5-HT3 Antagonist Research Articles

5-HT3 Antagonist for Pregnancy Associated Nausea and Vomiting

5-HT3 antagonists appear to be an effective treatment option in the treatment of nausea and vomiting associated with pregnancy. Literature suggests an increased risk of congenital defects in fetuses exposed to ondansetron during pregnancy, especially during first trimester. Health authorities now suggest that this drug should not be used during this period. However, this decision is debatable and whether ondansetron can be used in pregnant women is still controversial.

Autoradiographic labelling of 5-HT3 receptors in the hemi-parkinsonian rat brain

L-3,4-dihydroxyphenylalanine (l-DOPA) is the mainstay treatment for Parkinson’s disease, but its effectiveness during early disease is marred by the eventual development of l-DOPA induced dyskinesia. In hemi-parkinsonian rats, the serotonin type 3 (5-HT3) antagonists ondansetron and granisetron alleviated dyskinesia induced by l-DOPA without impeding its anti-parkinsonian action; in parkinsonian marmosets, ondansetron alleviated dyskinesia and enhanced l-DOPA anti-parkinsonian action. Here, we sought to gain insight into the mechanisms governing the anti-dyskinetic action of 5-HT3 antagonists and measured 5-HT3 receptor levels across different brain, using [3H]GR65630 autoradiographic binding. Brain sections were chosen from 6-hydroxydopamine (6-OHDA)-lesioned rats exhibiting abnormal involuntary movements (AIMs), as well as l-DOPA-naïve 6−OHDA and sham-lesioned animals. [3H]GR65630 binding increased in the ipsilateral subthalamic nucleus of 6-OHDA-lesioned rats with mild and severe AIMs, (3-fold changes, P < 0.001). [3H]GR65630 binding also increased in the ipsilateral entopeduncular nucleus and thalamus of 6-OHDA-lesioned rats with severe AIMs (75 % and 88 %, P < 0.05). AIMs scores negatively correlated with [3H]GR65630 binding in the ipsilateral dorsolateral striatum and contralateral subthalamic nucleus (P < 0.05). These results suggest that alterations in 5-HT3 mediated neurotransmission may contribute to the pathophysiology of l-DOPA induced dyskinesia.

Blockade of 5-HT2 receptors suppresses rate of torque development and motor unit discharge rate during rapid contractions.

Serotonin (5-HT) is a neuromodulator that is critical for regulating the excitability of spinal motoneurons and the generation of muscle torque. However, the role of 5-HT in modulating human motor unit activity during rapid contractions has yet to be assessed. Nine healthy participants (23.7 ± 2.2 yr) ingested 8 mg of the competitive 5-HT2 antagonist cyproheptadine in a double-blinded, placebo-controlled, repeated-measures experiment. Rapid dorsiflexion contractions were performed at 30%, 50%, and 70% of maximal voluntary contraction (MVC), where motor unit activity was assessed by high-density surface electromyographic decomposition. A second protocol was performed where a sustained, fatigue-inducing dorsiflexion contraction was completed before undertaking the same 30%, 50%, and 70% MVC rapid contractions and motor unit analysis. Motor unit discharge rate (P < 0.001) and rate of torque development (RTD; P = 0.019) for the unfatigued muscle were both significantly lower for the cyproheptadine condition. Following the fatigue inducing contraction, cyproheptadine reduced motor unit discharge rate (P < 0.001) and RTD (P = 0.024), whereas the effects of cyproheptadine on motor unit discharge rate and RTD increased with increasing contraction intensity. Overall, these results support the viewpoint that serotonergic effects in the central nervous system occur fast enough to regulate motor unit discharge rate during rapid powerful contractions.NEW & NOTEWORTHY We have shown that serotonin activity in the central nervous system plays a role in regulating human motor unit discharge rate during rapid contractions. Our findings support the viewpoint that serotonergic effects in the central nervous system are fast and are most prominent during contractions that are characterized by high motor unit discharge rates and large amounts of torque development.

Review article: current and future treatment approaches for pain in IBS.

