analogs contributes to their relatively low levels of self-administration.METHODS: Rhesus monkeys self-administered cocaine (0.03 mg/kg per injection, i.v.) under either a fixed-ratio 25 (FR 25; n=5) or progressive-ratio (PR; n=5) schedule until stable responding was established. Saline, cocaine (0.0003-0.1 mg/kg per injection), scopolamine (0.001-0.1 mg/kg per injection), or various combinations of cocaine and scopolamine were then made available for self-administration.RESULTS: Cocaine maintained dose-related self-administration under both schedules whereas scopolamine did not. In the majority of cases, combinations of cocaine and scopolamine maintained less self-administration than cocaine alone.CONCLUSIONS: This study supports the hypothesis that anticholinergic actions contribute to the diminished self-administration of BZT analogs relative to cocaine. The mechanism may involve antagonism of the reinforcing effect of cocaine and/or punishment of the self-administration response by the addition of an anticholinergic component of action.     

Stereoselective discriminative stimulus effects of zopiclone in rhesus monkeys

Abstract Rationale. The behavioral effects of racemic zopiclone are similar to those of benzodiazepines that positively modulate GABA at the GABA_A receptor complex; however, it is not clear how enantiomers or metabolites of zopiclone contribute to the benzodiazepine-like behavioral effects of racemic zopiclone. Objectives. Racemic zopiclone, its (R)- and (S)- enantiomers, and the (S)-N-desmethyl metabolite, were evaluated for discriminative stimulus effects in untreated and diazepam treated rhesus monkeys. Methods. One group of monkeys discriminated the benzodiazepine midazolam and another group, treated daily with the benzodiazepine diazepam (5.6 mg/kg, PO), discriminated the benzodiazepine antagonist flumazenil. Results. (RS)-Zopiclone (0.32–17.8 mg/kg) and (S)-zopiclone (0.1–10 mg/kg) substituted with similar potencies for midazolam (≥80% midazolam-appropriate responding). The midazolam-like discriminative stimulus effects of (RS)-zopiclone were antagonized by flumazenil (pK _B=7.52). (R)-Zopiclone occasioned a maximum 45% midazolam-appropriate responding at a dose of 100 mg/kg; (S)-desmethylzopiclone produced saline-appropriate responding up to a dose of 100 mg/kg. All four test compounds occasioned predominantly vehicle-appropriate responding in diazepam treated monkeys discriminating flumazenil. (RS)-Zopiclone (10 mg/kg) attenuated the discriminative stimulus effects of flumazenil in diazepam treated monkeys. Conclusions. These results clearly demonstrate that in rhesus monkeys the discriminative stimulus effects of zopiclone are stereoselective and qualitatively similar to those of midazolam. These results fail to show any benzodiazepine-like or benzodiazepine antagonist-like discriminative stimulus effects for (S)-N-desmethylzopiclone, suggesting that any behavioral (e.g. anxiolytic) effects of this compound are not the result of actions at benzodiazepine receptors. Electronic Publication     

Effects of buprenorphine on candy and sweetened fluid self-administration by rhesus monkeys

Abstract Rationale. Previous studies have shown that buprenorphine differentially suppresses the reinforcing effects of different drugs (cocaine, alfentanil), drug versus nondrug reinforcers (food, drug), and the same reinforcer (food) maintained under different schedules of reinforcement. Objectives. The purpose of the present study was to determine whether buprenorphine (0.03, 0.1, 0.3 mg/kg) differentially affects candy versus sweetened fluid self-administration. The hypotheses were that (1) candy would maintain higher rates of responding and would be chosen on more occasions than sweetened fluid, and (2) buprenorphine would produce smaller disruptions in responding for the more-preferred reinforcer. Methods. During separate sessions, rhesus monkeys self-administered candy alone, sweetened fluid alone, or had the opportunity to choose between candy and sweetened fluid. Monkeys responded under a second order, two-chain schedule of reinforcement. Results. Candy was a more-preferred reinforcer than sweetened fluid. Buprenorphine significantly decreased rates of responding for fluid, but increased rates of responding for candy. Although buprenorphine significantly decreased both candy and fluid intake, it produced a more robust, and longer-lasting suppression of sweetened-fluid intake than candy. Choice to self-administer candy or fluid was not affected by buprenorphine. Conclusions. These results demonstrate that behavior maintained by a less-preferred reinforcer is more easily disrupted by buprenorphine than is behavior maintained by a more-preferred reinforcer. Electronic Publication     

