囊性纤维化跨膜传导调节因子抑制药在分泌性腹泻中的应用研究进展

摘 要 分泌性腹泻威胁着全球健康,是儿童发病和死亡的主要原因之一。肠上皮细胞腔内Cl-通道激活导致肠道液体过度分泌是肠毒素引起腹泻的主要原因。在霍乱及其他细菌肠毒素引发的腹泻中,囊性纤维化跨膜传导调节因子（cystic fibrosis transmembrane conductance regulator, CFTR）是主要的cAMP-调节Cl 通道,其主要功能是促进上皮细胞液体分泌。利用肠上皮细胞CFTR抑制药抗分泌性腹泻是一种新途径。已有的CFTR抑制药有噻唑啉酮类、甘氨酸酰肼类和喹喔啉二酮等。同时,从天然植物中提取分离的一些成分也具有CFTR抑制作用,但研究还不够深入。因此,对CFTR抑制药的研究进展进行了综述。     

Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis

Background: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population.

Methods: In six randomized controlled trials (RCTs), patients received linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12–26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed.

Results: Overall, 3853 patients received ≥1 dose of linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea.

Conclusion: These pooled analyses of patients treated for ≤104 weeks confirm linaclotide’s overall safety.     

Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome

BACKGROUND & AIMS: Serotonin (5-HT) is a critical signaling molecule in the gut. 5-HT released from enterochromaffin cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both associated with clinical symptoms that include alterations in the normal patterns of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT signaling is defective in these disorders. METHODS: Rectal biopsy specimens were obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including measures of 5-HT content, release, and reuptake, were analyzed with these samples. RESULTS: Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin transporter messenger RNA, and serotonin transporter immunoreactivity were all significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell population was decreased in severe UC samples but was unchanged in IBS-C and IBS-D. When 5-HT release was investigated under basal and mechanical stimulation conditions, no changes were detected in any of the groups relative to controls. CONCLUSIONS: These data show that UC and IBS are associated with similar molecular changes in serotonergic signaling mechanisms. While UC and IBS have distinct pathophysiologic properties, these data suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation. These findings represent the first demonstration of significant molecular alterations specific to the gut in patients with IBS and support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel.     

Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome

Purpose

In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m²) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival.

Molecular characterization of diarrheagenic Escherichia coli pathotypes: Association of virulent genes,serogroups, and antibiotic resistance among moderate‐to‐severe diarrhea patients

Background

Diarrheagenic Escherichia coli (DEC) signifies as an important etiological agent of moderate‐to‐severe diarrhea. This study was primarily focused on molecular identification of DEC pathotypes; their association with serogroups and estimates of resistance profiles against different antibiotics regime.

Methods

Five hundred seventy‐two stool specimens from diarrhea patients were investigated for DEC pathotypes. Molecular pathotypes were identified by amplification of virulence genes associated with distinct pathotypes followed by sequencing. Diarrhea is a self‐limiting disease, however, severity and persistence of infection suggest antibiotic use. Therefore, AST and MIC were determined against common antibiotic regimen. Correlations between molecular pathotypes and serogroups were analyzed by somatic “O” antigen serotyping.

Results

The present findings reveal incidence of DEC as an etiological agent up to a level of 21% among all diarrheal age groups. DEC infection rate was higher in children. Enteropathogenic E. coliEPEC, a molecular pathotype of DEC, was found as a predominant pathotype with highest frequency of 13.7%. Two other molecular pathotypes enterotoxigenic E. coli (ETEC) and enteroaggregative E. coli (EAEC) accounted for 5.7% and 1.3%, respectively for all diarrhea incidences. Serological analysis deciphered somatic antigens O26, O2, and O3 as major serogroups identified among EPEC, ETEC, and EAEC pathotypes, respectively. All DEC pathotypes exhibited high levels of antibiotic resistance except for cotrimoxazole and norfloxacin.

Conclusion

Comprehensive molecular characterization of DEC pathotypes, their incidence estimates, and antibiogram patterns will help in ascertaining better diagnostic and therapeutic measures in management of diarrheal diseases.

     

药物炮制对参苓白术散健脾止泻作用的影响

目的：观察党参、甘草等药物不同炮制品组方的参苓白术散的药效作用。方法：①70只昆明种小鼠随机平均分为空白对照组,模型对照组,思密达组,参苓白术散1组、2组、3组、4组,除空白对照组外,其余各组均制作为脾虚泄泻模型。正常对照组和模型对照组每天按照0．02 mL·g－1剂量灌胃自来水1次,连续7d。其余各组均给予相同量的相应药物。观察各组胃排空和肠推进功能。②分组及给药方法同①,观察各组腹泻指数。③分组及给药方法同①,观察各组小鼠脾虚指数、小鼠尿D-木糖含量、淀粉酶活性。④分组同①,每组15只,空白对照组、模型组用0．02 mL·g－1自来水灌胃外,其余各组每鼠灌胃100％不同炮制品组成的参苓白术散1组、2组、3组、4组药液0．02 mL·g－1,1次·d－1,连续给药12 d。第7天除正常对照组外,其余各组每鼠腹腔注射环磷酰100 mg·kg－1,1次·d－1,观察各组腹腔巨噬细胞吞噬功能。结果：由党参、甘草的蜜炙品与白术、山药的土炒品、薏苡仁麸炒品组方的参苓白术散有明显的止泻作用,能抑制小鼠的碳末推进率和胃排空率,与模型组比较,差异有显著统计学意义（P＜0．01）;由党参、甘草的蜜炙品与白术、山药、薏苡仁麸炒品组方的参苓白术散能显著提高脾虚小鼠血清淀粉酶和D-木糖的含量,与模型组比较,差异有显著统计学意义（P＜0．01）;党参、甘草的蜜制品与白术、山药、薏苡仁生品组方的参苓白术散组可明显提高腹腔巨噬细胞吞噬作用,与模型组比较,差异有显著统计学意义（P＜0．01）。结论：思密达虽有止泻作用,但没有提高脾虚小鼠免疫机能的作用。参苓白术散在临床上用于脾虚泄泻引起的腹泻便溏、纳呆,组方时党参、甘草应用蜜炙品,白术、山药应用土炒品、薏苡仁应用麸炒品;用于健脾消食时,组方时党参、甘草应用蜜炙品,白术、山药、薏苡仁应用麸炒品;用于提高机体免疫力时,党参、甘草应用蜜制品,白术、山药、薏苡仁应用生品。     

Comparison of Porcine Epidemic Diarrhea Viruses from Germany and the United States, 2014

Since 2013, highly virulent porcine epidemic diarrhea virus has caused considerable economic losses in the United States. To determine the relation of US strains to those recently causing disease in Germany, we compared genomes and found that the strain from Germany is closely related to variants in the United States.