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The article "In memoriam Lambertus (\"Bert\") A. Peletier 29 March 1937–16 December 2023: Furthering quantitative pharmacology through applied mathematics" published in CPT: Pharmacometrics & Systems Pharmacology honors the life and contributions of Lambertus (Bert) A. Peletier, a respected mathematician known for his work in partial differential equations. Peletier's career spanned from academia to mathematical pharmacology, where he applied advanced mathematical concepts to PK–PD modeling, impacting drug discovery and development. His mentorship and teaching style emphasized the importance of mathematical rigor and cross-disciplinary collaboration, leaving a lasting legacy in the scientific community. [Extracted from the article]

Background Purpose Cyclic vomiting syndrome (CVS) is identified as one of the “episodic syndromes that may be associated with migraine,” along with benign paroxysmal torticollis, benign paroxysmal vertigo, and abdominal migraine. It has been proposed that CVS and migraine may share pathophysiologic mechanisms of hypothalamic activation and altered dopaminergic signaling, and impaired sensorimotor intrinsic connectivity. The past decade has brought groundbreaking advances in the treatment of migraine and other headache disorders. While many of these therapies have yet to be studied in episodic syndromes associated with migraine including CVS and abdominal migraine, the potential shared pathophysiology among these conditions suggests that use of migraine‐specific treatments may have a beneficial role even in those for whom headache is not the primary symptom.This manuscript highlights newer therapies in migraine. Calcitonin gene‐related peptide (CGRP) and its relation to migraine pathophysiology and the therapies that target the CGRP pathway, as well as a 5HT1F receptor agonist and neuromodulation devices used to treat migraine are briefly discussed as they may potentially prove to be useful in the future treatment of CVS. [ABSTRACT FROM AUTHOR]

Aim: Diet, including foods and beverages, affects migraine. Conversely, the influence of migraine therapies on dietary habits is largely unknown. This study aimed at investigating the effects of triptan intake on foods and drinks consumed by adults with migraine with and/or without aura. Methods: An exploratory questionnaire‐based survey took place online between November 2022 and June 2023. Participants were recruited through advertisements shared on social media accounts (e.g., Facebook and Instagram) and seasonal newsletters of three Danish patient associations. In addition, posters and flyers in headache and pain centers at Danish hospitals and private neurological, pain, and physiotherapeutic clinics were utilized. Results: A total of 314 adults with migraine with and/or without aura completed the survey. Among the respondents, 236 individuals (75.2%) regularly used triptans to treat their migraines. Compared with non‐triptan users, individuals using triptans were characterized by significantly more foods and/or drinks triggering migraine (74.2% vs. 56.4%, p = 0.005). Alcoholic beverages and most specifically red wine were overreported as migraine triggers by triptan users (48.3% vs. 21.8%, p < 0.001). In the week preceding the survey, red wine was significantly less consumed by triptan users than non‐triptan users (92.4% vs. 76.9%, p < 0.001). Conclusions: Patients who regularly consume triptans report red wine most frequently as a migraine trigger. Triptan users are characterized by a lower consumption of red wine than non‐triptan users, suggesting that a regular triptan intake may promote an increased sensitivity to red wine‐induced migraine. [ABSTRACT FROM AUTHOR]

A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13‐17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure–response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13‐17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model‐based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13‐17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long‐term open‐label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia. [ABSTRACT FROM AUTHOR]

Cerebral ischemia and reperfusion are related to various situations like injuries after various traumas, oxidative stress, increased calcium ion, capillary hypoperfusion, microvascular hyperpermeability, leukocyte infiltration, and blood–brain barrier disruption. An antidepressant Agomelatine which is a melatonin receptor (MT1/MT2) agonist and serotonin receptor (5‐HT2C) antagonist has been reported by studies to have antioxidant and anti‐inflammatory effects. In our study, we aimed to detect the effects of citrate‐coated silver nanoparticle‐loaded agomelatine application on neurodegeneration, endoplasmic reticulum stress, autophagic and apoptotic cell death, inflammation, and P2X7R expression in the cerebral ischemia–reperfusion model to facilitate the passage of blood–brain barrier. Forty two Sprague–Dawley rats in total were divided into six equal groups (n:7) and applications were performed. Acute cerebral injury in the ischemia–reperfusion model was created 2 h after internal carotid artery ligation in rats and then at the 2nd hour of reperfusion citrate‐coated silver nanoparticles loaded with Agomelatine were applied. Twenty four hours later, neurologic analysis on animals in experimental groups was performed, animals were decapitated and GSH, GPx, SOD, CAT, MDA, IL‐1β, and TNF‐α parameters were examined after taking blood and the cerebral tissue samples. As a result, it was determined that ischemia–reperfusion caused endoplasmic reticulum stress in the cerebral tissues and thus caused cellular injury. [ABSTRACT FROM AUTHOR]

Lasmiditan is an in vitro inhibitor of P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) efflux transporters. We aimed to confirm predictions from physiologically based pharmacokinetic models of lasmiditan, and assess the safety and tolerability of rosuvastatin and dabigatran co‐administered with lasmiditan. In this open‐label, post‐marketing drug–drug interaction, phase 1 clinical trial, eligible participants were adults aged 21‐70 years with a body mass index of 18.5‐35.0 kg/m2. Part 1 (P‐gp, 150 mg dabigatran etexilate with 200 mg lasmiditan) and part 2 (BCRP, 10 mg rosuvastatin with 200 mg lasmiditan) employed similar designs: a single dose of probe substrate administered on day −2 with pharmacokinetic evaluation; 1‐week washout; lasmiditan administered on days 8 and 9 alone; lasmiditan co‐administered with a single dose of probe substrate on day 10, with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty‐six participants were included in part 1 and 30 participants were included in part 2. Following dabigatran co‐administration with lasmiditan, versus dabigatran alone, 90% confidence intervals for geometric least‐squares (LS) mean ratios of area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and maximum observed drug concentration (Cmax) were not contained within the non‐effect boundaries (0.80 to 1.25). Dabigatran AUC0–∞ increased by 25% and Cmax increased by 22%. The median time of maximum observed drug concentration (tmax) for dabigatran was 2.0 to 3.0 hours. Following rosuvastatin co‐administration with lasmiditan, versus rosuvastatin alone, 90%CIs for geometric LS mean ratios of AUC0–∞ and Cmax were contained within non‐effect boundaries (0.80‐1.25). Rosuvastatin AUC0–∞ increased by 15% and Cmax increased by 7%. The median tmax for rosuvastatin was 4.0 hours. Results suggest that lasmiditan has a weak effect on P‐gp substrates and no clinically relevant effect on BCRP substrates. [ABSTRACT FROM AUTHOR]

Plain Language Summary: A suicidal patient with Short‐lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT) whose excruciating condition did not respond to various treatments discovered that ayahuasca, a psychoactive concoction used by indigenous populations of South America, caused his attacks to cease entirely. Inhaled N,N‐dimethyltryptamine (DMT), the principal psychoactive component of ayahuasca, also caused symptoms to disappear temporarily, as did a strong dose of lysergic acid diethylamide (LSD). This case study supports the potential of serotonergic psychedelics for the treatment of SUNCT and related headache disorders. [ABSTRACT FROM AUTHOR]

