Pre-treatment with Tandospirone attenuates fentanyl-induced respiratory depression without affecting the analgesic effects of fentanyl in rodents.

Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the "TS + fentanyl" and "saline + fentanyl" group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management.

Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling: a double-blind, randomised, controlled, phase 3 trial in nine countries.

BACKGROUND: Major depressive disorder is a severe illness that frequently manifests before the age of 18 years, often recurring later in life. Paediatric medical treatment options are scarce. The melatonin receptor agonist and 5-hydroxytryptamine2C receptor antagonist agomelatine is used to treat adults, and could offer a new therapeutic option for paediatric patients. Therefore, we aimed to investigate the short-term antidepressant efficacy and safety of agomelatine in children and adolescents with major depressive disorder. METHODS: We performed a 12 week, randomised, double-blind, parallel-group, multicentre, phase 3 trial in 46 specialist psychiatric units or centres in Bulgaria, Finland, Hungary, Poland, Romania, Russia, Serbia, South Africa, and Ukraine. Participants (aged 7-17 years) were eligible if they were unresponsive to psychosocial therapy during the 3-week run-in period (Children's Depression Rating Scale-revised [CDRS-R] score of ≥45). Ethnicity was not recorded. We investigated short-term antidepressant efficacy of agomelatine (10 mg or 25 mg per day) versus placebo with an active control (fluoxetine 10-20 mg depending on symptom severity) after 12 weeks of treatment in children (aged 7-11 years) and adolescents (12-17 years) with major depressive disorder. Patients were randomly assigned (1:1:1:1) to agomelatine 10 mg, agomelatine 25 mg, placebo, or fluoxetine via an interactive response system with permuted-block randomisation. Standardised manualised psychosocial counselling, developed for this trial, was initiated from selection and continued throughout the study, including the open-label extension. All people involved in the conduct of the clinical trial and patients were masked to treatment allocation. Study outcomes were measured using standardised interviews at each study visit. The primary endpoint was change in CDRS-R raw score from baseline to week 12. This study is registered with EudraCT, 2015-002181-23. FINDINGS: Between Feb 23, 2016, and Jan 14, 2020, 466 individuals were assessed for eligibility and of 400 included patients, 396 (247 [62%] girls, 149 [38%] boys; mean age 13·7 years [SD 2·7]) were analysed (full analysis set). The primary objective was met; 25 mg/day agomelatine (n=94, with n=102 receiving 10 mg/day) resulted in an improvement versus placebo (n=101) in CDRS-R raw score of 4·22 (95% CI 0·63-7·82; p=0·040) at 12 weeks, with a similar effect for fluoxetine (n=99), establishing assay sensitivity. The overall effect was confirmed in adolescents (n=317), but not in children (n=79). No unexpected safety signals were observed with agomelatine, with no significant weight gain or effect on suicidal behaviours. INTERPRETATION: This first study in a paediatric population supports the efficacy of 25 mg/day agomelatine, in addition to psychosocial counselling, in treating adolescent patients with major depressive disorder, with no unexpected safety signals. This medication could provide another option in the limited psychopharmaceutical repertoire for management of major depressive disorder. FUNDING: Servier. VIDEO ABSTRACT.

Pharmacokinetic Study of Frovatriptan Succinate Tablet After Single and Multiple Oral Doses in Chinese Healthy Subjects.

PURPOSE: The present report describes findings from a Phase I clinical study that evaluated the single- and multiple-dose pharmacokinetics of frovatriptan succinate tablet in Chinese healthy subjects. METHODS: A total of 24 healthy subjects were enrolled. In single-dose study, 2.5, 5, and 10 mg oral doses of frovatriptan succinate tablet were administrated. A 2.5 mg frovatriptan succinate tablet was administrated 12 times in 7 days in the multiple-dose study. Blood samples were collected at scheduled time points. RESULTS: The results in single-dose study indicated that the blood levels were proportional to the administered dose, with the mean Cmax and AUClast ranging from approximately 6.27 ng/mL-17.35 ng/mL and 92.52 h⋅ng/mL - 287.40 h⋅ng/mL over the dose range. In the multiple-dose study, moderate drug accumulation was noted, which was attributable to forvatriptan's long t1/2 of about 26.47 to 30.63 h. Gender differences were noticed in both single- and multiple-dose study; exposure PK parameters were consistently higher in female than in male. CONCLUSION: These pharmacokinetic evaluations in healthy Chinese subjects found that frovatriptan succinate tablet has an acceptable pharmacokinetic profile in Chinese subjects.

