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Simple Summary: The MAP kinase cascades are the most important oncogenic drivers of human cancers, including gastric cancer, and blocking this pathway with targeted inhibitors is an important antitumor strategy. Tegaserod maleate binds to MEK1 and MEK2, inhibiting kinase activity and thus suppressing the MEK1/2-ERK1/2 signaling pathway. Thus, tegaserod maleate may have potential as a MEK1/2 inhibitor for gastric cancer. Gastric cancer (GC) ranks fifth in global incidence and fourth in mortality. The current treatments for GC include surgery, chemotherapy and radiotherapy. Although treatment strategies for GC have been improved over the last decade, the overall five-year survival rate remains less than 30%. Therefore, there is an urgent need to find novel therapeutic or preventive strategies to increase GC patient survival rates. In the current study, we found that tegaserod maleate, an FDA-approved drug, inhibited the proliferation of gastric cancer cells, bound to MEK1/2 and suppressed MEK1/2 kinase activity. Moreover, tegaserod maleate inhibited the progress of gastric cancer by depending on MEK1/2. Notably, we found that tegaserod maleate suppressed tumor growth in the patient-derived gastric xenograft (PDX) model. We further compared the effect between tegaserod maleate and trametinib, which is a clinical MEK1/2 inhibitor, and confirmed that tegaserod maleate has the same effect as trametinib in inhibiting the growth of GC. Our findings suggest that tegaserod maleate inhibited GC proliferation by targeting MEK1/2. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two major types of esophageal cancer (EC). ESCC accounts for 90% of EC. Recurrence after primary treatment is the main reason for poor survival. Therefore, recurrence prevention is a promising strategy for extending the 5-year survival rate. Here, we found tegaserod maleate could inhibit ESCC proliferation both in vivo and in vitro. Proteomics analysis revealed that tegaserod maleate suppressed the peroxisome signaling pathway, in which the key molecules peroxisome membrane protein 11B (PEX11B) and peroxisome membrane protein 13 (PEX13) were downregulated. The immunofluorescence, catalase activity assay, and reactive oxygen species (ROS) confirmed that downregulation of these proteins was related to impaired peroxisome function. Furthermore, we found that PEX11B and PEX13 were highly expressed in ESCC, and knockout of PEX11B and PEX13 further demonstrated the antitumor effect of tegaserod maleate. Importantly, tegaserod maleate repressed ESCC tumor growth in a patient-derived xenograft (PDX) model in vivo. Our findings conclusively demonstrated that tegaserod maleate inhibits the proliferation of ESCC by suppressing the peroxisome pathway.

Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two major types of esophageal cancer (EC). ESCC accounts for 90% of EC. Recurrence after primary treatment is the main reason for poor survival. Therefore, recurrence prevention is a promising strategy for extending the 5-year survival rate. Here, we found tegaserod maleate could inhibit ESCC proliferation both in vivo and in vitro. Proteomics analysis revealed that tegaserod maleate suppressed the peroxisome signaling pathway, in which the key molecules peroxisome membrane protein 11B (PEX11B) and peroxisome membrane protein 13 (PEX13) were downregulated. The immunofluorescence, catalase activity assay, and reactive oxygen species (ROS) confirmed that downregulation of these proteins was related to impaired peroxisome function. Furthermore, we found that PEX11B and PEX13 were highly expressed in ESCC, and knockout of PEX11B and PEX13 further demonstrated the antitumor effect of tegaserod maleate. Importantly, tegaserod maleate repressed ESCC tumor growth in a patient-derived xenograft (PDX) model in vivo. Our findings conclusively demonstrated that tegaserod maleate inhibits the proliferation of ESCC by suppressing the peroxisome pathway. [ABSTRACT FROM AUTHOR]

