5-HT3 Receptor Blocker Research Articles

Adequate antiemetic treatment in patients receiving antitumor drug therapy

Despite the widespread use of immuno-oncological and targeted therapy in the treatment of malignant tumors, in real clinical practice the role of chemotherapy is still significant, used both in mono regimen and in combination with other antitumor drugs. Cytostatics cause a wide range of adverse events, which are often the cause of dose reduction, cyclical disorders, or even discontinuation of therapy. One of the most common symptoms is chemotherapy-induced nausea and vomiting which affect not only the quality of life, but also the results of treatment. It is important to address these issues from prevention and treatment perspectives so that patients remain committed to their treatment regimens. Since nausea and vomiting induced by chemotherapy are classified into 5 different types, the main medications for prevention and treatment include 5-hydroxytryptamine type 3 (5-HT3) and neurokinin-1 (NK1) receptor antagonists and corticosteroids. Simultaneous use of drugs from the groups of second-generation NK1 receptor blockers and 5-HT3 receptor blockers, for example: netupitant + palonosetron in combination with corticosteroids, makes it possible to achieve maximum antiemetic effect, even with the most emetogenic antitumor treatment regimens.

ЭФФЕКТИВНОСТЬ СТАНДАРТНОЙ ПРОФИЛАКТИКИ ТОШНОТЫ И РВОТЫ У ДЕТЕЙ, ПОЛУЧАЮЩИХ ВЫСОКОЭМЕТОГЕННУЮ ХИМИОТЕРАПИЮ: ДАННЫЕ РЕАЛЬНОЙ КЛИНИЧЕСКОЙ ПРАКТИКИ

The chemotherapy-induced nausea and vomiting (CINV) are of the most difficult to tolerate, often distressing, complications from a patient's point of view. Despite the success of modern antiemetic therapy this problem is far from being solved and the real effectiveness of antiemetic prophylaxis in children in Russia has not been studied as yet. The purpose of the study was to evaluate the effectiveness of routine CINV prevention against the highly emetogenic chemo in real clinical practice. Materials and methods of the study: the study included 88 patients aged 5 to 18 years old who received treatment from October, 2020, till June, 2021. The median age of patients was 14 [12.5-16] years old; the boys/girls ratio was 53%/47%. During the observation period the studied patients received 456 cycles of highly emetogenic chemo - Me (Q1-Q3) 5 (3-7). All of the patients included in this single-center prospective cohort study have received a standard three-component prophylaxis regimen that consisted of aprepitant, dexamethasone and a 5HT-3 receptor blocker on days of cytostatic therapy. Nausea and vomiting were assessed using the MASCC Antiemesis Tool (MAT) questionnaire and Baxter Retching Faces (BARF) and Pediatric Nausea Assessment Tool (PeNAT) graphic scales. Results: thanks to the use of the standard antiemetic prophylaxis the total control of CINV was achieved in 312 (68%), 239 (52%) and 198 (43%) cycles in the acute, delayed and general periods, respectively. The factors that were statistically significantly associated with an increase in the incidence of CINV were as follows: multi-day chemo regimens (p=0.016), high doses of cisplatin or carboplatin in the treatment regimen (p<0.001) and anticancer therapy for a solid tumor (p=0.002). The presence of vomiting at the previous stage of cytostatic treatment also statistically significantly increased the incidence of CINV (p<0.001). Conclusion: against the background of standard antiemetic prophylaxis more than a half of all the children receiving highly emetogenic cytostatic therapy continue to suffer from CINV. This requires the development and implementation of a modern, more effective approaches to the CINV prevention. The risk factors for the development of CINV identified in the study could be of help in further studies in order to stratify patients into groups. The fact of a significant increase in the risk of CINV development in patients who experienced these complications during initial therapy indicates the need for the most effective prevention of CINV from the very first cycle of treatment.

