胍法新对保存内皮与去内皮离体大鼠胸主动脉环的作用

本实验观察了选择性较高的α_2受体激动剂胍法新(guanfacine)对离体大鼠胸主动脉环的收缩与舒张作用和对血管组织中cGMP含量的影响。去内皮以及用美兰和血红蛋白预处理均可使胍法新对标本的收缩作用明显增强。对经垂体后叶素预收缩的保存内皮的标本,胍法新有舒张作用。这种作用可因去内皮或用育亨宾处理而消失。胍法新使保存内皮标本组织中cGMP含量明显增加。这些结果提示在大鼠胸主动脉内皮细胞上可能存在着能引起EDRF释放的α_2受体。     

The antiulcer and antisecretory activity of WHR-1370A 1-n-butoxy-3-(2,6 dimethylphenylcarbamoyl) guanidine hydrochloride

WHR-1370A in the rat reduces volume (ED50 = 1.3 mg/kg p.o.) acidity (1.8 p.o.), and pepsin (2.8 p.o.) in the 4-hr pylorus ligation model, delays gastric emptying (0.75 p.o.), and protects against the development of stress (18-hr restraint)-, indomethanic-, aspirin-, reserpine-, and cysteamine-induced ulcers (ED50s: 10.0 s.c., .65 p.o., 0.59 p.o., 3.0 p.o., and 8.0 s.c., respectively); also WHR-1370A can completely suppress the cysteamine-induced rise in serum gastrin. In the pylorus-ligated rat, the activity of WHR-1370A is not appreciably altered by methysergide, pimozide, propranolol, corynanthine, or phentolamine but is significantly and competitively antagonized by yohimbine. The pharmacological basis of WHR-1370A probably can be attributed to an alpha-2-mediated inhibition of acetylcholine release at vagal nerve endings.     

Systematic review: the lower gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs

BACKGROUND: Lower gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs) are much more poorly characterized than upper gastrointestinal effects. AIM: To determine if NSAIDs increase lower gastrointestinal adverse effects and if the risk with non-selective NSAIDs is greater than with cyclooxygenase-2-selective inhibitors (coxibs). METHODS: Computerized databases were searched to identify studies of NSAID use reporting on lower gastrointestinal integrity (e.g. permeability), visualization (e.g. erosions, ulcers) and clinical events. RESULTS: Designs in 47 studies were randomized (18), case-control (14), cohort (eight) and before-after (seven). Non-selective-NSAIDs had significantly more adverse effects vs. no NSAIDs in 20 of 22 lower gastrointestinal integrity studies, five of seven visualization studies, seven of 11 bleeding studies (OR: 1.9-18.4 in case-control studies), two of two perforation studies (OR: 2.5-8.1) and five of seven diverticular disease studies (OR: 1.5-11.2). Coxibs had significantly less effect vs. non-selective-NSAIDs in three of four integrity studies, one endoscopic study (RR mucosal breaks: 0.3), and two randomized studies (RR lower gastrointestinal clinical events: 0.5; haematochezia: 0.4). CONCLUSIONS: An increase in lower gastrointestinal injury and clinical events with non-selective-NSAIDs appears relatively consistent across the heterogeneous collection of trials. Coxibs are associated with lower rates of lower gastrointestinal injury than non-selective-NSAIDs. More high-quality trials are warranted to more precisely estimate the effects of non-selective-NSAIDs and coxibs on the lower gastrointestinal tract.     

A critical review of the toxicological effects of carrageenan and processed eucheuma seaweed on the gastrointestinal tract