Agonists of dopamine D2 receptors (D2R), 5‐hydroxytryptamine (5‐HT, serotonin) receptors (5‐HTR) and ghrelin receptors (GHSR) activate neurons in the lumbosacral defecation centre, and act as 'colokinetics', leading to increased propulsive colonic motility, in vivo. In the present study, we investigated which neurons in the lumbosacral defecation centre express the receptors and whether dopamine, serotonin and ghrelin receptor agonists act on the same lumbosacral preganglionic neurons (PGNs). We used whole cell electrophysiology to record responses from neurons in the lumbosacral defecation centre, following colokinetic application, and investigated their expression profiles and the chemistries of their neural inputs. Fluorescence in situ hybridisation revealed Drd2, Ghsr and Htr2C transcripts were colocalised in lumbosacral PGNs of mice, and immunohistochemistry showed that these neurons have closely associated tyrosine hydroxylase and 5‐HT boutons. Previous studies showed that they do not receive ghrelin inputs. Whole cell electrophysiology in adult mice spinal cord revealed that dopamine, serotonin, α‐methylserotonin and capromorelin each caused inward, excitatory currents in overlapping populations of lumbosacral PGNs. Furthermore, dopamine caused increased frequency of both IPSCs and EPSCs in a cohort of D2R neurons. Tetrodotoxin blocked the IPSCs and EPSCs, revealing a post‐synaptic excitatory action of dopamine. In lumbosacral PGNs of postnatal day 7–14 rats, only dopamine's postsynaptic effects were observed. Furthermore, inward, excitatory currents evoked by dopamine were reduced by the GHSR antagonist, YIL781. We conclude that lumbosacral PGNs are the site where the action of endogenous ligands of D2R and 5‐HT2R converge, and that GHSR act as a cis‐modulator of D2R expressed by the same neurons. Key points: Dopamine, 5‐hydroxytryptamine (5‐HT, serotonin) and ghrelin (GHSR) receptor agonists increase colorectal motility and have been postulated to act at receptors on parasympathetic preganglionic neurons (PGNs) in the lumbosacral spinal cord.We aimed to determine which neurons in the lumbosacral spinal cord express dopamine, serotonin and GHSR receptors, their neural inputs, and whether agonists at these receptors excite them.We show that dopamine, serotonin and ghrelin receptor transcripts are contained in the same PGNs and that these neurons have closely associated tyrosine hydroxylase and serotonin boutons.Whole cell electrophysiology revealed that dopamine, serotonin and GHSR receptor agonists induce an inward excitatory current in overlapping populations of lumbosacral PGNs. Dopamine‐induced excitation was reversed by GHSR antagonism.The present study demonstrates that lumbosacral PGNs are the site at which actions of endogenous ligands of dopamine D2 receptors and 5‐HT type 2 receptors converge. Ghrelin receptors are functional, but their role appears to be as modulators of dopamine effects at D2 receptors. [ABSTRACT FROM AUTHOR]

Aim: Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT1B‐receptor agonist) would alter glucose homeostasis in humans. Materials and Methods: We conducted a two‐visit random‐order double‐blinded placebo‐controlled cross‐over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60‐min intravenous glucose tolerance test, followed by a 120‐min hyperinsulinaemic euglycaemic clamp. Results: Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo [iAUC0‐60 min 316 (268‐333) vs. 251 (197‐319) min/mmol/L p =.047]. This was probably explained by a combination of reduced circulating insulin levels [iAUC0‐10 min 1626 (1103‐2733) vs. 2336 (1702‐3269) min/pmol/L, p =.005], reduced insulin sensitivity [M/I‐value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p =.010] and glucose effectiveness [SG 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p =.027]. Conclusions: 5HT1B receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness. [ABSTRACT FROM AUTHOR]

The article focuses on the potential of prucalopride, a serotonin 4 receptor agonist, to reduce depression risk, with topics including a cohort study comparing prucalopride to other anti-constipation medications and lower incidences of neuropsychiatric disorders among prucalopride users.

The article discusses the role of prokinetics in managing ineffective esophageal motility (IEM) and calls for a broader consideration of these drugs in treatment. While the effectiveness of prokinetics in improving esophageal symptoms is still debated, some studies suggest potential benefits, especially in patients with concomitant delayed gastric emptying. New prokinetic agents are being explored, with ongoing trials like Naronapride offering hope for new therapies. The authors advocate for a more detailed discussion on prokinetics as an alternative or adjunct to conservative care for managing this challenging condition. [Extracted from the article]

A call for papers on psychedelic-assisted treatment for substance use disorders is presented.

Objective: To determine the impact of the 2018 Japan Floods, one of the largest water disasters in Japan, on the number of prescriptions for triptans and ergotamine (acute treatment). Background: Natural disasters frequently occur worldwide and may cause psychological stress–related diseases. Acute migraine attacks can be triggered by psychological stress. Disaster victims are likely to experience tremendous psychological stress; however, the relationship between natural disasters and migraine attacks is not well investigated. Methods: A retrospective longitudinal cohort study was conducted using the National Database of Health Insurance Claims in the hardest‐hit areas of the disaster 1 year before and after the disaster. We included people between the ages of 15 and 64 years. Those who had a victim code that was certificated by a local government were assigned to the victim group, and others to the nonvictim group. For those who were not prescribed acute treatment before the disaster (i.e., group without previous acute treatment), the cumulative incidence of new prescriptions for acute treatment at 12 months of follow‐up was calculated and compared between victims and nonvictims with survival analysis. Results: Of 3,475,515 people aged 15 to 64 years enrolled in the study, 16,103 (0.46%) were assigned to the victim group. In the group without previous acute treatment, 111 (0.70%) of 15,933 victims and 14,626 (0.43%) of 3,431,423 nonvictims were newly prescribed acute treatment after the disaster, and new prescriptions for acute treatment were significantly more likely to occur in victims than in nonvictims (adjusted hazard ratio, 1.68; 95% CI, 1.39–2.02). Conclusions: The 2018 Japan Floods increased the number of prescriptions for acute migraine medications among victims, suggesting that acute migraine attacks occurred more frequently after a natural disaster. [ABSTRACT FROM AUTHOR]

Objective: The objective of this paper is to present a narrative review of the use of triptans in the treatment of trigeminal neuralgia (TN), as well as to outline possible therapeutic mechanisms of action. Background: TN is a debilitating neuropathic disorder with a variety of surgical and pharmacological treatments currently available. Despite treatment being heavily individually tailored, some patients remain refractory to management. The use of triptans for the treatment of TN has been commented on in the literature, yet major trials showing their effectiveness are lacking. Methods: A narrative review of current literature was conducted to identify published original research analyzing the usage of triptans in TN via PubMed and Google Scholar. Results: Limited case reports and studies have been done to analyze the use of triptans for the treatment of TN. Despite the limited results, the studies that have been done show some promise for triptans as an alternative treatment, in particular to those with refractory TN. Given the incapacitating nature of TN, another alternative treatment may be of benefit to those patients and can help reduce its associated morbidity. Conclusion: Patients with refractory TN may find relief of symptoms from the use of triptans. Larger clinical trials are needed to help determine which patients would benefit from their use as well as specific dosing. Caution should be given regarding the long‐term use of triptans, in particular for the typical patient population with TN. [ABSTRACT FROM AUTHOR]

Transaminase enzymes have significant potential for the stereoselective synthesis of drugs or drug precursors. Here, starting from one prochiral β‐tetralone, a short and efficient chemoenzymatic synthesis of four agonists of the serotonin/melatonin receptors have been developed. The key step is the stereoselective transamination of the prochiral ketone to produce both enantiomers of 8‐methoxy‐2‐aminotetraline in high yields and enantiomeric excesses. This was followed by either amidation to give the 8‐methoxy‐2‐acetimidotetralines or several facile chemical steps to the 8‐hydroxy‐2‐aminodipropyltetralines. [ABSTRACT FROM AUTHOR]

Disruption of neuronal chloride ion (Cl- ) homeostasis has been linked to several pathological conditions, including substance use disorder, yet targeted pharmacotherapies are lacking. In this study, we explored the potential of serotonin 2A receptor (5-HT2A R) agonism to reduce alcohol consumption in male wild-type C57Bl/6J mice and to ameliorate alcohol-induced inhibitory plasticity in the midbrain. We found that administration of the putative 5-HT2A R agonist TCB-2 attenuated alcohol consumption and preference but did not alter water or saccharin consumption. We hypothesized that the selective behavioural effects of TCB-2 on alcohol drinking were due, at least in part, to effects of the agonist on ventral tegmental area (VTA) neurocircuitry. Alcohol consumption impairs Cl- transport in VTA GABA neurons, which acts as a molecular adaptation leading to increased alcohol self-administration. Using ex vivo electrophysiological recordings, we found that exposure to either intermittent volitional alcohol drinking or an acute alcohol injection diminished homeostatic Cl- transport in VTA GABA neurons. Critically, in vivo TCB-2 administration normalized Cl- transport in the VTA after alcohol exposure. Thus, we show a potent effect of alcohol consumption on VTA inhibitory circuitry, in the form of dysregulated Cl- homeostasis that is reversible with agonism of 5-HT2A Rs. Our results provide insight into the potential therapeutic action of 5-HT2A R agonists for alcohol abuse. [ABSTRACT FROM AUTHOR]

The article focuses on the resurgence of psychedelic drugs as therapeutic agents, particularly the study of 3,4-methylenedioxymethamphetamine (MDMA) for treating post-traumatic stress disorder (PTSD). Topics include the categorization of psychedelics, the results of a Phase 3 study on MDMA-assisted therapy, and concerns about potential misuse, hype, and legalization, emphasizing the need for a cautious approach in incorporating these drugs into psychiatric treatment.

