CSTI-300 (SMP-100); a Novel 5-HT3 Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome.

The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT3 receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g., severe constipation). The present study investigates the potential of a novel 5-HT3 receptor partial agonist, CSTI-300, to treat patients with IBS-d and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo preclinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human and rat 5-HT3 receptor (Ki approximately 2.0 nM) and acted as a partial agonist (approximately 30%-50% intrinsic efficacy) in vitro. In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the Ki value for the 5-HT3 receptor failed to either evoke emesis or alter the state of feces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t 1/2 range of 1.6-4.4 hours. The preclinical pharmacology of the lead candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with irritable bowel syndrome and carcinoid syndrome with a rationale for a reduced "on-target" side-effect profile relative to 5-HT3 receptor antagonists, such as alosetron. SIGNIFICANCE STATEMENT: There is a lack of effective current treatment for diarrhea-predominant irritable bowel syndrome and carcinoid syndrome, and in both conditions, overactivity of the 5-hydroxytryptamine (5-HT) 5-HT3 receptor is thought to be implicated in the pathophysiology. Because 5-HT3 receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT3 receptor partial agonist will alleviate some symptoms associated with these conditions yet, without fully inhibiting the receptor, predict a less pronounced side-effect profile associated with this therapeutic strategy.

Evolution of antiemetic studies for radiation-induced nausea and vomiting within an outpatient palliative radiotherapy clinic.

PURPOSE: Radiation-induced nausea and vomiting (RINV) is a common side effect of radiotherapy and can affect up to 50-80% of patients, potentially causing detrimental effects to physical health, clinical efficacy, and patient quality of life. Antiemetic drugs act on receptors involved in the emesis pathway to block the uptake of neurotransmitters and inhibit stimulation of vomiting centers in the brain to prevent and treat RINV. The most commonly prescribed antiemetics for RINV are 5-hydroxytryptamine receptor antagonists (5-HT3 RA). Guidelines describing the optimal management of RINV are produced by the Multinational Association for Supportive Care in Cancer, the European Society of Medical Oncology, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network. This review will present findings from research on antiemetic management for RINV conducted at our center. METHODS: A selective review of research conducted in a palliative outpatient radiotherapy clinic relating to antiemetic management for RINV was performed. RESULTS: Several studies investigating the efficacy of different routes of administration, new antiemetic drug types, and novel combinations of antiemetics have been tested at our clinic to elucidate which approach provides the best response. These include studies on the use of ondansetron rapidly dissolving film, palonosetron, and the addition of a neurokinin-1 receptor antagonist to traditional 5-HT3 RA regimens. CONCLUSIONS: These studies provide a framework for future research and could potentially inform changes to future guidelines to include the use of these novel regimens and techniques.

The Human Serotonin Type 3 Receptor Gene (HTR3A-E) Allelic Variant Database.

Serotonin type 3 (5-HT3 ) receptors are ligand-gated ion channels formed by five subunits (5-HT3A-E), which are encoded by the HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E genes. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes confer a predisposition to nausea and vomiting during chemotherapy, pregnancy, and following surgery. In addition, different subtypes contribute to neurogastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as comorbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS and are beneficial in the treatment of psychiatric diseases. Several case-control and pharmacogenetic studies have demonstrated an association between HTR3 variants and psychiatric and neurogastroenterologic phenotypes. Recently, their potential as predictors of nausea and vomiting and treatment of psychiatric disorders became evident. This information is now available in the serotonin receptor 3 HTR3 gene allelic variant database (www.htr3.uni-hd.de), which contains five sub-databases, one for each of the five different serotonin receptor genes HTR3A-E. Information on HTR3 variants, their functional relevance, associated phenotypes, and pharmacogenetic data such as drug response and side effects are available. This central information pool should help clinicians as well as scientists to evaluate their findings and to use the relevant information for subsequent genotype-phenotype correlation studies and pharmacogenetic approaches.

Serotonergic mechanism of the relieving effect of bee venom acupuncture on oxaliplatin-induced neuropathic cold allodynia in rats.