Abdominal pain is a core symptom of IBS and a primary driver of care seeking. Visceral hypersensitivity is a key pathophysiological mechanism and therapeutic target for pain in IBS, with components of peripheral and central sensitisation and psychological factors. To review current and future treatment approaches specifically for the pain component of IBS. Pubmed search terms included combinations of irritable bowel, pain, visceral hypersensitivity, novel, new, emerging, future and advances. Established non-pharmacological treatments for IBS pain include the low FODMAP diet, probiotics and psychological interventions, especially hypnotherapy. Tricyclics remain the best evidenced pharmacological approach with GCC agonists, tenapanor, lubiprostone, eluxadoline and 5HT3 antagonists second line according to patient characteristics and availability. Less well-evidenced current options include anti-spasmodics, peppermint oil, SSRIs, SNRIs, alpha 2 delta ligands, melatonin and histamine antagonists. Patients are vulnerable to iatrogenesis and harmful approaches to be avoided include opioids and unwarranted surgical interventions. For severe pain, the concept of augmentation with combined gut-brain neuromodulators and psychotherapy in a multi-disciplinary setting is considered. A plethora of molecular targets and ligands are emerging from pre-clinical studies, together with early clinical evidence for a range of pharmacological, dietary, neurostimulation and novel psychological treatment delivery methods which are reviewed. The history of such emerging approaches, however, merits both caution and optimism in equal measure. Despite good in-roads and emerging options, the management of abdominal pain remains one of the biggest challenges and research priorities for patients with IBS.

5-hydroxytryptamine in migraine: The puzzling role of ionotropic 5-HT3 receptor in the context of established therapeutic effect of metabotropic 5-HT1 subtypes.

5-hydroxytryptamine (5-HT; serotonin) is traditionally considered as a key mediator implicated in migraine. Multiple 5-HT receptor subtypes contribute to a variety of region-specific functional effects. The raphé nuclei control nociceptive inputs by releasing 5-HT in the brainstem, whereas dural mast cells provide the humoral source of 5-HT in the meninges. Triptans (5-HT1B/D agonists) and ditans (5-HT1F agonists) are the best established 5-HT anti-migraine agents. However, activation of meningeal afferents via ionotropic 5-HT3 receptors results in long-lasting excitatory drive suggesting a pro-nociceptive role for these receptors in migraine. Nevertheless, clinical data do not clearly support the applicability of currently available 5-HT3 antagonists to migraine treatment. The reasons for this might be the presence of 5-HT3 receptors on inhibitory interneurons dampening the excitatory drive, a lack of 5-HT3 A-E subunit-selective antagonists and gender/age-dependent effects. This review is focusing on the controversial role of 5-HT3 receptors in migraine pathology and related pharmacological perspectives of 5-HT ligands. LINKED ARTICLES: This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Influence of CYP2D6 metabolizer status on ondansetron efficacy in pediatric patients undergoing hematopoietic stem cell transplantation: A case series.

Chemotherapy‐induced nausea and vomiting (CINV) is commonly experienced by patients receiving antineoplastic agents prior to hemopoietic stem cell transplant (HSCT). Ondansetron, a 5‐HT3 antagonist metabolized by CYP2D6, is an antiemetic prescribed to treat short‐term CINV, but some patients still experience uncontrolled nausea and vomiting while taking ondansetron. Adult CYP2D6 ultrarapid metabolizers (UMs) are at higher risk for CINV due to rapid ondansetron clearance, but similar studies have not been performed in pediatric patients. We performed a retrospective chart review of 128 pediatric HSCT recipients who received ondansetron for CINV prevention and had CYP2D6 genotyping for 20 alleles and duplication detection. The number of emetic episodes for each patient was collected from the start of chemotherapy through 7 days after HSCT. The average age of the cohort was 6.6 years (range: 0.2–16.7) and included three UMs, 72 normal metabolizers, 47 intermediate metabolizers, and six poor metabolizers. Because UMs are the population at risk for inefficacy, we describe the course of treatment for these three patients, as well as the factors influencing emesis: chemotherapy emetogenicity, diagnosis, and duration of ondansetron administration. The cases described support guidelines recommending non‐CYP2D6 metabolized antiemetics (e.g., granisetron) when a patient is a known CYP2D6 UM, but pediatric studies with a larger sample of CYP2D6 UMs are needed to validate our findings.

