大鼠坐骨神经传导速度测定的方法学考察

目的:比较3种测定大鼠外周运动神经传导速度(MNCV)方法的结果。方法:采用在体直接测定、在体间接测定、离体直接测定考察正常大鼠坐骨神经MNCV值,并将研究结果在链脲佐菌素引起的糖尿病模型大鼠以及用降糖药格列奇特进行治疗的模型大鼠上进行验证。结果:在体间接测定和离体直接测定正常大鼠坐骨神经MNCV值均与在体直接测定值有显著性相关关系(r=0.8328、0.9781,P<0.01);在体直接测定和在体间接测定模型大鼠坐骨神经MNCV值有相关关系(r=0.8797,P<0.05)。结论:3种方法测得的大鼠MNCV值间均具有一致性,均能反映MNCV的变化情况。     

65例糖尿病肌电图和运动神经传导速度的检测分析

目的：为探讨电生理诊断糖尿病早期周围神经病变的敏感指标即肌电图（EMG）、运动神经传导速度（MCV）和末端潜伏期（ML）与病程的关系。方法：对65例糖尿病（DM）患者379块肌肉、368条MCV和ML进行了检测。结果：318条肌电异常（83．9％）,302条MCV减慢（821％）,341条ML延长（92．7％）,糖尿病周围神经病变在电生理检测中有很高的异常率且与病程有密切关系。结论：肌电图多相波、单纯相、混合相、腓总神经与股神经MCV以及正中神经、尺神经、腓总神经和胫神经的ML均是糖尿病周围神经病变早期诊断的敏感指标。     

桑白皮提取物对糖尿病大鼠坐骨神经传导速度及生化功能的影响

目的探讨桑白皮提取物对糖尿病大鼠坐骨神经传导速度及功能的影响。方法采用四氧嘧啶复制糖尿病(DM)大鼠模型。将大鼠随机分为正常组、模型组、桑白皮提取物(高、低剂量)组、弥可保对照组,灌胃给药,1次.d-1,用药2wk后,观察各组大鼠坐骨神经突触素的变化。同时测定大鼠坐骨神经运动传导速度、感觉传导速度及感觉潜伏期,并进行感觉神经检测的摇尾实验。结果桑白皮提取物可明显增加坐骨神经突触素的含量(P<0.01或P<0.05),改善和增加糖尿病大鼠坐骨神经的感觉及运动传导速度(P<0.01或P<0.05),缩短其感觉潜伏期(P<0.01或P<0.05)。结论桑白皮提取物对实验性糖尿病大鼠坐骨神经损害有一定的治疗作用。     

Improving the 18F‐fluoromethylcholine (18F‐FCH) radiochemical yield via optimising the azeotropic drying of non‐carrier‐added 18F‐fluorine

¹⁸F‐Fluoromethylcholine (¹⁸F‐FCH) has been suggested as one of the reputable imaging tracers for diagnosis of prostate tumour in PET/CT examination. Nevertheless, it has never been synthesised in Malaysia. We acknowledged the major problem with ¹⁸F‐FCH is due to its relatively low radiochemical yield at the end of synthesis (EOS). Therefore, this technical note presents improved ¹⁸F‐FCH radiochemical yields after carrying out optimisation on azeotropic drying of non‐carrier‐added ¹⁸F‐Fluorine.     

硫辛酸联用甲钴胺对糖尿病周围神经病变患者神经传导速度的改善作用

目的探讨硫辛酸联合甲钴胺对糖尿病周围神经病变（DPN）患者的疗效及神经传导速度的改善作用。方法将医院2010年5月至2012年5月收治的101例DPN患者随机分为对照组49例和治疗组52例,对照组患者肌肉注射甲钴胺500μg,每日1次;治疗组肌肉注射甲钴胺500μg,每日1次,并静脉滴注硫辛酸600 mg/d。疗程结束后评价疗效,对两组患者的运动、感觉神经传导速度进行比较,并通过症状总评分（TSS）和疼痛视觉模拟评分（VAS）对病情进行评估。结果治疗组总有效率为90.38%,明显高于对照组的75.5l%（P〈0.05）;两组患者治疗后神经传导速度较治疗前均有所提高,治疗组提高更明显（P〈0.05）;治疗后对照组和治疗组TSS评分分别为（6.37±1.21）分和（4.33±0.96）分,VAS评分为（5.43±0.67）分和（4.35±0.51）分,与治疗前相比均有降低,且治疗组明显低于对照组（P〈0.05）。结论硫辛酸联合甲钴胺可明显改善糖尿病患者的周围神经病变,疗效显著,值得临床推广。     