BACKGROUND: Oxaliplatin, an important chemotherapy drug for advanced colorectal cancer, often induces peripheral neuropathy, especially cold allodynia. Our previous study showed that bee venom acupuncture (BVA), which has been traditionally used in Korea to treat various pain symptoms, potently relieves oxaliplatin-induced cold allodynia in rats. However, the mechanism for this anti-allodynic effect of BVA remains poorly understood. We investigated whether and how the central serotonergic system, a well-known pathway for acupuncture analgesia, mediates the relieving effect of BVA on cold allodynia in oxaliplatin-injected rats. METHODS: The behavioral signs of cold allodynia in Sprague-Dawley (SD) rats were induced by a single injection of oxaliplatin (6 mg/kg, i.p.). Before and after BVA treatment, the cold allodynia signs were evaluated by immersing the rat's tail into cold water (4°C) and measuring the withdrawal latency. For BVA treatment, a diluted BV (0.25 mg/kg) was subcutaneously administered into Yaoyangguan (GV3) acupoint, which is located between the spinous processes of the fourth and the fifth lumbar vertebra. Serotonin was depleted by a daily injection of DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for 3 days. The amount of serotonin in the spinal cord was measured by ELISA. Serotonergic receptor antagonists were administered intraperitoneally or intrathecally before BVA treatment. RESULTS: The serotonin levels in the spinal cord were significantly increased by BVA treatment and such increase was significantly reduced by PCPA. This PCPA pretreatment abolished the relieving effect of BVA on oxaliplatin-induced cold allodynia. Either of methysergide (mixed 5-HT1/5-HT2 receptor antagonist, 1 mg/kg, i.p.) or MDL-72222 (5-HT3 receptor antagonist, 1 mg/kg, i.p) blocked the anti-allodynic effect of BVA. Further, an intrathecal injection of MDL-72222 (12 µg) completely blocked the BVA-induced anti-allodynic action, whereas NAN-190 (5-HT1A receptor antagonist, 15 µg, i.t.) or ketanserin (5-HT2A receptor antagonist, 30 µg, i.t.) did not. CONCLUSIONS: These results suggest that BVA treatment alleviates oxaliplatin-induced acute cold allodynia in rats via activation of the serotonergic system, especially spinal 5-HT3 receptors. Thus, our findings may provide a clinically useful evidence for the application of BVA as an alternative therapeutic option for the management of peripheral neuropathy, a dose-limiting side effect that occurs after an administration of oxaliplatin.

Novel serotonin type 3 receptor partial agonists for the potential treatment of irritable bowel syndrome.

Serotonin type 3 (5-HT(3)) receptor partial agonists are being targeted as potential new drugs for the treatment of irritable bowel syndrome (IBS). Two new chemical series bearing indazole and indole cores have exhibited nanomolar binding affinity for the h5-HT(3)A receptor. A range of partial agonist activities in HEK cells heterologously expressing the h5-HT(3)A receptor were measured for the indazole series. Excellent 5-HT(3) receptor selectivity, favorable in vitro metabolic stability and CYP inhibition properties, and good oral in vivo potency in the murine von Bezold-Jarisch reflex model is exemplified thereby indicating the series to have potential utility as improved IBS agents.

Effects of mosapride citrate, a 5-HT4-receptor agonist, on gastric distension-induced visceromotor response in conscious rats.

Mosapride citrate (mosapride), a prokinetic agent with 5-HT(4)-receptor agonistic activity, is known to enhance gastric emptying and alleviate symptoms in patients with functional dyspepsia (FD). As hyperalgesia and delayed gastric emptying play an important role in the pathogenesis of FD, we used in this study balloon gastric distension to enable abdominal muscle contractions and characterized the visceromotor response (VMR) to such distension in conscious rats. We also investigated the effects of mosapride on gastric distension-induced VMR in the same model. Mosapride (3-10 mg/kg, p.o.) dose-dependently inhibited gastric distension-induced VMR in rats. However, itopride even at 100 mg/kg failed to inhibit gastric distension-induced VMR in rats. Additionally, a major metabolite M1 of mosapride, which possesses 5-HT(3)-receptor antagonistic activity, inhibited gastric distension-induced VMR. The inhibitory effect of mosapride on gastric distension-induced visceral pain was partially, but significantly inhibited by SB-207266, a selective 5-HT(4)-receptor antagonist. This study shows that mosapride inhibits gastric distension-induced VMR in conscious rats. The inhibitory effect of mosapride is mediated via activation of 5-HT(4) receptors and blockage of 5-HT(3) receptors by a mosapride metabolite. This finding indicates that mosapride may be useful in alleviating FD-associated gastrointestinal symptoms via increase in pain threshold.

