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Objectives: This study aimed to evaluate the effects of prucalopride, a prokinetic agent that acts as a potent serotonin agonist of 5-HT4 receptors, on gastric emptying and small bowel transit and assess its impact on the absorption of metronidazole. Methods: Six healthy volunteers, three men and three women, aged between 20 and 27 years, with a body weight ranging from 50 to 80 kg, were enrolled in this study. The pharmacokinetics and gastrointestinal transit parameters were evaluated simultaneously through pharmacomagnetography assessment, combining alternating current biosusceptometry and blood analysis. Key findings: The results showed that prucalopride enhances gastric emptying and small bowel transit when administered orally and significantly impacts the rate of metronidazole absorption, leading to enhanced bioavailability and rapid therapeutic response. Conclusion: Pharmacomagnetography assessment allows simultaneous tracking of transit by images and is a valuable method for analysing drug absorption using multiple instruments. [ABSTRACT FROM AUTHOR]

Background Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While ulotaront demonstrated efficacy in a recent Phase II trial, a corresponding study studies of ralmitaront failed to show efficacy as a monotherapy or as an adjunct to atypical antipsychotics. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT1AR). However, little is known about ralmitaront. Methods We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and dopamine D2 using luciferase complementation-based G protein recruitment, cAMP accumulation, and G protein–coupled inward rectifier potassium channel activation assays. Results Ralmitaront showed lower efficacy at TAAR1 in G protein recruitment, cAMP accumulation, and GIRK activation assays. Moreover, ralmitaront lacked detectable activity at 5-HT1AR and dopamine D2. Conclusions Compared with ulotaront, ralmitaront shows lower efficacy and slower kinetics at TAAR1 and lacks efficacy at 5-HT1AR. These data may be relevant to understanding differences in clinical profiles of these 2 compounds. [ABSTRACT FROM AUTHOR]

This study aims to assess the therapeutic potentials of novel serotonergic compounds in treating alcohol use disorders by investigating the effects of SB242084 and buspirone on intermittent and continuous alcohol consumption in male and female mice. Adult male and female C57BL/6J mice were given two-bottle choice to 20% ethanol and water on an intermittent or continuous availability schedule. Drug testing consisted of intraperitoneal injections of 0.3, 1, 3 mg/kg SB242084 or 1, 3, 10 mg/kg buspirone, and subsequent alcohol and water consumption were measured. To monitor the drug effects on anxiety-like and locomotor behavior, the highest dose of each compound was administered before free activity in an open field. SB242084 dose-dependently attenuated alcohol drinking for intermittent alcohol drinking in male mice but did not significantly alter alcohol drinking in mice given continuous access. Two-hour and four-hour female drinking behavior was unaffected by SB242084. In comparison, buspirone not only suppressed intermittent and continuous alcohol drinking in both males and females but also reduced distance traveled in the open field test. Observed differences in responses to SB242084 between drinking groups may imply differing neural mechanisms between episodic and continuous drinking driven by serotonin. Reductions in drinking after buspirone treatment may be related to non-specific properties. These findings suggest the therapeutic potential of compounds blocking the 5-HT2C receptor for alcohol use disorders. [ABSTRACT FROM AUTHOR]

The article examines that addressing intrathecal morphine (ITM) analgesic outcomes after total joint replacement. Topics include focuses on avoiding ITM until recently because of high opioid-induced nausea and vomiting (OINV) rates in Veterans' Hospital with its use as there is no guidance from recent or preceding antiemetic consensus guidelines addressing antiemetic/antipruritic prophylaxis (AEPPx) for the specific use of ITM.