Serotonin 5-HT4 receptors play a critical role in the action of fenfluramine to block seizure-induced sudden death in a mouse model of SUDEP

RationaleOur previous study showed that the recently approved anticonvulsant drug, fenfluramine, which enhances the release of serotonin (5-hydroxytryptamine, 5-HT) in the brain, prevents seizure-induced respiratory arrest (S-IRA) in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP). The present study examined the role of 5-HT receptor subtypes in mediating the effect of this agent by combined administration of fenfluramine with selective 5-HT receptor antagonists prior to seizure in DBA/1 mice. MethodsFenfluramine (15 mg/kg, i.p.) was administered to primed DBA/1 mice, and audiogenic seizure (Sz) was induced 16 h later. Thirty min prior to Sz induction a selective antagonist acting on 5-HT1A, 5-HT2, 5-HT3 5-HT4, 5-HT5A, 5-HT6 or 5-HT7 receptors at a sub-toxic dose was administered, and changes in seizure-induced behaviors were evaluated. Follow-up studies examined the effect of administration of a 5-HT4 receptor agonist, BIMU 8, as well as the effect of co-administration of ineffective doses of fenfluramine and BIMU-8 on Sz behaviors. ResultsThe 5-HT4 antagonist (GR125487) was the only 5-HT receptor antagonist that was able to reverse the action of fenfluramine to block Sz and S-IRA. Treatment with the 5-HT4 receptor agonist (BIMU-8), or co-administration of ineffective doses of BIMU-8 and fenfluramine significantly reduced the incidence of S-IRA and tonic Sz in DBA/1 mice. The antagonists for 5-HT3, 5-HT5A 5-HT6, and 5-HT7 receptors did not significantly affect the action of fenfluramine. However, the 5-HT1A and the 5-HT2 antagonists enhanced the anticonvulsant effects of fenfluramine. ConclusionsThese findings suggest that the action of fenfluramine to prevent seizure-induced sudden death in DBA/1 mice is mediated primarily by activation of 5-HT4 receptors. These studies are the first to indicate the therapeutic potential of 5-HT4 receptor agonists either alone or in combination with fenfluramine for preventing SUDEP. Enhancement of the anticonvulsant effect of fenfluramine by 5-HT1A and 5-HT2 antagonists may involve presynaptic actions of these antagonists. Thus, the Sz and S-IRA blocking actions of fenfluramine involve complex interactions with several 5-HT receptor subtypes. These data also provide further support for the serotonin hypothesis of SUDEP.

Roles of 5-HT3 and 5-HT7 receptors in acute pruriceptive processing in mice

The roles of serotonin (5-HT) and/or noradrenaline in acute pruriceptive processing have been demonstrated using antidepressants, such as milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant; however, the involvement of 5-HT in acute pruriceptive processing has not yet been elucidated in detail. Scratching events induced by chloroquine (CQ) were attenuated by the administration of milnacipran or mirtazapine, and these effects were reversed by a treatment with ondansetron, a 5-HT3 antagonist, or SB26970, a 5-HT7 antagonist. CQ-induced scratching events were also ameliorated by the intrathecal administration of 5-HT, SR572227A and RS56812 (5-HT3 agonists), and LP211 and LP44 (5-HT7 agonists), indicating the modulation of CQ-induced scratching events by 5-HT and noradrenaline. By contrast, histamine-induced scratching events were not markedly affected by the administration of 5-HT and 5-HT7 agonists, whereas 5-HT3 agonists exerted attenuating effects. Similarly, they were not clearly reversed by the administration of the 5-HT7 antagonist, unlike a 5-HT3 antagonist. Therefore, 5-HT is involved in the attenuating effects of milnacipran and mirtazapine on CQ- and histamine-induced scratching events, and 5-HT3 and 5-HT7 receptors play different roles in pruriceptive processing induced by histamine or CQ.