Expression of the relaxin family peptide 4 receptor by enterochromaffin cells of the mouse large intestine

The gastrointestinal hormone, insulin-like peptide 5 (INSL5), is found in large intestinal enteroendocrine cells (EEC). One of its functions is to stimulate nerve circuits that increase propulsive activity of the colon through its receptor, the relaxin family peptide 4 receptor (RXFP4). To investigate the mechanisms that link INSL5 to stimulation of propulsion, we have determined the localisation of cells expressing Rxfp4 in the mouse colon, using a reporter mouse to locate cells expressing the gene. The fluorescent signal indicating the location of Rxfp4 expression was in EEC, the greatest overlap of Rxfp4-dependent labelling being with cells containing 5-HT. In fact, > 90% of 5-HT cells were positive for Rxfp4 labelling. A small proportion of cells with Rxfp4-dependent labelling was 5-HT-negative, 11–15% in the distal colon and rectum, and 35% in the proximal colon. Of these, some were identified as L-cells by immunoreactivity for oxyntomodulin. Rxfp4-dependent fluorescence was also found in a sparse population of nerve endings, where it was colocalised with CGRP. We used the RXFP4 agonist, INSL5-A13, to activate the receptor and probe the role of the 5-HT cells in which it is expressed. INSL5-A13 administered by i.p. injection to conscious mice caused an increase in colorectal propulsion that was antagonised by the 5-HT3 receptor blocker, alosetron, also given i.p. We conclude that stimuli that excite INSL5-containing colonic L-cells release INSL5 that, through RXFP4, excites 5-HT release from neighbouring endocrine cells, which in turn acts on 5-HT3 receptors of enteric sensory neurons to elicit propulsive reflexes.

Comparison of Efficacy of Ondansetron Pre-treatment in Alleviating Pain due to Propofol during General Anaesthesia with Placebo

Background: Ondansetron is a 5HT3 receptor blocker and has multifaceted action like sodium channel blocker and µ - opioid agonist. Objective: To compare the efficiency of ondansetron pre-treatment in alleviating pain caused by propofol during induction of general anaesthesia with placebo. Material & Method: In this randomized controlled trail 120 patients of ASA grade I & II undergoing elective surgery were included and divided into two equal groups A & B by using lottery method. Each group comprised of 60 patients. In group A two ml 0.9 % normal saline and in group B, 2 ml ondansetron (4mg) given intravenously. In both groups propofol was given in a dose of 2.5 mg / Kg intravenously. Results: The mean age of patients in group A was 29.95 ± 4.79 year and in group B was 30.30 ± 4.87 year. Majority of patients 67(55.83 %) were between 18 to 30 year of age. Out of 120 patients. 63 (52.50 %) were ASA I & 52 (47.50 %) were ASA II. Efficacy of group A (placebo) was seen in 11 (18.33 %) while in group B (ondansetron) was seen in 56 (93.33 %). Conclusion: Ondansetron pre-treatment in alleviating pain cause by propofol is very effective. Keywords: Pain, ondansetron, propofol, general anaesthesia.

Palonosetron/Methyllycaconitine Deactivate Hippocampal Microglia 1, Inflammasome Assembly and Pyroptosis to Enhance Cognition in a Novel Model of Neuroinflammation.

Since westernized diet-induced insulin resistance is a risk factor in Alzheimer’s disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid β (Aβ)1-42 in these patients, our AD novel model was developed to resemble sporadic AD by injecting LPS into high fat/fructose diet (HFFD)-fed rats. The neuroprotective potential of palonosetron and/or methyllycaconitine, 5-HT3 receptor and α7 nAChR blockers, respectively, was evaluated after 8 days of daily administration in HFFD/LPS rats. All regimens improved histopathological findings and enhanced spatial memory (Morris Water Maze); however, palonosetron alone or with methyllycaconitine promoted animal performance during novel object recognition tests. In the hippocampus, all regimens reduced the expression of glial fibrillary acidic protein and skewed microglia M1 to M2 phenotype, indicated by the decreased M1 markers and the enhanced M2 related parameters. Additionally, palonosetron and its combination regimen downregulated the expression of ASC/TMS1, as well as levels of inflammasome downstream molecules and abated cleaved caspase-1, interleukin (IL)-1β, IL-18 and caspase-11. Furthermore, ACh and 5-HT were augmented after being hampered by the insult. Our study speculates that blocking 5-HT3 receptor using palonosetron overrides methyllycaconitine to combat AD-induced neuroinflammation and inflammasome cascade, as well as to restore microglial function in a HFFD/LPS novel model for sporadic AD.