NBOMes are N -benzylmethoxy derivatives of the 2C family compounds with N -2-methoxybenzyl moiety substituted by the methoxy group at the 2- and 5-position and the halogen group at the 4-position of the phenyl ring. These substances are a new class of potent serotonin 5-HT2A receptor agonist hallucinogens with potential harmful effects. The substitution with halogen of the already psychoactive phenethylamine produces a derivative (2C-I) with increased hallucinogenic effects. This class of hallucinogens has chemical structures very similar to natural hallucinogenic alkaloid mescaline and these are sold mainly via internet as a 'legal' alternative to other hallucinogenic drug-lysergic acid diethylamide (LSD). 25I-NBOMe is the first synthesized and one of the most common compound from NBOMes. Knowledge of pharmacological properties of 25I-NBOMe is very limited so far. There are only a few in vivo and in vitro so far published studies. The behavioral experiments are mainly related with the hallucinogenic effect of 25I-NBOMe while the in vitro studies concerning mainly the affinity for 5-HT2A receptors. The 25I-NBOMe Critical Review 2016 reported 51 non-fatal intoxications and 21 deaths associated with 25I-NBOMe across Europe. Case reports describe various toxic effects of 25I-NBOMe usage including tachycardia, hypertension, hallucinations, rhabdomyolysis, acute kidney injury and death. The growing number of fatal and non-fatal intoxication cases indicates that 25I-NBOMe should be considered as a serious danger to public health. This review aims to present the current state of knowledge on pharmacological effects and chemical properties of 25I-NBOMe and to describe reported clinical cases and analytical methods available for identification of this agent in biological material. [ABSTRACT FROM AUTHOR]

Background Several cases of autism spectrum disorder have been linked to mutations in the SHANK3 gene. Haploinsufficiency of the SHANK3 gene contributes to Phelan-McDermid syndrome, which often presents an autism spectrum disorder phenotype along with moderate to severe intellectual disability. A SHANK3 gene deletion in mice results in elevated excitation of cortical pyramidal neurons that alters signaling to other brain areas. Serotonin 1A receptors are highly expressed on layer 2 cortical neurons and are known to have inhibitory actions. Serotonin 1A receptor agonist treatment in autistic cases with SHANK3 mutations and possibly other cases may restore excitatory and inhibitory balance that attenuates core symptoms. Methods A series of experiments investigated the effects of acute tandospirone treatment on spatial learning and self-grooming, subchronic treatment of tandospirone on self-grooming behavior, and the effect of tandospirone infusion into the anterior cingulate on self-grooming behavior. Results Only male Shank3B+/− mice exhibited a spatial learning deficit and elevated self-grooming. Acute i.p. injection of tandospirone, 0.01 and 0.06 mg/kg in male Shank3B+/− mice, attenuated a spatial acquisition deficit by improving sensitivity to positive reinforcement and reduced elevated self-grooming behavior. Repeated tandospirone (0.06 mg/kg) treatment attenuated elevated self-grooming behavior in male Shank3B+/− mice. Tandospirone injected into the anterior cingulate/premotor area reduced self-grooming behavior in male Shank3B+/− mice. Conclusions These results suggest that stimulation of cortical serotonin 1A receptors may reduce repetitive behaviors and cognitive impairments as observed in autism spectrum disorder, possibly by attenuating an excitation/inhibition imbalance. Further, tandospirone may serve as a treatment in autism spectrum disorder and other disorders associated with SHANK3 mutations. [ABSTRACT FROM AUTHOR]

Introduction: Hypoactive sexual desire disorder (HSDD) is a subtype of persistent low sexual desire (LSD) associated with marked distress with no known cause. LSD/HSDD in men frequently occurs with other sexual dysfunctions. Flibanserin is a centrally-acting multifunctional serotonin agonist and antagonist approved in the United States (US) to treat acquired, generalized HSDD in certain premenopausal women. Based on its proposed mechanism of action, flibanserin is prescribed off-label to treat sexual dysfunction in men. Objective: Given the lack of safety data in men, this study was conducted to capture insights from physicians on the safety of flibanserin in their male patients. Methods: Dispensing data from two specialty pharmacies were used to identify physicians with experience treating male patients with flibanserin (physicians). Physicians were invited via email to participate in a brief 10-minute interview. All interviews were conducted using a standardized questionnaire containing 6 questions. The questionnaire captured general safety information and types of sexual dysfunction treated with flibanserin. Physicians were instructed not to share any patient-specific information. Interviews were conducted with each physician individually via video conference. Responses to questions were documented verbatim and summarized descriptively. Results: Six physicians from different sexual health clinics in the US were invited to participate in the study, 5 of which accepted the invitation and completed the interview. All physicians prescribed flibanserin to treat LSD/HSDD. Other sexual dysfunctions treated with flibanserin included delayed orgasm (n=4), post-orgasmic illness syndrome (n=2), antidepressant (SSRI)-induced sexual dysfunction (n=2), and post-finasteride-associated sexual dysfunction (n=1). Physicians reported their male patients experienced similar but less frequent or severe side effects than reported in premenopausal women during the HSDD clinical trials, including somnolence/sleepiness (n=3), insomnia (n=2), fatigue (n=1) and dry mouth (n=1). The most frequent physician-cited side effects leading to flibanserin discontinuation were insomnia (n=2), somnolence (n=1), fatigue (n=1), and dizziness (n=1). Lack of effect was another common reason (n=3) for treatment discontinuation. No physicians reported any unanticipated flibanserin-related side effects in their male patients. Although interviews included no efficacy-related questions, physicians provided insight into flibanserin response rates they observed in their male patients when responding to safety questions, including positive response rates in LSD/HSDD and other sexual dysfunctions such as delayed orgasm. Conclusions: Feedback from the participating sexual medicine physicians suggests that flibanserin may have a similar safety profile in men as observed in premenopausal women. It is reassuring that physicians reported no unanticipated or severe safety concerns in their male patients. In addition to LSD/HSDD, physicians reported positive response rates with flibanserin in their male patients treated for other sexual dysfunctions. The generalizability of these findings to other practice settings is limited. However, these safety findings and reports of positive response rates in male patients with LSD/HSDD and other sexual dysfunctions suggest that more research on the use of flibanserin in men with sexual dysfunctions is warranted. Disclosure: Yes, this is sponsored by industry/sponsor: Sprout Pharmaceuticals, Inc. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Sprout Pharmaceuticals, Inc. [ABSTRACT FROM AUTHOR]

