New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders.
Ontology highlight
ABSTRACT:
SUBMITTER: Camilleri M
PROVIDER: S-EPMC8380736 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders.
Gastroenterology 20210511 3
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Project description:NK1 and NK3 receptors do not appear to play significant roles in normal GI functions, but both may be involved in defensive or pathological processes. NK1 receptor antagonists are antiemetic, operating via vagal sensory and motor systems, so there is a need to study their effects on other gastro-vagal functions thought to play roles in functional bowel disorders. Interactions between NK1 receptors and enteric nonadrenergic, noncholinergic motorneurones suggest a need to explore the role of this receptor in disrupted colonic motility. NK1 receptor antagonism does not exert consistent analgesic activity in humans, but similar studies have not been carried out against pain of GI origin, where NK1 receptors may have additional influences on mucosal inflammatory or "irritant" processes. NK3 receptors mediate certain disruptions of intestinal motility. The activity may be driven by tachykinins released from intrinsic primary afferent neurones (IPANs), which induce slow EPSP activity in connecting IPANs and hence, a degree of hypersensitivity within the enteric nervous system. The same process is also proposed to increase C-fibre sensitivity, either indirectly or directly. Thus, NK3 receptor antagonists inhibit intestinal nociception via a "peripheral" mechanism that may be intestine-specific. Studies with talnetant and other selective NK3 receptor antagonists are, therefore, revealing an exciting and novel pathway by which pathological changes in intestinal motility and nociception can be induced, suggesting a role for NK3 receptor antagonism in irritable bowel syndrome.
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Project description:Kirsten Rat Sarcoma (KRAS) is a master oncogene involved in cellular proliferation and survival and is the most commonly mutated oncogene in all cancers. Activating KRAS mutations are present in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases and are implicated in tumor initiation and progression. Although KRAS is a critical oncogene, and therefore an important therapeutic target, its therapeutic inhibition has been very challenging, and only recently specific mutant KRAS inhibitors have been discovered. In this review, we discuss the activation of KRAS signaling and the role of mutant KRAS in PDAC development. KRAS has long been considered undruggable, and many drug discovery efforts which focused on indirect targeting have been unsuccessful. We discuss the various efforts for therapeutic targeting of KRAS. Further, we explore the reasons behind these obstacles, novel successful approaches to target mutant KRAS including G12C mutation as well as the mechanisms of resistance.
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Project description:Motility disorders of the upper gastrointestinal tract encompass a wide range of different diseases. Esophageal achalasia and functional dyspepsia are representative disorders of impaired motility of the esophagus and stomach, respectively. In spite of their variable prevalence, what both diseases have in common is poor knowledge of their etiology and pathophysiology. There is some evidence showing that there is a genetic predisposition towards these diseases, especially for achalasia. Many authors have investigated the possible genes involved, stressing the autoimmune or the neurological hypothesis, but there is very little data available. Similarly, studies supporting a post-infective etiology, based on an altered immune response in susceptible individuals, need to be validated. Further association studies can help to explain this complex picture and find new therapeutic targets. The aim of this review is to summarize current knowledge of genetics in motility disorders of the upper gastrointestinal tract, addressing how genetics contributes to the development of achalasia and functional dyspepsia respectively.
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Project description:The Rome II pediatric criteria for functional gastrointestinal disorders (FGIDs) were defined in 1999 to be used as diagnostic tools and to advance empirical research. In this document, the Rome III Committee aimed to update and revise the pediatric criteria. The decision-making process to define Rome III criteria for children aged 4-18 years consisted of arriving at a consensus based on clinical experience and review of the literature. Whenever possible, changes in the criteria were evidence based. Otherwise, clinical experience was used when deemed necessary. Few publications addressing Rome II criteria were available to guide the committee. The clinical entities addressed include (1) cyclic vomiting syndrome, rumination, and aerophagia; 2) abdominal pain-related FGIDs including functional dyspepsia, irritable bowel syndrome, abdominal migraine, and functional abdominal pain; and (3) functional constipation and non-retentive fecal incontinence. Adolescent rumination and functional constipation are newly defined for this age group, and the previously designated functional fecal retention is now included in functional constipation. Other notable changes from Rome II to Rome III criteria include the decrease from 3 to 2 months in required symptom duration for noncyclic disorders and the modification of the criteria for functional abdominal pain. The Rome III child and adolescent criteria represent an evolution from Rome II and should prove useful for both clinicians and researchers dealing with childhood FGIDs. The future availability of additional evidence-based data will likely continue to modify pediatric criteria for FGIDs.