Involvement of 5-HT1A receptor-mediated histone acetylation in the regulation of depression.

Depression is one of the most common and disabling mental disorders. There is growing evidence that 5-HT1A receptor is involved in the regulation of depressive-related behaviors. However, the exact mechanism underlying the role of 5-HT1A receptor in depression remains unknown. Histone acetylation is associated with the pathophysiology and treatment of depression. In the current study, we investigated whether the epigenetic histone deacetylase (HDAC)-induced histone acetylation mediates the regulation of 5-HT1A receptor in depressive behaviors. We showed that 5-HT1A receptor selective agonist (±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide led to significant increase in acetylation of H3 at lysine 9 (Ac-H3K9) and H4 at lysine 5 (Ac-H4K5) and lysine 12 (Ac-H4K12) with obviously decreasing histone deacetylase 1 (HDAC1), histone deacetylase 2 (HDAC2), histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5) expression in hippocampus of mice. Conversely, 5-HT1A receptor selective antagonist NAN-190 decreased the level of acetylation of H3 and H4 with increasing the expression of HDAC1, HDAC2, HDAC4 and HDAC5 in the hippocampus. Furthermore, we found that HDAC inhibitors, trichostatin A or suberoylanilide hydroxamic acid infusion to hippocampus prevented the depressive behaviors induced by NAN-190, as well as histone H3 and H4 acetylation in mice. Our results suggested that epigenetic histone acetylation coupled with 5-HT1A receptor may play vital role in the pathophysiology and treatment of depressive disorders.

Effect of a change in lasmiditan dose on efficacy and safety in patients with migraine.

Background: Lasmiditan is a selective serotonin (1F) receptor agonist approved for acute treatment of migraine with 3 doses: 50, 100, and 200 mg.Objective: To help provide dosing insights, we assessed the efficacy and safety of lasmiditan in patients who treated two migraine attacks with the same or different lasmiditan doses.Methods: Integrated analyses used data from the migraine attack treated in either of two controlled, Phase 3, single attack studies (SAMURAI/SPARTAN), and after the first attack treated in the open-label GLADIATOR extension study. Eight patient groups were created based on the initial dose received in SAMURAI or SPARTAN and the subsequent dose in GLADIATOR: placebo-100, placebo-200, 50-100, 50-200, 100-100, 100-200, 200-100, 200-200. Migraine pain freedom, migraine-related functional disability freedom, most bothersome symptom (MBS) freedom, and pain relief were evaluated at 2-h post-dose. The occurrence of most common treatment-emergent adverse events (MC-TEAE) was evaluated. Shift analyses were performed for pain freedom and ≥1 MC-TEAE. The incidence of patients with a specific outcome from the first and subsequent doses were compared within each dose change group using McNemar's test.Results: Small, but consistent, increases in incidences of pain freedom, migraine-related functional disability freedom, MBS freedom, and pain relief occurred when the second lasmiditan dose was higher than the initial dose. For patients starting on 50 mg, increasing to 100 or 200 mg provided a positive efficacy-TEAE balance, despite an increase in incidence of ≥1 MC-TEAE. For patients starting on 100 mg, increasing to 200 mg provided a positive efficacy-TEAE balance. If the initial dose was 100 or 200 mg, the incidence of patients experiencing ≥1 MC-TEAE decreased or stayed the same with their subsequent dose, regardless of dose. Decreasing from 200 to 100 mg led to a decrease in patients with pain freedom and ≥1 MC-TEAE, resulting in a neutral efficacy-TEAE balance. Shift analyses supported these findings.Conclusion: A positive efficacy-TEAE balance exists for patients increasing their lasmiditan dose for treatment of a subsequent migraine attack. These results could be important for optimizing dosing for individual patients.Clinicaltrials.gov: SAMURAI (NCT02439320); SPARTAN (NCT02605174); GLADIATOR (NCT02565186).

Chronic Lorcaserin Treatment Reverses the Nicotine Withdrawal-Induced Disruptions to Behavior and Maturation in Developing Neurons in the Hippocampus of Rats.