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study. [ABSTRACT FROM AUTHOR]

Background Most previous studies have focused on the effects of social defeat in male juvenile individuals. Whether chronic social defeat stress in adulthood affects female emotion and the underlying mechanisms remains unclear. Methods Using highly aggressive adult female mandarin voles (Microtus mandarinus), the present study aimed to determine the effects of chronic social defeat stress on anxiety- and depression-like behaviors in adult female rodents and investigate the neurobiological mechanisms underlying these effects. Results Exposure of adult female voles to social defeat stress for 14 days reduced the time spent in the central area of the open field test and in the open arms of the elevated plus maze and lengthened the immobility time in the tail suspension and forced swimming tests, indicating increased anxiety- and depression-like behaviors. Meanwhile, defeated voles exhibited increased neural activity in the prelimbic cortex of the medial prefrontal cortex. Furthermore, chronic social defeat stress reduced serotonin projections and levels of serotonin 1A receptors in the medial prefrontal cortex-prelimbic cortex. Intra-prelimbic cortex microinjections of the serotonin 1A receptor agonist 8-OH-DPAT reversed the alterations in emotional behaviors, whereas injections of the serotonin 1A receptor antagonist WAY-100635 into the prelimbic cortex of control voles increased the levels of anxiety- and depression-like behaviors. Conclusions Taken together, our results demonstrated that chronic social defeat stress increased anxiety- and depression-like behaviors in adult female voles, and these effects were mediated by the action of serotonin on the serotonin 1A receptors in the prelimbic cortex. The serotonin system may be a promising target to treat emotional disorders induced by chronic social defeat stress. [ABSTRACT FROM AUTHOR]

Background: Comprehensive description of ketamine's molecular binding profile becomes increasingly pressing as use in real-life patient cohorts widens. Animal studies attribute a significant role in the substance's antidepressant effects to the serotonergic system. The serotonin transporter is a highly relevant target in this context, because it is central to depressive pathophysiology and treatment. This is, to our knowledge, the first study investigating ketamine's serotonin transporter binding in vivo in humans. Methods: Twelve healthy subjects were assessed twice using [11C]DASB positron emission tomography. A total of 0.50 mg/kg bodyweight ketamine was administered once i.v. prior to the second positron emission tomography scan. Ketamine plasma levels were determined during positron emission tomography. Serotonin transporter nondisplaceable binding potential was computed using a reference region model, and occupancy was calculated for 4 serotonin transporter-rich regions (caudate, putamen, thalamus, midbrain) and a whole-brain region of interest. Results: After administration of the routine antidepressant dose, ketamine showed <10% occupancy of the serotonin transporter, which is within the test-retest variability of [11C]DASB. A positive correlation between ketamine plasma levels and occupancy was shown. Conclusions: Measurable occupancy of the serotonin transporter was not detectable after administration of an antidepressant dose of ketamine. This might suggest that ketamine binding of the serotonin transporter is unlikely to be a primary antidepressant mechanism at routine antidepressant doses, as substances that facilitate antidepressant effects via serotonin transporter binding (e.g., selective serotonin reuptake inhibitors) show 70% to 80% occupancy. Administration of high-dose ketamine is widening. Based on the positive relationship we find between ketamine plasma levels and occupancy, there is a need for investigation of ketamine's serotonin transporter binding at higher doses. [ABSTRACT FROM AUTHOR]

Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain. Methods: Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region. Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex. Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain. [ABSTRACT FROM AUTHOR]

Serotonin syndrome (SS) is a potentially life-threatening adverse drug reaction that may occur in patients treated with serotonin agonist medications. Medications responsible for serotonin syndrome include commonly prescribed antidepressants, anxiolytics, analgesics, and antiemetics. Veterans with post-traumatic stress disorder (PTSD) are at risk for polypharmacy with serotoninergic medications, given their psychological comorbidities and service-related musculoskeletal injuries. The perioperative period is a particularly vulnerable time owing to the use of high-dose anxiolytics and antiemetics frequently administered in this period, and places PTSD patients at higher risk of SS. Herein, we present the first case of SS in a young veteran with combat-related PTSD following an uncomplicated L5-S1 revision discectomy that highlights the unique set of clinical challenges and dilemmas faced when treating SS in a patient with severe postsurgical pain. As we are likely to encounter increasing numbers of veterans treated for PTSD who require multiple surgical procedures to treat their service-related injuries, health care providers need to be familiar with prevention, recognition, and the clinical challenges in the management of SS in the postoperative period. [ABSTRACT FROM AUTHOR]

The present research project involves development and validation of a stability-indicating HPTLC method for the estimation of naratriptan-HCI in their pharmaceutical dosage forms and its content uniformity testing. Naratriptan-HCI was subjected to alkaline, acidic, oxidative, neutral, thermal (dry heat) and photo-degradation conditions. The chromatographic separation was carried out using a precoated silica gel G 60 F254 TLC plate as the stationary phase and dichloromethane-toluene-methanol-triethylamine (4:4:2:1, v/v/v/v) as the mobile phase. The spots of NRT-HCI and its degradation products were detected at 290 nm. The Rf value of NRT-HCI was found to be 0.60 ± 0.02. The linearity was obtained in the range of 100-500 ng/spot. The limit of detection and limit of quantitation were found to be 6.07 ng/spot and 18.41 ng/spot, respectively. The percentage recovery was found in the range of 98.87-99.55%. NRT-HCI was degraded under acidic, alkaline and oxidative conditions while stable under photolytic, neutral and dry heat conditions. The developed method was applied for estimation of naratriptan-HCI in marketed formulations and its content uniformity testing. [ABSTRACT FROM AUTHOR]

The article presents a study which aimed to evaluate the efficacy and safety of noninvasive stimulation of the vagal nerve (NVNS) in a population of patients with chronic migraine (CM) and medication overuse headache (MOH) during and after in-patient withdrawal period. The study suggests that nVNS can represent an innovative and interesting therapeutic option for patients having CM-MOH that might help avoid excessive drug consumption and associated toxicities.

Introduction: Flibanserin, is a postsynaptic agonist of serotonin receptor 1A and an antagonist of serotonin receptor 2A, has been shown to increase sexual desire and reduce distress in women with hypoactive sexual desire disorder (HSDD). Aim: We carried out a systematic review and meta-analysis to assess the efficacy and safety of the drug in women with HSDD. Methods: A literature review was performed to identify all published randomized double-blind, placebo-controlled trials of flibanserin for the treatment of HSDD. The search included the following databases: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. Main Outcome Measures. Four publications involving a total of 3,414 patients were used in the analysis, including four randomized controlled trials that compared flibanserin with placebo. Results: For the comparison of flibanserin with placebo, primary efficacy endpoints: satisfying sexual events (the standardized mean difference [SMD] = 0.59, 95% confidence interval [CI] = 0.37-0.80, P < 0.00001); sexual desire score (the SMD = 1.91, 95% CI = 0.21 to 3.60, P = 0.03) and Female Sexual Function Index (FSFI) desire domain score (the SMD = 0.32, 95% CI = 0.19-0.46, P < 0.00001) and key secondary efficacy endpoints: FSFI total score, Female Sexual Distress Scale-Revised (FSDS-R) total score, FSDS-R Item 13 score, Patient's Global Impression of Improvement score and Patient Benefit Evaluation indicated that flibanserin was more effective than the placebo. Safety assessments included the proportion of women who experienced an adverse event (odds ratio = 1.54, 95% CI = 1.34 to 1.76, P < 0.00001), nervous system disorders and fatigue indicated that flibanserin was well tolerated. Conclusions: This meta-analysis indicates that flibanserin to be an effective and safe treatment for HSDD in women. [ABSTRACT FROM AUTHOR]