Carrageenan is a high-molecular-weight, strongly anionic polymer derived from several species of red seaweed that is used for the textural stabilization of foods. Processed Eucheuma Seaweed (PES) is a form of carrageenan with a higher cellulose content. Food-grade carrageenan has a weight average molecular weight greater than 100,000 Da, with a low percentage of smaller fragments. Carrageenan is not degraded to any extent in the gastrointestinal tract and is not absorbed from it in species examined, such as rodents, dogs, and non-human primates. Systemically administered carrageenan has been reported to have a variety of effects, particularly on the immune system, but these are not pertinent to orally administered carrageenan. The substance poligeenan (formerly referred to as degraded carrageenan) is not a food additive. It exhibits toxicological properties at high doses that do not occur with the food additive carrageenan. In-long term bioassays, carrageenan has not been found to be carcinogenic, and there is no credible evidence supporting a carcinogenic effect or a tumor-promoting effect on the colon in rodents. Also, like many dietary fibers, there is significant cecal enlargement in rodents when it is administered at high doses, but this does not appear to be associated with any toxicological consequences to the rodent. Many toxicological studies on carrageenan have involved administration at doses in excess of today's standards for dietary feeding levels in bioassays, and they are orders of magnitude in excess of those to which humans are exposed. Previous reviews of carrageenan and PES by the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives (JECFA) have recommended a group allowable daily intake (ADI) of "not specified". The lack of carcinogenic, genotoxic, or tumor-promoting activity with carrageenan strongly supports continuing such an ADI, and JECFA, during its most recent review in 2001, continued this recommendation. The various toxicological studies related to orally administered food-grade carrageenan are summarized along with a brief discussion of critical factors in intestinal carcinogenesis.     

Serotonin pharmacology in the gastrointestinal tract: a review

Serotonin (5-hydroxytryptamine or 5-HT) plays a critical physiological role in the regulation of gastrointestinal (GI) function. 5-HT dysfunction may also be involved in the pathophysiology of a number of functional GI disorders, such as chronic constipation, irritable bowel syndrome and functional dyspepsia. This article describes the role of 5-HT in the enteric nervous system (ENS) of the mammalian GI tract and the receptors with which it interacts. Existing serotonergic therapies that have proven effective in the treatment of GI functional disorders and the potential of drugs currently in development are also highlighted. Advances in our understanding of the physiological and pathophysiological roles of 5-HT in the ENS and the identification of selective receptor ligands bodes well for the future development of more efficacious therapies for patients with functional GI disorders.     

A comparison of the antidiarrheal and some other pharmacological effects of clonidine,lidamidine, and loperamide in the rat

Clonidine, lidamidine, and loperamide each inhibited castor oil-induced diarrhea in the rat. Clonidine and lidamidine, but not loperamide, also induced diuresis but at doeses above those producing antidiarrheal activity. Clonidine and lidamidine, but not loperamide, produced autonomic and central effects including piloerection, hypotonia, exopthalmus and ataxia at doeses similar to those producing antidiarrheal activity. These data suggest that only loperamide possesses selective antidiarrheal activity.     

抗哮喘药物β2受体激动剂的研究进展

β2肾上腺素受体(β2AR)激动剂是哮喘治疗中的一线药物,选择性β2AR激动剂由于具有心脏毒副作用低的优点而成为临床应用最广、最有效的支气管扩张剂.对β2AR激动剂的研究概况及进展进行综述.     

NKH477: A novel bronchodilator produces potentiation and tachyphylaxis reversal to salbutamol in isolated guinea pig trachea

The relaxant responses of the β₂‐adrenoceptor agonist salbutamol and NKH477, an activator of adenylate cyclase, were compared and the possible potentiating effect of NKH477 on salbutamol‐induced bronchodilatation was measured together with the effectiveness of NKH477 in reversing tachyphylaxis development to salbutamol. The in vitro bronchodilator effect of salbutamol and NKH477 (10^–9 – 10^–5 M) was measured on isolated guinea pig tracheal ring segments precontracted with carbachol (10^–6 M). Both salbutamol and NKH477 produced a concentration‐dependent relaxation. EC₅₀ values were determined from cumulative concentration–response curves. Salbutamol was more potent than NKH477 in relaxing the tracheal preparations (7.1 ± 0.1 compared to 6.1 ± 0.2, respectively). NKH477 produced a significant increase in the salbutamol‐induced bronchodilator effect. The potency values recorded for salbutamol were 7.1 ± 0.1, 7.4 ± 0.2, 7.6 ± 0.1, and 8.6 ± 0.4 in the absence and presence of NKH477 (3 × 10^–8 M, 10^–7 M, and 3 × 10^–7 M, respectively). Reproducible relaxant responses could be elicited to salbutamol and NKH477 after 24 h incubation in Krebs' solution. Tachyphylaxis to the relaxant effects of salbutamol was experimentally induced by 24‐h incubation of the preparations in Krebs' solution containing salbutamol (10^–6, 3 × 10^–6 or 10^–5 M). The potency of salbutamol was reduced to 6.9 ± 0.2, 6.8 ± 0.2, and 6.0 ± 0.2 after 24 h incubation with salbutamol 10^–6 M, 3 × 10^–6 M or 10^–5 M, respectively. NKH477 (3 × 10^–7 M) produced a complete reversal of tachyphylaxis to salbutamol‐induced relaxation in salbutamol pretreated tissues. The potency of salbutamol was increased to 7.4 ± 0.2, 7.1 ± 0.1, and 7.3 ± 0.1 after the addition of NKH477 (3 × 10^–7 M) to the preparations preincubated (24 h) with salbutamol 10^–6, 3 × 10^–6, or 10^–5 M, respectively. NKH477 shares with salbutamol the ability to relax airway smooth muscle and produces an apparent increase of the bronchodilator effects of salbutamol and reverses tachyphylaxis. Drug Dev. Res. 48:154–159, 1999. © 1999 Wiley‐Liss, Inc.     