Tremor, as in our case, is also reported.2,4 The differential diagnosis of tremor caused by metoclopramide is acute cerebellar ataxia/acute cerebellitis (ACA/AC), which is often accompanied by prodromal viral infections. Although long-term use and overdose have been reported as risk factors for its development, even a single dose of metoclopramide can cause substantial motor symptoms, as in our case.3 Treatment of metoclopramide-induced tremor is supportive. Keywords: metoclopramide; tremor; children EN metoclopramide tremor children 987 989 3 10/13/22 20221001 NES 221001 Metoclopramide is a dopamine receptor antagonist that, despite no evidence to support its use in children with acute gastroenteritis,1 is frequently used for the symptomatic treatment of nausea and vomiting in pediatric acute gastroenteritis in Japan, where ondansetron and other serotonin receptor agonists are not approved for this condition. [Extracted from the article]

Monotherapy with triptans in acute migraine is ineffective in many patients and contraindicated in certain cardiovascular diseases where alternative therapeutic options are necessary to explore. This meta‐analysis has evaluated the efficacy and safety of lasmiditan for the treatment of acute migraine in adults. After performing a literature search on MEDLINE/PubMed, Scopus, Cochrane databases, and International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from 4 relevant articles. Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines were followed in the selection, analysis, and reporting of findings. A random‐effects model was used to estimate effect size. Quality assessment was done using the risk of bias assessment tool and meta‐regression for probable variables affecting effect size. Subgroup analysis was done depending on the dose of lasmiditan. Lasmiditan use was associated with a significantly higher percentage of patients with pain freedom (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.72‐2.39; P <.00001), sustained pain freedom (OR, 1.93; 95%CI, 1.55‐2.39; P <.00001), headache response (OR, 2.05; 95%CI, 1.77‐2.36; P <.00001), clinical disability level (OR, 1.36; 95%CI, 1.20‐1.55; P <.00001), patients' global impression (OR, 1.88; 95%CI, 1.69‐2.10; P <.00001), and significantly lower use of rescue medication (OR, 0.49; 95%CI, 0.38‐0.63; P <.00001) compared to placebo. Lasmiditan use was also associated with a higher likelihood of adverse effects like dizziness (OR, 6.54; 95%CI, 4.24‐10.07; P <.00001), paresthesia (OR, 4.28; 95%CI, 2.97‐6.17; P <.00001), and fatigue (OR, 5.67; 95%CI, 3.78‐8.52; P <.00001) compared to placebo. Subgroup analysis showed a dose‐dependent effect of lasmiditan on pain freedom, sustained pain freedom, patient's global impression, and occurrence of adverse drug reactions. Prediction probability for effect estimate favoring placebo was calculated to be 0.0017%. Lasmiditan has shown a favorable effect in terms of efficacy and safety in the treatment of an acute attack of migraine in comparison to placebo. Further studies are needed to evaluate long‐term safety, efficacy, and use in specific subgroups of patients. PROSPERO Registration Number: CRD42020177838 [ABSTRACT FROM AUTHOR]

Background. Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT1F receptor agonist appears more promising for aborting migraine attacks. Objective. To evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks. Methods. The literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model. Results. Based on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75 , 95% CI (0.61, 0.92), P = 0.007 ; 200 mg: RR = 0.81 , 95% CI (0.66, 0.99), P = 0.04) at 2-24 h postdose, compared with placebo. Safety data showed that the proportion of patients reporting at least one treatment-emergent adverse event (TEAE) and the incidence of most common TEAEs such as dizziness, paresthesia, fatigue, somnolence, and nausea was higher in the lasmiditan groups (50 mg, 100 mg, and 200 mg), compared with placebo. There was no significant difference between lasmiditan and placebo in terms of cardiovascular-related TEAEs (RR = 2.75 , 95% CI (0.81, 9.37), P = 0.11). Compared with lasmiditan 100 mg, lasmiditan 200 mg was more effective in pain freedom at 2 h after the first dose (RR = 0.83 , 95% CI (0.74, 0.94), P = 0.004) but associated with a higher risk of reporting at least one TEAE (RR = 0.88 , 95% CI (0.81, 0.96), P = 0.006). Conclusions. Lasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term. [ABSTRACT FROM AUTHOR]

The serotonin (5‐HT) system has been implicated in the pathophysiology of alcohol (ethanol; EtOH) use disorders. Lorcaserin, a 5‐HT2C receptor agonist, attenuates drug self‐administration in animal models. We investigated the effects of lorcaserin on EtOH intake using the drinking‐in‐the‐dark (DID) procedure, an animal model of binge‐like drinking. We compared the effects of lorcaserin to those of the Food and Drug Administration (FDA)‐approved drug naltrexone and examined the effects of combining lorcaserin and naltrexone. To examine whether effects were specific for EtOH, we examined the effects of lorcaserin and naltrexone, administered alone and in combination, on saccharin intake. Adult male C57BL/6J mice received EtOH access (20% v/v) for 2 h in the home‐cage during the first 3 days of the DID procedure, beginning 3 h into the dark cycle. On day 4, mice were injected with lorcaserin, naltrexone, or a combination of lorcaserin and naltrexone prior to a 4‐h EtOH access. Intake was measured at 2 and 4 h. Lorcaserin reduced EtOH intake in a dose‐dependent fashion over the 2‐ and 4‐h measurement periods. Naltrexone also reduced EtOH intake when administered alone, with dose‐dependent effects being more pronounced over 2 h rather than the full 4‐h session. Combining lorcaserin and naltrexone reduced binge‐like EtOH drinking to a greater extent than either drug alone. A similar pattern of results was obtained for saccharin intake. These results suggest that lorcaserin and naltrexone can have additive effects on binge‐like EtOH drinking. They also support continued research into the therapeutic potential of lorcaserin for alcohol use disorders. [ABSTRACT FROM AUTHOR]

Background: Gastric motor function alterations have been implicated in the pathogenesis of functional dyspepsia with postprandial distress syndrome (PDS). Prucalopride, a 5‐TH4 agonist, is known to stimulate gastrointestinal motility. We aimed to evaluate the effect of prucalopride on gastric sensorimotor function in healthy subjects (HV). Methods: Barostat and intragastric pressure (IGP) measurements were performed in 17 HV (59% females, age 29.4 ± 2.7 y) after treatment with placebo or prucalopride (2 mg) (single‐blind cross‐over). Isobaric stepwise distensions and gastric sensations were assessed to determine gastric compliance and sensitivity. Gastric accommodation (GA) with the barostat was quantified before and after ingestion of 200 ml of a nutrient drink (ND). GA measured by IGP was quantified as the drop of IGP from baseline during the intragastric infusion of ND until maximal satiation (60 ml/min). Key Results: Prucalopride did not affect barostat assessed gastric compliance or sensitivity. No differences were observed in GA after prucalopride. During the barostat study, 10 min after the meal, 7 HVs reported significantly higher ratings for nausea after prucalopride (p < 0.001), and vomiting was induced in 4 of the HVs. A positive correlation was observed between the delta mean perception of nausea with the delta mean increase of intra‐balloon volume before and after meal ingestion (r = 0.37, p = 0.03). During IGP measurements, no effect on nutrient tolerance was observed and increased cramp severity scores were observed which were associated with a significant increase of distal IGP (r = 0.78, p < 0.0001). Conclusions & Inferences: Prucalopride does not enhances gastric accommodation but it might increase sensitivity to gastric distention. Furthermore, the increase in sensitivity seems to be related to an increase in nausea with distension. Clinicaltrials.gov: NCT04429802. [ABSTRACT FROM AUTHOR]