The colon is being extensively investigated as a drug delivery site. Colonic drug delivery is a relatively recent approach for the treatment of diseases like ulcerative colitis, Crohn's disease, and irritable bowel syndrome. To achieve successful colon targeted drug delivery, a drug needs to be protected from degradation, release and /or absorption in upper portion of GI tract and then ensure abrupt or controlled release in proximal colon. The purpose of this research is to develop and evaluate the polysaccharide based compression coated tablets of Tegaserod maleate for the treatment of irritable bowel syndrome. Core tablets of Tegaserod maleate were compression coated with various proportions of Galactosol, xanthan gum and chitosan. This work aimed to prepare compression coated tablets by direct compression method using single polymer and combination of polymers. And to evaluate prepared tablets parameters like hardness, friability, thickness, diameter, weight variation, drug content, swelling index, in vitro drug release. [ABSTRACT FROM AUTHOR]

To identify therapeutic targets in acute myeloid leukemia (AML), we conducted growth inhibition screens of 2040 small molecules from a library of FDA-approved drugs using a panel of 12 AML cell lines. Tegaserod maleate, a 5-hydroxytryptamine 4 receptor partial agonist, elicits strong anti-AML effects in vitro and in vivo by targeting transient receptor potential melastatin subtype 8 (TRPM8), which plays critical roles in several important processes. However, the role of TRPM8 remains incompletely described in AML, whose treatment is based mostly on antimitotic chemotherapy. Here, we report an unexpected role of TRPM8 in leukemogenesis. Strikingly, TRPM8 knockout inhibits AML cell survival/proliferation by promoting apoptosis. Mechanistically, TRPM8 exerts its oncogenic effect by regulating the ERK–CREB/c-Fos signaling axis. Hyperactivation of ERK signaling can be reversed by TRPM8 inhibition. Importantly, TRPM8 is overexpressed in AML patients, indicating that it is a new prognostic factor in AML. Collectively, our work demonstrates the anti-AML effects of tegaserod maleate via targeting TRPM8 and indicates that TRPM8 is a regulator of leukemogenesis with therapeutic potential in AML. [Display omitted] • TRPM8 is a direct target of tegaserod meleate, a 5-hydroxytryptamine 4 receptor partial agonist. • Tegaserod meleate suppresses AML development in vitro and in vivo. • Deletion of TRPM8 delays leukemogenesis. • Depletion of TRPM8 decreases the levels of p-ERK1/2, p-CREB and c-Fos. • TRPM8 is highly expressed in AML. [ABSTRACT FROM AUTHOR]

The overall objective of this study was to develop a pH-dependent sustained release tablet formulation of a model drug, tegaserod maleate (TM), which is a poorly water soluble and acid labile drug in gastric milieu. The formulation's goal was to allow the dosage form to pass through the stomach intact, start disintegrating in the upper small intestine and slowly release the active in a controlled manner. Partition coefficient, contact angle and drug-excipient compatibility were investigated as part of the preformulation studies. A pH-dependent sustained release tablet was prepared using a combination of Eudragit® L100 and Eudragit® S100. The effects of solubilizer, disintegrant, binder, coating polymer concentration, pore former, and plasticizer on the drug release rate were determined. The results demonstrated that approximately 90% of the drug was released in a sustained release manner in the pH 6.8 phosphate buffer within 12 h while no drug was detected when subjected to drug release studies in 0.1 mol/L hydrochloric acid for 2 h. The drug release mechanism involved stress points and/or pore formation in the coated film. The coated tablets were stable at 40°C/75% RH for 3 months. These results highlighted the feasibility of this coated tablet system containing TM, which may contribute to the successful treatment of irritable bowel syndrome. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to prepare tegaserod maleate (TM) pH-dependent tablets and evaluate their advantages as a sustained release delivery system. TM, insoluble in water and unstable in gastric milieu, was formulated into pH-dependent tablets coated with combinations of two methacrylic acid copolymers – Eudragit® L100 and Eudragit® S100. The influence of core tablet compositions, polymer combination ratios and coating levels on the in vitro release rate of TM from coated tablets was investigated. The optimum formulation was evaluated for in vitro release rate and in vivo bioavailability study on beagle dogs. In addition, physico-chemical properties of the drug, including solubility at different pH and temperatures, and dissociation constant were determined. The results showed that no drug was released in 0.1mol/L hydrochloric acid within 2h, and about 90% of the drug was released in the pH 6.8 phosphate buffer within 12h in a sustained manner. The pharmacokinetic investigation showed that TM pH-dependent tablets exhibited a sustained plasma concentration, a lag time of approximately 2.3h and a relative bioavailability of 159% compared to plain tablets. A close correlation existed between the in vitro release rate of the pH-dependent system and its in vivo absorption percentage. The results of the present study have demonstrated that the pH-dependent tablet system is a promising vehicle for preventing rapid hydrolysis in gastric milieu and improving oral bioavailability of TM for the treatment of irritable bowel syndrome. [Copyright &y& Elsevier]