Preclinical data have shown that treatment with serotonin (5-HT)2C receptor agonists inhibits the behavioral effects of nicotine, including self-administration, reinstatement, and locomotor responses to nicotine. Since the data on the effects of 5-HT2C receptor agonism on nicotine withdrawal signs are limited, we aimed to investigate whether 5-HT2C receptor agonism alleviated the behavioral and neurobiochemical (hippocampal neurogenesis) consequences of nicotine withdrawal in Sprague-Dawley rats. Our data indicate that withdrawal from nicotine self-administration induced locomotor hyperactivity, lengthened immobility time (the forced swim test), induced 'drug-seeking' behavior and deficits in cognition-like behavior (the novel object recognition task). A two-week exposure to the 5-HT2C receptor agonist lorcaserin attenuated locomotor hyperactivity and induced recovery from depression-like behavior. Analyses of brain slices from nicotine-withdrawn animals revealed that lorcaserin treatment recovered the reduced number of doublecortin (DCX)-positive cells, but it did not affect the number of Ki-67- or 5-bromo-2'-deoxyuridine (BrdU)-positive cells or the maturation of proliferating neurons in drug-weaned rats. To summarize, we show that lorcaserin alleviated locomotor responses and depression-like state during nicotine withdrawal. We propose that the modulatory effect of lorcaserin on the 'affective' aspects of nicotine cessation may be linked to the positive changes caused by the compound in hippocampal neurogenesis during nicotine withdrawal.

Activation of 5-HT1A and 5-HT7 receptors enhanced a positively reinforced long-term memory.

Memory is one of the most important capabilities of our mind since it determines our individuality. Memory formation involves different stages: acquisition, consolidation and retrieval. There are many studies about early stages, however little is known about memory retrieval. Retrieval is the use of learned information and represents a big problem in patients with memory deficits where the main issue is that they can learn but cannot remember. Previous findings have demonstrated that 5-hydroxytryptamine (5-HT) is a neurotransmitter involved in memory process. Hence, here we are exploring the role of 5-HT in memory retrieval by using its metabolic precursor l-tryptophan and several ligands at 5-HT1A and 5-HT7 receptors. Experimental protocol consisted of evaluating conditioned responses (%CR) after one week of interruption following autoshaping sessions for memory formation; a decrease of %CR was interpreted as memory decay. Systemic administration of: (1) l-tryptophan (50 and 100 mg/kg), (2) 5-HT1A receptor agonist 8-OH-DPAT (0.031 and 0.062 mg/kg), (3) the selective antagonist 5-HT1A receptor WAY 100635 (0.3 and 0.6 mg/kg), (4) the 5-HT7 receptor agonist, LP 211, in a dose-dependent manner (1, 2.5, 5.0 and 10.0 mg/kg) enhanced memory retrieval. Further, the 5-HT7 receptor antagonist, SB 269970 (10.0 mg/kg), had no effect. Finally, SB 269970 (10.0 mg/kg) significantly blocked memory retrieval enhancement produced by 10.0 mg/kg LP 211, but not that induced by 2.5 mg/kg LP 211.These results, taken together, suggest that activation of 5-HT1A and 5-HT7 receptors enhanced memory retrieval and these receptors may be therapeutic targets to improve long-term memory retrieval.

Effects of repeated RU 24969 treatment on the locomotor activity, motoric capacity, and axillary temperatures of male and female preweanling rats.

Serotonin (5-HT) 1A and 1B receptors have been implicated in behavioral sensitization, but adult rats appear to develop tolerance to RU 24969 (a 5-HT1A/1B receptor agonist) rather than a sensitized response. The purpose of the present study was to determine whether a one- or four-day pretreatment regimen of RU 24969 would cause sensitization or tolerance in male and female preweanling rats. Depending on experiment, rats were pretreated with RU 24969 (0, 2.5, or 5 mg/kg) for 1 or 4 days (PD 17-20), while testing with lower or higher doses of RU 24969 occurred on PD 22. Locomotor activity, motoric capacity, and axillary temperatures were recorded. The role of Pavlovian contextual conditioning was assessed by administering RU 24969 to rats in either the home cage or a novel environment. On the first pretreatment day, RU 24969 caused both an increase in forward locomotion and motoric impairment, along with a substantial decrease in axillary temperatures. Repeated treatment with the same dose of RU 24969 caused all three dependent measures to show a tolerance response. When given a higher dose of RU 24969 on the test day, the responses lost due to repeated drug treatment were fully (locomotor activity) or partially (motoric capacity and axillary temperatures) reinstated. There was no evidence of behavioral tolerance. Results are consistent with the hypothesis that a subsensitivity of 5-HT1A/1B receptors is at least partially responsible for the tolerance caused by RU 24969, but dispositional tolerance cannot be excluded as a contributing factor.

