冬凌草片对炎症后肠易激综合征大鼠的治疗作用

目的 研究冬凌草片对炎症后肠易激综合征（Post-inflammatory Irritable Bowel Syndrome,PI-IBS）大鼠的治疗作用及其机制。方法 用2,4,6-三硝基苯磺酸制备PI-IBS大鼠模型,动物灌胃给予冬凌草片0.4,0.8,1.2 g·kg^-1·d^-1,连续2周。采用腹壁收缩实验测内脏痛阈值;水应激法评价结肠运动;免疫组化法考察嗜铬细胞数;液质联用法测血清素含量,并用免疫印迹法考察色氨酸羟化酶的表达。结果 与正常对照组相比,PI-IBS大鼠内脏痛阈值明显降低、结肠排便增多、肠嗜铬细胞增生、色氨酸羟化酶表达增多及血清素含量增高（P<0.05）。冬凌草片高剂量和中剂量给药可显著提高PI-IBS大鼠内脏痛阈值;显著减少结肠排便数量、肠嗜铬细胞数量、血清素含量和色氨酸羟化酶表达（P<0.05）。结论 冬凌草片通过减少肠道嗜铬细胞增生和血清素含量治疗PI-IBS大鼠内脏痛及结肠运动障碍。     

A novel role for the metabotropic glutamate receptor-7: modulation of faecal water content and colonic electrolyte transport in the mouse

Background and purpose:

Increasing evidence implicates metabotropic glutamate receptor mGlu₇ in the pathophysiology of stress-related disorders such as depression and anxiety. Mood disorders are frequently associated with gastrointestinal (GI) dysfunction; however, the role of mGlu₇ receptors outside the CNS is unknown. This present study investigated the expression and possible functional role of mGlu₇ receptors in the mouse colon.

Experimental approach:

Expression of mGlu₇ receptor mRNA and protein was studied in mouse colon by in situ hybridization and Western blotting. Effects of the selective mGlu₇ receptor agonist AMN082 on defecation and faecal parameters were studied in an isolation-induced stress model. AMN082 effects on ion transport and neuronal intracellular signalling were examined via Ussing chambers and calcium imaging.

Key results:

mGlu₇ receptor mRNA and protein were highly expressed in colon mucosa. Stress-induced faecal output was unaffected by AMN082, although faecal water content was increased. In mucosa/submucosa preparations, 100 nM and 1 µM AMN082 increased bethanechol-induced changes in short-circuit current in the Ussing chamber. This was sensitive to tetrodotoxin. Also, 100 nM AMN082 significantly increased calcium signalling in a subset of submucosal neurons.

Conclusions and implications:

Activating mGlu₇ receptors increased colonic secretory function in vivo and ex vivo. In a group of submucosal neurons, AMN082 strongly induced calcium signalling and the presence of submucosal nerves was required for the AMN082-dependent increase in secretion. These data suggest that targeting mGlu₇ receptors may be useful in the treatment of central components of stress disorders and also stress-associated GI dysfunction such as diarrhoea or constipation.     

Tenapanor hydrochloride for the treatment of constipation-predominant irritable bowel syndrome

Introduction: Constipation-predominant irritable bowel syndrome (IBS-C) is a common functional gastrointestinal (GI) disorder characterized by recurrent abdominal pain and prolonged GI transit. The pathogenesis of IBS-C has still not been established; therefore, drugs currently in use in IBS-C act mainly symptomatically, whereas novel pharmacological targets are urgently needed. Tenapanor is a potent inhibitor of Na⁺/H⁺ exchanger 3 [NHE3], localized in the apical membrane of intestinal epithelial cells. NHE3 participates in the uptake of sodium ions and water from the intestinal lumen.

Areas covered: In this review, the authors discuss pharmacodynamics and pharmacokinetics of tenapanor, focusing on animal models and in vitro studies. They also summarize clinical trials on tenapanor’s safety and efficacy in view of its potential role in IBS-C therapy.

Expert opinion: Tenapanor possesses an excellent preclinical safety profile and, as of now, there are no serious concerns about its side effects. The non-systemic action of tenapanor constitutes a significant advantage, as it minimizes possible adverse effects or drug–drug interactions. However, Phase III clinical trials are still needed to confirm results obtained in earlier phases and optimize the dose–response for tenapanor, whereas limiting diarrhea, its major adverse effect.     