Serotonin 2C receptor (5-HT2CR) agonists attenuate reinstatement of cocaine-seeking behavior. These receptors are found throughout the limbic system, including the basolateral amygdala (B1A), which is involved in forming associations between emotional stimuli and environmental cues, and the central amygdala (CeA), which is implicated in the expression of conditioned responding to emotional stimuli. This study investigated whether 5-HT2cRs in the amygdala are involved in cue and cocaine-primed reinstatement of cocaine-seeking behavior. Rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) which that was paired with light and tone cues, and then subsequently they underwent daily extinction training. Rats then received bilateral microinfusions of the 5-HT2cR agonist CP809101 (0.01-1.0µ(0.2µ1/side) into either the B1A or CeA prior to tests for cue or cocaine-primed (10 mg/kg, i.p.) reinstatement. Rats were also tested for CP809101 effects on anxiety-like behavior on the elevated plus-maze (EPM). Surprisingly, intra-BlA CP809101 had no effect on cue reinstatement, though it did increase anxiety-like behavior on the EPM. Intra-CeA infusions of CP809101 attenuated cocaine-primed reinstatement, an effect that was prevented with concurrent administration of the 5-HT2CR antagonist SB242084 (0.1µg/0.2µl/side). CP809101 had no effect on cue reinstatement or anxiety-like behavior on the EPM. These findings suggest that 5-HT2cRs in the B1A modulate anxiety, whereas those in the CeA modulate incentive motivational effects induced by cocaine priming injections. [ABSTRACT FROM AUTHOR]

Serotonin 2C receptors (5-HT2CR) are G-protein-coupled receptors with various actions, including involvement in drug addiction. 5-HT2CR undergoes mRNA editing, converting genomically encoded adenosine residues to inosines via adenosine deaminases acting on RNA (ADARs). Here we show that enhanced alcohol drinking behaviour in mice is associated with the degree of 5-HT2CR mRNA editing in the nucleus accumbens and dorsal raphe nuceus, brain regions important for reward and addiction. Following chronic alcohol vapour exposure, voluntary alcohol intake increased in C57BL/6J mice, but remained unchanged in C3H/HeJ and DBA/2J mice. 5-HT2CR mRNA editing frequency in both regions increased significantly in C57BL/6J mice, as did expressions of 5-HT2CR, ADAR1 and ADAR2, but not in other strains. Moreover, mice that exclusively express the unedited isoform (INI) of 5-HT2CR mRNA on a C57BL/6J background did not exhibit increased alcohol intake compared with wild-type mice. Our results indicate that alterations in 5-HT2CR mRNA editing underlie alcohol preference in mice. [ABSTRACT FROM PUBLISHER]

Flibanserin is a multifunctional serotonin agonist and antagonist for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD). Flibanserin is approved for use in premenopausal women in the US and in both premenopausal and postmenopausal women ≤60 years old in Canada. A post-hoc analysis of Female Sexual Function Index (FSFI) scores from pivotal trials in premenopausal women with HSDD indicated significant improvements in total and individual domain scores after treatment initiation with flibanserin compared to placebo. The purpose of this case report study is to examine the postmarketing database to determine whether improvements in other aspects of sexual function have also been reported by women who were prescribed flibanserin in real world use outside of clinical trials. A search was performed in the global safety database to identify postmarketing case reports from August 2015 to March 2021. "Therapeutic response unexpected" was the Medical Dictionary for Regulatory Affairs (MedDRA 23.1) preferred term used in this search strategy. Study results include only case reports with narratives containing verbatim terms relevant to the domains on the FSFI (arousal, lubrication, orgasm, pain, satisfaction), excluding desire as this is an expected response. Thirty-two postmarketing case reports, including 13 patient testimonials of "therapeutic response unexpected", were identified during this period. Of these 32 case reports, 12 (38%) contained terms related to unexpected improvements in sexual function. Among the 12 reports of improved sexual function, 10 (83%) included terms related to increases in frequency, intensity, or duration of orgasms, one of which also mentioned improvement in arousal. The remaining 2 cases included 1 report of improvement in lubrication and 1 report of improvement in pain. These postmarketing case reports are consistent with the post-hoc analyses of the data from the flibanserin clinical trials and provide further support that flibanserin therapy can lead to improvement in multiple aspects of sexual function in addition to sexual desire. Yes, this is sponsored by industry/sponsor: Sprout Pharmaceuticals Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Sprout Pharmaceuticals [ABSTRACT FROM AUTHOR]