Dark cell change of the cerebellar Purkinje cells induced by terbutaline under transient disruption of the blood-brain barrier in adult rats: morphological evaluation

This study aimed to establish a cerebellar degeneration animal model and to characterize the dark cell change of Purkinje cells. We hypothesized that terbutaline, a β2-adrenoceptor agonist, induces cerebellar degeneration not only in neonatal rats, but also in adult rats. Nine-week-old adult male Sprague-Dawley rats were anesthetized and infused with 25% mannitol via the left common carotid artery. Thirty seconds later, terbutaline was infused via the same artery. Dark-stained Purkinje cells were observed in the entire cerebellum on day 3. Prominent Bergmann glial cells accompanied by swelling of the glial processes were present, and were closely associated with the dark-stained Purkinje cells. These findings were found continuously throughout day 30. Ultrastructurally, dilated Golgi vesicles and/or endoplasmic reticulum and large lamella bodies were present in both severely changed and slightly changed Purkinje cells. Bergmann glial cells in the area of synaptic contacts of the severely changed Purkinje cells showed swelling. The Bergmann glial process in close contact with the slightly changed Purkinje cell dendrite in molecular layer showed slight swelling, and large lamella bodies in the dendrite were observed close to the dendritic spines. These findings may suggest that terbutaline induced a failure of Bergmann glial cell and resulted in dark cell degeneration of the Purkinje cells due to glutamate excitotoxicity.     

右美托咪定用于困难气道清醒气管插管的研究进展

清醒气管插管常用于困难气道患者,能有效减小困难气道患者的麻醉风险,目前已研究报道多种麻醉药都能用于清醒气管插管.右美托嘧啶是一种高选择性的α2肾上腺素受体激动剂,具有镇静、镇痛、抗焦虑及抗交感等作用,且呼吸抑制作用轻微,适合用于清醒气管插管.本文对右美托嘧啶用于困难气道清醒气管插管的相关研究进展予以综述.     

Role of the cholinergic system and of apamin-sensitive Ca2+-activated K+ channels on rabbit jejunum spontaneous activity and on the inhibitory effects of adrenoceptor agonists

