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Sphingosine-1-phosphate (S1P) is generated intracellularly and, when transported to the extracellular compartment, predominantly signals through S1P receptors. The S1P signalling pathway has been implicated in the pathophysiology of neurological injury following aneurysmal subarachnoid haemorrhage (aSAH). In this review, we bring together all the available data regarding the role of S1P in neurological injury following aSAH. There is agreement in the literature that S1P increases in the cerebrospinal fluid following aSAH and leads to cerebral artery vasospasm. On the other hand, the role of S1P in the parenchyma is less clear cut, with different studies arguing for beneficial and deleterious effects. A parsimonious interpretation of this apparently conflicting data is presented. We discuss the potential of S1P receptor modulators, in clinical use for multiple sclerosis, to be repurposed for aSAH. Finally, we highlight the gaps in our knowledge of S1P signalling in humans, the clinical challenges of targeting the S1P pathway after aSAH and other research priorities. [ABSTRACT FROM AUTHOR]

Ulcerative colitis is a chronic, immune-mediated disease characterized by recurring episodes of mucosal inflammation in the colon and rectum. The primary pathogenic mechanism of ulcerative colitis is the dysregulation of the mucosal immune response. The disease follows a relapsing-remitting course, and the goal of management is to successfully induce and then maintain remission. Effectively managing this chronic disease requires addressing all aspects of it. Currently, we have various antitumor necrosis factor agents and novel biologics available for treating ulcerative colitis patients with moderate-to-severe disease. However, none of the existing treatments are considered entirely satisfactory or ideal in these cases. After extensive progressive research, oral small molecule therapies targeting mediators of ongoing inflammation represent an exciting and revolutionary change in the treatment of ulcerative colitis, especially for patients with moderate-to-severe disease. In this review, we aimed to summarize the available experience and ongoing research on oral small molecule agents in the management of ulcerative colitis. The available experience and ongoing research with promising outcomes provide convincing evidence that the value of oral small molecule agents is fact not fancy. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a term used to represent a group of chronic, relapsing inflammatory disorders of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are the two major clinical forms. The global incidence and prevalence of IBD have increased over the last 2–4 decades. Despite the specific etiopathogenesis of IBD still being unknown, it is widely recognized that immunological, genetic, and environmental factors are implicated. A greater understanding of the multiple signaling pathways involved has led to the development of biologic therapies in the last two decades. Although these treatments have dramatically transformed the course of IBD, there is not a definitive cure and available therapies may cause adverse events (AEs), limiting their use, or have an inadequate effect in some patients. In this context, emerging therapies addressing new specific pathogenetic mechanisms have shown promising efficacy and safety data in early clinical trials. The purpose of this review is to highlight the available clinical trial data for these new drugs, such as more preferential JAK inhibitors, anti-IL-23 antibodies, sphingosine-1-phosphate receptor modulators, anti-integrin therapies, and other small molecules that are currently under research. We will emphasize the potential significance of these agents in shaping future treatment options. [ABSTRACT FROM AUTHOR]

Sphingosine‐1‐phosphate (S1P) is a bioactive lysophospholipid that can influence a broad range of biological processes through its binding to five distinct G‐protein‐coupled receptors. S1P receptor modulators are a new group of immunosuppressive agents currently used in the immunotherapy of multiple sclerosis. Inflammation following stroke can exacerbate neuronal injury. Given that S1P signaling is linked to multiple immune processes, therapies targeting the S1P axis may be suitable for treating stroke. In this review, we outline S1P metabolism and S1P receptors, discuss the mechanisms of action of S1P receptor modulators in lymphocyte migration and their direct action on cells of the central nervous system, and provide a concise summary of the efficacy of S1P receptor modulators in animal studies and clinical trials on treatments for stroke. [ABSTRACT FROM AUTHOR]