The novel peripherally active cannabinoid type 1 and serotonin type 3 receptor agonist AM9405 inhibits gastrointestinal motility and reduces abdominal pain in mouse models mimicking irritable bowel syndrome.

The endocannabinoid system (ECS) plays a crucial role in numerous physiological processes in the central and peripheral nervous systems. In the gastrointestinal (GI) tract, selective cannabinoid (CB) receptor agonists exert potent inhibitory actions on motility and pain signalling. In the present study, we used mouse models of diarrhea, hypermotility, and abdominal pain to examine whether a novel synthetic CB1 receptor agonist AM9405 [(2-(2,6-dihydroxy-4-(2-methyloctan-2-yl)phenyl)-1,3-dimethyl-1H-benzo[d]imidazol-3-ium bromide); also known as GAT379] exhibits effects of potential therapeutic relevance. AM9405 significantly slowed mouse intestinal motility in physiological conditions. Moreover, AM9405 reversed hypermotility and reduced pain in mouse models mimicking symptoms of functional GI disorders, such as stress-induced diarrhea and writhing test. Interestingly, some of the effects of AM9405 were blocked by a 5-HT3 antagonist suggesting interaction with 5-HT3 receptors. In our study we show that combining CB1 agonism with 5-HT3 agonism may alter physiological functions and experimental pathophysiologies in a manner that make such compounds promising drugs for the future treatment of functional GI disorders.

Efficacy, safety and effectiveness of ondansetron compared to other serotonin-3 receptor antagonists (5-HT3RAs) used to control chemotherapy-induced nausea and vomiting: systematic review and meta-analysis.

INTRODUCTION: Chemotherapy-induced nausea and vomiting are adverse effects responsible for worsening quality of life in cancer patients. To assess the efficacy, safety and effectiveness of serotonin receptor antagonist in cancer patients undergoing chemotherapy, comparing ondansetron with granisetron, dolasetron, tropisetron and palonosetron. AREAS COVERED: Systematic review and meta-analysis. The data were collected using CINAHL; CENTRAL; MEDLINE/PubMed; and LILACS databases; grey literature; and manual search. The methodological quality was assessed using the modified Jadad scale; Cochrane Collaboration's tool for assessing risk of bias in randomized clinical trials and the Newcastle-Ottawa Scale for observational studies. The search was completed in November, 2015. 26 studies were included in the meta-analysis. Ondansetron exhibited similar efficacy than granisetron and tropisetron, as well as greater efficacy than dolasetron for acute vomiting. Palonosetron exhibited greater efficacy than ondansetron for delayed nausea and acute and delayed vomiting. The comparison of granisetron with ondansetron in the cohort studies showed no difference. Expert commentary: In this review, palonosetron had increased efficiency compared with ondansetron, except in the subgroup analysis and acute nausea. Few cohort studies have been published addressing this topic.

Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron.

Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.

Aprepitant in the prevention of vomiting induced by moderately and highly emetogenic chemotherapy.

Chemotherapy is a major therapeutic approach for malignant neoplasms; however, due to the most common adverse events of nausea and vomiting, scheduled chemotherapeutic programs may be impeded or even interrupted, which severely impairs the efficacy. Aprepitants, 5-HT3 antagonists and dexamethasone are primary drugs used to prevent chemotherapy-induced nausea and vomiting (CINV). These drugs have excellent efficacy for control of acute vomiting but are relatively ineffective for delayed vomiting. Aprepitant may remedy this deficiency. Substance P was discovered in the 1930s and its association with vomiting was confirmed in the 1950s. This was followed by a period of non-peptide neurokinin-1 (NK-1) receptor antagonist synthesis and investigation in preclinical studies and clinical trials (phases I, II and III). The FDA granted permission for the clinical chemotherapeutic use of aprepitant in 2003. At present, the combined use of aprepitant, 5-HT3 antagonists and dexamethasone satisfactorily controls vomiting but not nausea. Therefore, new therapeutic approaches and drugs are still needed.