The relative value of and motivation for abused drugs often increases with drug experience and differs based on drug availability. Here, we determined how different intake patterns of fentanyl, a μ-opioid agonist, alter economic demand for fentanyl and how 5-HT2A receptor stimulation affects economic demand for fentanyl. We used a within-session demand threshold procedure to characterize changes in economic demand for fentanyl before and after intermittent or continuous access schedules. We subsequently tested the acute effects of 5-HT2A receptor stimulation with psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on economic demand for fentanyl. Extended fentanyl experience with both intermittent and continuous schedules increased fentanyl consumption at low cost (Q0 ), increased total fentanyl consumption, and decreased demand elasticity (α), indicating both schedules elevated motivation to self-administer fentanyl. Overall, the two schedules produced similar alterations in economic demand for fentanyl, although low-cost consumption (Q0 ) increased more in the continuous access group. Systemic injections of DOI (0.0-0.4 mg/kg, i.p.) dose-dependently produced economic demand changes in the opposite direction produced by fentanyl experience. DOI decreased motivation (increased "α"), decreased Q0 , and decreased total fentanyl consumption. The selective 5-HT2A antagonist, M100907 (0.3 mg/kg, i.p.), blocked the effects of DOI, indicating that DOI is acting through 5-HT2A receptors to alter economic demand for fentanyl. In an economic food demand experiment, DOI (0.4 mg/kg) also increased demand elasticity and reduced food consumption. These results demonstrate that both intermittent and continuous fentanyl experience raise the economic demand for fentanyl, and acute 5-HT2A receptor activation reduces economic demand for fentanyl and food. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of lasmiditan in Japanese adults with migraine. Background: Global clinical studies have demonstrated the efficacy and safety of lasmiditan in the acute treatment of migraine. Methods: This was a multicenter, randomized, double‐blind, placebo‐controlled, phase 2 study in Japan (NCT03962738), which enrolled adults with migraine with or without aura. Participants were randomized 7:3:7:6 to placebo, lasmiditan 50 mg, 100 mg, or 200 mg to be self‐administered orally within 4 h of onset of a single moderate‐to‐severe migraine attack. Participants recorded their response to treatment prior to dosing and for 48 h postdose. The primary endpoint was headache pain freedom at 2 h postdose. Results: Participants (N = 846) were randomized and treated (N = 691, safety; N = 682, modified intent‐to‐treat). At 2 h postdose, a significantly higher proportion of participants were headache pain‐free in the lasmiditan 200 mg (40.8%, 73/179; odds ratio 3.46 [95% confidence interval 2.17 to 5.54]; p < 0.001; primary objective) and 100 mg groups (32.4%, 67/207; odds ratio 2.41 [1.51 to 3.83]; p < 0.001) compared with the placebo group (16.6%, 35/211), whereas the lasmiditan 50 mg group had a numerically higher proportion of participants headache pain‐free (23.5%, 20/85; odds ratio 1.55 [0.83 to 2.87]; p = 0.167) compared with placebo. A statistically significant linear dose–response relationship for pain freedom was achieved at 2 h by a Cochran–Armitage trend test (p < 0.001). Lasmiditan treatment was also associated with headache pain relief, most bothersome symptom freedom, and improvement on disability and Patient Global Impression of Change outcomes. The majority of treatment‐emergent adverse events were mild and of short duration, the most common of which were dizziness (39.4%; 188/477), somnolence (19.3%; 92/477), and malaise (10.5%; 50/477) in all lasmiditan groups, with no serious adverse events reported. Conclusions: Lasmiditan was well tolerated and effective for the acute treatment of Japanese patients with migraine, consistent with global phase 3 studies. [ABSTRACT FROM AUTHOR]

Hyperserotonemia, in the early developmental phase, generates a variety of behavioural and biochemical phenotypes associated with autism spectrum disorder (ASD) in rats. Papaverine is known to provide benefits in various brain conditions. We investigated the role of a selective phosphodiesterase‐10A (PDE10A) inhibitor, papaverine on ASD related behavioural phenotypes (social behaviour deficits, repetitive behaviour, anxiety and hyperlocomotion) in developmental hyperserotonemia (DHS) rat model. Also, effects on important biochemical markers related with neuronal function (brain‐derived neurotrophic factor (BDNF)‐neuronal survival and phosphorylated‐cAMP response element binding protein (pCREB)‐neuronal transcription factor), brain inflammation (interleukin (IL)‐6, IL‐10 and tumour necrosis factor (TNF)‐α) and brain oxidative stress (TBARS and GSH) were studied in important brain areas (frontal cortex, cerebellum, hippocampus and striatum). Administration of a non‐selective serotonin receptor agonist, such as 5‐methoxytryptamine (5‐MT) to rats prenatally (gestational day 12 – day of parturition) and during early stages (postnatal day (PND) 0 –PND20) of development, resulted in impaired behaviour and brain biochemistry. Administration of papaverine (15/30 mg/kg ip) to 5‐MT administered rats from PND21 to PND48, resulted in improvement of behavioural deficits. Also, papaverine administration significantly increased the levels of BDNF, pCREB/CREB, IL‐10, GSH and significantly decreased TNF‐α, IL‐6 and TBARS levels in different brain areas. Papaverine, in both doses rectified important behavioural phenotypes related with ASD, the higher dose (30 mg/kg ip) showed significantly greater improvement than 15 mg/kg ip, possibly by improving neuronal function, brain inflammation and brain oxidative stress. Thus, PDE10A could be a probable target for pharmacological interventions and furthering our understanding of ASD pathogenesis. [ABSTRACT FROM AUTHOR]

The study published in the Journal of Physiology explores the role of ghrelin receptor (GHSR) in modulating dopamine and serotonin actions on preganglionic neurons (PGNs) in the lumbosacral defecation center of the spinal cord. Researchers found that GHSR interacts with dopamine D2 receptors to induce excitatory responses in PGNs, contrary to the typical inhibitory effects of D2 receptor activation. This interaction may have implications for regulating colorectal motility and could potentially lead to new pharmacotherapies for gastrointestinal and autonomic functions. The study sheds light on the complex interplay of GPCRs in the spinal cord and their impact on neural regulation of colorectal activity. [Extracted from the article]

Objective: The goal of this study is to determine the strength of association between treatment with triptans and acute myocardial infarction, heart failure, and death. Background: Case reports in the literature have raised concerns over an association between treatment of migraine headaches with triptans and cardiovascular events. This study aims to systematically evaluate this association in a contemporary population‐based cohort. We hypothesized that triptan exposure is not associated with increased cardiovascular events. Methods: A retrospective cohort study was conducted within an integrated healthcare delivery system in Southern California. From January 2009 to December 2018, 189,684 patients age ≥18 years had a diagnosis of migraine. In this group, 130,656 were exposed to triptans. Patients treated with triptans were matched 1:1 to those not exposed to triptans by using a propensity score. The primary outcome was acute myocardial infarction; secondary outcomes were heart failure, all‐cause death, and combined acute myocardial infarction, heart failure, and death. Results: The incidence rate of acute myocardial infarction was 0.67 per 1000 person‐year in triptan‐exposed vs 1.44 per 1000 person‐year in not exposed patients. In propensity‐matched analyses, the adjusted hazard ratio for triptan exposure was 0.95 (95% confidence interval [CI] 0.84‐1.08) for acute myocardial infarction; 1.00 (95% CI 0.93‐1.08) for all‐cause death; 0.93 (95% CI 0.81‐1.08) for heart failure; and 0.99 (95% CI 0.93‐1.06) for a composite of acute myocardial infarction, heart failure, or death. Sensitivity analyses focusing on stratified subgroups based on age, gender, ethnicity, and several cardiac risk factors also revealed no significant association between triptan exposure and cardiovascular events. Conclusions: No association was found between exposure to triptans and an increased risk of cardiovascular events. These data provide reassurance regarding the cardiovascular safety of utilizing triptans for the medical management of migraine headaches. [ABSTRACT FROM AUTHOR]