The implementation of biologic therapy has improved the treatment and clinical course of patients with inflammatory bowel disease since the initial approval of infliximab for Crohn's disease in 1998. However, the efficacy and safety profiles of currently available therapies are still less than optimal in several ways, highlighting the need for novel therapeutic targets. Several new drug classes (Janus kinase inhibitors, anti-integrins, sphingosine-1-phosphate receptor modulators, anti-interleukin-23 antibodies, and stem cell therapies) are currently being studied in Crohn's disease and ulcerative colitis with promising results. This article reviews the current literature and provides an updated overview of the emerging therapies. [ABSTRACT FROM AUTHOR]

New classes of antibiotics are urgently needed in the fight against multidrug-resistant bacteria. Drug repurposing has emerged as an alternative approach to accelerate antimicrobial research and development. In this study, we screened a library of sphingosine-1-phosphate receptor (S1PR) modulators against Staphylococcus aureus and identified five active compounds. Among them, etrasimod (APD334), an investigational drug for the treatment of ulcerative colitis, displayed the best inhibitory activity against S. aureus when growing as free-floating planktonic cells and within biofilms. In follow-up studies, etrasimod showed bactericidal activity and drastic reduction of viable bacteria within 1 h of exposure. It also displayed a potent activity against other Gram-positive bacteria, including penicillin- and methicillin-resistant S. aureus strains, S. epidermidis , and Enterococcus faecalis , with a minimum inhibitory concentration (MIC) ranging from 5 to 10 μM (2.3–4.6 μg/mL). However, no inhibition of viability was observed against Gram-negative bacteria Acinetobacter baumannii , Escherichia coli , and Pseudomonas aeruginosa , showing that etrasimod preferably acts against Gram-positive bacteria. On the other hand, etrasimod was shown to inhibit quorum sensing (QS) signaling in Chromobacterium violaceum , suggesting that it may block the biofilm formation by targeting QS in certain Gram-negative bacteria. Furthermore, etrasimod displayed a synergistic effect with gentamicin against S. aureus , thus showing potential to be used in antibiotic combination therapy. Finally, no in vitro toxicity toward mammalian cells was observed. In conclusion, our study reports for the first time the potential of etrasimod as a repurposed antibacterial compound against Gram-positive bacteria. [ABSTRACT FROM AUTHOR]

New classes of antibiotics are urgently needed in the fight against multidrug-resistant bacteria. Drug repurposing has emerged as an alternative approach to accelerate antimicrobial research and development. In this study, we screened a library of sphingosine-1-phosphate receptor (S1PR) modulators against Staphylococcus aureus and identified five active compounds. Among them, etrasimod (APD334), an investigational drug for the treatment of ulcerative colitis, displayed the best inhibitory activity against S. aureus when growing as free-floating planktonic cells and within biofilms. In follow-up studies, etrasimod showed bactericidal activity and drastic reduction of viable bacteria within 1 h of exposure. It also displayed a potent activity against other Gram-positive bacteria, including penicillin- and methicillin-resistant S. aureus strains, S. epidermidis, and Enterococcus faecalis, with a minimum inhibitory concentration (MIC) ranging from 5 to 10 μM (2.3–4.6 μg/mL). However, no inhibition of viability was observed against Gram-negative bacteria Acinetobacter baumannii, Escherichia coli, and Pseudomonas aeruginosa, showing that etrasimod preferably acts against Gram-positive bacteria. On the other hand, etrasimod was shown to inhibit quorum sensing (QS) signaling in Chromobacterium violaceum, suggesting that it may block the biofilm formation by targeting QS in certain Gram-negative bacteria. Furthermore, etrasimod displayed a synergistic effect with gentamicin against S. aureus, thus showing potential to be used in antibiotic combination therapy. Finally, no in vitro toxicity toward mammalian cells was observed. In conclusion, our study reports for the first time the potential of etrasimod as a repurposed antibacterial compound against Gram-positive bacteria.