Novel partial 5HT3 agonist pumosetrag reduces acid reflux events in uninvestigated GERD patients after a standard refluxogenic meal: a randomized, double-blind, placebo-controlled pharmacodynamic study.

BACKGROUND: Low basal lower esophageal sphincter (LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease (GERD). Pumosetrag, a novel selective partial 5HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure (LESP), and specific symptoms in patients with GERD receiving a refluxogenic meal. METHODS: Patients with GERD, who developed heartburn and/or regurgitation after ingestion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichannel, intraluminal impedance and pH after a standard refluxogenic meal. KEY RESULTS: A total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled. No overall treatment effects were detected for the total number of reflux episodes (acidic and weakly acidic) (p > 0.5); however, significant treatment effects (p < 0.05) on the number of acid reflux episodes were observed with lower values on pumosetrag 0.2 mg (10.8 ± 1.1), 0.5 mg (9.5 ± 1.1), and 0.8 mg (9.9 ± 1.1) compared with placebo (13.3 ± 1.1). Significant treatment effects (p < 0.05) were also observed for the percentage of time pH was <4, with less time for pumosetrag at 0.5 mg (10%) and 0.8 mg (10%) compared with placebo (16%). CONCLUSIONS & INFERENCES: In GERD, the partial 5HT3 agonist pumosetrag significantly reduced the rate of acid reflux events but did not result in a significant change in LESP or symptomatic improvement over a 1-week treatment period.

Partial agonism of 5-HT3 receptors: a novel approach to the symptomatic treatment of IBS-D.

Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain, discomfort, and altered bowel habits, which have a significant impact on quality of life for approximately 10-20% of the population. IBS can be divided into three main types IBS-D (diarrhea predominant), IBS-C (constipation predominant), and mixed or alternating IBS. 5-HT(3) receptor antagonism has proved to be an efficacious treatment option for IBS-D. For example, alosetron displays efficacy in the treatment of multiple symptoms, including abdominal pain, discomfort, urgency, stool frequency and consistency. However, significant constipation occurred in approximately 25% of patients, leading to withdrawal of up to 10% of patients in clinical trials. Targeting compounds with partial agonist activity at the 5-HT(3) receptor represents a mechanistic departure from the classic 5-HT(3) receptor antagonist approach and should result in agents that are applicable to a broader array of IBS patient populations. Attenuation of the activity of the ion channel without completely abolishing its function may control or normalize bowel function without leading to a total block associated with severe constipation. We have identified a new class of selective, orally active 5-HT(3) receptor ligands with high 5-HT(3) receptor affinity and low partial agonist activity currently in preclinical development that should offer a significant advantage over existing therapies.

Discriminating between 5-HT3A and 5-HT3AB receptors.

The 5-HT3B subunit was first cloned in 1999, and co-expression with the 5-HT3A subunit results in heteromeric 5-HT3AB receptors that are functionally distinct from homomeric 5-HT3A receptors. The affinities of competitive ligands at the two receptor subtypes are usually similar, but those of non-competitive antagonists that bind in the pore often differ. A competitive ligand and allosteric modulator that distinguishes 5-HT3A from 5-HT3AB receptors has recently been described, and the number of non-competitive antagonists identified with this ability has increased in recent years. In this review, we discuss the differences between 5-HT3A and 5-HT3AB receptors and describe the possible sites of action of compounds that can distinguish between them.

5-HT3 receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells.