Comparison of weight-adjusted dose versus fixed dose ondansetron in Prevention of shivering following spinal anaesthesia for caesarean deliveries

Spinal anaesthesia is a safe and efficient procedure for regional anaesthesia, Shivering is a prevalent side effect of spinal anaesthesia. Ondansetron, a 5-HT3 receptor blocker, should be used to treat and avoid shivering after spinal anaesthesia. The aim of this study was to decide if a weight-adjusted dose of ondansetron is superior to a fixed-dose in preventing shivering following spinal anaesthesia for caesarean delivery. While secondary objectives included determining the prevalence of ondansetron and pethidine adverse reactions. Patients and methods; This was a prospective, randomised, double-blinded, controlled clinical trial involving 129 people, Three equal groups of women were randomly assigned. 1st. received a fixed dose of ondansetron (4mg), 2nd. received ondansetron at a weight controlled dose of 0.1mg/kg, and 3rd. received 0.5 mg/kg pethidine after spinal anaesthesia. the incidence and severity of shivering were measured, as well as the incidence of headache, pruritus, nausea, and vomiting perioperatively were studied. Results; Shivering was observed in 13 patients (30.2 %) in the first group (FDO), 11 patients (25.6 %) in the second group (WAO), and 11 patients (25.6 %) in the third group (PC), but no significant difference between the groups was observed (p-value˃ 0.05). Shivering was more severe (grade II) in the first group (FDO) 5 patients (11.6 %) than in the second group (WAO) 3 patients (6.9 %). Conclusions: A weight-adjusted dosage of 0.1 mg/kg significantly decreased the rate and severity of postspinal shivering while causing less adverse effects and improving hemodynamic stability.

Evaluation of Efficacy of Mirtazapine on Pruritus and Serum Histamine and Serotonin Levels in Patients Undergoing Hemodialysis: A Before-After Pilot Clinical Trial.

BackgroundAlthough chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and frustrating symptom in patients with advanced kidney diseases, its optimal treatments are not well defined. Based on its mechanism of action, as a histamine-1 (H1), 5-(hydroxytryptamine) HT2, and 5HT3-receptor blocker, mirtazapine may be effective in the treatment of CKD-aP. Hence, this study aimed to investigate the efficacy of mirtazapine for the treatment of pruritus in patients undergoing hemodialysis (HD).MethodsA before–after clinical trial was conducted from September 2018 until March 2019, on 30 HD-patients that had been referred to the HD ward of a tertiary hospital, in Hamadan, Iran. After the 2-week washout period, mirtazapine was administered with a dosage of 15 mg/day for an additional 2 weeks. At baseline and at each dialysis session, the effects of the mirtazapine on the pruritus severity based on the visual analogue scale (VAS) and degree of sleep interference resulting from the pruritus were asked and recorded. Additionally, at the baseline and the end of 2 weeks of treatment, the serum histamine and serotonin levels, as the main chemical pruritogens evoking pruritus symptoms, were also determined.ResultsTwenty-seven patients completed the entire course of the study. Based on the general linear model analysis, a progressive decline in the mean VAS score was observed over time during the study. The mean VAS score decreased from 8.48 ± 1.01 at baseline to 1.04 ±0.79 at the end of treatment (P-value<0.001). Similarly, the mean sleep interference scores were also significantly improved throughout treatment (decreased from 8.07±1.43 to 2.81± 0.74; P-value<0.001). Further, at the end of the treatment, a noticeable decrement in the serum histamine level was also seen (P-value = 0.006). The drug was acceptably well-tolerated and a majority of the patients were satisfied with this treatment.ConclusionThis pilot study suggests that mirtazapine may be an effective treatment option for the management of CKD-aP. However, further studies would be needed to confirm these results.