Sphingosine 1-phosphate (S1P) receptors are bioactive lipid metabolites that bind five different types of receptors expressed ubiquitously in human body and mediate a broad range of biological functions. Targeting S1P receptors is nowadays a well-established pharmacological strategy to treat multiple sclerosis (MS). However, the adverse events associated with the ancestor (fingolimod), especially in terms of heart conduction and slow reversibility of its pharmacodynamics effect on lymphocytes, have stimulated a search for a S1P modulator with greater selectivity for S1P1 (the most important immune mechanism to prevent MS-related neuroinflammation). Ponesimod is a second-generation, orally active, directly bioavailable, highly selective, and rapidly reversible modulator of the S1P1 receptor. Gradual 14-day up-titration of ponesimod mitigates its first-dose effects on heart rate and facilitates its use over fingolimod, as it does not require first-dose cardiac monitoring. Ponesimod is rapidly eliminated within 1 week of discontinuation, thereby representing a more manageable approach in case of vaccination, pregnancy, or adverse events. However, the fast reversibility of ponesimod may also raise concerns about the possibility of a rapid reactivation of disease activity following its discontinuation. Ponesimod was recently approved for the treatment of relapsing MS forms on the basis of a Phase III, double-blind, double-dummy, randomized clinical trial (OPTIMUM) that demonstrated the superiority of ponesimod over teriflunomide on disease activity markers, without unexpected safety concerns. This review summarizes the pharmacodynamic and pharmacokinetic characteristics of ponesimod, and the main Phase II and III studies that led to its approval. Comparisons of ponesimod with other S1P receptor modulators currently available for MS (fingolimod, ozanimod, siponimod) are also provided. [ABSTRACT FROM AUTHOR]

Abdominal pain is a frequent reason to see a doctor. At the same time, it is very important in the first stage of diagnosis to determine the degree of pain risk, as in some diseases such as acute ulcer, myocardial infarction, acute pancreatitis, the urgency of medical care is directly related to the survival of patients or the development of related complications. The most typical clinical manifestations of abdominal pain are pain of varying intensity, signs of peritoneal irritation and disturbance of intestinal motility. In some cases, the clinical picture may be accompanied by fever, nausea and vomiting, signs of pain or toxic shock, etc. The diagnosis of abdominal pain is based on a thorough analysis of the examination results, which includes not only laboratory examinations of blood, urine and feces, but also echography of abdominal organs, endoscopic (esophagogastroduodenoscopy, colonoscopy) and, if necessary, methods of radiation diagnostics (in particular, computer tomography, magnetic resonance imaging).The article presents the classification and mechanisms of development of abdominal pain. The main attention is paid to inflammatory intestinal diseases (Crohn's disease and ulcerative colitis) for which etiology, pathogenesis, clinical signs, diagnostics and treatment are considered, taking into account modern trends in clinical practice. The main diagnostic measures to determine inflammatory bowel diseases are given, based on the analysis of the clinical picture and the results of laboratory, radiological and endoscopic examinations. It is emphasized that the results of the study, its diagnostic accuracy and therapeutic safety largely depend on the quality of patients' preparation for diagnostic activities. The main drugs used to prepare the intestines for research are solutions based on polyethylene glycol. The choice of medication therapy depends on the degree, location and severity of the disease. The same medications may be prescribed for different diagnoses - ulcerative colitis and Crohn's disease.