Background: Approved in July 2002, tegaserod maleate is a partial 5-hydroxytryptamine 4-receptor agonist used to improve symptoms of constipationpredominant irritable bowel syndrome (IBS). The physiologic actions of tegaserod relate to its ability to stimulate gastric and intestinal motility.Objective: This article reviews available data on the pharmacokinetic and pharmacodynamic properties and clinical efficacy of tegaserod.Methods: Searches of MEDLINE and PubMed from 1966 to the present were conducted using the search terms tegaserod, tegaserod maleate, irritable bowel syndrome, and Rome criteria. Abstracts presented at national meetings between 1997 and 2002 were reviewed and included if perceived to be reliable and relevant.Results: In clinical trials, tegaserod was associated with significantly better scores on the subject''s global assessment of relief compared with placebo (P < 0.05). The absolute efficacy of tegaserod compared with placebo varied between trials and averaged 10% to 12%. Tegaserod had a good safety profile; diarrhea was the only adverse effect that occurred more often in tegaserod recipients than in placebo recipients. No electrocardiographic changes were observed at therapeutic concentrations of tegaserod. Long-term (1-year) treatment with tegaserod appeared to be well tolerated. The recommended dosage for patients aged >18 years with constipation-predominant IBS is 6 mg PO BID before meals for 4 to 6 weeks, with an additional 4 to 6 weeks of treatment if initial therapy is partially effective.Conclusions: The addition of tegaserod to the arsenal of moderately effective medication currecntly used in the treatment of IBS may be helpful in patients with constipation-predominant IBS. Constinuous postmarketing surveillance and reporting of adverse reactions are essential to further characterize the safety profile of this new agent. [Copyright &y& Elsevier]

Background: Tegaserod (Zelnorm®) is a 5-hydroxytryptamine (serotonin) type 4 receptor agonist for the treatment of hypomotility disorders of the lower gastrointestinal tract associated with the irritable bowel syndrome with constipation (IBS-C)., Objective: The authors provide the reader with a better understanding on tegaserod mechanism of action, on its pharmacodynamics and pharmacokinetic properties, on safety and tolerability, with a summary of the key published clinical trials conducted in patients with irritable bowel syndrome (IBS). Its effects on colon inflammation have also been described., Results: Tegaserod was withdrawn in 2007 due to increased risks of cardiovascular adverse effects. The manufacturer denied this, because pre-existing cardiovascular disease or risk factors were attributed to all affected patients. Thus, no causal relationship between tegaserod use and cardiovascular events was clearly shown. A matched case-control study of tegaserod-treated with untreated patients found no association between tegaserod and adverse cardiovascular outcomes. Despite its adverse effects, tegaserod resulted to be effective in treating chronic constipation in adult women aged < 65 years with IBS-C, while the safety and effectiveness of tegaserod in men with IBS-C have not been established. Tegaserod was resubmitted to the Food and Drug Administration in 2018 for use in a low-risk population. Moreover, tegaserod has also been shown to improve symptoms, enhance gastric accommodation and significantly attenuate visceral pain arising from the colon in functional dyspepsia patients. Treatment with tegaserod seems also to exert a protective effect in inflamed colons, reducing the severity of colitis in animal models., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)