1 One reason why rabbit jejunum is suitable for studying the mechanisms underlying the actions of the various neurotransmitters and their interactions is its spontaneous motility. The main regulator of spontaneous motility is the cholinergic system. How the cholinergic system regulates the spontaneous activity in the rabbit jejunum and how it affects the inhibitory action of α‐ and β‐adrenoceptor agonists remains unclear. 2 We studied the influence of the cholinergic system and apamin‐sensitive Ca²⁺‐activated K⁺ channels on spontaneous contractions in the rabbit jejunum and on the inhibitory effects ofα₁‐ and β‐adrenoceptor agonists. 3 In naïve tissues, atropine (ATR, 7.4 × 10^?8 m ) and tetrodotoxin (8 × 10^?8 m ) almost completely inhibited – to a similar extent – the amplitude of spontaneous activity. Despite the presence of ATR or TDX, tissue contraction gradually recovered to about 50% of the baseline amplitude within 5–10 min. When ATR or TDX, respectively, were added to the TDX‐ or ATR‐treated tissues, the recovered activity decreased weakly but significantly. After washout and a 45‐min rest the contraction amplitude returned to baseline values. A further exposure to ATR or TDX reduced the contraction to a level significantly lower than the one obtained after TDX or ATR added 5 min after ATR or TDX, respectively. In preparations prestimulated for 10 min with acetylcholine (ACh), ATR abolished the TDX‐resistant recovered spontaneous activity. 4 Adrenaline (ADR, 0.5–5 × 10^?7 m ) and phenylephrine (PHE, 1–10 × 10^?7 m ) inhibited tissue motility in naïve and in ATR‐ and in TDX‐exposed preparations. But whereas in naïve preparations the α₁‐adrenoceptor antagonists completely antagonized inhibition induced by both drugs, in ATR‐ and TDX‐exposed tissues they did so only partially for ADR. Agonist‐induced inhibition had a rapid onset but rapidly faded; pendular movements took significantly longer to recover in ATR‐ and TDX‐treated tissues than in naïve tissues. In tissues exposed for 2 min to ADR (0.5–5 × 10^?7 m ) or PHE (1–10 × 10^?7 m ), washout or addition of α₁‐adrenoceptor antagonists caused an immediate short‐lasting increase in contraction amplitude. 5 Apamin (APAM, 5 × 10^?9 m ) caused a rapid and persistent increase in the amplitude of contractions. It also blocked the inhibitory responses to ADR and PHE, and removed washout‐induced contractions. The APAM‐induced increase in the contraction amplitude correlated with the increase obtained by washing out ADR or PHE. 6 Isoprenaline (at concentrations up to 2.8 × 10^?7 m ) produced no inhibitory response in naïve tissues, but it invariably blocked (at a concentration of 0.7 × 10^?7 m ) the recovered spontaneous activity (and sometimes depressed muscletone) in tissues exposed to ATR or TDX. Neither propranolol (3.4 × 10^?7 m ) nor APAM (5 × 10^?9 m ) counteracted these inhibitory effects. 7 These results indicate that spontaneous motility in the rabbit jejunum is predominantly mediated by neuronal release of ACh and by some other unidentified neuronal activity. Released ACh inhibits myogenic activity and strongly antagonizes β‐adrenoceptor‐induced APAM‐insensitive inhibition but leaves α₁ agonist‐induced APAM‐sensitive inhibition unchanged.     

Toxicity of transition metal nanoparticles: A review of different experimental models in the gastrointestinal tract

The development of nanotechnology is becoming a major trend nowadays. Nanoparticles (NPs) have been widely used in fields including food, biomedicine, and cosmetics, endowing NPs more opportunities to enter the human body. It is well-known that the gut microbiome plays a key role in human health, and the exposure of intestines to NPs is unavoidable. Accordingly, the toxicity of NPs has attracted more attention than before. This review mainly highlights recent advances in the evaluation of NPs' toxicity in the gastrointestinal system from the existing cell-based experimental models, such as the original mono-culture models, co-culture models, three-dimensional (3D) culture models, and the models established on microfluidic chips, to those in vivo experiments, such as mice models, Caenorhabditis elegans models, zebrafish models, human volunteers, as well as computer-simulated toxicity models. Owing to these models, especially those more biomimetic models, the outcome of the toxicity of NPs acting in the gastrointestinal tract can get results closer to what happened inside the real human microenvironment.     

可乐定对苯二氮受体激动剂和反相激动剂与大鼠皮层受体结合特性的影响(英文)

本研究旨在探讨α_2受体激动剂可乐定对苯二氮(艹卓)受体激动剂抗焦虑和反相激动剂致焦虑作用影响的可能的分子机理。在10nmol/L至1μmol/L浓度范围内,可乐定对[~3H]氟硝安定与大鼠皮层相应受体低亲和位点结合无显著影响,但非竞争性拮抗其与高亲和位点的结合。在竞争取代实验中,激动剂安定和CL218 872均表现为双位点结合的亲和力,对低亲和位点无显著影响。反相激动剂DMCM竞争结合曲线亦具有双位点结合特性。可乐定可使这种双位点结合转变成三位点结合,出现一个超高亲和位点。可乐定对拮抗剂Ro15-1788竞争结合特性无显著影响。结果提示,α_2受体激动剂可乐定与受体结合可能导致与之相邻的苯二氮(艹卓)受体发生构象变化,这种构象变化有利于激动剂与受体结合,而不利于反相激动剂的结合。     

Alpha-2 agonists in acute pain management

Importance of the field: This review explores the significance of alpha-2 agonists used clinically in acute pain management.