Introduction: Ulcerative colitis is a chronic inflammatory bowel disease, affecting the colorectal mucosae, with a relapsing-remitting course, characterized by the trafficking and gathering of lymphocytes in the inflammatory intestinal mucosa. Sphingosine-1-phosphate (S1P) receptor modulators preventing lymphocytes egress from lymphoid tissues to the active inflammation site is an alternative therapeutic option in this condition., Area Covered: We carried out a comprehensive review of the literature available on Medline, Scopus and Embase regarding the pharmacokinetics of S1P receptor modulators. For each compound, we reviewed the mechanism of action, pharmacokinetic data and efficacy and safety data from phase 3 studies and real-life studies when available., Expert Opinion: S1P receptor modulators, including ozanimod and etrasimod (both currently on the market) as well as VTX002 (under development), are a new class of drugs for the treatment of moderate to severe ulcerative colitis, inducing and maintaining the remission. Due to its pharmacokinetic features, this class of drugs has certain advantages such as an oral administration, a short half-life, a high volume of distribution, and no immunogenicity. On the other hand, there are risks of cardiological and ophthalmological side-effects, as well as drug-drug interactions risk, that require special attention from the healthcare providers.

Background: Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease. Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients. However, issues of primary non-response (PNR) and secondary loss of response (SLOR) to non-tumour necrosis factor inhibitor (TNFi) therapies remains a common problem. Specific issues include the choice of optimization of therapy, identifying when dose optimization will recapture response, establishing optimal dose for escalation and when to switch therapy., Aim: To explores the issues of PNR and SLOR to non-TNFi therapies., Methods: This review explores the current evidence and literature to elucidate management options in cases of PNR/SLOR. It will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring (TDM)., Results: In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin (IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture response. For Janus kinase inhibitors dose optimization can be utilized to recapture response with loss of response., Conclusion: The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Inflammatory bowel diseases (IBDs) are immune-mediated chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is not yet fully understood. Despite the advent of biological agents, there are still unmet needs for IBD patients, due to suboptimal rate of sustained remission achieved. Small molecule drugs (SMDs), the next generation of selective drugs in IBD, show promising results in ongoing trials. We describe the pharmacodynamics and pharmacokinetic features of novel SMDs and their main differences with biologic agents. Small molecule drugs are a promising class of drugs for the treatment of ulcerative colitis and Crohn's disease with good results in inducing and maintaining remission. Hence, over the next few years physicians will have numerous options of small molecule drugs for the treatment of patients with IBD. This group of drugs are potentially easier to use over biological agents due to pharmacokinetic features such as oral administration, short half-life, high volume of distribution, and lack of immunogenicity. On the other hand, drug–drug interactions can happen with small-molecule drugs, principally due to competitive metabolic and clearance mechanisms. [ABSTRACT FROM AUTHOR]

• Disease-modifying therapies (DMTs) are the largest cost driver in MS. • Three sphingosine-1-phosphate receptor (S1PR) modulators are used for relapsing MS. • Our model compares sequences of up to 5 DMTs in terms of health (relapses, progression) and costs. • Comparing sequences including S1PR modulators, ponesimod is the most cost-effective drug. • Cost-effectiveness research helps to prioritize when prescribing drugs of a similar class. Three sphingosine-1-phosphate receptor (S1PR) modulators are currently available as disease-modifying therapies (DMTs) for relapsing MS in the Netherlands (i.e. fingolimod, ozanimod and ponesimod). We aimed to identify which S1PR modulator yields the highest benefit from a health-economic and societal perspective during a patient's lifespan. Incorporating Dutch DMT list prices, we used the ErasmusMC/iMTA MS model to compare DMT sequences, including S1PR modulators and eight other DMT classes, for treatment-naïve patients with relapsing MS in terms of health outcomes (number of lifetime relapses, time to Expanded Disability Status Scale (EDSS) 6, lifetime quality-adjusted life years (QALYs)) and cost-effectiveness (net health benefit (NHB)). We estimated the influence of list price and EDSS progression on cost-effectiveness outcomes. In deterministic and probabilistic analysis, DMT sequences with ponesimod have lower lifetime costs and higher QALYs resulting in a higher average NHB compared to sequences with other S1PR modulators. Ponesimod remains the most cost-effective S1PR modulator when EDSS progression is class-averaged. Given the variable effects on disability progression, list price reductions could make fingolimod but not ozanimod more cost-effective than ponesimod. Our model favours ponesimod among the S1PR modulators for the treatment of relapsing MS. This implies that prioritizing ponesimod over other S1PR modulators translates into a more efficacious spending of national healthcare budget without reducing benefit for people with MS. Prioritizing cost-effective choices when counselling patients contributes to affordable and accessible MS care. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a progressive neurological autoimmune disease that usually starts in the late third and early forth decades of life. Demyelination of neurons in the central nervous system (CNS) and, subsequently, loss of nerve cells is the known disease pathogenesis. The disease is controlled by a class of medicines which are mainly immunomodulators. Fingolimod (FIN) is the first approved oral medication for controlling relapsing-remitting type of MS. It is chemically modified form of a fungus metabolite with long history of use in traditional Chinese medicine. Its mechanism of action is through functional antagonism of sphingosine-1 phosphate receptors which leads to lymphocyte entrapment in lymphoid tissues and reduction of their circulating number in the CNS. FIN efficacy comparing with placebo and first line therapies for MS (e.g. Interferon) has been proved through several clinical trials. Common side effects of FIN are usually mild and are well tolerated. FIN can pass through placenta and has been assigned to pregnancy category C according to the observed effects in animal studies. Since the drug molecule is secreted into milk, lactation during consumption is not recommended. Considering oral administration and mild side effects of FIN, it can be useful in management of MS. However, due to the incidence of some rare but serious adverse effects such as systemic viral infections, macular edema, and cardiovascular complications, physicians should investigate patient's clinical status and underlying comorbidities carefully. [ABSTRACT FROM AUTHOR]