Vasomotor effects of noradrenaline, 5-hydroxytryptamine, angiotensin II, bradykinin, histamine, and acetylcholine on the bat (Rhinolophus ferrumequinum) basilar artery

The responsiveness of the basilar artery to intrinsic vasoactive substances is species-specific and can be a unique characteristic. We investigated the responsiveness of the bat (Rhinolophus ferrumequinum) basilar artery to noradrenaline (NA), 5-hydroxytryptamine (5-HT), angiotensin (Ang) II, bradykinin (BK), histamine (His), and acetylcholine (ACh). NA, 5-HT, Ang II, and BK induced contraction, whereas His and ACh induced relaxation, in a concentration-dependent manner. The NA cumulative concentration–response curve was shifted to the right in parallel with phentolamine (an α-antagonist). However, propranolol, a β-antagonist, had no significant effect. The 5-HT curve was shifted to the right in parallel by ketanserin (a 5-HT2 antagonist) and methiothepin (a 5-HT1 and 5-HT2 antagonist). Losartan (an AT1 antagonist) shifted the Ang II curve to the right, whereas PD123319 (an AT2 antagonist) had no significant effect. L-NA, indomethacin, and des-Arg9-[Leu8]-BK (a B1 antagonist) did not significantly affect BK-induced contractions. HOE140 (a B2 antagonist) shifted the BK concentration–response curve to the right. The His curve was shifted to the right weakly by diphenhydramine (an H1 antagonist) and strongly by cimetidine (a H2 antagonist). ACh-induced relaxation was significantly inhibited by L-NA, atropine, and pFHHSiD (a muscarinic M3 antagonist), whereas pirenzepine and methoctramine (muscarinic M1 and M2 antagonists, respectively) showed no significant effects. At a resting vascular tone, L-NA-induced contraction and indomethacin induced relaxation. These results suggest that α-adrenergic, 5-HT1, 5-HT2, AT1, and B2 receptors might be important in arterial contraction, whereas M3 and H2 (>H1) receptors might modify these contractions, inducing relaxation.

A comparative clinical study of methylprednisolone with ondansetron versus methylprednisolone with ramosetron in preventing postoperative nausea and vomiting in patients undergoing middle ear surgeries

Background: Postoperative nausea and vomiting (PONV) is one of the most unpleasant complications of anaesthesia and is more common following middle ear surgeries. Ondansetron, a 5-HT3 (5-hydroxytryptamine type 3) receptor antagonist provides significant reduction in early PONV. The other 5-HT3 antagonist ramosetron, with long duration of action, has been found to be more effective than ondansetron in reducing the early as well as delayed PONV. The antiemetic effects of glucocorticoids (dexamethasone and methylprednisolone) are well documented. So, the present study was designed to compare the efficacy of the combination of intravenous methylprednisolone and ondansetron with combination of intravenous methylprednisolone and ramosterone in preventing postoperative nausea and vomiting in patients undergoing middle ear surgeries. Methods: Sixty patients in the age group of 18-60 years, with American Society of Anaesthesiologists (ASA) physical status classification I or II, undergoing middle ear surgery were randomly allocated to receive a combination of methylprednisolone 40 mg (given at the beginning of surgery) and ondansetron 4 mg (given near the end of surgery) (group MO, n=30) or combination of intravenous methylprednisolone 40 mg and ramosetron 0.3 mg (near the end of surgery) (group R, n=30), by a computer-generated randomization table. Incidence of PONV in the both groups were studied and compared. Results: There was no significant difference in PONV between the groups in the first 2 h after the surgery. Between 2 and 24 h, the incidence of nausea was significantly lower in the methylprednisolone and ondansetron group compared to the methylprednisolone and ramosetron group (P=0.01). Between 24 and 48 h, there was no difference between the two groups with respect to incidence of nausea and vomiting. Conclusion: The combination of methylprednisolone and ondansetron is superior to combination of methylprednisolone and ramosetron for prevention of PONV after middle ear surgery especially in treatment of early PONV. Therefore, we recommend combination of methylprednisolone and ondansetron for prophylaxis for PONV in middle ear surgeries.