Areas covered in this review: Although alpha-2 agonists have been reported to have an analgesic effect, they are not commonly used clinically for acute pain management. Clinical studies on use of alpha-2 agonists for acute pain management are reviewed and discussed. A literature search was done using Medline with the keywords ‘alpha-2 agonist’, ‘clonidine’, ‘dexmedetomidine’, ‘fadolmidine’, ‘pharmacokinetics’, ‘pharmacodynamics’, ‘postoperative analgesia’, ‘epidural’, ‘intrathecal’, ‘peripheral nerve block’ and various combinations with these keywords. The years 1977 – 2009 have been included, with particular focus on clinical studies from between 1990 and 2009.

What the reader will gain: This article helps to clarify the clinical use of alpha-2 agonists in acute pain management according to current, up-to-date evidence. Clinically, available alpha-2 agonists, including clonidine and dexmedetomidine, are discussed in detail.

Take home message: Alpha-2 agonists, especially clonidine, seem to be promising with regard to acute postoperative pain management. However, more clinical evidence on dexmedetomidine is necessary to confirm its definite role in acute postoperative pain control.     

TARGIT technology: coated starch capsules for site-specific drug delivery into the lower gastrointestinal tract

TARGIT technology (West Pharmaceutical Services) is designed for site-specific delivery of drugs in the gastrointestinal (GI) tract and, in particular, targeted release into the colonic region. A key area of application is the delivery of therapeutic agents for local treatment of lower GI diseases. The technology is based on the application of pH-sensitive coatings onto injection-moulded starch capsules. An extensive body of clinical data has been generated showing reliable in vivo performance of the capsules. In gamma-scintigraphy studies around 90% of TARGIT capsules (n = 84) delivered their contents to the target site of the terminal ileum and colon. TARGIT-based products are in active clinical development for the treatment of conditions including inflammatory bowel diseases.     

Systematic review: the use of nitrous oxide gas for lower gastrointestinal endoscopy

Aliment Pharmacol Ther 2010; 32: 324–333

Summary

Background Nitrous oxide gas (N₂O) has been proposed as an alternative to intravenous (i.v.) analgesia in patients undergoing lower gastrointestinal endoscopy . Aim To perform a systematic review of randomized studies where N₂O was compared against control in patients undergoing either flexible sigmoidoscopy or colonoscopy. Methods Electronic databases were searched; reference lists were checked and letters were sent to authors requesting data. Methodological quality was assessed. Data were tabulated on the duration and difficulty of the procedure, quality of sedation and speed of patient recovery. Results A total of 11 studies were identified containing 623 patients. No differences were seen between groups for duration, difficulty of procedure or complications. Patient‐reported pain was similar for N₂O when undergoing flexible sigmoidoscopy vs. no sedation and when undergoing colonoscopy vs. i.v. sedation. Differences in delivery of N₂O were identified. In all studies, N₂O was associated with a more rapid recovery than i.v. sedation. Conclusion For patients undergoing colonoscopy, N₂O provides comparable analgesia to i.v. sedation. The rapid psychomotor recovery with N₂O enables quicker patient discharge and removes the need for a patient to be chaperoned. Benefit was not seen from N₂O in patients undergoing flexible sigmoidoscopy possibly because it was delivered on demand rather than continuously.     

Enzyme therapy for the lysosomal storage disorders: principles,patents, practice and prospects

AstraZeneca progressed the long acting β₂ agonist into Phase II studies for the treatment of asthma and chronic obstructive pulmonary disease in August 2008. These three applications claim specific salt forms of three different long acting β₂ agonists, all benzothiazolone derivatives. It would seem that one claims AZD-3199 whereas the other two claim backup compounds.