Effect of domperidone and dopamine on colonic motor activity in patients with the irritable bowel syndrome

Summary The effect of domperidone, a peripheral antidopaminergic drug, on sigmoid motor activity in the irritable bowel syndrome, has been evaluated by measuring pressures in 3 opentipped tubes perfused with distilled water at a constant flow rate of 0.636 ml/min and inserted into the sigmoid colon. Domperidone 20 mg i.v. in 10 patients, did not induce any significant change in basal motility, but prevented the increase in motor activity produced by the infusion of dopamine 5 µg/kg/min for 10 min. It appears that domperidone had no effect on sigmoid motor activity, although the inhibition of dopamine-induced motility confirms the presence of specific dopaminergic receptors in the colon and the antidopaminergic action of domperidone.     

5-HT and the brain–gut axis: opportunities for pharmacologic intervention

Interactions between the enteric nervous system of the gut and the brain occur bidirectionally over sympathetic and parasympathetic pathways. Coordinated actions of the central, autonomic and enteric nervous systems modulate intestinal motor, sensory and secretory activities by neuromodulators, including 5-HT, noradrenaline and dopamine. 5-HT is an important signaling molecule in the brain–gut axis and the 5-HT released from enterochromaffin cells modulates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. Irritable bowel syndrome is associated with altered motility, secretion and sensation; enteric 5-HT signaling may be defective in this disorder. In this editorial, recent data are reviewed and the potential for the development of pharmacologic intervention is assessed.     

Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof‐of‐concept

Irritable bowel syndrome (IBS) is a chronic disease characterized by abdominal pain and changes in bowel habits. Patients with IBS comprise a significant portion of attendants at the outpatient clinics. Targeting intestinal opioid receptors was found successful in alleviating pain and diarrhea—two major symptoms of IBS. In this study, we aimed to evaluate a novel potential pharmacological option: the use of enkephalinase inhibitors in therapy of visceral pain occurring in the course of IBS. We thus assessed the antinociceptive efficacy of enkephalins: Leu‐enkephalin and Met‐enkephalin, and enkephalinase inhibitors: opiorphin and sialorphin in the mouse model of visceral pain induced by colorectal distension. Leu‐enkephalin, Met‐enkephalin, and sialorphin, but not opiorphin, at the dose of 1 mg/kg injected subcutaneously potently decreased the visceromotor response to colon distension as compared to control. To conclude, enkephalinase inhibitors are worth being considered as potential therapeutics in patients with chronic abdominal pain and/or changed bowel habits, that is, suffering from IBS.     

Interleukin-19 is a negative regulator of innate immunity and critical for colonic protection

The cytokine, interleukin (IL)-19, is a member of the IL-10 family that includes IL-20, IL-22, IL-24, and IL-26. Recent studies have shown that IL-19 is produced by keratinocytes, epithelial cells, macrophages, and B-cells. Little is known about the exact biological role of IL-19 in immunological regulation, although there is an increasing body of data demonstrating that IL-19 is associated with the development of Th2 responses and the pathogenesis of psoriasis. In this review, I shall attempt to discuss current knowledge about the role of IL-19 on macrophages and the potential role in inflammatory bowel disease.     

Algorithms to identify colonic ischemia, complications of constipation and irritable bowel syndrome in medical claims data: development and validation

PURPOSE: A challenge in the use of insurance claims databases for epidemiologic research is accurate identification and verification of medical conditions. This report describes the development and validation of claims-based algorithms to identify colonic ischemia, hospitalized complications of constipation, and irritable bowel syndrome (IBS). METHODS: From the research claims databases of a large healthcare company, we selected at random 120 potential cases of IBS and 59 potential cases each of colonic ischemia and hospitalized complications of constipation. We sought the written medical records and were able to abstract 107, 57, and 51 records, respectively. We established a 'true' case status for each subject by applying standard clinical criteria to the available chart data. Comparing the insurance claims histories to the assigned case status, we iteratively developed, tested, and refined claims-based algorithms that would capture the diagnoses obtained from the medical records. We set goals of high specificity for colonic ischemia and hospitalized complications of constipation, and high sensitivity for IBS. RESULTS: The resulting algorithms substantially improved on the accuracy achievable from a na?ve acceptance of the diagnostic codes attached to insurance claims. The specificities for colonic ischemia and serious complications of constipation were 87.2 and 92.7%, respectively, and the sensitivity for IBS was 98.9%. CONCLUSIONS: U.S. commercial insurance claims data appear to be usable for the study of colonic ischemia, IBS, and serious complications of constipation.     

Modulation of gastrointestinal function by MuDelta,a mixed μ opioid receptor agonist/ μ opioid receptor antagonist

BACKGROUND & PURPOSE

Loperamide is a selective µ opioid receptor agonist acting locally in the gastrointestinal (GI) tract as an effective anti-diarrhoeal but can cause constipation. We tested whether modulating µ opioid receptor agonism with δ opioid receptor antagonism, by combining reference compounds or using a novel compound (‘MuDelta’), could normalize GI motility without constipation.