Objective: To identify factors predicting response (2‐hour headache pain freedom or most bothersome symptom freedom) to lasmiditan based on individual patient characteristics, migraine disease characteristics, and migraine attack characteristics. Further, efficacy specifically in difficult‐to‐treat patient/migraine disease characteristics or attack characteristics (ie, historically considered less responsive to certain acute therapies) subgroups was analyzed. Background: Knowledge of factors associated with a positive or negative response to acute treatment would be useful to practitioners prescribing acute treatments for migraine. Additionally, practitioners and patients would benefit from understanding the efficacy of lasmiditan specifically in subgroups of patients with migraine disease characteristics and migraine attack characteristics historically associated with decreased pain threshold, reduced efficacy of acute treatment, or increased burden of migraine. Methods: Pooled analyses were completed from 2 Phase 3 double‐blind clinical trials, SPARTAN and SAMURAI. Data from baseline to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to assess efficacy based on patient characteristics, migraine disease characteristics, and migraine attack characteristics. A total of 3981 patients comprising the intent‐to‐treat population were treated with placebo (N = 1130), lasmiditan 50 mg (N = 598), lasmiditan 100 mg (N = 1133), or lasmiditan 200 mg (N = 1120). Data were analyzed for the following efficacy measures at 2 hours: headache pain freedom and most bothersome symptom freedom. Results: None of the analyzed subgroups based on individual patient characteristics, migraine disease characteristics, or migraine attack characteristics predicted headache pain freedom or most bothersome symptom freedom response at 2 hours following lasmiditan treatment (interaction P ≥.1). For the difficult‐to‐treat patient/migraine disease characteristics subgroups (defined as those with ≥24 headache days in the past 3 months, duration of migraine history ≥20 years, severe disability [Migraine Disability Assessment score ≥21], obesity [≥30 kg/m2], and history of psychiatric disorder), single doses of lasmiditan (100 or 200 mg) were significantly more effective than placebo (P ≤.002) in achieving both endpoints. Headache pain freedom response rates for higher doses of lasmiditan were numerically greater than for lower doses of lasmiditan. For the difficult‐to‐treat migraine attack subgroups, patients with severe headache, co‐existent nausea at the time of treatment, or who delayed treatment for ≥2 hours from the time of headache onset, both endpoint response rates after lasmiditan 100 or 200 mg were significantly greater than after placebo. Among those who delayed treatment for ≥4 hours from the time of headache onset, headache pain freedom response rates for the 200 mg dose of lasmiditan met statistical significance vs placebo (32.4% vs 15.9%; odds ratio = 2.7 [1.17, 6.07]; P =.018). While the predictors of response interaction test showed similar efficacy of lasmiditan vs placebo across subgroups defined by baseline functional disability (mild, moderate, or needs complete bed rest) at the time of treatment, analyses of lasmiditan efficacy within the subgroup "needs complete bed rest" appeared to show less efficacy (eg, in the 200 mg vs placebo group, 25.9% vs 18.5%; odds ratio = 1.56 [0.96, 2.53]; P =.070). Conclusions: Efficacy of lasmiditan 200 and 100 mg for headache pain freedom and most bothersome symptom freedom at 2 hours post‐treatment was generally not influenced by the individual patient characteristics, migraine disease history, or migraine attack characteristics that were analyzed. In the analyses of difficult‐to‐treat subgroups, patients receiving lasmiditan achieved greater responses (2‐hour headache pain freedom and most bothersome symptom freedom) vs placebo recipients. [ABSTRACT FROM AUTHOR]

The article focuses on the Institute for Clinical and Economic Review final evidence report on the clinical and economic value of novel acute treatments for migraine, rimegepant, and lasmiditan. Topics include the randomized trials of acute therapies for migraine has designed to assess the primary outcomes, and the U.S. Food and Drug Administration guidance and the guidelines for clinical trials of drugs has issued by the International Headache Society Clinical Trial Standing Committee.

Objective: We explore factors that may have contributed to differences in treatment‐emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials. Background: Phase 2 and phase 3 trials showed that the centrally penetrant 5‐HT1F agonist, lasmiditan, was effective; higher frequency and severity of adverse events (AEs) were seen in phase 2. Methods: This work represents a hybrid of a review of primary documents and study reports with additional post hoc analyses. Protocols, informed consents, data collection forms, and methodologies were reviewed. This information was supplemented by results from the clinical study reports and post hoc analyses of individual patient data from each trial. Results: For lasmiditan 100 and 200 mg, in phase 2, the incidence of ≥1 AE was 72‐86% (26% severe), while in phase 3 was 36‐43% (2% severe). The most common AEs in all studies were CNS‐related. The phase 2 consent form was more descriptive of AEs than phase 3. In phase 2, patients recorded AEs and severity in a paper diary that warned about drowsiness and dizziness. In phase 3, patients recorded in electronic diaries whether they experienced unusual feelings after dosing with lasmiditan that they had not felt with a migraine before, and were contacted to determine if an AE had occurred. In phase 2, the AE Schwindel was variably translated from German as "vertigo" or "dizziness," while phase 3 vertigo cases were queried to ensure there was a sensation of rotation or movement. History of recurrent dizziness and/or vertigo was exclusionary in phase 3. Conclusions: This work illustrates how informed consent wording, AE collection methods, translation, exclusion criteria, and other factors may be important determinants for reporting of the frequency and severity of AEs in clinical trials. [ABSTRACT FROM AUTHOR]

Objective: To expand on available information on the efficacy of oral lasmiditan for the acute treatment of migraine with particular focus on the timing of the effect and on its impact on migraine‐associated symptoms. Background: Lasmiditan is a novel selective 5‐hydroxytryptamine 1F receptor agonist that lacks vasoconstrictive activity. In 2 phase 3 studies, SAMURAI and SPARTAN, lasmiditan met primary and key secondary efficacy endpoints at 2 hours following initial dose. Methods: Integrated analyses were completed from 2 phase 3 clinical trials, SPARTAN and SAMURAI. Baseline data and data collected every 30 minutes up to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to determine the onset of efficacy. A total of 5236 patients were randomized to be treated with placebo (N = 1493), lasmiditan 50 mg (N = 750), lasmiditan 100 mg (N = 1498), or lasmiditan 200 mg (N = 1495). Data were analyzed to determine the onset of improvement for the following efficacy measures: pain freedom, most bothersome symptom freedom, pain relief, freedom from associated individual symptoms (photophobia, phonophobia, or nausea), total migraine freedom (defined as pain freedom and freedom from associated symptoms), and freedom from migraine‐related functional disability. Time to meaningful headache relief and time to first become pain free were also analyzed. Results: Significantly higher rates of pain freedom (100 mg, 10.0%, P = .012; 200 mg, 15.5%, P < .001; Placebo, 7.0%) and total migraine freedom (100 mg, 8.9%, P = .017; 200 mg, 12.4%, P < .001; Placebo, 6.1%) were achieved starting at 60 minutes in 100‐ and 200‐mg lasmiditan‐treated groups compared with placebo group. Rates of freedom from most bothersome symptom (100 mg, 11.1%, P = .015; 200 mg, 13.0%, P < .001; Placebo, 7.9%), and pain relief (100 mg, 17.5%, P = .007; 200 mg, 19.1%, P < .001; Placebo, 13.4%) were significantly higher starting as early as 30 minutes in lasmiditan 100‐ and 200‐mg lasmiditan‐treated groups. A significantly higher percentage of patients in the 200‐mg lasmiditan‐treated group achieved freedom from photophobia (13.7%, P = .005; Placebo, 9.2%) and phonophobia (17.4%, P = .042; Placebo, 13.4%) starting at 30 minutes. A significantly greater proportion of patients in the 200‐mg lasmiditan‐treated group achieved freedom from migraine‐related functional disability starting at 60 minutes (16.4%, P < .001; Placebo, 11.1%). All efficacy measures, except for freedom from nausea, were statistically significant after lasmiditan treatment (50, 100, or 200 mg) compared with placebo at 90 and 120 minutes. Finally, patients taking lasmiditan had a higher likelihood of achieving meaningful headache relief and becoming headache pain free within 24 hours compared with those taking placebo (P < .001). Conclusions: Patients treated with lasmiditan for a migraine attack reported an earlier onset of efficacy compared with those treated with placebo. Some of the efficacy measures such as pain relief demonstrated improvement as early as the first assessment at 30 minutes after 100‐ or 200‐mg lasmiditan treatment. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 31-year-old woman with a history of migraine without aura for 5 years occurring twice a month. It discusses the diagnosis of the status migrainosus, along with discussion on the pathophysiology of the disease. It mentions the risk factors associated with the status migrainosus.