BACKGROUND AND PURPOSE: Chemotherapeutic agents, including 5-fluorouracil (5-FU), frequently cause intestinal mucositis resulting in severe diarrhoea and morphological mucosal damage. 5-HT3 receptor antagonists are clinically effective in the treatment of nausea and emesis during cancer chemotherapy. Therefore we here have examined the effects of 5-HT3 receptor antagonists on 5-FU-induced intestinal mucositis in mice. EXPERIMENTAL APPROACH: Intestinal mucositis was induced in male C57BL/6 mice by daily administration of 5-FU (50 mg·kg⁻¹) for 5 days. Effects of 5-HT3 receptor antagonists, ramosetron (0.01-0.1 mg·kg⁻¹) and ondansetron (5 mg·kg⁻¹), on the accompanying histology, cytokine production and apoptosis were assessed. KEY RESULTS: Continuous administration of 5-FU to mice caused severe intestinal mucositis, which was histologically characterized by the shortening of villi and destruction of intestinal crypts, accompanied by body weight loss and diarrhoea. Daily ramosetron administration dose-dependently reduced the severity of intestinal mucositis, body weight loss and diarrhoea. Similar beneficial effects were observed with ondansetron. The number of apoptotic, caspase-3- and caspase-8-activated cells increased 24 h after the first 5-FU administration, and these responses were reduced by ramosetron. The up-regulation of TNF-α, IL-1ß and IL-6 following 5-FU treatment was also attenuated by ramosetron. CONCLUSIONS AND IMPLICATIONS: 5-HT3 receptor antagonists ameliorated 5-FU-induced intestinal mucositis in mice, and this action could result from suppression of apoptotic responses in the intestinal crypt cells via inhibition of cytokine expression. Thus, 5-HT3 receptor antagonists may be useful for preventing not only nausea and emesis but also intestinal mucositis during 5-FU chemotherapy.

¿Antidepresivos jóvenes para pacientes ancianos? / No disponible

La depresión es el trastorno psiquiátrico más frecuente en la población de edad avanzada, con una prevalencia aumentada en personas mayores y muy mayores hospitalizadas o institucionalizadas. La depresión en población geriátrica asocia importantes consecuencias en forma de pérdidas en la funcionalidad, incapacidad, disminución de calidad de vida, incremento de morbi-mortalidad, elevados costes en salud y alto riesgo de suicidio. Pese a su impacto, es una situación clínica con frecuencia infradiagnosticada e infratratada. A ello pueden contribuir las particularidades de la expresión clínica de la depresión en pacientes ancianos y las dificultades en el diagnóstico diferencial y el tratamiento. Entre las dificultades que encontramos en el tratamiento psicofarmacológico de la depresión en el anciano se encuentran la presencia de comorbilidades con otras enfermedades médicas, la frecuente polifarmacia y los cambios farmacocinéticos y farmacodinámicos asociados al envejecimiento, tanto fisiológicos como secundarios a otras enfermedades y tratamientos, que confieren mayor vulnerabilidad a la aparición de reacciones adversas medicamentosas; así como la tendencia a las recurrencias, la cronicidad y la refractariedad a los tratamientos de primera línea. En las últimas décadas, con el desarrollo de antidepresivos con mecanismos de acción selectivos se ha mejorado la tolerabilidad general a los tratamientos en comparación con los antidepresivos clásicos como los tríciclicos y los inhibidores de la monoamino-oxidasa, sin embargo la tolerabilidad y las tasas de efectos adversos distan de ser óptimas en población geriátrica. Por otro lado, los datos de eficacia de los tratamientos antidepresivos en personas mayores y sobre todo en octogenarios son limitados, puesto que esta población está claramente infrarrepresentada en los ensayos clínicos. En la presentación se abordarán las aportaciones de los antidepresivos que han aparecido en los últimos años en nuestro medio al tratamiento de la depresión geriátrica

Depression is the most common psychiatric disorder in the elderly population, with an increased prevalence in old and very old hospitalized or institutionalized patients. Depression in the geriatric population associates important consequences in the form of loss of functionality, disability, decreased quality of life, increased morbidity and mortality, high health care costs and high risk of suicide. Despite its impact, this clinical situation is often underdiagnosed and under-treated. The particularities of the clinical expression of depression in elderly patients and the difficulties in differential diagnosis and treatment can contribute to this improvable picture. Among the difficulties encountered in the psychopharmacological treatment of depression in the elderly are the presence of comorbidities with other medical diseases, frequent polypharmacy, pharmacokinetic and pharmacodynamic changes associated with aging, both physiological and secondary to other diseases and treatments, which confer greater vulnerability to the appearance of adverse drug reactions; as well as the tendency to recurrences, chronicity and refractoriness to first-line treatments. In the last decades, with the development of antidepressants with selective mechanisms of action, the general tolerability has been improved compared to the classic antidepressants such as tricyclics and monoamine oxidase inhibitors. However, tolerability and adverse effects are far from optimal in the geriatric population. On the other hand, data about the efficacy of antidepressant treatments in the elderly, and especially in octogenarians, are limited, since this population is clearly underrepresented in clinical trials. This paper will address the contributions of antidepressants that have appeared in recent years in our country to the treatment of depression in the elderly

Targeting the 5-HT(3) receptor in the treatment of irritable bowel syndrome.