EXPERIMENTAL APPROACH

MuDelta was characterized in vitro as a potent µ opioid receptor agonist and high-affinity δ opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following ex vivo and in vivo experiments: guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport and upper GI tract transit, entire GI transit or faecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post-inflammatory). Colonic δ opioid receptor immunoreactivity was quantified.

KEY RESULTS

δ Opioid receptor antagonism opposed µ opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically-mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up-regulated δ opioid receptor expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and faecal output to control levels over a wide dose range, whereas loperamide had a narrow dose range. MuDelta and loperamide reduced upper GI transit in the post-inflammatory model.

CONCLUSIONS AND IMPLICATIONS

MuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea-predominant irritable bowel syndrome.     

Therapeutic potential of CRF receptor antagonists: a gut-brain perspective

Activation of the corticotropin-releasing factor (CRF) family of neuropeptide receptors in the brain and periphery appears to mediate stress-related changes in a variety of physiological and functional domains. Comparative pharmacology of CRF receptor agonists suggests that CRF, urocortin, sauvagine and urotensin consistently mimic, and conversely peptide CRF receptor antagonists lessen, the functional consequences of stressor exposure. Together with the development of novel non-peptide CRF receptor antagonists, a growing number of CRF receptor selective ligands are available to elucidate the neurobiology and physiological role of CRF systems. The present review considers available preclinical evidence as well as results from one Phase II clinical trial which address the hypothesis that CRF receptor antagonists may represent a new option for pharmacotherapy of stress-related disorders.     

益生菌治疗肠易激综合征疗效的Meta分析

目的探讨益生菌治疗肠易激综合征(IBS)的临床疗效及安全性。方法计算机检索PubMed、国际Cochrane中心、Embase、中国生物医学文献数据库、中国期刊全文数据库、万方数据库、维普数据库,收集益生菌治疗IBS的随机对照试验(RCT),并手工检索已获文献的参考文献,由两位评价者按照纳入和排除标准筛选、提取资料并行方法学质量评价,采用RevMan 5.0软件对数据行Meta分析。结果共纳入19个RCT,2172例患者。Meta分析结果显示,益生菌较安慰剂在改善患者总体症状积分[SMD=-0.18,95%CI(-0.28,-0.08),P=0.000 6]、腹痛[SMD=-0.13,95%CI(-0.21,-0.04),P=0.0031、腹胀[SMD=-0.15,95%CI(-0.25,-0.05),P=0.004]、排便不适感[SMD=-0.15,95%CI(-0.27,-0.02),P=0.02】方面均有显著意义,在总体生活质量[SMD:0.09,95%CI(-0.08,0.25),P=0.301、不良反应发生率[RR=0.91,95%CI(0.71,1.16),P=0.45]方面无显著意义。结论目前证据显示益生菌制剂能有效改善IBS患者的临床症状,且安全性好,但现有RCT在方法质量学以及研究设计上存在一定不足,今后的研究应在菌株、剂量、疗程、IBS亚组患者方面进行严谨、高质量、大样本长期随访的临床研究予以证实。     

柱前衍生化液相色谱-质谱联用法测定大鼠血浆中5-羟色胺的浓度

目的:建立应用液相色谱-质谱联用(LC-MS/MS)测定大鼠血浆(包括富含血小板血浆)中5-羟色胺浓度的方法,并将其应用于感染后肠易激综合征模型大鼠体内5-HT的测定。方法:血浆样品在加入甲巯咪唑(内标)后用苯甲酰氯作为衍生试剂,以四硼酸钠为催化试剂,室温下进行柱前衍生。样品在甲醇沉淀蛋白后采用ESI电离源在正离子模式下检测,用Agilent Zorbax eclipse plus C18色谱柱,甲醇-水溶液为流动相洗脱,流速为1.0 ml·min^-1。结果:经衍生后5-HT在大鼠富含血小板血浆及血浆中其线性范围及定量限均符合测定要求,日内、日间精密度及基质效应均<15%;肠易激综合征大鼠血浆中游离5-HT相较正常组大鼠显著增高。结论:本方法快速、灵敏、专属性强且重现性好,可用于大鼠血浆中5-HT浓度的测定。     

Multiple levels of sensory integration in the intrinsic sensory neurons of the enteric nervous system