Aims: To evaluate the effect of ASP2205, a selective serotonin 5‐HT2c receptor agonist, and Duloxetine on the urethral pressure in healthy female subjects. Methods: Healthy females aged 18 to 55 years were recruited for this phase 1, single site, placebo‐controlled, randomized, four‐period, cross‐over study. The interventions were single oral doses of 10 and 60 mg ASP2205, 80 mg duloxetine, and placebo. As a pharmacodynamics endpoint, opening urethral pressure (OUP), corrected for placebo, was measured using urethral pressure reflectometry under both resting and squeezing condition of the pelvic floor at predose and 3, 6, 12, and 24 hours after dosing. Safety and tolerability of ASP2205 were also compared with duloxetine and placebo. Results: Eighteen healthy women signed informed consent, however, one dropped out before dosing and one dropped out after the first period, therefore, 16 subjects completed the study. Duloxetine significantly increased the OUP during both resting and squeezing condition (maximal increase 18.1 and 16.8 cmH2O, respectively). Both doses of ASP2205 did not increase OUP at any time point. During squeezing OUP decreased significantly in the ASP2205 60 mg group from 6 to 24 hours after dosing. All subjects experienced predominantly central nervous system‐related side effects (eg, dizziness and nausea) during ASP2205 treatment, which was most pronounced at 60 mg. Conclusions: ASP2205, a serotonin 5‐HT2c receptor agonist, does not increase the urethral pressure and it is therefore unlikely that 5‐HT 2c receptor agonists can be used as a treatment for stress urinary incontinence. ASP2205 was less well tolerated than the high dose of duloxetine. [ABSTRACT FROM AUTHOR]

Objective: To review and highlight current literature on emerging acute migraine treatments, focusing on CGRP receptor antagonists, gepants, and 5‐HT1F receptor agonists (ditans). Background: Current acute migraine therapy consists of nonspecific analgesia and triptans. Limitations to these medicines, including lack of efficacy in many patients, side effects and the contraindication of triptans in patients with cardiovascular disease, suggest that there is an unmet need for new treatments. Studies of serotonin pharmacology led to the development of triptans, 5‐HT1B/1D receptor agonists, some of which have actions at the 5‐HT1F receptor. Exploration of the role of calcitonin gene‐related peptide (CGRP) has resulted in the development of CGRP receptor antagonists. Method: The authors performed a literature search of Pubmed and Cochrane databases as well as reviewed abstracts presented at meetings: American Headache Society, American Academy of Neurology, European Headache Federation and the Migraine Trust International Symposium, as well as on‐line sources. The authors briefly detail the relevant migraine pathophysiology pertaining to 5‐HT1F receptor and the CGRP pathway relevant to acute therapies. Recent clinical trials of acute therapies in which 5‐HT1F receptor agonists or CGRP receptor antagonists were studied are summarized. Results: Two 5‐HT1F receptor agonists have reached phase II clinical trials. One, lasmiditan, has completed 2 phase III clinical trials, demonstrating a significant effect for pain freedom and most bothersome symptom at 2 hours. Among the 6 gepants tested for the acute treatment of migraine to date, after issues for some of hepatic safety or efficacy, 2 CGRP receptor antagonists, rimegepant and ubrogepant, have completed phase III trials showing efficacy and safety. Conclusion: Current available therapies have either been nonspecific or had important limitations, including in patients with cardiovascular risk factors. Phase III clinical trials of lasmiditan, rimegepant and ubrogepant all met their primary endpoints, so the options for migraine‐targeted acute therapy will likely soon increase. [ABSTRACT FROM AUTHOR]

Trial Design: SAMURAI and SPARTAN were double‐blind, placebo‐controlled Phase 3 studies conducted in the United States, as well as the United Kingdom and Germany (SPARTAN only). Individuals with migraine were randomized to receive oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo within 4 hours of onset of a migraine attack. The aim of this analysis was to characterize dizziness reported with lasmiditan treatment. Methods: Data from SAMURAI and SPARTAN were pooled for the current post hoc analyses. Onset time and duration of dizziness were analyzed using descriptive statistics. Subgroup analyses based on presence/absence of dizziness were performed for the endpoints of interference with daily activity, patient global impression of change (PGIC), pain at 2 hours, and most bothersome symptom (MBS) at 2 hours based on adverse events occurring within 2 hours of taking study drug. Results: Dizziness incidence was as follows: Placebo (N = 1262), 2.9% (0.1% severe); lasmiditan 50 mg (N = 654), 8.6% (0.3% severe); lasmiditan 100 mg (N = 1265), 14.9% (0.7% severe); and lasmiditan 200 mg (N = 1258), 16.8% (1.4% severe). Among participants who received lasmiditan as their first dose, risk factors for dizziness were higher lasmiditan dosage, being non‐Hispanic/Latino, mild or moderate severity of migraine attack, and lower body mass index. The median time to onset of dizziness was generally 30‐40 minutes, and the median duration was 1.5‐2 hours. The presence of dizziness did not appear to have a negative influence on lasmiditan's effect on daily activity, PGIC, freedom from pain, or MBS. Overall, 21 participants experienced vertigo: Lasmiditan 50 mg, n = 2 (0.3%); 100 mg, n = 11 (0.9%); 200 mg, n = 7 (0.6%); and placebo, n = 1 (<0.1%). Conclusion: The incidence of dizziness with lasmiditan increased with dose. Dizziness was generally mild or moderate in severity and of quick onset and short duration. The presence of dizziness did not influence drug efficacy. [ABSTRACT FROM AUTHOR]

To determine the bioavailability and pharmacokinetic properties of the serotonin 5‐HT1A receptor agonist R‐8‐OH‐DPAT in goats, and 0.1 mg kg−1 R‐8‐OH‐DPAT hydrobromide was administered intramuscularly (i.m.) and intravenously (i.v.) to six goats in a two‐phase cross‐over design experiment. Venous blood samples were collected from the jugular vein 2, 5, 10, 15, 20, 30, 40 and 60 min following treatment and analysed by liquid chromatography tandem mass spectrometry. Bioavailability and pharmacokinetic parameters were determined by a one‐compartment analysis. Mean bioavailability of R‐8‐OH‐DPAT when injected i.m. was 66%. The mean volume of distribution in the central compartment was 1.47 L kg−1. The mean plasma body clearance was 0.056 L kg−1 min−1. All goats injected i.v. and two of six goats injected i.m. showed signs of serotonin toxicity. In conclusion, R‐8‐OH‐DPAT is well absorbed following i.m. injection and the observed pharmacokinetics suggest that administration via dart is feasible. Administration of R‐8‐OH‐DPAT hydrobromide, at a dosage of 0.1 mg kg−1, resulted in the observation of clinical signs of serotonin toxicity in the goats. It is suggested that dosages for the clinical use of the compound should be lower in order to achieve the desired clinical effect without causing serotonin toxicity. [ABSTRACT FROM AUTHOR]

Objectives: Sumatriptan (Imigran) is a potent and highly selective 5‐HT1 receptor agonist often used in treating acute migraine. Intranasal sumatriptan is well absorbed and is generally effective in relieving headache. However, the effects of Imigran on human nasal mucosa have rarely been well explored, to verify the effect of Imigran, which act on human nasal mucosa directly in vitro. Design and participants: We examined the effectiveness of Imigran on human nasal mucosa by testing: (i) effect on human nasal mucosa resting tension; (ii) effect on contraction caused by 10−6 mol/L methoxamine as a sympathetic mimetic; and (iii) effect of the drugs on electrically induced on human nasal mucosa contractions. Results: The results indicated that addition of methoxamine to the incubation medium caused the nasal mucosa to contract in a dose‐dependent manner. Addition of Imigran at doses of 10−4 mol/L elicited a significant relaxation response to 10−6 mol/L methoxamine‐induced contraction. Imigran could not inhibit electrical field stimulation‐induced spike contraction. It also had a minimal effect on the basal tension of nasal mucosa as the concentration increased. Conclusions: The study indicated that high concentrations of Imigran had a significant spasmolytic effect by antagonising α‐adreoceptors and nasal obstruction could not be released in the patient combined with acute migraine and stuffy nose by concomitant α‐adrenergic agonist nasal spray plus Imigran nasal spray. [ABSTRACT FROM AUTHOR]