Bvgp: A Novel Protocol for Hodgkin's with Excellent Response, Minimal Acute Toxicities and Reduced Risk of Late Effects

Pediatric and Young Adult Hodgkin lymphoma (HL) has a five-year survival rate over 90%. The downside is use of chemotherapy with a lifetime risk of cardiac deaths, second malignancies, pulmonary disease and infertility. Because of effective salvage therapy, ultimate outcomes may be improved by using effective but less toxic initial therapy. To this end, we have piloted a regimen in low and intermediate risk HL using agents not known to be associated with significant late effects. The BVG regimen {bortezomib 1.3 mg/m2 IV day 1,4,8,11; vinorelbine (25 mg/m2 IV day 1,8); gemcitabine (1000 mg/m2 IV day 1,8) every 21 days} was derived from BIGEV [Ding 2009] with elimination of ifosfamide, etoposide and prednisone. Initial use was to consolidate 3 patients after ABVE-PC. Subsequently we treated 5 newly diagnosed patients with non-bulk stage IIA (n=4) or IIB (n=1) HD. Two received BVG and 3 received BVGP with the addition of prednisone (20 mg/m2/dose PO BID x 11 days). Nausea was mild and controlled with 5HT3 antagonists and scopolamine patch. Pegfilgrastim was not necessary due the high absolute neutrophil count nadir (median 1.16 & minimum 0.56 x 109/L). There were no episodes of febrile neutropenia, infections or need for transfusions. There were no significant abnormalities in electrolytes, renal or liver function tests. No patients had any hair loss. One patient developed sensory neuropathy, after dose 8 of bortezomib, that responded to gabapentin and a switch to subcutaneous administration. Newly diagnosed patients were all PET negative after 1 or 2 cycles and remained PET negative at the end of four cycles of therapy. Status of the five newly diagnosed patients ages 10 to 18 is: one is still on therapy; three in remission at 158, 312, 1015 days; one relapsed at 861 days in previous disease sites. This retrospective chart review was approved by Children's Minnesota IRB. For each patient an in depth discussion was held on the benefits and risks of BVGP vs. standard therapy. The chief barrier to use of the protocol was insurance coverage for bortezomib in patients under the age of 18. We hope this abstract will provide early evidence to allow expansion of this pilot experience leading to a randomized trial comparing BVGP with current chemotherapy for low and intermediate Young Adult and Pediatric HL. DisclosuresNo relevant conflicts of interest to declare.

English

BACKGROUND The incidence of pain on propofol injection varies between 28 – 90 % during induction and may be severe. Ramosetron has been proved efficacious in reducing propofol pain in adults but not in children, therefore we conducted this double blinded randomized controlled study to determine the effectiveness of ramosetron in attenuating propofol induced pain in children. The purpose of this study was to compare the effectiveness of injection ramosetron, a 5HT3 antagonist and lidocaine, the commonest drug for attenuation of pain caused by injection propofol. METHODS This is a randomised double-blinded study. Eighty children of American Society of Anaesthesiologist (ASA) grade I - II, aged 4 - 14 years, undergoing elective surgical procedures under general anaesthesia were randomly assigned to two groups of 40 each. Group PR received 6 µg/kg of ramosetron and Group PL received 0.2 mg/kg of 2 % lidocaine. After injection of study drug, occlusion of venous drainage was done manually by a trained assistant at mid-arm for 60 seconds. After releasing manual occlusion Injection propofol (1 %) 2 mg/kg was administered slowly over a period of 5 seconds. A four point scale was used to assess the severity of pain. The results were analysed by using unpaired student’s t - test and chi-square test/Fisher’s exact test. P value of &lt; 0.05 was considered statistically significant. RESULTS The demographic characteristics were comparable in both groups. The incidence of no pain in Group PR and Group PL was 60 % (N = 24) and 65 % (N = 26) respectively which was comparable. The incidence of mild, moderate and severe pain was comparable in both groups. The overall incidence of propofol injection pain in group PL and group PR was 35 % and 40 % respectively (P = 0.862). CONCLUSIONS Intravenous ramosetron at a dose of 6 µg/kg can effectively attenuate the propofol induced pain comparable to 0.2 mg/kg of lidocaine in children. KEYWORDS Children, Lidocaine, Propofol Induced Pain, Ramosetron

In Vitro Inhibition of Renal OCT2 and MATE1 Secretion by Antiemetic Drugs.

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT3 antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT3 antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP+ was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP+ uptake by OCT2 listed in order of potency was palonosetron (IC50: 2.6 μM) > ondansetron > granisetron > tropisetron > dolasetron (IC50: 85.4 μM) and the inhibition of ASP+ uptake by MATE1 in order of potency was ondansetron (IC50: 0.1 μM) > palonosetron = tropisetron > granisetron > dolasetron (IC50: 27.4 μM). Ondansetron (0.5–20 μM) inhibited the basolateral-to-apical transcellular transport of ASP+ up to 64%. Higher concentrations (10 and 20 μM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP+. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 μM caused significant intracellular accumulation of ASP+. Taken together, these data suggest that 5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.