Granisetron and carvedilol can protect experimental rats againstadjuvant-induced arthritis

Context: Rheumatoid arthritis (RA), a disabling autoimmune disorder of the joints as well as other organs, affects about 1% of population. Unfortunately, all current treatments of RA cause severe gastrointestinal, renal and other complications.Objective: We aimed to evaluate the possible antiarthritic effects of a serotonin 5-HT3 receptor blocker, granisetron, and a nonselective adrenergic receptor blocker, carvedilol, on complete Freund's adjuvant-induced RA in adult female albino rats.Materials and methods: Rats were allocated into a normal control group, an arthritis control group, two reference treatment groups receiving dexamethasone (1.5 mg/kg/day) and methotrexate (1 mg/kg/day), and two treatment groups receiving granisetron (2.5 mg/kg/day) and carvedilol (10 mg/kg/day). Serum-specific rheumatoid, immunological, inflammatory and oxidative stress biomarkers were assessed. A confirmatory histopathological study on joints and spleens was performed.Results: Granisetron administration significantly improved all the measured biomarkers, with the values of rheumatoid factor, matrix metalloproteinase-3, cartilage oligomeric matrix protein, immunoglobulin G, antinuclear antibody and myeloperoxidase being restored back to normal levels. Carvedilol administration significantly improved all biomarkers, with serum MPO value restored back to normal levels.Discussion and conclusions: Serotonin 5-HT3 receptor blockers and adrenergic receptor blockers, represented by granisetron and carvedilol, may represent new promising protective strategies against RA, at least owing to immune-modulator, anti-inflammatory and antioxidant potentials.

The effect of Flos Lonicerae Japonicae extract on gastro-intestinal motility function

Ethnopharmacological relevanceFlos Lonicerae Japonicae is a well-known herb of traditional Chinese medicine that has been used for heat-clearing, detoxification, anti-inflammation, throat pain and gastro-intestinal (GI) disorder. In order to verify the effect of Flos Lonicerae Japonicae on GI disorder, we investigated the prokinetic effect of GC-7101 on GI motility function. Materials and methodsGC-7101 is the standardized extract of Flos Lonicerae Japonicae. The contractile action of GC-7101 on feline esophageal smooth muscle cell (ESMC) was evaluated by measuring dispersed cell length. The isometric tension study was performed to investigate the effect of GC-7101 on feline lower esophageal sphincther (LES). The prokinetic effect of GC-7101 was investigated by gastric emptying (GE) and gastro-intestinal transit (GIT) in rats. ResultsGC-7101 produced concentration-dependent contractions in ESMCs. Pretreatment with 5-HT3 and 5-HT4 receptor blocker (ondansetron and GR113808) inhibited the contractile responses of the GC-7101-induced ESMCs. In isometric tension study, GC-7101 recovered the HCl-induced decreased tone of LES muscle strips. The treatment of GC-7101 enhanced the carbachol-induced contractile responses and the electric field stimulation (EFS)-induced on-contraction. The oral administration of GC-7101 not only significantly accelerated GE and GIT in normal rats but also recovered the delayed GE and GIT, and its effect was more potent than that of conventional prokinetics (e.g., domperidone, a dopamine-receptor antagonist, and mosapride, a 5-HT4-receptor agonist). ConclusionGC-7101 revealed a prokinetic effect through enhancing the contractile responses of ESMCs, tone increases, enhancing the carbarchol- or EFS-induced contractile responses of LES muscle strips, and the acceleration of GE and GIT. We have identified the significant potential of GC-7101 for the development of new prokinetic drugs through this study.

Sex-related differences in small intestinal transit and serotonin dynamics in high-fat-diet-induced obesity in mice.