Summary: Aims: The serotonin 7 receptor (5‐HT7R) subtype, coded by Htr7 gene, is broadly expressed in the central nervous system (CNS) with clear involvement in behavioral functions such as learning/memory, regulation of mood, and circadian rhythms. In this study, we assessed effects of 5‐HT7R stimulation by administration of its selective agonist, LP‐211 (0.25 mg/kg i.p.), in adult Wistar‐Han rats. Methods: We used two different explorative‐curiosity tests. Drug was administered either before one side‐chamber familiarization (CF/V group) or immediately after it, to act on consolidation of familiarization (V/CF group). Results: Exp. 1 for novelty seeking in black/white boxes (BWB), with door opening after 5 minutes in the familiar chamber, showed that (i) time spent in the novel environment (significantly higher than in familiar chamber for controls) is enhanced in V/CF group (potentiated recognition for a “visual” consolidation) and not different in CF/V group; (ii) activity and chamber transitions, made by CF/V rats, are significantly higher than for other groups (interference on recognition for a “spatial” acquisition). Exp. 2 for novelty preference in D‐ vs L‐shaped chambers (D/L), with start from neutral center, gave different results: (i) time spent in the novel environment by CF/V group is significantly higher than other groups (potentiated “cognitive” acquisition); (ii) chamber transitions made by V/CF group are significantly higher than other groups (potentiated “emotional” consolidation). Conclusion: These apparently conflicting results may reflect LP‐211 effects on visual vs spatial memory (D/L apparatus has more pronounced hippocampal components than BWB). However, further experiments are needed to analyze more in depth the mechanisms involved. [ABSTRACT FROM AUTHOR]

The early stress of Maternal Separation (MS) contributes to the establishment of adult psychopathology. The serotonergic (5-HT) system is implicated during this temporal window in mediating the development of mood-related behaviors. MS is reported to evoke altered 5-HT 2A receptor function in adulthood. However, the ontogeny of altered 5-HT 2A receptor responsivity following MS remains unknown. Here, we examined 5-HT 2A receptor agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) (2 mg/kg) evoked responses, namely stereotypical head-twitch behaviors in control and MS Sprague-Dawley rat pups at postnatal day 21 (P21). MS involved a separation of pups from the dam for 3 h daily from postnatal day 2–14. MS pups at P21 exhibited significantly enhanced head-twitch behaviors compared to controls. Using c-Fos cell counting we examined neural activation in control and MS pups following DOI treatment. MS pups exhibited altered DOI-evoked c-Fos expression within all mPFC subdivisions, but not in the hippocampus, lateral septum and hypothalamus, suggesting differential prefrontal neural activation upon 5-HT 2A receptor stimulation following early stress. Gene profiling of 5-HT 2A receptor-regulated immediate early genes (IEGs) indicated a decline in the expression of Fos , Fra1 and Egr1 mRNA under baseline conditions in the mPFC of MS pups. MS pups also showed an altered pattern in the regulation of several 5-HT 2A receptor-regulated IEGs ( Fos , Fra1 , Bdnf , Egr1 , Egr3 ) following DOI treatment. Collectively, these results highlight an early emergence of altered 5-HT 2A receptor-evoked behavioral responses and neural activation patterns in multiple brain regions in animals with a history of MS. [ABSTRACT FROM AUTHOR]

The mammalian circadian clock is synchronized to the day : night cycle by light. Serotonin modulates the circadian effects of light, with agonists inhibiting response to light and antagonists enhancing responses to light. A special class of serotonergic compounds, the mixed 5- HT1A agonist/antagonists, potentiates light-induced phase advances by up to 400% when administered acutely. In this study, we examine the effects of one of these mixed 5- HT1A agonist/antagonists, BMY7378, when administered chronically. Thirty adult male hamsters were administered either vehicle or BMY7378 via surgically implanted osmotic mini pumps over a period of 28 days. In a light : dark cycle, chronic BMY7378 advanced the phase angle of entrainment, prolonged the duration of the active phase and attenuated the amplitude of the wheel-running rhythm during the early night. In constant darkness, chronic treatment with BMY7378 significantly attenuated light-induced phase advances, but had no significant effect on light-induced phase delays. Non-photic phase shifts to daytime administration of a 5- HT1A/7 agonist were also attenuated by chronic BMY7378 treatment. qRT- PCR analysis revealed that chronic BMY7378 treatment upregulated mRNA for 5- HT1A and 5- HT1B receptors in the hypothalamus and downregulated mRNA for 5- HT1A and monoamine oxidase-A in the brainstem. These results highlight adaptive changes of serotonin receptors in the brain to chronic treatment with BMY7378 and link such up- and downregulation to changes in important circadian parameters. Such long-term changes to the circadian system should be considered when patients are treated chronically with drugs that alter serotonergic function. [ABSTRACT FROM AUTHOR]

Objective: Weakness induced by critical illness (intensive care unit acquired weakness) is a major cause of disability in patients and is currently untreatable. We recently identified a defect in repetitive firing of lower motor neurons as a novel contributor to intensive care unit acquired weakness. To develop therapy for intensive care unit acquired weakness, it was necessary to determine the mechanism underlying the defect in repetitive firing.Methods: Both computer simulation and in vivo dynamic voltage clamp of spinal motor neurons in septic rats were employed to explore potential mechanisms underlying defective repetitive firing.Results: Our results suggest alteration in subthreshold voltage-activated currents might be the mechanism underlying defective repetitive firing. It has been shown previously that pharmacologic activation of serotonin receptors on motor neurons increases motor neuron excitability, in part by enhancing subthreshold voltage-activated inward currents. Administration of a U.S. Food and Drug Administration-approved serotonin agonist (lorcaserin) to septic rats greatly improved repetitive firing and motor unit force generation.Interpretation: Our findings suggest activation of serotonin receptors with lorcaserin may provide the first ever therapy for intensive care unit acquired weakness in patients. Ann Neurol 2017;82:961-971. [ABSTRACT FROM AUTHOR]

Background: Separation anxiety disorder was recently recognized by fifth edition of the Diagnostic and Statistical Manual of Mental Disorders as a diagnosis in adults, but no publications to date have characterized a sample of patients seeking treatment for adult separation anxiety disorder (ASAD) or assessed treatment efficacy. We hypothesized that vilazodone, a selective serotonin reuptake inhibitor (SSRI) and serotonin 1a (5HT1a ) receptor partial agonist, would have efficacy in ASAD, because SSRIs have appeared efficacious in children with mixed diagnoses including separation anxiety disorder and in animal models of separation anxiety.Methods: In this pilot study, 24 adults (ages 18-60) with a principal diagnosis of ASAD were randomized to 12 weeks of double-blind treatment with vilazodone (n = 13) or placebo (n = 11). Outcome was assessed by an independent evaluator and self-ratings, and analyzed with mixed effect models.Results: This sample was predominantly female (67%), with comorbid psychiatric disorders (58%), and adult onset of separation anxiety disorder (62%). Response rates at week 12 did not differ significantly between groups. Across all time points, the vilazodone group evidenced greater improvement on the Structured Clinical Interview for Separation Anxiety Symptoms (P = .026) and the Quality of Life Enjoyment and Satisfaction Questionnaire (P = .011), and trends toward greater improvement on the Adult Separation Anxiety Questionnaire (P = .054) and the Clinical Global Impression-Change Scale (P = .086), all with large between-group effect sizes.Conclusions: Findings demonstrate feasibility of a clinical trial in ASAD, and they suggest that vilazodone may have efficacy in the treatment of ASAD and warrants further study. [ABSTRACT FROM AUTHOR]