Comparative study of ondansetron, granisetron and granisetron with dexamethasone for prevention of postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic cholecystectomy

An assortment of drugs are being used for managing postoperative nausea and vomiting after laparoscopic surgeries. Combination anti-emetic therapy using 5HT3 antagonists with dexamethasone as an adjunct is being tried owing to its improved efficacy for prevention or treatment of PONV. This was a prospective, randomized, double blind, comparative study conducted on 150 patients aged between 18 to 65 years scheduled for laparoscopic cholecystectomy. Group O received 0.1 mg/Kg IV ondansetron upto a maximum dose of 8 mg, Group G received 0.04 mg/kg IV granisetron upto a maximum dose of 3mg, Group G+D will receive 0.04mg/kg IV granisetron and 8mg Dexamethasone. The three groups were comparable in terms of demographic data. Our results showed that the patients who had received combination of granisetron and Dexamethasone showed a better complete response as compared to patients who received ondansetron and patients who received granisetron alone. This was seen in all three time periods of 2-6 hours, 6-12 hours and 12-24 hours postoperatively with a p value less than 0.001 making it statistically significant. : Combination therapy with granisetron and dexamethasone IV used as prophylactic antiemetic is better than granisetron or ondansetron given IV alone. IV granisetron and dexamethasone combination has fewer side effects compared to ondansetron or granisetron. Need for the rescue antiemetic was least in the patients receiving granisetron and dexamethasone combination as compared to in patient receiving ondansetron and granisetron alone.

In vivo blockade of 5HT3 receptors in the infralimbic medial prefrontal cortex enhances fear extinction in a rat model of PTSD.

Objective(s):Treatments that reverse deficits in fear extinction are promising for the management of post-traumatic stress disorder (PTSD). 5-Hydroxytryptamine type 3 (5-HT3) receptor is involved involved in the extinction of fear memories. The present work aims to investigate the role of 5HT3 receptors in the infralimbic part of the medial prefrontal cortex (IL-mPFC) in extinction of conditioned fear in the single prolonged stress (SPS) model of PTSD in rats.Materials and Methods: The effect of SPS administration was evaluated on the freezing behavior in contextual and cued fear conditioning models. After the behavioral tests, levels of 5HT3 transcription in IL-mPFC were also measured in the same animals using the real-time RT-PCR method. To evaluate the possible role of local 5HT3 receptors on fear extinction, conditioned freezing was evaluated in another cohort of animals that received local microinjections of ondansetron (a 5HT3 antagonist) and ondansetron plus a 5HT3 agonist (SR 57227A) after extinction sessions. Results:Our findings showed that exposure to SPS increased the freezing response in both contextual and cued fear models. We also found that SPS is associated with increased expression of 5HT3 receptors in the IL-mPFC region. Ondansetron enhanced the fear of extinction in these animals and the enhancement was blocked by the 5HT3 agonist, SR 57227A.Conclusion:It seems that up-regulation of 5HT3 receptors in IL-mPFC is an important factor in the neurobiology of PTSD and blockade of these receptors could be considered a potential treatment for this condition.

Vascular sympathetic neurotransmission and its serotonergic regulation are modified by chronic fluoxetine treatment