1. The enteric nervous system (ENS) is present in the wall of the gastrointestinal tract and contains all the functional classes of neuron required for complete reflex arcs. One of the most important and intriguing classes of neuron is that responsive to sensory stimuli: sensory neurons with cell bodies intrinsic to the ENS. 2. These neurons have three outstanding and interrelated features: (i) reciprocal connections with each other; (ii) a slow excitatory post-synaptic potential (EPSP) resulting from high-speed firing in other sensory neurons; and (iii) a large after-hyperpolarizing potential (AHP) at the soma. Slow EPSP depolarize the cell body, generate action potentials (APs) and reduce the AHP. Conversely, the AHP limits the firing rate and, hence, reduces transmission of slow EPSP. 3. Processing of sensory information starts at the input terminals as different patterns of APs depending on the sensory modality and recent sensory history. At the soma, the ability to fire APs and, hence, drive outputs is also strongly determined by the recent firing history of the neuron (through the AHP) and network activity (through the slow EPSP). Positive feedback within the population of intrinsic sensory neurons means that the network is able to drive outputs well beyond the duration of the stimuli that triggered them. 4. Thus, sensory input and subsequent reflex generation are integrated over several hierarchical levels within the network on intrinsic sensory neurons.     

UHPLC-MS/MS同时检测IBS-D模型大鼠血浆中痛泻要方6种成分的含量及其药动学

目的：建立超高效液相色谱-质谱法（UHPLC-MS/MS）同时测定腹泻型肠易激综合征（IBS-D）模型大鼠血浆中6种成分（芍药苷、橙皮苷、新橙皮苷、升麻素苷、5-O-甲基维斯阿米醇苷、升麻素）的分析方法,并研究这6种成分的药动学特征。方法：采用Phenomenex-C₁₈色谱柱（4.6 mm×50 mm,5 μm）,乙腈-0.1%甲酸水溶液为流动相梯度洗脱,流速0.7 mL·min^-1,ESI离子源,柱温35 ℃,SRM检测模式。结果：各成分的线性关系良好（r>0.9974）;精密度RSD<13.89%;血浆中无内源性基质干扰,稳定性良好。6种成分的达峰时间（t_max）分别为（0.5±0）,（0.36±0.06）,（0.33±0）,（0.44±0.08）,（0.31±0.13）,（0.67±0.26） h,半衰期（t_1/2）分别为（6.63±1.60）,（4.31±1.14）,（5.43±0.88）,（5.98±1.91）,（7.80±4.39）,（4.33±0.40） h,药峰浓度（C_max）分别为（145.42±9.81）,（166.11±4.83）,（167.69±2.98）,（46.29±3.88）,（18.98±1.85）,（374.71±7.54） ng·mL^-1。结论：该方法简便、灵敏、准确,分析速度快,可用于痛泻要方的药代动力学研究。     

肠炎宁糖浆联合奥替溴铵治疗肠易激综合征的临床研究

目的探讨肠炎宁糖浆联合奥替溴铵片治疗肠易激综合征的临床疗效。方法选取2019年4月—2020年8月河南医学高等专科学校附属医院收治的92例肠易激综合征患者为研究对象,根据随机数字表法将92例分为对照组和治疗组,每组各46例。对照组口服奥替溴铵片,40 mg/次,3次/d。治疗组在对照组基础上口服肠炎宁糖浆,10 m L/次,3次/d。两组患者连续治疗4周。观察两组的临床疗效,比较两组的腹痛、腹胀、腹泻消失时间,肠易激综合征的特征指数生活质量量表(IBS-QOL)评分和血清中白细胞介素-6(IL-6)、白细胞介素-18(IL-18)、神经肽Y(NRY)、血管活性肠肽(VIP)、胆囊收缩素(CCK)、胃动素(MTL)水平。结果治疗后,治疗组患者的总有效率为93.48%,对照组的总有效率为78.26%,组间有明显差异(P<0.05)。治疗后,治疗组患者腹痛、腹胀、腹泻消失时间均比对照组短(P<0.05)。治疗后,两组患者的IBS-QOL评分明显升高,差异有统计学意义(P<0.05);且治疗组患者IBS-QOL评分升高的更明显,差异有统计学意义(P<0.05)。治疗后,两组的IL-6、IL-18水平明显降低,NRY水平明显升高(P<0.05);且治疗后治疗组的IL-6、IL-18水平低于对照组,NRY水平高于对照组(P<0.05)。治疗后,两组的CCK水平明显升高,VIP、MTL水平明显降低(P<0.05);且治疗后治疗组的CCK水平比对照组高,VIP、MTL水平低于对照组,差异有统计学意义(P<0.05)。结论肠炎宁糖浆联合奥替溴铵片可提高肠易激综合征的临床疗效,改善临床症状,增强患者的生活质量,减轻炎症反应,调节胃肠激素,安全性良好。