Guanylate cyclase C(GC-C) is an important receptor protein expressed by intestinal epithelial cells, and its dysregulation leads to severe intestinal diseases. Linaclotide is a 14-amino acid peptide approved by the FD...Guanylate cyclase C(GC-C) is an important receptor protein expressed by intestinal epithelial cells, and its dysregulation leads to severe intestinal diseases. Linaclotide is a 14-amino acid peptide approved by the FDA for the treatment of irritable bowel syndrome with constipation(IBS-C), which activates guanylate cyclase C to accelerate intestinal transit. Drug molecule design based on structural information plays a crucial role and the activity of linaclotide still need to improve, while the structure of linaclotide remains unknown. In this work, linaclotide and its D-enantiomer were obtained through Fmoc solid phase peptide synthesis method and co-crystalized through racemic crystallization. The crystal structure showed that linaclotide has a tight, three-beta turns structure immobilized by three pairs of disulfide bonds.展开更多
Constipation is a common medical problem and when standard laxatives fail it can be difficult to treat.Different aetiologies require tailored therapeutic approaches.Simple constipation may only require dietary manipul...Constipation is a common medical problem and when standard laxatives fail it can be difficult to treat.Different aetiologies require tailored therapeutic approaches.Simple constipation may only require dietary manipulation while severe neurological or slow transit constipation may need pharmacologic intervention.Recently new drug therapies have been introduced.PubMed and Ovid were searched for reviews,systematic reviews and meta-analysis published since 2003 using the terms:constipation,Prucalopride,Linaclotide and Lubiprostone.This review summarizes potential novel therapies identified as effective in the management of chronic constipation.Prucalopride is a selective 5-hydroxytryptamine receptor agonist.The prucalopride study was in patients,largely women with idiopathic constipation showed improved spontaneous complete bowel movement(SCBM)at a dose of 2 mg a day with few adverse events reported.Linaclotide is a 14-amino acid peptide guanylate cyclase-C agonist.The linaclotide study was carried out in patients with irritable bowel syndrome,constipation group(IBS-C).There was significant improvement of bowel evacuation and symptom resolution in patients on the active treatment arm.Lubiprostone activates type-2 chloride channels,increasing intestinal fluid secretion.In the trials of this drug,the lubiprostone arms had a greater mean number of SCBM.The novel therapies,prucalopride,lubiprostone,and linaclotide had very different modes of action yet,all three have been shown to be efficacious and safe in the treatment dose for constipation.展开更多
AIM:To study the efficacy and safety of pharmacolo-gical treatment of constipation in geriatrics.METHODS:Pub Med,MEDLINE,google scholar,and Ovid were searched to identify human studies performed on the use of laxative...AIM:To study the efficacy and safety of pharmacolo-gical treatment of constipation in geriatrics.METHODS:Pub Med,MEDLINE,google scholar,and Ovid were searched to identify human studies performed on the use of laxatives in elderly with constipation,which were conducted between January1990 and January 2013 using the specified keywords.Controlled studies that enrolled geriatric patients with a diagnosis of constipation and addressed the efficacy and/or the safety of pharmacological treatments were included.Studies were excluded from this review if they were non-controlled trials,case series,or case reports.RESULTS:Out of twenty three studies we initially retrieved in our search,only nine studies met the eligibility criteria of being controlled trials within geriatrics.The laxatives examined in the nine studies were senna,lactulose,sorbital,polyethylene glycol(PEG),lubiprostone,linaclotide,and prucalopride.In those studies,senna combinations had a higher efficacy than sorbitol or lactulose as well as,a very good adverse effect profile.PEG was also shown to be safe and effective in geriatric population.Furthermore,it has been shown that PEG is as safe in geriatrics as in general population.New agents like lubiprostone and prucalopride show promising results but the data about these agents in geriatrics are still limited which warrant further investigation.CONCLUSION:Senna combinations and PEG appear to have a more favorable profile over the other traditionally used laxatives in elderly patients with constipation.展开更多
基金supported by the National Natural Science Foundation of China (NSFC No. 21572043)the Fundamental Research Funds for the Central Universities (No. PA2017GDQT0021)
文摘Guanylate cyclase C(GC-C) is an important receptor protein expressed by intestinal epithelial cells, and its dysregulation leads to severe intestinal diseases. Linaclotide is a 14-amino acid peptide approved by the FDA for the treatment of irritable bowel syndrome with constipation(IBS-C), which activates guanylate cyclase C to accelerate intestinal transit. Drug molecule design based on structural information plays a crucial role and the activity of linaclotide still need to improve, while the structure of linaclotide remains unknown. In this work, linaclotide and its D-enantiomer were obtained through Fmoc solid phase peptide synthesis method and co-crystalized through racemic crystallization. The crystal structure showed that linaclotide has a tight, three-beta turns structure immobilized by three pairs of disulfide bonds.
文摘Constipation is a common medical problem and when standard laxatives fail it can be difficult to treat.Different aetiologies require tailored therapeutic approaches.Simple constipation may only require dietary manipulation while severe neurological or slow transit constipation may need pharmacologic intervention.Recently new drug therapies have been introduced.PubMed and Ovid were searched for reviews,systematic reviews and meta-analysis published since 2003 using the terms:constipation,Prucalopride,Linaclotide and Lubiprostone.This review summarizes potential novel therapies identified as effective in the management of chronic constipation.Prucalopride is a selective 5-hydroxytryptamine receptor agonist.The prucalopride study was in patients,largely women with idiopathic constipation showed improved spontaneous complete bowel movement(SCBM)at a dose of 2 mg a day with few adverse events reported.Linaclotide is a 14-amino acid peptide guanylate cyclase-C agonist.The linaclotide study was carried out in patients with irritable bowel syndrome,constipation group(IBS-C).There was significant improvement of bowel evacuation and symptom resolution in patients on the active treatment arm.Lubiprostone activates type-2 chloride channels,increasing intestinal fluid secretion.In the trials of this drug,the lubiprostone arms had a greater mean number of SCBM.The novel therapies,prucalopride,lubiprostone,and linaclotide had very different modes of action yet,all three have been shown to be efficacious and safe in the treatment dose for constipation.
文摘AIM:To study the efficacy and safety of pharmacolo-gical treatment of constipation in geriatrics.METHODS:Pub Med,MEDLINE,google scholar,and Ovid were searched to identify human studies performed on the use of laxatives in elderly with constipation,which were conducted between January1990 and January 2013 using the specified keywords.Controlled studies that enrolled geriatric patients with a diagnosis of constipation and addressed the efficacy and/or the safety of pharmacological treatments were included.Studies were excluded from this review if they were non-controlled trials,case series,or case reports.RESULTS:Out of twenty three studies we initially retrieved in our search,only nine studies met the eligibility criteria of being controlled trials within geriatrics.The laxatives examined in the nine studies were senna,lactulose,sorbital,polyethylene glycol(PEG),lubiprostone,linaclotide,and prucalopride.In those studies,senna combinations had a higher efficacy than sorbitol or lactulose as well as,a very good adverse effect profile.PEG was also shown to be safe and effective in geriatric population.Furthermore,it has been shown that PEG is as safe in geriatrics as in general population.New agents like lubiprostone and prucalopride show promising results but the data about these agents in geriatrics are still limited which warrant further investigation.CONCLUSION:Senna combinations and PEG appear to have a more favorable profile over the other traditionally used laxatives in elderly patients with constipation.