Obesity alters gastrointestinal (GI) motility and 5-HT signalling. Altered 5-HT signalling disrupts control of GI motility. Levels of extracellular 5-HT depend on enterochromaffin (EC) cell release and serotonin transporter (SERT) uptake. We assessed GI transit and 5-HT signalling in the jejunum of normal and obese mice. Male and female mice were fed a control diet (CD; 10% of kilocalories as fat) or a high-fat diet (HFD; 60% of kilocalories as fat). Gastrointestinal transit was increased in male HFD-fed and female CD-fed compared with male CD-fed mice. The 5-HT3 receptor blocker, alosetron, increased gastric emptying in male CD-fed mice, but decreased transit in female CD-fed mice. The 5-HT-induced jejunal longitudinal muscle contractions in vitro were similar in all mice. In contrast to male CD-fed mice, 5-HT uptake (measured using continuous amperometry in vitro) in male HFD-fed mice was fluoxetine insensitive, yet sensitive to cocaine and the dopamine transporter (DAT) blocker GBR 12909. Immunoreactivity for DAT was present in the mucosa, and protein levels were greater in male HFD-fed compared with CD-fed mice. Extracellular 5-HT and mucosal 5-hydroxyindolacetic acid (5-HT metabolite) were similar in male HFD-fed compared with CD-fed mice. 5-Hydroxytryptamine uptake was fluoxetine sensitive in all females. Greater SERT protein, decreased extracellular 5-HT and greater mucosal 5-hydroxyindolacetic acid were observed in female HFD-fed compared with CD-fed mice. Mucosal 5-HT and EC cell numbers were similar in CD-fed and HFD-fed mice of both sexes; female 5-HT and EC cell numbers were increased compared with males. The HFD did not alter plasma sex hormone levels in any mice. Overall, obesity alters GI transit and 5-HT signalling in a sex-dependent manner.

Finding the 'Ideal' Regimen for Fentanyl-Based Intravenous Patient-Controlled Analgesia: How to Give and What to Mix?

PurposeThis analysis was done to investigate the optimal regimen for fentanyl-based intravenous patient-controlled analgesia (IV-PCA) by finding a safe and effective background infusion rate and assessing the effect of adding adjuvant drugs to the PCA regimen.Materials and MethodsBackground infusion rate of fentanyl, type of adjuvant analgesic and/or antiemetic that was added to the IV-PCA, and patients that required rescue analgesics and/or antiemetics were retrospectively reviewed in 1827 patients who underwent laparoscopic abdominal surgery at a single tertiary hospital.ResultsUpon multivariate analysis, lower background infusion rates, younger age, and IV-PCA without adjuvant analgesics were identified as independent risk factors of rescue analgesic administration. Higher background infusion rates, female gender, and IV-PCA without additional 5HT3 receptor blockers were identified as risk factors of rescue antiemetics administration. A background infusion rate of 0.38 µg/kg/hr [area under the curve (AUC) 0.638] or lower required rescue analgesics in general, whereas, addition of adjuvant analgesics decreased the rate to 0.37 µg/kg/hr (AUC 0.712) or lower. A background infusion rate of 0.36 µg/kg/hr (AUC 0.638) or higher was found to require rescue antiemetics in general, whereas, mixing antiemetics with IV-PCA increased the rate to 0.37 µg/kg/hr (AUC 0.651) or higher.ConclusionBackground infusion rates of fentanyl between 0.12 and 0.67 µg/kg/hr may safely be used without any serious side effects for IV-PCA. In order to approach the most reasonable background infusion rate for effective analgesia without increasing postoperative nausea and vomiting, adding an adjuvant analgesic and an antiemetic should always be considered.

Abstract P3-09-03: Final result of randomised controlled phase II study of the efficiency of palonosetron, aprepitant, and dexamethasone for day1 with or without dexamethasone on days2 and 3