Given the interconnection between depressive and cardiovascular disorders, we investigated whether antidepressant treatment (fluoxetine) modifies the serotonergic influence on rat vascular noradrenergic outflow. Twelve-week-old male Wistar rats received fluoxetine treatment (10 mg/kg/day; p.o.) for 14 days; then, they were pithed and prepared for sympathetic stimulation. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1, 0.5, 1, and 5 Hz) or i.v. noradrenaline (NA; 0.01, 0.05, 0.1, and 0.5 μg/kg). In fluoxetine-treated group, the electrical-induced vasoconstrictions were lower compared to non-treated rats. Intravenous infusion of 5-HT (10 μg/kg/min) inhibited the sympathetically-induced vasoconstrictions. Only 5-CT, 8-OH-DPAT and L-694,247 (5-HT1/7, 5-HT1A and 5-HT1D agonists, respectively) mimicked 5-HT-induced inhibition, while α-methyl-5-HT (5-HT2 agonist) increased the vasopressor responses. The inhibitory effect of 5-HT was: a) no modified by SB269970 (5-HT7 antagonist); b) abolished by WAY-100,635 (5-HT1A antagonist) plus LY310762 (5-HT1D antagonist); and c) potentiated by ritanserin (5-HT2A receptor antagonist). The vasoconstrictions induced by exogenous NA were not modified by 5-CT but were increased by α-methyl-5-HT. Our results suggest that fluoxetine treatment decreases NA release at vascular level and changes 5-HT modulation on rat vascular noradrenergic neurotransmission, inducing sympatho-inhibition via prejunctional 5-HT1A/1D receptors, and sympatho-potentiation via pre and/or postjunctional 5-HT2A receptors.

Interventions for preventing nausea and vomiting in women undergoing regional anaesthesia for caesarean section.

Interventions for preventing nausea and vomiting in women undergoing regional anaesthesia for caesarean section.

Molecular signaling pathways underlying schizophrenia

The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. We used Ingenuity Pathway Analysis to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA–related pathway, compared to those time periods when the same individual did not use the drug. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA-related purine, oxidative stress, and glutamatergic signaling pathways are among primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists – which have shown beneficial effects in an experimental Adcyap1−/− mouse model for schizophrenia – could be potential treatments even before the full manifestation of illness involving dopaminergic abnormalities.

Prophylactic ondansetron eight milligrams versus four milligrams against post spinal anaesthesia shivering

Background: Shivering is one of the commonly encountered adverse affect after spinal anaesthesia. Shivering can be very discomforting to the patient and hampers operative maneuvering. Pharmacological therapies have been studied for control and management of shivering. One such drug is ondansetron, a 5-HT3 antagonist. Aim of current study is to evaluate the efficacy of prophylactic administration of ondansetron 8 mg vs. 4 mg for prevention of shivering.Methods: A prospective, randomized, and double blind study was conducted on 100 patients, from either gender, aged 20-60 years, of the American society of anesthesiologists grade I or II, scheduled for various surgeries under spinal anesthesia. The patients were randomly divided into two groups of 50 each to receive either ondansetron 8 mg (group E) or ondansetron 4 mg, (group F) as slow intravenous infusion prior to spinal anesthesia. The primary end point were intraoperative shivering and secondary outcomes included hypotension, adverse reaction, cardiac dysrhythmia’s.Results: A total of 10 patients in group E (20%) and 20 (40%) patients in group F experienced shivering (p=0.029). Incidence of nausea was similar in both groups, total of 8 (16%) patients in group E and 5 (10%) in group B had hypotension (p=0.27). 1 (2%) patient in group E experienced bradycardia.Conclusions: Prophylactic administration of ondansetron 8 mg has better efficacy in prevention of spinal anaesthesia induced shivering with minimal side effects as compared to 4 mg dosage.

Radiation-induced nausea and vomiting: a clinical audit of prophylactic antiemetic use

AbstractIntroduction:Radiation-induced nausea and vomiting (RINV) is a common side effect of single fraction palliative radiotherapy. Patients experiencing RINV have significantly reduced quality of life and a prescription of prophylactic antiemetics, principally 5-HT3 antagonists, is recommended. There is a growing body of evidence relating to indications for this, but as yet there are no national guidelines.Methods:A retrospective audit aimed to determine the extent to which patients at high and moderate emetogenic risk receiving single fraction radiotherapy were prescribed prophylactic emetic medication in line with the current evidence base.Results:A total of 60 patients were included in the audit; of these patients, 50 were consented for the risk of nausea and/or vomiting. Prophylactic antiemetics were only prescribed to 28 (46·7%) of all audited patients. Out of the 50 patients who provided informed consent, only 24 (48%) were prescribed an antiemetic prior to their treatment.Conclusion:Antiemetic prescribing for single fraction patients at moderate to high emetogenic risk at a large regional centre is underutilised in relation to published evidence. Amended guidance and further audits are recommended to ensure that this patient group is best supported.