col-144 and Fatigue

The effective anti-migraine drugs triptans, all bind with high affinity to three serotonin (5-HT) subtypes, the 5-HT1B, 5-HT1D and 5-HT1F. 5-HT1B mRNA is densely localized within smooth muscle, and less in the endothelium of cerebral blood vessels. This vascular distribution of 5-HT1B receptor has been shown to mediate the vasoconstrictive properties of the triptans, responsible for potential cardiac adverse events. Activation of 5-HT1D subtype, although effective in animal models of migraine, was not enough efficient to attenuate migraine attacks in clinical trials. The 5-HT1F receptor is located both in vessels and within the trigeminal ganglion (TG) and the trigeminal nucleus caudalis (Sp5C), but with the difference that the 5-HT1F receptor lack vasoconstrictive properties, making it an attractive target for new anti-migraine drugs. Selective activation of 5-HT1F receptor potently inhibited markers associated with electrical stimulation of the TG. Thus 5-HT1F receptor represents an ideal target for anti-migraine drugs. So far two selective 5-HT1F agonists have been tested in human trials for migraine: LY334370 and lasmiditan. Both molecules were efficient in attenuating migraine attacks with efficacy in the same range as oral sumatriptan 100mg, the gold standard for triptans. The LY334370 project withdrew because of toxicity in animals, while lasmiditan is still testing. In this review we present all the available preclinical and clinical data on the 5-HT1F agonists as a potential new class of anti-migraine drugs lacking vascular activity and we discuss related issues on the vascular and neuronal aspects of migraine pathogenesis.

Topics: Animals; Benzamides; Carbazoles; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Fatigue; Fluorobenzenes; Humans; Indoles; Migraine Disorders; Models, Neurological; Molecular Targeted Therapy; Nausea; Paresthesia; Pilot Projects; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists; Treatment Outcome; Vertigo

We assessed the safety profile of lasmiditan, a selective 5-HT. SAMURAI and SPARTAN were Phase 3 double-blind studies of patients with migraine, randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo to be taken within 4 hours of onset of migraine pain. Safety data from the studies were integrated. Treatment-emergent adverse events (occurring within 48 hours of first dose) were considered in the analyses.. The safety population comprised 1262 patients assigned placebo, and 654, 1265, and 1258 assigned lasmiditan 50 mg, 100 mg, and 200 mg, respectively. There were no deaths; serious adverse events were reported for seven patients (placebo, n = 2 [0.2%]; lasmiditan 50 mg, n = 1 [0.2%]; lasmiditan 100 mg, n = 1 [0.2%]; lasmiditan 200 mg, n = 3 [0.2%]). Patients reporting ≥ 1 treatment-emergent adverse events were: Placebo, n = 174 (13.5%); lasmiditan 50 mg, n = 166 (25.4%); lasmiditan 100 mg, n = 458 (36.2%); and lasmiditan 200 mg, n = 510 (40.6%). Treatment-emergent adverse events were generally mild or moderate in severity. The most common treatment-emergent adverse events with lasmiditan were dizziness, paresthesia, somnolence, fatigue, nausea, muscular weakness and hypoesthesia. There were no ischemic events.. As a centrally-penetrant drug, lasmiditan use was associated with neurologic treatment-emergent adverse events; most were mild or moderate in severity and self-limiting.. SAMURAI (NCT02439320) and SPARTAN (NCT02605174).

Topics: Administration, Oral; Adult; Benzamides; Double-Blind Method; Fatigue; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Vertigo