Background:
- Acid-related gastrointestinal disorders are numerous and may require chronic treatment and maintenance, but they are often difficult to diagnose and treat. Gastric analysis is a critical tool for diagnosing and treating acid-related disorders; however, at present it requires a technically difficult procedure, using a nasogastric tube, that is costly, invasive, and uncomfortable. Recently a new tool, the SmartPill, has been developed that can measure acid levels, temperature, and pressure throughout the stomach, small intestine, and colon by swallowing a small capsule. Researchers are interested in comparing current methods of measuring stomach acid with the SmartPill by studying both healthy volunteers and individuals with acid-related gastrointestinal disorders.
Objectives:
- To evaluate the usefulness and accuracy of the SmartPill for gastric analysis, compared with current procedures.
Eligibility:
* Phase 1A/1B: Healthy volunteers between 18 and 60 years of age.
* Phase 2: Individuals at least 18 years of age who have been diagnosed with Zollinger-Ellison Syndrome or acid hypersecretion.
* Phase 3: Individuals at least 18 years of age who have been diagnosed with refractory gastroesophageal reflux disease, peptic ulcer disease, or idiopathic gastric hypersecretion.
Design:
* This study involves a screening visit, a 3-day inpatient study visit, and possible additional outpatient visits.
* Participants will be screened with a medical history and physical examination, as well as blood and urine samples.
* Phase 1A/1B: Participants will have a 3-day inpatient study visit with the following procedures:
* Imaging study of the stomach (simultaneous gastric emptying scintigraphy), followed by a special diet for the next day s test.
* Gastric analysis using a nasogastric tube to collect stomach acid secretions.
* SmartPill study, in which participants will ingest a SmartPill and wear a monitor for 24 to 48 hours to collect readings.
* Participants in Phase 1A will have a second outpatient SmartPill study 7 days after the first SmartPill study. Participants in Phase 1B will not have the second SmartPill study.
* Phase 2 and Phase 3: Participants will have a 3-day inpatient study visit with the following procedures:
* Imaging study of the stomach (simultaneous gastric emptying scintigraphy), followed by a special diet for the next day s test.
* Gastric analysis using a nasogastric tube to collect stomach acid secretions.
* SmartPill study, in which participants will ingest a SmartPill and wear a monitor for 24 to 48 hours to collect readings.
* Phase 2 and 3 participants will have outpatient study visits only if directed by the study researchers.

开始日期2008-06-18

申办/合作机构

National Institute of Diabetes & Digestive & Kidney Diseases

100 项与五肽胃泌素相关的临床结果

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100 项与五肽胃泌素相关的转化医学

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100 项与五肽胃泌素相关的专利（医药）

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3,720

项与五肽胃泌素相关的文献（医药）

2024-11-28·JOURNAL OF MEDICINAL CHEMISTRY

Prodrug Strategy to Address Impaired Oral Absorption of a Weakly Basic TYK2 Inhibitor Caused by a Gastric Acid-Reducing Agent

Article

作者: Ramar, Thangeswaran ; Desai, Salil ; A M Subbaiah, Murugaiah ; Weinstein, David S. ; Mathur, Arvind ; Sivaprasad Lvj, Sankara ; Chiney, Manoj ; Yeshwante, Shekhar ; Sivaprasad LVJ, Sankara ; Dierks, Elizabeth A ; Reddy, Maheswara ; Weinstein, David S ; Dierks, Elizabeth A. ; Sridhar, Srikanth ; Moslin, Ryan

The pH-dependent solubility of the weakly basic TYK2 inhibitor 1 posed a risk to its advancement, given that drugs with such profiles have exhibited drug-drug interaction (DDI) with stomach acid-reducing agents in humans. In a rat model of pH dependence, preadministration of famotidine caused a 2.4-fold lower exposure of 1 when compared to control rats, implying that pH-dependent oral absorption can reduce the active drug's exposure and translate to subtherapeutic treatment. As part of risk mitigation, a prodrug strategy was explored by synthesizing solubility-enhancing prodrugs, resulting in the identification of lead prodrug 3c with acceptable stability and solubility profiles. In rats, the prodrug eliminated the significant difference in AUC and C_max between pentagastrin and famotidine arms, thereby effectively mitigating the impaired drug absorption at the elevated pH relevant for absorption and DDI with famotidine. The prodrug also facilitated dose-proportional systemic exposure of 1 following dose escalation in rats and monkeys.