续断通络片对糖尿病大鼠坐骨神经传导速度影响的实验研究

摘 要：目的：观察中药复方制剂续断通络片对糖尿病大鼠神经传导速度的影响。方法：采用链脲佐菌素（STZ）诱导的糖尿病大鼠模型,随机分为模型组、甲钴胺组、续断通络片低剂量组、续断通络片中剂量组和续断通络片高剂量组,给予续断通络片（生药）灌胃,以甲钴胺作为对照,疗程8周,分别于给药的2、4、6、8周检测大鼠的坐骨神经传导速度。结果：经续断通络片中、高剂量治疗的DM大鼠在造模8周后血糖明显下降（P<0.05）,在4、6、8周均可明显改善神经传导速度（P<0.05或P<0.01）,低剂量续断通络片治疗组在6周时可明显改善神经传导速度（P<0.05）,余无明显差异。 结论：续断通络片能够改善STZ-DM大鼠的神经传导速度,各个剂量及各个时间均有较为明显的改善,显示续断通络片对糖尿病大鼠周围神经病变有明显改善作用。     

Improvement of Motor Nerve Conduction Velocity in Diabetic Rats Requires Normalization of the Polyol Pathway Metabolites Flux

Using ranirestat, an aldose reductase (AR) inhibitor, we investigated the relationship between sorbitol and fructose levels in the sciatic nerve and motor nerve conduction velocity (MNCV) in streptozotocin (STZ)-treated diabetic rats. Ranirestat inhibited rat and recombinant human AR with similar IC₅₀ values and equipotently prevented sorbitol accumulation in rat erythrocytes and sciatic nerves in vitro. One week after STZ administration, sorbitol levels in rat erythrocytes and sciatic nerves significantly increased while MNCV decreased. Oral administration of ranirestat (0.03 – 1.0 mg/kg per day) for 3 weeks dose-dependently decreased the elevated sorbitol and fructose levels in the rat sciatic nerves without affecting blood glucose level. Particularly, at doses of 0.1 mg/kg per day or higher, ranirestat normalized both sorbitol and fructose levels in the sciatic nerves of STZ-treated rats. Ranirestat (0.1 – 1.0 mg/kg per day) also improved the STZ-induced decrease in MNCV in a dose-dependent manner. This improvement correlated with the decrease of sorbitol and fructose levels in the rat sciatic nerves. These findings indicate that ranirestat improves MNCV via normalization of sorbitol and fructose accumulation in the sciatic nerve.     

依帕司他联合甲钴胺治疗老年2型糖尿病周围神经病变腓总神经及正中神经传导速度的影响

目的探讨依帕司他联合甲钴胺治疗老年2型糖尿病周围神经病变腓总神经及正中神经传导速度的影响。方法选取2016年7月至2017年7月在大连市友谊医院内分泌科就诊的80例,2型糖尿病周围神经病变患者,随机分组,试验组40例,采取依帕司他联合甲钴胺,对照组40例,采取甲钴胺治疗,比较两组患者腓总神经及正中神经传导速度。结果试验组腓总神经及正中神经传导速度优于对照组,差异有统计系意义(P<0.05)。结论对2型糖尿病周围神经病变患者采取依帕司他联合甲钴胺治疗可以明显改善其神经传导速度,值得在临床推广。     

Effects of Fly Ash and its Constituents on Sensory Irritation in Mice

Effects of Fly Ash and its Constituents on Sensory Irritationin Mice. Hatch, G.E., Boykin, E., Miller, F.J. and Graham, J.A.(1982). Fundam. Appl. Toxicol. 2:77–81. Sensory irritationcaused by fly ash from oil-fired (OF), fluidized bed coal (FB)combustion and conventional coal (CC) combustion power plants,and from Mt. St. Helens volcano (VA) was studied in mice. Theirritating sensation due to contact with fly ash or its constituentswas quantitated by observing a characteristic flexing of thedorsal musculature of the mouse following intraperitoneal injectionof the ash suspension. Construction of dose-effect curves wasbased on the percentage of animals showing a positive responseat each ash concentration. The order of irritant potency offly ash samples was as follows: OF and OF leachate >>FB > CC > VA. Saline leachates of ash samples other thanOF fly ash showed no irritating effects. OF fly ash was about160xmore irritating than VA and 5x more irritating than thereference detergent compound, sodium dodecyl sulfate. Studyof chemicals known to be present in fly ash or chemicals similarto those present indicated that acidic or basic compounds, heavymetal ions and metal oxides, and insoluble particles could allcontribute to the irritancy of an ash. Soluble heavy metalsappeared to be mainly responsible for the irritant effects ofOF ash, while insoluble particles including metal oxides couldhave accounted for the irritancy of the other fly ash samplesstudied. Comparison of data from the peritoneal irritation testused here with previously published data from the upper respiratorytract irritation test of Alarie confirmed the previously notedcorrelation between these two tests for chemicals in solution.     