Ethanol induces persistent potentiation of 5-HT3 receptor-stimulated GABA release at synapses on rat hippocampal CA1 neurons.

Several studies have shown that ethanol (EtOH) can enhance the activity of GABAergic synapses via presynaptic mechanisms, including in hippocampal CA1 neurons. The serotonin type 3 receptor (5-HT3-R) has been implicated in the neural actions of ethanol (EtOH) and in modulation of GABA release from presynaptic terminals. In the present study, we investigated EtOH modulation of GABA release induced by 5-HT3-R activation using the mechanically isolated neuron/bouton preparation from the rat CA1 hippocampal subregion. EtOH application before and during exposure to the selective 5-HT3 receptor agonist, m-chlorophenylbiguanide (mCPBG) potentiated the mCPBG-induced increases in the peak frequency and charge transfer of spontaneous GABAergic inhibitory postsynaptic currents. Interestingly, the potentiation was maintained even after EtOH was removed from the preparation. A protein kinase A inhibitor reduced the magnitude of EtOH potentiation. Fluorescent Ca2+ imaging showed that Ca2+ transients in the presynaptic terminals increased during EtOH exposure. These findings indicate that EtOH produces long-lasting potentiation of 5-HT3-induced GABA release by modulating calcium levels, via a process involving cAMP-mediated signaling in presynaptic terminals.

YH12852, a Potent and Selective Receptor Agonist of 5-hydroxytryptamine, Increased Gastrointestinal Motility in Healthy Volunteers and Patients With Functional Constipation.

Gastrointestinal (GI) motility disorders are common, decreases quality of life, and imposes a substantial economic burden. YH12852 is a novel agonist of 5-hydroxytryptamine for the treatment of GI motility disorders. This phase I/IIa study assessed the tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of YH12852. In the multiple dose (MD) cohort, healthy subjects and patients with functional constipation were randomized and received orally YH12852 at 0.3, 0.5, 1, 2, or 3 mg or prucalopride 2 mg or their matching placebo, once daily for 14 days after breakfast. In the multiple low-dose cohort (MLD), healthy subjects randomly received once-daily oral doses of YH12852 at 0.05 or 0.1 mg for 14 days after breakfast. Questionnaires, gastric emptying breath test for PDs, and plasma samples for PKs were collected. In the MD cohort, a total of 56 subjects (29 healthy volunteers and 27 patients with functional constipation) were randomized, of whom 48 completed the study. In the MLD cohort, a total of 16 healthy subjects were randomized, and 15 subjects completed the study. YH12852 increased the average weekly frequency of spontaneous bowel movements and loosened the stool. In addition, YH12852 increased quality of life satisfaction, and decreased severity of constipation symptom and GI symptoms. YH12852 was safe and well-tolerated up to 3 mg and showed nearly dose proportional PKs. In conclusion, YH12852 was safe and enhanced GI motility. YH12852 can be developed as an effective treatment option for GI motility disorders, including functional constipation. Further studies are warranted to confirm this possibility.

Oral mosapride can provide additional anti-emetic efficacy following total joint arthroplasty under general anesthesia: a randomized, double-blinded clinical trial.

BACKGROUND: We sought to determine (1) whether the addition of prophylactic oral mosapride to a protocol including dexamethasone and ondansetron further reduces postoperative nausea and vomiting (PONV) compared with ondansetron alone or the combination of both; (2) whether preemptive application of oral mosapride provides additional clinical benefits for bowel function and appetite, thus improving functional recovery. METHODS: We randomized 240 patients undergoing total hip and knee arthroplasty to receive placebo (Control, n = 80), dexamethasone (10 mg) before anesthesia induction (Dexa, n = 82), or dexamethasone (10 mg) before anesthesia induction as well as oral mosapride (5 mg) before and after surgery (Mosa+Dexa, n = 78). Patients were assessed at 0-6, 6-12, 12-24, and 24-48 h postoperatively. Primary outcomes were incidence and severity of PONV as well as complete response. Secondary outcomes were appetite, time until first defecation and ambulation, patient satisfaction score, and length of hospital stay. RESULTS: Mosa+Dexa patients showed significantly lower incidence of nausea at 6-12 h (3.8%) and over the entire evaluation period (6.4%), as well as a higher rate of complete response (89.7%) than other patients. Mosa+Dexa patients required less time to achieve first defecation and ambulation, they were hospitalized for shorter time, and they were more satisfied with clinical care. CONCLUSION: Addition of oral mosapride further reduced incidence of PONV, especially postoperative nausea, during 6-12 h postoperatively. Moreover, preemptive application of oral mosapride can further improve appetite, bowel function, ambulation and length of hospital stay. TRIAL REGISTRATION: The study protocol was registered at the Chinese Clinical Trial Registry ( ChiCTR1800015896 ), prospectively registered on 27/04/2018.