Introduction: Fingolimod was the first oral disease-modifying treatment approved for relapsing-remitting multiple sclerosis (MS) that serves as a sphingosine-1-phosphate receptor (S1PR) agonist. The efficacy is primarily mediated by S1PR subtype 1 activation, leading to agonist-induced down-modulation of receptor expression and further functional antagonism, blocking the egression of auto-aggressive lymphocytes from the lymph nodes in the peripheral compartment. The role of S1P signaling in the regulation of other pathways in human organisms through different S1PR subtypes has received much attention due to its immune-modulatory function and its significance for the regeneration of the central nervous system. The more selective second-generation S1PR modulators have improved safety and tolerability profiles., Areas Covered: This review has been carried out based on current data on S1PR modulators, emphasizing the benefits of recent advances in this emergent class of immunomodulatory treatment for MS., Expert Opinion: Ongoing clinical research suggests that S1PR modulators represent an alternative to first-line therapies in selected cases of MS. A better understanding of the relevance of selective S1PR pathways and the ambition to optimize selective modulation has improved the safety and tolerability of S1PR modulators in MS therapy and opened new perspectives for the treatment of other diseases.

Introduction: Ulcerative colitis (UC) is a chronic inflammatory condition of the gastrointestinal tract involving a dysregulated immune response. Sphingosine-1-phosphate (S1P) is involved in immune cell regulation. S1P-receptor modulators, such as ozanimod, inhibit lymphocyte migration and have therapeutic potential in UC., Areas Covered: Ozanimod is the first S1P-receptor modulator approved for the treatment of UC. It acts as a functional antagonist, causing internalization of S1P receptors on T-cells. Lymphocyte egress from lymph nodes is inhibited, and migration to sites of active inflammation is curtailed. There are several S1P-receptor subtypes, present in various organs, which inform understanding of ozanimod's side-effect profile including bradycardia and macular edema. In this review, the authors discuss the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of ozanimod in the treatment of patients with moderate-to-severe UC., Expert Opinion: The S1P-receptor modulator ozanimod is an oral small molecule with a rapid onset of action and a novel therapeutic mechanism in the treatment of UC. It is an effective treatment both in bio-naïve and bio-exposed patients. Although the safety profile of ozanimod looks favorable, more long-term data are needed. Further studies are required to compare ozanimod to currently available therapies to best define its positioning in UC treatment algorithms.