Irritable bowel syndrome, which affects 5-10% of the population includes around 25% with predominantly diarrhoea (IBS-D). Several lines of evidence suggest an increase in mucosal 5-HT availability in IBS-D including a decrease in the serotonin transporter (SERT) which is also seen following acute diverticulitis. 5-HT(3) receptor antagonists have proved effective in suppressing urgency, prolonging small and large bowel transit and relieving symptoms in IBS-D. Alosetron continues to be used under restricted availability without any serious morbidity despite ischemic colitis which occurs at a rate of <1/1000 patient year. Other agents such as ramosetron and ondansetron are still in use and have not been associated with ischemic colitis. 5-HT(3) receptor agonists stimulate intestinal motility, shorten transit times and in a pilot trial accelerated transit in patients with IBS-C.

Moringa oleifera induced potentiation of serotonin release by 5-HT(3) receptors in experimental ulcer model.

ETHNOPHARMACOLOGICAL RELEVANCE: moringa oleifera (Moringaceae), a perennial plant is widely cultivated throughout the world. Extensive pharmacological studies revealed its promising role in modulation of various disorders like antispasmodic, diuretic, abortifacient, antimicrobial antibacterial, antitubercular, antiviral, antifertility, depressant, anti-inflammatory and anticancer property which promoted us to conduct the study to elucidate its role on experimental gastric ulceration. AIM OF THE STUDY: the aim of the present study was to assess the efficacy of its aqueous leaf extract on protection of gastric ulceration and characterize the possible modulatory mechanism underlying the phenomenon. MATERIALS AND METHODS: adult Holtzman strain albino rats (weight 150-200 g) of either sex were used for the study. Ulceration was induced using aspirin (500 mg/kg body weight) and using Moringa oleifera (MO), a herbal formulation, the modulatory mechanism has been studied and compared with a commonly used antagonist of 5-HT(3) receptors, ondansetron by assessing parameters like mean ulcer index, 5-HT content, EC cell count and mucosal thickness. RESULTS: the results of our study suggest that MO protects ulcer formation by modulating 5-HT secretion through EC cell via 5-HT(3) receptors in gastrointestinal tract. INTERPRETATION AND CONCLUSION: MO showed maximum protective activity at a dose of 300 mg/kg body weight against above-mentioned experimental rat ulcer model by modulating 5-HT secretion through EC cell via 5-HT(3) receptors in gastrointestinal tract which has given a glimpse of a therapeutic approach for gastric ulcer management, which may be beneficially used in contrast to the classical antacid, antihistamine or surgical treatment. Further investigations and proper screening regarding various phytochemicals, alkaloids present within MO leaf will help to formulate effective herbal preparation that will be used to combat gastrointestinal disorders in future.

Heterogeneity amongst 5-HT3 receptor subunits: is this significant?

The serotonin 3 (5-HT3) receptor is a ligand gated ion channel unlike the other 5-HT receptors which are G protein coupled receptors. The functional 5-HT3 receptor forms a pentamer of five symmetrically arranged subunits surrounding a central pore. The 5-HT(3A) subunit was first identified at a molecular level and can form functional homomers or heteromers with the 5-HT(3B) subunit. Recently, three new 5-HT3 subunits have been discovered and these can also form functional heteromers with the 5-HT(3A) subunit. In addition, splice variants of the 5-HT3 subunits have also been reported. These findings have markedly increased the complexity of the 5-HT3 receptor and may form part of the explanation of unresolved differences between studies investigating 5-HT3 receptor function in cell lines compared with native tissues. In this review we discuss the properties of the different subunits and their distribution to determine if they contribute to functional changes in the 5-HT3 receptor. Several recent pharmacogenomic studies have revealed single nucleotide polymorphisms (SNPs) and other variations in the different 5-HT3 receptor subunits that are associated with various clinical conditions. We discuss the implications of these findings with respect to drug design and tailored pharmacogenomic therapies.