Objectives The aim was to examine the biological activity of 5-methoxytryptamine derivatives at the 5-hydroxytryptamine (5-HT)4 receptor to explore the effect of substitution on the aliphatic amine of the 5-methoxyamine scaffold. Methods Three compounds were tested for affinity at the 5-HT4 receptor by radioligand binding and functional activity using guinea-pig ileum and human colon circular muscle preparations and also in the mouse whole gut transit test. Key findings The three compounds all had agonist properties at the 5-HT4 receptor but their efficacy differed in the different functional tests. Compound 3 had the highest affinity for the 5-HT4 receptor and was a full agonist at relaxing human colon circular muscle with efficacy closest to 5-HT. Compounds 1 and 2 were partial agonists in this assay with lower efficacies; compound 2 was a full agonist in the guinea-pig ileum assay whereas compound 3 was a partial agonist. Compounds 1 and 2 also showed activity in the mouse gut transit assay while compound 3 had no activity. Conclusions Of the compounds tested, compound 3 was the most promising 5-HT4 receptor agonist and the results highlight the value of using human tissue in functional tests when assessing compounds for potential activity. [ABSTRACT FROM AUTHOR]

Summary Background Serotonin (5-hydroxytryptamine, 5-HT) levels are increased by light exposure but the role and mechanism of 5-HT in the pigmentation of skin cells are unclear. Objectives To clarify the effect of 5-HT on melanogenesis and to determine the 5-HT receptor subtype involved. Methods B16F10, SK-MEL-2 and Melan-A cells were cultured in Dulbecco's modified Eagle's medium with low fetal bovine serum. The three cell lines were treated with various concentrations of 5-HT, and 5-HT receptor agonists and antagonists. The involvement of the 5-HT receptor 2A (5-HTR2A) was examined by gene silencing and use of 5-HTR2A antagonists. Results 5-HT and the 5-HTR2A agonist, DOI, increased melanogenesis in the three cell lines. These increased events were suppressed by 5-HTR2A antagonists or gene silencing of the HTR2A gene. Conclusions 5-HTR2A is involved in melanogenesis. These findings highlight the role of 5-HT and suggest new ways of controlling melanogenesis. [ABSTRACT FROM AUTHOR]

Purpose. The pharmacology, pharmacokinetics, and adverse effects of the selective serotonin (5-HT) agonist lorcaserin are reviewed, with an emphasis on efficacy and safety data from Phase III clinical trials. Summary. Lorcaserin is highly selective for a subtype of 5-HT receptors important in appetite regulation, with low affinity for other 5-HT-receptor subtypes whose activation is thought to underlie serious cardiovascular adverse effects; such effects have been seen with nonselective serotonergic agents for weight loss (e.g., fenfluramine). In two Phase III trials of lorcaserin, the cumulative proportion of patients who achieved weight loss of ≥5% over 12 months was about 47% with lorcaserin use versus 20-5% among placebo users (p < 0.0001 for both trials). Lorcaserin was generally well tolerated in the clinical trials to date; nausea and vomiting, headache, and dizziness were the most commonly reported adverse effects. In two of the three Phase III trials to date, lorcaserin use was not found to increase the risk of cardiac valvulopathy; however, in the other Phase III trial, which focused on patients with diabetes, lorcaserin use was associated with an increased rate of new valvulopathy. In a carcinogenicity evaluation involving laboratory rats, lorcaserin was linked to the development of various malignancies, a finding with uncertain implications for its potential future use in humans. Conclusion. Lorcaserin, a 5-HT2C agonist, has demonstrated efficacy in patients who are obese or are overweight with associated comorbidities. Phase III trials have found that more than 35% of patients lost greater than 5% of their baseline weight. The maker of lorcaserin has indicated it will continue to seek U.S. marketing approval of the drug for the indications of long-term weight loss and weight-loss maintenance in specific patient populations. [ABSTRACT FROM AUTHOR]