Abstract Background: Emesis is one of the major non-hematologic toxicity caused by chemotherapy. The control of Chemotherapy Induced Nausea and Vomiting (CINV) is conducted to a life lengthening. Recently, CINV is controlled by the second generation 5-HT3 receptor blocker (Palonosetron; PALO) and a NK-1 receptor antagonist (Aprepitant; APR). It has been shown that dexamethasone (DEX) with 5-HT3 receptor blocker improves acute / delayed CINV. However, it has not been determined the medication schedule for DEX with PALO and APR. The purpose of this study is evaluated the efficiency of palonosetron, aprepitant and dexamethasone for day1 with or without dexamethasone on days2 and 3. This is final result of current study. Methods: Breast cancer patients who administered anthracyclin drug regimen have been eligible from April, 2011 to June, 2013. The patients were randomised to group A (PALO/APR/DEX one day) and group B (PALO/APR/DEX three days). Trial designAprepitant125mg80mg80mg Palonosetron0.75mg dexamethasone9.9mg6.6 mg or placebo6.6 mg or placebo Chemotherapydo days12345 Eighty patients were estimate as study samples. The primary endpoint was a complete response (CR) rate of vomiting, the secondary endpoint was a complete control (CC) rate of vomiting. Results: Eighty two patients were enrolled in this study. There was not inferiority about CR rate of five days after chemotherapy (81.1% of group A, 82.1% of group B). CC rate of group A (62.2%) was better than that of group B (46.2%). However, CC rate was no significant difference between group A and B. There was no significant difference about any level of nausea between group A and B. Conclusions: One day of dexamethasone with Palonosetron and Aprepitant treatment is enough to control the emesis of high emetogenic chemotherapeutic agents. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-03.

Comparative Pharmacokinetic Studies of Fast Dissolving Film and Oral Solution of Ondansetron in Rats

Ondansetron, selective serotonin (5-HT3) receptor blocker, is used in treating chemotherapy induced nausea and vomiting in cancer patients. Mouth dissolving films containing ondansetron were developed to have better onset and patient compliances. The drug content of prepared films was within 85%-115%. The films were found to be stable for 4 months when stored at 40 %°C and 75% RH. In-vitro dissolution studies suggested a rapid disintegration, in which most of ondansetron was released (91.5±3.4%) within 90 sec. Subsequently, Sprague-Dawley rats were used to compare pharmacokinetic parameters of the formulated films with oral administration of pure drug solution. Pharmacokinetic parameters were similar between the two groups in which AUC0-t (ng h/ml), AUC0-∞ (ng h/ml), Cmax (ng/ml), Tmax (min), Kel (h(-1)) and t1/2 (h) of reference was 109.091±15.73, 130.32±18.56, 28.5±4.053, 60, 0.1860±0.0226, and 3.771±0.498 respectively; and for formulated film 113.663±16.64, 151.79±16.54, 30±3.51, 60, 0.1521±0.0310 and 4.755±0.653 respectively. These results suggest that the fast dissolving film containing ondansetron is likely to become one of the choices to treat chemotherapy induced nausea and vomiting.

Abstract P2-12-13: Results of randomised controlled phase II study (KBCSG02 trial) of the efficiency of palonosetron, aprepitant, and dexamethasone for day1 with or without dexamethasone on days2 and 3.

Abstract Background: Emesis is one of the major non-hematologic toxicity caused by chemotherapy. The control of Chemotherapy Induced Nausea and Vomiting (CINV) is conducted to a life lengthening. Recently, CINV is controlled by the second generation 5-HT3 receptor blocker (Palonosetron; PALO) and a NK-1 receptor antagonist (Aprepitant; APR). It has been shown that dexamethasone (DEX) with 5-HT3 receptor blocker improves acute/delayed CINV. However, it has not been determined the medication schedule of DEX with PALO and APR. The purpose of this study is evaluated the efficiency of palonosetron, aprepitant and dexamethasone for day1 with or without dexamethasone on days2 and 3. Methods: Breast cancer patients who administered anthracyclin drug regimen have been eligible from April, 2011 to June, 2012. The patients were randomised to group A (PALO/APR/DEX one day) and group B (PALO/APR/DEX three days). Eighty patients was estimate as study samples. The primary endpoint was a complete response (CR) rate of vomiting, the secondary endpoint was a complete control (CC) rate of vomiting. Results: Forty patients were enrolled in this study, and patient recruitment is continued. CR rate was no significant difference in both groups (76.9% of group A, 73.3% of group B). CC rate of group A (61.5%) did not show inferiority compared with group B (40.0%). Conclusions: In this current study, we suggest that one day dexamethasone treatment could reduce enough the emesis of high emetogenic chemotherapeutic agents. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-13.