Effects of local anesthetics on fixed-interval responding in rhesus monkeys

Several local anesthetics of both the ester and amide type were administered IM to rhesus monkeys trained to respond on a fixed-interval 5 min schedule of food delivery. With the exception of procainamide, all local anesthetics produced dose-related decreases in response rates. Effects on pattern of responding varied between local anesthetics. With some (cocaine, dimethocaine and lidocaine), rate-dependent effects were apparent. When control rates were low, these compounds increased rates; when control rates were high, they decreased rates. However, with others (procaine, chloroprocaine, tetracaine and propoxycaine) no rate-dependent effects were noted; i.e., these compounds had little or no effect on the pattern of responding, even at doses that substantially reduced response rates. Consistent with other experiments with these compounds, cocaine was the most potent of the group. In several instances, local anesthetics which had similar stimulus properties in other behavioral paradigms differed in terms of their effects on fixed-interval behavior.     

Reinforcing effects of smoked methamphetamine in rhesus monkeys

Rationale The occurrence of methamphetamine (METH) use by the smoking route is increasing. A nonhuman primate model for examining the reinforcing effects of smoked METH would be valuable for testing potential interventions for treating METH abuse disorders.Objective The purpose of the present study was to examine the reinforcing effects of smoked METH in monkeys.Materials and methods Four rhesus monkeys were trained to smoke cocaine (COC) under a chain fixed-ratio (FR) 64 lever press, FR 5 inhalation schedule of reinforcement. Upon observing stable levels of self-administration, METH was substituted for COC and a dose-response function for METH (0.08–0.8 mg/kg) was determined. Subsequently, the number of deliveries of COC (1 mg/kg), and 0.2 and 0.8 mg/kg METH were examined across increasing response requirements.Results METH was dose-dependently self-administered. Higher doses of METH (0.2, 0.4, and 0.8 mg/kg) produced asymptotic levels of responding that were slightly lower than those obtained with 1 mg/kg COC. Numbers of deliveries of COC and METH decreased as response requirement increased. METH, however, maintained fewer deliveries than 1 mg/kg COC at most response requirements.Conclusions METH is readily self-administered by smoking in rhesus monkeys when substituted for COC. METH may have a lower reinforcing strength than COC, but further research is needed to fully characterize its relative reinforcing strength.An erratum to this article can be found at     

Effects of alcohol on cerebrospinal fluid norepinephrine in rhesus monkeys

Alcohol (1–3 g/kg) significantly increased the concentration of cerebrospinal fluid (CSF) norepinephrine (NE) in rhesus monkeys. This effect is consistent with the previously demonstrated activational and possible antidepressant effect of low doses of alcohol. The greatest increase was observed in subjects with low baseline levels of CSF NE. Individual differences in activation or euphoria could be related to differential increases in CSF NE following alcohol consumption.     

Neuroleptic-induced acute dyskinesias in rhesus monkeys

Rhesus monkeys, previously subjected to twiceweekly injections of various neuroleptics, subsequently respond to acute IM injections of haloperidol with marked bucco-lingual and whole body movement disturbances consisting of mouth opening, protrusion, retraction or curling of the tongue together with writhing movements of the neck, trunk and/or limbs. These phenomena, which closely resemble the acute dyskinetic or dystonic reactions described in patients at the beginning of neuroleptic treatment, were also observed after acute IM injections of other neuroleptics such as fluphenazine, metoclopramide, oxiperomide, sulpiride, sultopride and tiapride. No dyskinesias were observed after chlorpromazine, chlordiazepoxide, clozapine, RMI 81582 or thioridazine at doses which otherwise had marked behavioural effects. The dyskinesias induced by haloperidol could be suppressed by prior treatment with the anticholinergic scopolamine.These observations, which correlate well with clinical findings, suggest that neuroleptic induced acute dyskinesias in the Rhesus monkey might be a useful model for predicting the liability of new anti-psychotics for inducing acute dyskinetic reactions in man.