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Project description:In this paper, we provide a general framework for understanding the functional gastrointestinal disorders (FGID) from a biopsychosocial perspective. More specifically, we provide an overview of the recent research on how the complex interactions of environmental, psychological, and biological factors contribute to the development and maintenance of the FGID. We emphasize that considering and addressing all these factors is a conditio sine qua non for appropriate treatment of these conditions. First, we provide an overview of what is currently known about how each of these factors - the environment, including the influence of those in an individual's family, the individual's own psychological states and traits, and the individual's (neuro)physiological make-up - interact to ultimately result in the generation of FGID symptoms. Second, we provide an overview of commonly used assessment tools which can assist clinicians in obtaining a more comprehensive assessment of these factors in their patients. Finally, the broader perspective outlined earlier is applied to provide an overview of centrally acting treatment strategies, both psychological and pharmacological, which have been shown to be efficacious to treat FGID.
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Project description:There is growing appreciation that functional gastrointestinal disorders (FGIDs) such as functional dyspepsia and irritable bowel syndrome are heterogeneous conditions linked by subtle inflammation within the gastrointestinal (GI) tract. The literature suggests that while the symptoms of these diseases may manifest with similar clinical presentations, there are significant differences in triggers and disease severity among patients classified into the same subtype. It is hypothesized that the subtle inflammation observed in these patients is related to an imbalance in GI homeostasis. Disruption of the delicate homeostatic balance within the GI tract can result from any number or combination of factors, including dysbiosis, loss of barrier integrity, genetic predisposition, or immune responses to dietary or luminal antigens. This article discusses the interplay between the immune system, microbiota, and luminal environment in FGIDs. In addition, the article proposes emerging immune pathways, including those involving T-helper type 17 response and innate lymphoid cells, as potential regulators of the subtle inflammation characteristic of FGIDs that warrant investigation in future studies.
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Project description:Functional gastrointestinal disorders are complex symptom-based disorders without agreed upon biomarkers or pathophysiology. A better understanding of the genetic architecture of these disorders would help to better identify their complex biology and explain the common comorbidity with other disorders of persistent pain, mood, and affect, as well as possibly make it possible to identify subgroups of patients who respond to customized therapies. In contrast to monogenic diseases, polygenic diseases and traits are characterized by the contribution of common variants in a large number of genes, as well as environmental factors, to the vulnerability of an individual. Family and twin studies have clearly established a genetic component in irritable bowel syndrome. Although candidate gene studies have identified a few gene polymorphisms that may be correlated with the syndrome, small sample size, lack of reproducibility in large data sets, and the unreliability of the clinical phenotype require caution when extrapolating to a major role of any of the reported polymorphisms in the pathophysiology of irritable bowel syndrome. Future progress in this area will require better characterization of intermediate phenotypes with large effect size for the clinical phenotype, as well as consideration of gene-gene, environment-gene (epigenetics), and sex-gene interactions, genome-wide association, and whole genome sequencing approaches in large data sets.