Abolishment of Serotonergic Neurotransmission to Cardiac Vagal Neurons During and After Hypoxia and Hypercapnia With Prenatal Nicotine Exposure

Cardioinhibitory cardiac vagal neurons (CVNs) do not receive inspiratory-related excitatory inputs under normal conditions. However, excitatory purinergic and serotonergic pathways are recruited during inspiratory activity after episodes of hypoxia and hypercapnia (H/H). Prenatal nicotine (PNN) exposure is known to dramatically change cardiorespiratory responses and decrease the ability to resuscitate from H/H. This study tested whether PNN exposure alters excitatory neurotransmission to CVNs in the nucleus ambiguus during and after H/H. Spontaneous and inspiratory evoked excitatory postsynaptic currents were recorded in CVNs from rats that were exposed to nicotine (6 mg x kg(-1) x d(-1)) throughout the prenatal period. In contrast to unexposed animals, in PNN animals H/H recruited excitatory neurotransmission to CVNs during inspiratory-related activity that was blocked by the alpha3beta4 nicotinic acetylcholine receptor (nAChR) blocker alpha-conotoxin AuIB (alpha-CTX AuIB, 100 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 50 microM) and d(-)-2-amino-5-phosphonopentanoic acid (AP5, 50 microM), selective AMPA/kainate and N-methyl-d-aspartate receptor blockers, respectively. Following H/H, there was a significant increase in inspiratory-related excitatory postsynaptic currents that were unaltered by alpha-CTX AuIB or ondansetron, a 5-HT3 receptor blocker, but were subsequently inhibited by pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (100 microM), a purinergic receptor blocker and CNQX and AP5. The results from this study demonstrate that with PNN exposure, an excitatory neurotransmission to CVNs is recruited during H/H that is glutamatergic and dependent on activation of alpha3beta4-containing nAChRs. Furthermore, exposure to PNN abolishes a serotonergic long-lasting inspiratory-related excitation of CVNs that is replaced by recruitment of a glutamatergic pathway to CVNs post H/H.

Serotonin-3 receptors in gastric mechanisms of cholecystokinin-induced satiety

our understanding of the controls of food intake has increased substantially during the last 30 years. Important in this has been the recognition of the meal as a controlled, physiologically relevant unit of energy intake. During a meal, ingested nutrients accumulate in the stomach and gradually

Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: Long-term survival in its adjuvant use

To evaluate the efficacy of streptozocin and o.p'DDD (SO) in adrenocortical cancer (ACC) patients since other chemotherapeutic regimens have limited effects. We performed a phase II study with SO therapy in 40 ACC patients (median age 44 years). Oral o,p'DDD administration (1-4 g/d, every day) was given together with intravenous streptozocin (1 g/d for five days, thereafter 2 g once every three weeks). 5HT3-receptor blocker was used as standard premedication for streptozocin. The SO therapy was found to have significant effects on disease-free interval (P = 0.02) as well as on survival (P = 0.01) in adjuvantly treated cases (n = 17) in comparison to the patients who did not get any therapy after complete resection (n = 11). Complete or partial response was obtained in 36.4% of patients with measurable disease (n = 22). The overall two-year and five-year survival rates were 70% and 32.5%, respectively. The presence of metastases at diagnosis was identified as a poor prognostic factor (P = 0.02). The present study necessitates further randomized clinical study of SO therapy in the treatment of ACC, mainly as adjuvant treatment immediately after curative intended surgery, and could be developed into a regular treatment regimen.

Involvement of serotonin and calcium channels in the intestinal fluid secretion evoked by bile salt and cholera toxin.

1. The enteric nervous system (ENS) is activated when exposing the intestinal mucosa to cholera toxin or certain bile salts. Cholera toxin stimulates ENS, at least in part, by the release of 5-hydroxytryptamine (5-HT) from the enterochromaffin cells. Calcium channel blockers of the L-type markedly attenuate the fluid secretion and the luminal release of 5-HT caused by cholera toxin. 2. The objective of the present study was to elucidate if sodium deoxycholate activated ENS in a similar manner as cholera toxin. Furthermore, the effect of several calcium channel blockers was tested on the fluid secretion caused by cholera toxin or bile salt. 3. Sodium deoxycholate (4 mM) caused a release of 5-HT into the intestinal lumen, which was inhibited by calcium channel blockade. Granisetron, a 5-HT3 receptor blocker, partly inhibited the fluid secretion caused by bile salt. 4. The effects of nifedipine, felodipine, R-felodipine, H186/86 (t-butyl analogue of felodipine) on the fluid secretion caused by cholera toxin or sodium deoxycholate were studied. Both secretory states were markedly attenuated in a dose dependent manner by all calcium channel blockers tested regardless of their effects on arterial pressure. 5. It is concluded that both cholera toxin and bile salt activate ENS, at least in part, via a release of 5-HT from the enterochromaffin cells. The antisecretory effect calcium channel blockers is partly explained by an inhibition of this release of 5-HT.