A Whole‐Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat

Colistin is a polymyxin antibiotic used to treat patients infected with multidrug‐resistant Gram‐negative bacteria (MDR‐GNB). The objective of this work was to develop a whole‐body physiologically based pharmacokinetic (WB‐PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue‐to‐plasma partition coefficient, K_p. Colistin and its prodrug, colistin methanesulfonate (CMS) K_p priors, were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting in vivo their plasma concentration–time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a nonlinear mixed effect (NLME) modelling approach. A WB‐PBPK model was developed assuming a well‐stirred and perfusion‐limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: K_p was estimated using in silico K_p priors (I) or K_p was estimated using experimental K_p priors (II) or K_p was fixed to the experimental values (III). The WB‐PBPK model best described colistin and CMS plasma concentration–time profiles in scenario II. Colistin‐predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental K_p prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico K_p priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigate the impact of disease state on colistin disposition.     

Synthesis and pharmacology of new psychoactive substance 5F‐CUMYL‐P7AICA,a scaffold‐ hopping analog of synthetic cannabinoid receptor agonists 5F‐CUMYL‐PICA and 5F‐CUMYL‐PINACA

Synthetic cannabinoid receptor agonists (SCRAs) are a dynamic class of new psychoactive substances (NPS), with novel chemotypes emerging each year. Following the putative detection of 5F‐CUMYL‐P7AICA in Australia in 2016, the scaffold‐hopping SCRAs 5F‐CUMYL‐PICA, 5F‐CUMYL‐PINACA, and 5F‐CUMYL‐P7AICA were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy, gas chromatography–mass spectrometry (GC–MS), and liquid chromatography–quadrupole time‐of‐flight–MS (LC–QTOF–MS). Since little is known of the pharmacology of 7‐azaindole SCRAs like 5F‐CUMYL‐P7AICA, the binding affinities and functional activities of all compounds at cannabinoid type 1 and type 2 receptors (CB₁ and CB₂, respectively) were assessed using tritiated radioligand competition experiments and fluorescence‐based plate reader membrane potential assays. Despite CB₁ binding affinities differing by over two orders of magnitude (K_i = 2.95–174 nM), all compounds were potent and efficacious CB₁ agonists (EC₅₀ = 0.43–4.7 nM), with consistent rank order for binding and functional activity (5F‐CUMYL‐PINACA >5F‐CUMYL‐PICA >5F‐CUMYL‐P7AICA). Additionally, 5F‐CUMYL‐P7AICA was found to exert potent cannabimimetic effects in mice, inducing hypothermia (6°C, 3 mg/kg) through a CB₁‐dependent mechanism.     

Effects of Different Component Contents of Colistin Methanesulfonate on the Pharmacokinetics of Prodrug and Formed Colistin in Human

Pharmaceutical Research - To evaluate the effects of component contents in different colistin methanesulfonate (CMS) formulas on their clinical pharmacokinetics of the prodrug CMS and the formed...     

Synthesis and Bio‐Evaluation of New 18F‐Labeled Pyridaben Analogs with Improved Stability for Myocardial Perfusion Imaging in Mice

To improve the stability of ¹⁸F‐labeled pyridaben analogs for myocardial perfusion imaging, three new analogs of pyridaben ([¹⁸F]FPTP2, [¹⁸F]FPTP‐P2, and [¹⁸F]FPTP‐P3) were synthesized with ‘side chain’ modifications. The radiolabeled tracers and corresponding non‐radioactive compounds were obtained by substituting tosyl group with ^18/19F. The effect of structure modification on myocardial targeting and physicochemical properties of new tracers were evaluated in vitro and in vivo. The total radiosynthesis time of these tracers was approximately 70–90 min with high decay‐corrected radiochemical yields (36–65%) and good radiochemical purity (> 98%). These lipophilic tracers exhibited obvious improved stability in water. Studies of their biodistribution in normal Kunming mice demonstrated that [¹⁸F]FPTP2 exhibited very high initial heart uptake (39.70 ± 2.81 %ID/g at 2 min after injection) and low background in the liver, blood, and soft tissues. The heart‐to‐liver, heart‐to‐lung, and heart‐to‐blood ratios were 3.59, 19.34, and 67.34 at 15 min postinjection, respectively. Favorable myocardial targeting property and remarkable improvement of stability of [¹⁸F]FPTP2 suggest that the substitution of the phenyl ‘sidechain’ with other non‐phenyl rings has no effect on the myocardial targeting property of ¹⁸F‐labeled pyridaben analogs.     