The novel antidepressant, agomelatine, behaves as an agonist at melatonergic receptors, and as an antagonist at edited, human serotonin2C(VSV) receptors [h5-HT2C(VSV)Rs]. However, its actions at constitutively active 5-HT2CRs have yet to be characterized, an issue addressed herein. At unedited h5-HT2C(INI)Rs expressed in HEK-293 cells, 5-HT enhanced [35S]GTPγS binding to Gαq, whereas the inverse agonists SB206,553 and S32006 inhibited binding and, by analogy to the neutral antagonist, SB242,084, agomelatine exerted no effect alone. Mirroring these observations, 5-HT stimulated, whereas SB206,553 and S32006 inhibited, [3H]inositol phosphate formation. Both the agonist actions of 5-HT and the inverse agonist actions of SB206,553 and S32006 were abolished by agomelatine and SB242,084. As demonstrated by bioluminescence resonance energy transfer, 5-HT enhanced, whereas SB206,553 and S32006 decreased, association of ‘h5-HT2C(INI)-Rluc-tagged’ receptors with yellow-fluorescence-protein-coupled β-arrestin2. These actions of 5-HT, SB206,553 and S32006 were prevented by agomelatine and SB242,084 were ineffective alone. As shown by ELISA and confocal microscopy, prolonged (18 h) exposure to SB206,553 or S32006 enhanced cell surface expression of N-terminal Flag-tagged h5-HT2C(INI)Rs: these effects were blocked by agomelatine and SB242,084, which were inactive alone. Finally, following pre-exposure to SB206,553 or S32006 for 18 h, 5-HT triggered 5-HT2CR-mediated elevations in cytosolic Ca2+ in primary cultures of mice cortical neurons. Agomelatine and SB242,084, inactive alone, prevented these actions of SB206,553 and S32006. In conclusion, agomelatine behaves as a neutral antagonist at constitutively active h5-HT2C(INI)Rs and native, cortical 5-HT2CRs. It will be of interest to determine whether the neutral antagonist properties of agomelatine are related to its favourable clinical profile of antidepressant properties with few side-effects and no discontinuation syndrome. [ABSTRACT FROM PUBLISHER]

The article presents the study on the accuracy and precision of the two simple and sensitive extractive spectrophotometric methods for the determination of zolmitriptan (ZTP) in tablets. The researchers developed the methods based on the formation of yellow ion-pair complexes between ZTP and tropaeolin OO and bromothymol blue in citrate-phosphate buffer. Statistical comparisons of the results reveal that the new methods show no significant differences in accuracy and precision.

The article presents a summary of changes in the safety labeling of drugs and therapeutic biologicals, including boxed warnings, as part of the U.S. Food and Drug Administration's MedWatch program from October to December 2019. These include revisions to boxed warnings including the adverse effect of isotretinoin on pregnant women, sections which address cardiovascular disorders, probable dementia, and breast cancer, and the link between antidepressant use and the risk of suicidal behaviors.

Background Clozapine was the first and the widely accepted gold standard treatment for refractory or treatment-resistant psychotic symptoms (hallucinations and delusions) which can occur in up to 30% of patients with schizophrenia. Clozapine has efficacy in about 50% of treatment-refractory cases and some responding patients have to discontinue it due to serious adverse effects like agranulocytosis, diabetes, myocarditis or ileus. The search for novel agents to use for clozapine-non-responders continues. One such possible agent is the non-dopaminergic antipsychotic pimavanserin, an inverse agonist of serotonin 5-HT2A receptors which was recently approved for the hallucinations and delusions of Parkinson's Disease Psychosis. We report here the successful results of using pimavanserin in patients with refractory hallucinations and delusions who failed to respond to clozapine. We also report similar results in refractory psychosis patients who did not receive clozapine Methods We present ten cases of patients with schizophrenia and schizoaffective disorder with refractory hallucinations and delusions who received a trial of pimavanserin when clozapine or multiple antipsychotics failed. Four of ten patients had not responded to a clozapine trial. The subjects' ages ranged between 21 and 77 years and were followed up for several months with clinical assessments of their psychotic symptoms as well as their negative symptoms and social cognition. Results All 10 patients with refractory hallucinations and delusions showed marked response to pimavanserin 34 mg/day within 4–8 weeks, with continuation of the response for several months of follow-up. Improvements in negative symptoms and social functioning were also observed in several patients. Discussion This series of 10 cases of patients with refractory psychosis who responded to pimavanserin is an important new finding that has never been reported before. It may herald a new direction in the treatment of patients who have either failed to respond to clozapine or even as an option before resorting to clozapine with its many adverse events and the need for frequent blood draws to measure white blood counts which many patients decline to do. Controlled studies comparing clozapine and pimavanserin in refractory schizophrenia are warranted to confirm these clinical observations. [ABSTRACT FROM AUTHOR]