The Efficacy of Lasmiditan for the Treatment of Migraine: A Meta-Analysis of Randomized Controlled Studies.

INTRODUCTION: The efficacy of lasmiditan is used to alleviate migraine. We conduct a systematic review and meta-analysis to explore the influence of lasmiditan versus placebo on pain control in patients with migraine. METHODS: We search the PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through June 2020 for randomized controlled trials (RCTs) assessing the effect of lasmiditan versus placebo on pain control in patients with migraine. This meta-analysis was performed using the random effects model. RESULTS: Four randomized controlled trials are included in the meta-analysis. Overall, compared with the control group, in patients with migraine, lasmiditan treatment shows positive impact on pain free at 2 hours [risk ratio (RR), 1.74; 95% confidence interval (CI), 1.47-2.07; P < 0.00001], headache response at 2 hours (RR, 1.38; 95% CI, 1.28-1.49; P < 0.00001), pain free at 24 hours (RR, 1.55; 95% CI, 1.16-2.07; P = 0.003), and no or mild disability level (RR, 1.20; 95% CI, 1.11-1.29; P < 0.00001), but has no obvious influence on nausea (RR, 2.22; 95% CI, 0.92-5.35; P = 0.08). In addition, lasmiditan seems to result in the increase in dizziness (RR, 6.36; 95% CI, 3.00-13.46; P < 0.0001) and paresthesia (RR, 5.10; 95% CI, 2.66-9.78; P < 0.00001). CONCLUSIONS: Lasmiditan treatment provides additional benefits for pain control in patients with migraine.

Targeting the 5-HT system: Potential side effects.

Targeting the serotonin (5-HT) system is no simple task: there are at least 15 5-HT receptors, in addition to a number of transporters and metabolizing enzymes. Multiple 5-HT receptor variants exist due to genetic variations and/or post translational modifications, splice variants or editing variants. Some receptors may form homo and heteromers. The 5-HT system is targeted by multiple drugs to treat a variety of diseases. Given the homology amongst the 5-HT and neighbouring receptor classes, only few drugs are actually selective for a single target. In fact, many 5-HT drugs act on a combination of targets, i.e. several receptors and/or transporters or enzymes. For instance, a number of antidepressants or antipsychotics act on 5-HT and other transmitter systems. Recently developed drugs may show target selectivity by design, based on the current state of knowledge, whereas many older compounds hit multiple targets since they were developed using phenotypic screens, as was done well into the 1980's. Ergot analogues, antipsychotics or antidepressants, fall into this category. As our knowledge developed over the last 25-30 years, some targets have very well-defined liabilities: for instance, 5HT2B or 5-HT2A receptor agonists, will produce valvulopathies or hallucinations, respectively, whereas 5-HT3 receptor antagonists, may lead to constipation. This short review will be limited in scope as there are multiple targets and even more compounds to discuss. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Lasmiditan in patients with common migraine comorbidities: a post hoc efficacy and safety analysis of two phase 3 randomized clinical trials.