一期显微外科修复在前臂及手部神经损伤中的应用及对感觉功能的影响研究

目的 探究分析一期显微外科修复与常规修复术在前臂及手部神经损伤上的治疗效果及对患者感觉功能的影响情况.方法 选取近期我院收治的前臂及手部神经损伤患者70例,随机分组,对照组患者行常规修复治疗,观察组行一期显微外科修复,对比分析两组患者的治疗效果.结果 观察组患者的感觉功能恢复情况显著优于对照组,且观察组患者的满意度情况也显著优于对照组(P<0.05).结论 一期显微外科修复能显著提高患者的感觉功能情况和满意度情况,是前臂及手部神经损伤治疗的重要方法.     

5F‐MDMB‐PICA metabolite identification and cannabinoid receptor activity

According to the European Monitoring Center for Drugs and Drug Addiction (EMCDDA), there were 179 different synthetic cannabinoids reported as of 2017. In the USA, 5F‐MDMB‐PINACA, or 5F‐ADB, accounted for 28% of cannabinoid seizures 2016–2018. The synthetic cannabinoid, 5F‐MDMB‐PICA, is structurally similar to 5F‐MDMB‐PINACA with an indole group replacing the indazole. Limited data exist from in vivo or in vitro metabolic studies of these synthetic cannabinoids, so potential metabolites to identify use may be missed. The goals of this study were to (a) investigate 5F‐MDMB‐PICA and 5F‐MDMB‐PINACA in vitro metabolism utilizing human hepatocytes; (b) to verify in vitro metabolites by analyzing authentic case specimens; and (c) to identify the potency and efficacy of 5F‐MDMB‐PICA and 5F‐MDMB‐PINACA by examining activity at the CB₁ receptor. Biotransformations found in this study included phase I transformations and phase II transformations. A total of 22 5F‐MDMB‐PICA metabolites (A1 to A22) were identified. From hepatocyte incubations and urine samples, 21 metabolites (B1 to B21) were identified with 3 compounds unique to urine specimens for 5F‐MDMB‐PINACA. Phase II glucuronides were identified in 5F‐MDMB‐PICA (n = 3) and 5F‐MDMB‐PINACA (n = 5). For both compounds, ester hydrolysis and ester hydrolysis in combination with oxidative defluorination were the most prevalent metabolites produced in vitro. Additionally, the conversion of ester hydrolysis with oxidative defluorination to pentanoic acid for the first time was identified for 5F‐MDMB‐PICA. Therefore, these metabolites would be potentially good biomarkers for screening urine of suspected intoxication of 5F‐MDMB‐PICA or 5F‐MDMB‐PINACA. Both 5F‐MDMB‐PICA and 5F‐MDMB‐PINACA were acting as full agonists at the CB₁ receptor with higher efficacy and similar potency as JWH‐018.     

Carrier‐effect on palladium‐catalyzed,nucleophilic 18F‐fluorination of aryl triflates

A recently published palladium‐catalyzed preparation of fluoroarenes starting from caesium fluoride attracted interest as a new alternative for radiofluorination. To test this method, a suitable protocol for the synthesis of 4‐[¹⁸F]fluorotoluene and 1‐[¹⁸F]fluoronaphthalene as model systems has been developed. The possibility to perform the reaction under no‐carrier‐added condition was of special interest. It was found out, however, that the reaction requires the presence of carrier, thus limiting the method to syntheses of radiotracers with low specific activity. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis of 18F‐labelled biotin analogues

A one‐step ¹⁸F‐labelling strategy was used to prepare three labelled analogues of the vitamin biotin, which can be useful as tracers because of biotin's high affinity for avidin. The labelled compounds were obtained in decay‐corrected yields of up to 35% and specific radioactivity of 320 GBq/µmol. When evaluated in situ, the analogues showed good affinity for avidin: 60–75% of the radiolabelled compounds were bound to avidin within 5 minutes. The binding was site‐specific, as shown by blocking experiments with native biotin.     