Background Schizophrenia is a complex and heterogeneous psychiatric disorder. The core features comprise positive and negative symptoms, including hallucinations and impaired motivation, as well as cognitive impairment. Current evidence implicates dysfunctions of different brain circuits, involving several neurotransmitters, among which dopamine and glutamate may play a prominent role. So far, the main treatment approach consists of antipsychotic drugs, mostly dopamine/serotonin antagonists, although there is an active search for drugs with novel mechanisms of action. In this regard, the drug SEP-363856 has demonstrated broad antipsychotic activity in preclinical models. The mechanism of action of SEP-363856 is distinct from currently available antipsychotics as it does not have affinity for D2 or 5-HT2A receptors, but it acts as an agonist at 5-HT1A and trace amine-associated (TAAR1) receptors. The aim of the present study was to investigate the ability of SEP-363856 to modulate the functional activity of selected brain areas relevant for schizophrenia and to test its potential in counteracting behavioural and molecular alterations induced by acute phencyclidine (PCP) administration, to mimic a condition of hypo-glutamatergia in the rat. Methods In order to investigate brain region-specific transcriptional mechanisms, adult male Sprague Dawley rats were treated with vehicle or SEP-363856 (1, 3 or 10 mg/kg, PO) and sacrificed 1h later for the dissection of brain areas for molecular analysis. In order to test the ability of SEP-363856 to correct the alterations under a condition of reduced glutamate activity, adult female Lister Hooded rats were pre-treated with the drug (1, 3 or 10 mg/kg, PO) 60 minutes before an acute injection of PCP (2 mg/kg, i.p). Locomotor activity was analysed during the following 90 minutes before sacrifice for the molecular analyses. Results We found that the prefrontal cortex (PFC) showed the most significant changes in response to acute administration of SEP-363856. Indeed, the drug induced a significant up-regulation of a number of activity-dependent genes, such as Arc, Zif268, c-Fos and Npas4. We also found that the expression of the pool of BDNF transcripts with the long 3'UTR, characterized by a prominent dendritic localisation, was significantly increased within the PFC of animals treated with SEP-363856. The prominent activation of PFC was associated with a significant increase of signalling pathways associated with glutamatergic and dopaminergic activity, including the phosphorylation levels of AMPA receptor subunit 1 (GluA1), protein kinase B (Akt) and, to a lesser extent, the MAP kinases ERK1/2. When investigating the activity of the drug in the acute PCP model, we found that SEP-363856 at all doses attenuated PCP-induced hyperlocomotion. At the molecular level, we found that acute PCP injection up-regulated mRNA levels of activity-dependent genes (Arc, Zif268, c-Fos and Npas4) as well as of BDNF within PFC and these changes were also prevented by SEP-363856 at all doses. Discussion In summary, the results of our studies indicate that SEP-363856 has a rather selective activity on prefrontal cortex, by promoting rapid transcriptional mechanisms that may be related to its ability in modulating glutamatergic as well as dopaminergic pathways. Moreover, we found that SEP-363856 was able to counteract the behavioural and molecular effects induced by NMDA receptor antagonism. Further studies will investigate its ability to restore cognitive functions known to be impaired in schizophrenia. [ABSTRACT FROM AUTHOR]

The article discusses information on several new drugs and dosage forms approved by the U.S. Food and Drug Administration as of February 15, 2019, including chlorhexidine gluconate cloths from Medline Industries, immune globulin subcutaneous (human)-hipp injection for subcutaneous infusion from Octapharma USA, and itraconazole capsules from Mayne Pharma.