OBJECTIVE: Determine whether common migraine comorbidities affect the efficacy and safety of lasmiditan, a 5-HT1F receptor agonist approved in the United States for the acute treatment of migraine. METHODS: In SPARTAN and SAMURAI (double-blind Phase 3 clinical trials), patients with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100mg, 200 mg, or placebo. Lasmiditan increased the proportion of pain-free and most bothersome symptom (MBS)-free patients at 2 h after dose compared with placebo. Most common treatment-emergent adverse events (TEAEs) were dizziness, paraesthesia, somnolence, fatigue, nausea, muscular weakness, and hypoesthesia. Based upon literature review of common migraine comorbidities, Anxiety, Allergy, Bronchial, Cardiac, Depression, Fatigue, Gastrointestinal, Hormonal, Musculoskeletal/Pain, Neurological, Obesity, Sleep, and Vascular Comorbidity Groups were created. Using pooled results, efficacy and TEAEs were assessed to compare patients with or without a given common migraine comorbidity. To compare treatment groups, p-values were calculated for treatment-by-subgroup interaction, based on logistic regression with treatment-by-comorbidity condition status (Yes/No) as the interaction term; study, treatment group, and comorbidity condition status (Yes/No) were covariates. Differential treatment effect based upon comorbidity status was also examined. Trial registration at clinicaltrials.gov: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). RESULTS: Across all the Comorbidity Groups, with the potential exception of fatigue, treatment-by-subgroup interaction analyses did not provide evidence of a lasmiditan-driven lasmiditan versus placebo differential treatment effect dependent on Yes versus No comorbidity subgroup for either efficacy or TEAE assessments. CONCLUSIONS: The efficacy and safety of lasmiditan for treatment of individual migraine attacks appear to be independent of comorbid conditions.

Lasmiditan for Acute Treatment of Migraine in Adults: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The US Food and Drug Administration has approved orally administered 100-mg and 200-mg doses of lasmiditan for the acute treatment of migraine, with or without aura. Having a unique mechanism of action, lasmiditan is the first and only Food and Drug Administration-approved serotonin 5-HT1F receptor agonist. OBJECTIVE: The objective of this study was to systematically evaluate the efficacy and safety of lasmiditan for the acute treatment of migraine in adult patients. METHODS: We systematically searched PUBMED, EMBASE, and Cochrane Library databases. Any relevant articles published before 3 March, 2020 were collected. Inclusion criteria were: (1) randomized clinical trials; (2) enrolled adult participants diagnosed with migraine; (3) compared lasmiditan at 100 mg or 200 mg with placebo; (4) enrolled more than 100 participants; and (5) provided any available data for predefined primary or secondary outcomes. RESULTS: Three high-quality, multi-centered randomized clinical trials with 4506 patients in total were included. We found that the use of lasmiditan was related to a significantly increased rate of pain freedom at 2 h post-dose with 31.60% patients achieving freedom of pain in the lasmiditan group compared with 17.55% patients in the placebo group (relative risk [RR] 1.80 [95% confidence interval (CI) 1.34-2.42]), with no significant heterogeneity. In addition, lasmiditan is reported to significantly increase the rate of absence of the most bothersome symptoms at 2 h compared with the placebo group with no significant heterogeneity (lasmiditan, 42.82%; placebo, 30.38%; RR 1.44 [95% CI 1.03-2.01], I2 = 0%). With regard to the safety endpoints, compared with the placebo group, participants in the lasmiditan group had a higher rate of fatigue, paresthesia, and somnolence (fatigue: lasmiditan, 1.94%; placebo, 0.24%; RR 7.96 [95% CI 0.4-158.86]; paresthesia: lasmiditan, 6.91%; placebo, 1.56%; RR 4.46 [95% CI 1.54-12.93], somnolence: lasmiditan, 5.9%; placebo, 2.15%; RR 2.76 [95% CI, 1.49-5.11]) with low heterogeneity. A subgroup analysis demonstrated that without safety differences, participants who received the 200-mg dose had a higher percentage of freedom of pain at 2 h and sustained pain relief at 2-24 h compared with the 100-mg dose (freedom of pain at 2 h: lasmiditan, 34.53%; placebo, 28.67%; RR 1.2 [95% CI 1.04-1.38]; lasmiditan, 20.62%; placebo, 16.33%; RR 1.26 [95% CI 1.19-1.34]), with low heterogeneity for both outcomes (I2 = 0%). CONCLUSIONS: In this meta-analysis, the use of lasmiditan as an acute treatment for episodic migraine in adults led to a greater percentage of freedom of pain and the absence of the most bothersome symptoms at 2 h post-dose. Lasmiditan 200 mg had superior efficacy to 100-mg dose without a significantly increased risk for adverse events.

Attenuation of stress-induced behavioral changes by activation of serotonin type 7 receptors in the median raphe nucleus of rats.