Although the notion that alcohol promotes violence is widespread, not all individuals are aggressive while intoxicated. Genetic variation could be a contributing factor to individual differences in alcohol-heightened aggression. The present study examines the effects of OPRM1C77G genotype on responses to threat in rhesus macaques under normal conditions and following alcohol administration. Prior studies have shown that a low CSF level of 5-HIAA is a trait marker for individuals prone to escalated aggression. We wanted to examine whether the predictive value for this marker on aggression was moderated by OPRM1 genotype. Animals were administered alcohol (BAC 100-200 mg%), were provoked by a human intruder, and aggressive responses were recorded. Factor analysis was performed to generate aggressive response factors, which were then used as dependent variables for ANOVA, with OPRM1 genotype and CSF 5-HIAA as independent variables. Factor analysis generated three factors ('Threatening', 'Distance Decreasing' and 'High Intensity'). We found that High Intensity aggression was increased among carriers of the OPRM1 G allele, especially among individuals with low CSF levels of 5-HIAA. Aggression in the non-intoxicated state was predicted by 5-HIAA, but not by genotype. This study demonstrates that OPRM1 genotype predicts alcohol-heightened aggression in rhesus macaques with low CSF levels of 5-HIAA. Because OPRM1 variation predicts similar effects on alcohol response and behavior in humans and macaques, this study could suggest a role for OPRM1 genotype in alcohol-heightened aggression in humans. If so, it may be that compounds that block this receptor could reduce alcohol-associated violence in selected patient populations. [ABSTRACT FROM AUTHOR]

What is known and objective Flibanserin is a serotonin 5-HT1A agonist and 5-HT2A antagonist approved for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Because of the increased risk of hypotension- and syncope-related adverse events (AEs) observed with coadministration of flibanserin and alcohol, alcohol use is contraindicated. To provide a more comprehensive understanding of the interaction between flibanserin and alcohol, the results of a dedicated phase 1 alcohol-interaction study and a pooled analysis of phase 3 studies of premenopausal women with HSDD are presented. Methods In the phase 1 study, healthy participants (males [n=23] and females [n=2]) were randomly assigned to one of five sequence groups, which determined the order in which they were to receive flibanserin 100 mg or placebo, with or without ethanol 0.4 g/kg or 0.8 g/kg. Change from baseline in seated blood pressure, orthostatic vital signs, AEs and visual analogue scale sedation outcomes were examined. Blood samples were collected at baseline and for up to 4 hours after dosing to determine flibanserin area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4). Pooled data from five phase 3 studies of patients receiving flibanserin 100 mg once daily (n=1543), or placebo (n=1905), were analysed. Results In the phase 1 study, the incidence of hypotension and syncope increased when flibanserin was coadministered with ethanol. Sedation increased 20% and 27% from baseline with flibanserin plus ethanol 0.4 g/kg and 0.8 g/kg, respectively, at 4 hours post-dose. In the pooled analysis of phase 3 studies, 58.2% and 63.6% of participants receiving flibanserin or placebo, respectively, reported baseline alcohol use. In patients receiving flibanserin, fatigue and dizziness occurred more frequently in patients with vs. without alcohol use. What is new and conclusion Results from this study suggest that increased incidence of hypotension- and syncope-related events may result from a pharmacodynamic interaction between flibanserin and alcohol, although the clinical significance of these interactions in real-world populations remains unclear. [ABSTRACT FROM AUTHOR]

Background Restless legs syndrome (RLS) is a sensorimotor disorder. It can be idiopathic, associated to other diseases or to pharmacologic treatments. RLS has been reported to occur more frequently in migraine patients, but a clear pathogenetic link seems still under debate. We aimed to evaluate RLS prevalence in migraine, impact on sleep quality and the main clinical determinants of this association. Methods Migraine patients and age- and sex-matched controls were enrolled from 1st January 2011 to 30th December 2012. Migraine and RLS diagnosis complied with already published clinical criteria. Medical and pharmacological histories, as well as structured questionnaires were collected. Results RLS was found in 29/180 (16.1%) patients and 11/180 (6.1%) controls. The odds ratio (OR) for RLS was 2.95 (CI 95%, 1.42-6.11). Among migraine patients, after adjustment for possible confounding factors, familial history (OR 3.863, CI 1.076-13.873), and serotoninergic overload (OR 3.654, CI 1.347-9.916) were significantly associated with RLS occurrence. Pittsburgh Sleep Quality Index score was higher in migraine patients with RLS than in subjects without RLS. Conclusions The confirmed association between migraine and RLS might be because of familial predisposition and to serotoninergic drugs effect, possibly interfering with the balance between dopaminergic and serotoninergic pathways. [ABSTRACT FROM AUTHOR]

Background and Purpose: Our previous studies revealed that hypidone hydrochloride (YL-0919), which acts as a selective 5-HT (serotonin) reuptake inhibitor (SSRI) and displays partial 5-HT1A receptor agonist properties, exerts a significant antidepressant effect in various animal models. The aim of present research was to further investigate the pharmacology of YL-0919.Experimental Approach: We first investigated the target profile of YL-0919 using [35 S]-GTPγS binding and microdialysis. To determine whether the 5-HT or noradrenergic systems are involved in the antidepressant-like effect of YL-0919, the 5-hydroxytryptophan (5-HTP)-induced head-twitch test and antagonism with a high dose of apomorphine were performed. Using the learned helplessness paradigm, the novelty suppressed feeding test, the Vogel-type conflict and elevated plus-maze test, we further verified the antidepressant-like and anxiolytic-like effects of YL-0919. The effects of YL-0919 on hippocampal long-term potentiation (LTP) and sexual behaviour were also evaluated.Key Results: Data from the present study demonstrated that YL-0919 displays partial 5-HT1A receptor agonist properties, producing a greater impact on extracellular 5-HT levels than a conventional SSRI (fluoxetine), as well as significant antidepressant and anxiolytic effects. Furthermore, YL-0919 treatment rapidly influenced the synaptic plasticity (enhancing LTP) of rats. Finally, at doses close to those producing antidepressant-like effects, YL-0919 did not result in a marked inhibition of sexual function.Conclusions and Implications: These data suggest that YL-0919 is probably a fast-onset potent antidepressant with few side effects. [ABSTRACT FROM AUTHOR]

The article presents the author's views regarding the pyschological aspects of childhood with respects with viewing their father. Details related to a child's perspective on considering their father's role of being an agonist, antagonists, or an inverse agonist are discussed, along with their inter-relations.

Background and Aim Prokinetics have been considered the first-line medicine for treating delayed gastric emptying. The aim of this study was to explore the effects and mechanisms of a new 5-HT4 receptor agonist, YKP10811, on gastric motility in dogs. Methods Four experiments were performed in dogs: (i) dose-response effects of YKP10811 on liquid gastric emptying; (ii) effects and mechanisms of YKP10811 on solid gastric emptying delayed by glucagon; (iii) effects of low-dose YKP10811 on antral contractions; and (iv) effects of low-dose YKP10811 on gastric accommodation. Results No adverse events or cardiac dysrhythmia was noted. (i) High-dose YKP10811 (30 mg/kg) accelerated liquid gastric emptying from 15 to 90 min without inducing adverse events or cardiac dysrhythmia. YKP10811 at low doses (0.3, 1, and 3 mg/kg) accelerated gastric emptying in a dose-dependent manner. (ii) YKP10811 (0.1 mg/kg), but not tegaserod (0.3 mg/kg), significantly accelerated glucagon-induced delayed gastric emptying of solid, and the effect was completely blocked by GR113808. (iii) YKP10811 (0.3 mg/kg) enhanced antral contractions. (iv) YKP10811 did not alter gastric accommodation. Conclusions YKP10811 seems to improve antral contractions and accelerate gastric emptying without altering gastric accommodation in dogs via the 5-HT4 mechanism and is substantially more potent than tegaserod. No adverse events were noted at a dose 300 times the lowest effective dose. YKP10811 may have a therapeutic potential for gastroparesis. [ABSTRACT FROM AUTHOR]