Identification and analytical characterization of six synthetic cannabinoids NNL‐3, 5F–NPB‐22‐7N, 5F–AKB‐48‐7N, 5F–EDMB‐PINACA,EMB‐FUBINACA,and EG‐018

Clinical and forensic toxicology laboratories are continuously confronted by analytical challenges when dealing with the new psychoactive substances phenomenon. The number of synthetic cannabinoids, the chemical diversity, and the speed of emergence make this group of compounds particularly challenging in terms of detection, monitoring, and responding. Three indazole 7N positional isomer synthetic cannabinoids, two ethyl 2‐amino‐3‐methylbutanoate‐type synthetic cannabinoids, and one 9H –carbazole substituted synthetic cannabinoid were identified in seized materials. These six synthetic cannabinoid derivatives included: 1H –benzo[d ] [1,2,3]triazol‐1‐yl 1‐(5‐fluoropentyl)‐1H –pyrrolo[2,3‐b ]pyridine‐3‐carboxylate (NNL‐3, 1 ), quinolin‐8‐yl 1‐(5‐fluoropentyl)‐1H –pyrrolo[2,3‐b ]pyridine‐3‐carboxylate (5F–NPB‐22‐7N , 2 ), N ‐((1 s,3 s)‐adamantan‐1‐yl)‐1‐(5‐fluoropentyl)‐1H –pyrrolo[2,3‐b ]pyridine‐3‐carboxamide (5F–AKB‐48‐7N , 3 ), ethyl 2‐(1‐(5‐fluoropentyl)‐1H –indazole‐3‐carboxamido)‐3,3‐dimethylbutanoate (5F–EDMB‐PINACA, 4 ), ethyl 2‐(1‐(4‐fluorobenzyl)‐1H –indazole‐3‐carboxamido)‐3‐methylbutanoate (EMB‐FUBINACA, 5 ), and naphthalen‐1‐yl(9‐pentyl‐9H ‐carbazol‐3‐yl)methanone (EG‐018, 6 ). The identification was based on ultra‐high‐performance liquid chromatography‐quadrupole time‐of‐flight‐mass spectrometry (UHPLC‐QTOF‐MS), gas chromatography–mass spectrometry (GC–MS), and nuclear magnetic resonance spectroscopy (NMR). The analytical characterization of these six synthetic cannabinoids was described, so as to assist forensic laboratories in identifying these compounds or other substances with similar structure in their case work. To our knowledge, no analytical data about the compounds 1 – 5 have appeared until now, making this the first report on these compounds. The GC–MS data of 6 has been reported, but this study added the LC–MS, NMR, and Fourier transform infrared (FTIR), data to render the analytical data collection process more complete. Copyright © 2017 John Wiley & Sons, Ltd.     

C‐Terminal 18F‐fluoroethylamidation exemplified on [Gly‐OH9] oxytocin

The no‐carrier‐added (n.c.a.) ¹⁸F‐fluoroethylamidation of the acid function of the protected nonapeptide Boc–Cys–Tyr(tBu)–Ile–Gln(Mtt)–Asn(Mtt)–Cys–Pro–Leu–Gly–OH forming the labelled peptide hormone derivative [Gly‐(2‐[¹⁸F]fluoroethyl)NH⁹]‐oxytocin is described. The labelling conditions were elaborated using a protected tripeptide, identical to the C‐terminal sequence of oxytocin. The prosthetic group n.c.a. 2‐[¹⁸F]fluoroethylamine was synthesised via cryptate mediated n.c.a. ¹⁸F‐fluorination of N‐Boc‐2‐(p‐toluenesulfonyloxy)ethylamine in DMSO (RCY: ca. 60%) and subsequent deprotection with a radiochemical yield of 46±5%. [¹⁸F]Fluoroethylamine was reacted with Z–Pro–Leu–Gly–OH in presence of the coupling reagent TBTU or with activated esters of the model‐tripeptide. The activated ester method as well as the condensation in presence of TBTU yielded ?90% of the ¹⁸F‐fluoroethyl‐amidated tripeptide. TBTU‐mediated condensation of n.c.a. 2‐[¹⁸F]fluoro‐ethylamine with the C‐terminal free acid group of protected oxytocin gave the radiochemical yield of about 75%. Deprotection under acidic conditions led to the formation of [Gly–(2‐[¹⁸F]fluoroethyl)NH⁹]oxytocin within 75 min with a radiochemical yield of about 30% as measured by analytical HPLC. Copyright © 2002 John Wiley & Sons, Ltd.