BACKGROUND: Exposure to stressful aversive situations induces physiological and behavioral changes. Serotonin has been suggested to mediate such changes, as well as adaptation to stressful events. Serotoninergic projections arising from the median raphe nucleus to the dorsal hippocampus have been suggested to promote adaptation to chronic aversive stimuli. Such pathway may involve serotonin type 1a receptor-mediated neurotransmission. However, the serotonin 7 receptor can also be found in the median raphe nucleus and may be involved in mechanisms underlying response to stress. AIMS: In this work we sought to investigate if activation of serotonin type 7 receptors would attenuate stress-induced deficits in different animal models of depression. METHODS: Male Wistar rats with a guide-cannula aimed to the median raphe nucleus were submitted to restraint or forced swim stress and were tested in an elevated plus maze or forced swim test, respectively, 24 h later. SB 258741 (serotonin type 7 receptor antagonist) and/or LP 44 (serotonin type 7 receptor agonist) were administered intra-median raphe nucleus immediately before or after exposure to stress or before test. Control groups received intra-median raphe nucleus treatment 24 h or immediately before test in the elevated plus maze or forced swim test. RESULTS: LP 44 attenuated restraint-induced exploratory deficits independently of the moment it was administered. Similar results were observed in the forced swim test, with the exception on post-stress condition. These effects on adaptation to stress induced by serotonin type 7 receptor activation were prevented by previous treatment with SB 258741. CONCLUSIONS: Our data support the idea that activation of median raphe nucleus serotonin 7 receptor is important to the development of adaptation to stress.

Evaluation of 2-Hour Post-Dose Efficacy of Lasmiditan for the Acute Treatment of Difficult-to-Treat Migraine Attacks.

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.

Comparative assessment of in vitro/in vivo performances of orodispersible electrospun and casting films containing rizatriptan benzoate.

The electrospinning process is a promising approach to produce various drug-loaded orodispersible films (ODFs) with a rapid onset of their actions. However, there is only limited number of studies comparing the pharmacological performances of electrospun ODFs (eODFs) with traditional casting films (CFs). In this study, rizatriptan benzoate (RB), a pain relieving agent was formulated with PVP and PVA into ODFs using electrospinning and casting methods. The ODFs were subsequently characterized with respect to their morphology, solid state properties and mechanical characteristics. The uniformity of the dosage units, disintegration behavior and dissolution patterns of the ODFs were also evaluated prior to the pharmacokinetic study. The obtained CFs and eODFs were semitransparent and white in appearance, respectively. The scanning electron microscopy revealed that the eODFs contained nanoporous structure, while the CFs showed no observable pores. RB was amorphously dispersed in both these films without drug-polymer interactions. The uniformity of dosage units for both eODFs and CFs was complied with European Pharmacopeia. As compared to the CFs, the eODFs were more flexible and lesser rigid in nature and showed faster disintegration and dissolution rates. In addition, the eODFs exhibited a higher bioavailability with a shorter Tmax relative to the CFs and commercial RB tablets. This study demonstrated that eODFs were superior to CFs with respect to in vivo pharmacological effects, which could be attributed to the submicron structure of eODFs obtained through the electrospinning process.

Quipazine Elicits Swallowing in the Arterially Perfused Rat Preparation: A Role for Medullary Raphe Nuclei?

Pharmacological neuromodulation of swallowing may represent a promising therapeutic option to treat dysphagia. Previous studies suggested a serotonergic control of swallowing, but mechanisms remain poorly understood. Here, we investigated the effects of the serotonergic agonist quipazine on swallowing, using the arterially perfused working heart-brainstem (in situ) preparation in rats. Systemic injection of quipazine produced single swallows with motor patterns and swallow-breathing coordination similar to spontaneous swallows, and increased swallow rate with moderate changes in cardiorespiratory functions. Methysergide, a 5-HT2 receptor antagonist, blocked the excitatory effect of quipazine on swallowing, but had no effect on spontaneous swallow rate. Microinjections of quipazine in the nucleus of the solitary tract were without effect. In contrast, similar injections in caudal medullary raphe nuclei increased swallow rate without changes in cardiorespiratory parameters. Thus, quipazine may exert an excitatory effect on raphe neurons via stimulation of 5-HT2A receptors, leading to increased excitability of the swallowing network. In conclusion, we suggest that pharmacological stimulation of swallowing by quipazine in situ represents a valuable model for experimental studies. This work paves the way for future investigations on brainstem serotonergic modulation, and further identification of neural populations and mechanisms involved in swallowing and/or swallow-breathing interaction.