2023-09-01·Journal of computer-aided molecular design

Polygalic acid inhibits african swine fever virus polymerase activity: findings from machine learning and in vitro testing.

Article

作者: Huynh, Trang T X ; Pham, Thuy X ; Lee, Hyundo ; Lim, Yun-Sook ; Cho, Soyoung ; Choi, Yorim ; Hwang, Soon B ; Choi, Jiwon

African swine fever virus (ASFV), an extremely contagious virus with high mortality rates, causes severe hemorrhagic viral disease in both domestic and wild pigs. Fortunately, ASFV cannot be transmitted from pigs to humans. However, ongoing ASFV outbreaks could have severe economic consequences for global food security. Although ASFV was discovered several years ago, no vaccines or treatments are commercially available yet; therefore, the identification of new anti-ASFV drugs is urgently warranted. Using molecular docking and machine learning, we have previously identified pentagastrin, cangrelor, and fostamatinib as potential antiviral drugs against ASFV. Here, using machine learning combined with docking simulations, we identified natural products with a high affinity for AsfvPolX proteins. We selected five natural products (NPs) that are located close in chemical space to the six known natural flavonoids that possess anti-ASFV activity. Polygalic acid markedly reduced AsfvPolX polymerase activity in a dose-dependent manner. We propose an efficient protocol for identifying NPs as potential antiviral drugs by identifying chemical spaces containing high-affinity binders against ASFV in NP databases.

2022-11-01·Journal of molecular graphics & modelling

Virtual drug repurposing study for the CGRPR identifies pentagastrin and leuprorelin as putative candidates

Article

作者: Durdagi, Serdar ; Aksoydan, Busecan

Calcitonin gene-related peptide receptor (CGRPR) is a heterodimer consisting of CLR and RAMP1 proteins. Activation of the CGRPR with the endogenous peptide CGRP is known to play a crucial role in migraine pathophysiology. CGRP occupies two regions in the CGRPR upon binding, namely ectodomain and transmembrane sites (sites 1 and 2, respectively). The disruption of the CGRPR heterodimer interface is one of the main strategies to prevent CGRPR activation and its resulting effects. So far, FDA approved monoclonal antibodies and small molecule gepant inhibitors are considered for the treatment of acute or chronic migraine symptoms. However, most of these gepants have severe side effects. Thus, in this study, a virtual drug repurposing approach is applied to CGRPR to find alternative or better molecules that would have a potential to inhibit or block the CLR - RAMP1 interface compared to known gepant molecules. A small molecule library of FDA-approved molecules was screened in these two different binding sites, further simulations were performed and analyzed. The objectives of this study are (i) to repurpose an FDA-approved drug having more potent features for CGRPR inhibition compared to gepants, and (ii) to examine whether the transmembrane binding site (site 2) accepts small molecules or small peptide analogues for binding. As a result of this extensive in silico analysis, two molecules were identified, namely pentagastrin and leuprorelin. It is shown that FDA approved compound rimegepant and the identified pentagastrin molecules form and maintain the interactions through CLR W72 and RAMP1 W74, which are the residues revealed to have an important role in CGRPR antagonism at binding site 1. At binding site 2, the interactions needed to be formed for CGRP binding are not captured by rimegepant nor leuprorelin, yet leuprorelin forms more interactions throughout the simulations, meaning that small molecules are also capable of binding to site 2. Moreover, it is found that the crucial interactions for receptor signaling and heterodimerization occurred between CLR and RAMP1 interface are disrupted more with the ligands bound to ectodomain site, rather than the transmembrane domain. These findings of pentagastrin and leuprorelin molecules are recommended to be considered in further de novo drug development and/or experimental studies related to CGRPR signaling blockade and antagonism.

100 项与五肽胃泌素相关的药物交易

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