Clozapine's antipsychotic effects do not depend on blockade of 5-HT3 receptors.

Sixteen known 5-HT3 receptor blockers, including clozapine, fully or partially reverse the inhibitory effect of 1 microM GABA on [35S]TBPS binding, indicating that they are also GABA(A) antagonists, some of them selective for subsets of GABA(A) receptors. The 5-HT3 receptor blocker, ondansetron, has been reported to produce some antipsychotic and anxiolytic effects. However, no antipsychotic effects have been reported for a large number of highly potent 5-HT3 receptor blockers. Like clozapine, ondansetron partially reverses the inhibitory effect of GABA on [35S]TBPS binding. Additivity experiments suggest that ten 5-HT3 receptor blockers tested at low concentrations preferentially block subtypes of GABA(A) receptors that are among those blocked by clozapine. Wiley and Porter (29) reported that MDL-72222, the most potent GABA(A) antagonist described here, partially generalizes (71%) with clozapine in rats trained to discriminate an interoceptive clozapine stimulus, but only at a dose that severely decreases responding. Tropisetron (ICS-205,930) exhibits both GABA-positive and GABA-negative effects. R-(+)-zacopride is 6-fold more potent than S-(-)-zacopride as a GABA(A) antagonist. We conclude that the observed antipsychotic and, possibly, anxiolytic effects of some 5-HT3 receptor blockers are due to selective antagonism of certain GABA(A) receptors, and not to blockade of 5-HT3 receptors. We speculate that the anxiolytic and sedative effects of clozapine and several other antipsychotic drugs may be due to selective blockade of alpha1beta2gamma2 GABA(A) receptors which are preferentially located on certain types of GABAergic interneurons (probably parvalbumin positive). Blockade of these receptors will increase the inhibitory output of these interneurons. So far, no highly potent GABA(A) antagonists with clozapine-like selectivity have been identified. Such compounds may exhibit improved clozapine-like antipsychotic activity.

Nervous control of alkaline secretion in the duodenum as studied by the use of cholera toxin in the anaesthetized rat.

There is experimental evidence for an axon reflex control of alkaline secretion in the rat duodenum. We have investigated if there is also an intramural reflex control of alkaline secretion similar to that demonstrated with regard to the control of the fluid transport in the rat jejunum. Alkaline secretion in the duodenum of an anesthetized rat was continuously monitored using an in situ titration technique. The segment was extrinsically denervated. Exposing the duodenal segment to 80 microg cholera toxin markedly increased alkaline secretion. This response was abolished by hexamethonium (28 micromol (10 mg) kg(-1) body wt), a nicotinic receptor blocker, lidocaine (0.5 mL of a 1% solution on the serosal surface), a local anaesthetic, and nifedipine (5.75 micromol (2 mg) kg(-1) body wt i.v.), a calcium channel blocker. The response to cholera toxin was partially abolished by granisetron (0.11 micromol (40 microg) kg(-1) body wt i.v.), a 5-HT3 receptor blocker. Atropine (1.7 micromol (0.5 mg) kg(-1) body wt i.v.), a muscarinic receptor blocker, had no effect. We therefore conclude that the alkaline secretion in the rat jejunum evoked by cholera toxin exhibits the same pharmacological properties as the fluid secretion caused by the toxin in the jejunum. This suggests that the alkaline secretion in the rat duodenum is controlled not only by an axon reflex but also by an intramural secretory reflex similar to that controlling fluid transport in the rat jejunum.