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Project description:About 15-20% of all breast cancers (BCs) are defined human epidermal growth factor receptor 2 (HER2)-positive, based on the overexpression of HER2 protein and/or amplification of ERBB2 gene. Such alterations lead to a more aggressive behavior of the disease, but also predict response to treatments targeting HER2. Indeed, several anti-HER2 compounds have been developed and approved in the last two decades, significantly improving our ability to cure patients in the early setting, and greatly extending their survival in the advanced setting. However, recent evolutions in this field promise to improve outcomes even further, through advancements in established HER2-targeting strategies, as well as the exploration of novel strategies. In particular, the engineering of new antibody-drug conjugates, with higher drug-to-antibody ratios (DARs) and cleavable linkers, has already led to the development of a highly effective drug, namely trastuzumab deruxtecan, recently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of advanced HER2-positive (HER2+) BC, and currently in study in the early setting. Moreover, the novel tyrosine kinase inhibitor tucatinib was recently approved by FDA and EMA, showing to improve survival of HER2+ advanced BC patients, particularly in those with brain metastasis. Immunotherapy is also being investigated in the HER2+ subtype, through immune-checkpoint inhibition, cancer vaccines and adoptive-cell therapies. Overall, the enlarging arsenal of promising anti-HER2 compounds is expected to deliver significant improvements in the prognosis of both early and advanced HER2+ BC in the years to come. Moreover, some of such agents are showing encouraging activity in the much wider population of HER2-low advanced BC patients, challenging current BC classifications. If confirmed, this new paradigm would potentially expand the population deriving benefit from HER2-targeted treatments to up to 70% of all advanced BC patients, leading to a revolution in current treatment algorithms, and possibly to a redefinition of HER2 classification.
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Project description:Functional gastrointestinal disorders (FGIDs) are common in the community. Many patients will consult a physician in primary care, but the burden that these diseases represent to secondary care has not been studied for many years. We therefore examined this subject.Unselected consecutive new adult patient referrals were recruited during a 3-year period from January 2010 until December 2012. Medical records were reviewed retrospectively and the following data were recorded: age and sex of the patient, symptoms reported or signs noted at the first consultation, all investigations requested and ultimate diagnosis after investigation to the level deemed appropriate by the consulting physician.A luminal gastroenterology clinic at a teaching hospital.There were a total of 613 new patient referrals (mean age 54.2 years, 357 (58.2%) female). In total, 214 (34.9%) patients were diagnosed as having an FGID. Among the 214 patients diagnosed with an FGID, 65.9% were female, compared with 54.1% without an FGID (p=0.005). Mean age of those with an FGID was 47.9 years, compared with 57.5 years among those without (p<0.001). The total number of symptoms reported was significantly higher among patients with an FGID, but the total number of investigations did not differ.More than one-third of new patient referrals to a luminal gastroenterology clinic were diagnosed with an FGID. These conditions form a large part of the workload in secondary care gastroenterology, and primary care commissioning needs to reflect this.
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Project description:BackgroundFunctional gastrointestinal disorders (FGIDs), also known as disorders of gut-brain interaction, occur not only in the elderly but also in young adults. This study aimed to evaluate the association between mental health conditions and FGIDs among Vietnamese new-entry medical students.MethodsThis cross-sectional study was conducted in February 2022 among new-entry medical students in Ho Chi Minh City, Vietnam. A printed questionnaire was distributed to all students on the day of freshmen health screening. Their urine samples were collected to screen for Helicobacter pylori infection using rapid urinary test. FGIDs were diagnosed using ROME IV criteria. Gastroesophageal reflux disease (GERD) was defined as the presence of typical reflux symptoms at least twice a week. Mental health conditions, including generalized anxiety disorder (GAD) and major depressive disorder (MDD), were identified using Generalized Anxiety Disorder Assessment-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) scales, respectively.ResultsAmong 400 new-entry medical students who participated in the study, the overall prevalence of FGIDs was 10.3% (functional dyspepsia 6.5%, irritable bowel disease 5.5%). The overlap syndrome (OS) of GERD-FGIDs or different FGIDs was present in 3.0% of participants. The prevalences of GAD and MDD were 6.8% and 10.2%, respectively. The urinary test was positive in 180 (45.0%) participants. In the multivariable logistic regression analysis, MDD was significantly associated with not only the risk of FGIDs (OR = 5.599, 95%CI: 2.173-14.430, p<0.001) but also the risk of OS (OR = 10.076, 95CI%: 2.243-45.266, p = 0.003).ConclusionsMDD is associated with FGIDs and OS among new-entry medical students.
| S-EPMC10368230 | biostudies-literature