piperidines and candesartan

To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications.. While lasmiditan has been proven to be an effective acute treatment for migraine, its effectiveness has not been examined when used concurrently with migraine preventives.. SAMURAI and SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies of patients 18 years or older with 3 to 8 migraine attacks per month. Patients were randomized to treat a migraine attack with oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Migraine preventives were allowed as long as doses were stable for 3 months prior to screening and were unchanged during the study. Preventive medications with established or probable efficacy, as recommended by the American Academy of Neurology, the American Headache Society, and the European Headache Federation, plus botulinum toxin type A and candesartan, were included. Within the subgroups of patients using and not using preventive therapies, lasmiditan and placebo groups were analyzed for the outcome of pain-free at 2 h and other efficacy outcomes. The subgroups of patients using and not using preventive therapies were compared and interaction p-values were calculated for safety and efficacy outcomes.. In these trials, 698 of 3981 patients (17.5%) used migraine preventive treatments. Among patients using preventives, all lasmiditan doses resulted in significantly more patients being pain-free at 2 h, compared to placebo (p < 0.05). Primary efficacy outcome (pain-free at 2 h), key secondary outcome (most bothersome symptom-free at 2 h) and all other efficacy outcomes were not significantly different between patients using or not using migraine preventives (all interaction p-values ≥0.1). Rates of adverse events were similar for patients using and not using preventive medications.. Lasmiditan was more effective than placebo for the acute treatment of migraine in patients concurrently using migraine preventive medications. Lasmiditan efficacy and safety measures were similar for patients using and not using preventive medications.. SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Registered 18 March 2015.

Topics: Adult; Benzamides; Benzimidazoles; Biphenyl Compounds; Botulinum Toxins, Type A; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Tetrazoles; Treatment Outcome

Hypertensive transgenic (mRen2)27 rats exhibit impaired baroreflex sensitivity (BRS) for control of heart rate (HR). Intracerebroventricular infusion of Ang-(1-7) improves indices of vagal BRS independent of lowering mean arterial pressure (MAP), whereas AT1 receptor blockade normalizes MAP and indices of sympathetic tone without correcting the vagal BRS. Scavenging cellular reactive oxygen species (ROS) with tempol in brain fails to correct either hypertension or sympathovagal balance in these animals, despite reports that mitochondrial ROS contributes to Ang II-infusion hypertension. To examine effects of a putative preferential mitochondrial ROS scavenger in the brain of (mRen2)27 rats, ICV infusions of Mito-TEMPO (3.2 μg/2.5 μL/h) were compared with artificial cerebrospinal fluid (aCSF; 2.5 μL/h) and combination AT1 receptor antagonist candesartan (CAN: 4 μg/2.5 μL/h) plus Ang-(1-7) (0.1 μg/2.5 μL/h) treatment. MAP was lower after CAN + Ang-(1-7) treatment, and both vagal and sympathetic components of BRS and sympathovagal balance were improved. By contrast, Mito-TEMPO improved sympathetic components of BRS and tended to improve overall sympathovagal balance but failed to alter MAP in this model of hypertension. Although further studies are required to determine whether Mito-TEMPO or CAN + Ang-(1-7) treatment at the doses used altered mitochondrial ROS, optimal therapeutic benefits are achieved by shifting the balance from Ang II toward Ang-(1-7) in this model of chronic RAS-dependent hypertension.

Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Arterial Pressure; Baroreflex; Benzimidazoles; Biphenyl Compounds; Brain; Disease Models, Animal; Drug Combinations; Free Radical Scavengers; Heart; Heart Rate; Hypertension; Male; Mitochondria; Organophosphorus Compounds; Peptide Fragments; Piperidines; Rats, Transgenic; Reactive Oxygen Species; Renin; Sympathetic Nervous System; Tetrazoles; Vagus Nerve

Studies have shown the involvement of angiotensin II (Ang II) in neurobehavioral aspects, but the exact role of Ang II in memory is still ambiguous.. This study explored the effect of central Ang II on spatial memory along with cholinergic neurotransmission, brain energy metabolism, cerebral blood flow (CBF), and brain-derived neurotrophic factor (BDNF) in rats.. Spatial memory was evaluated by Morris water maze (MWM) after Ang II (ICV) administration in male Sprague-Dawley rats. CBF was measured by laser Doppler flowmetry. Oxidative stress adenosine triphosphate (ATP), BDNF, acetylcholinesterase (AChE), and acetylcholine (ACh) were estimated in the cortex and hippocampus at 1, 24, and 48 h after Ang II administration. The effect of AT1 and AT2 receptor blocker (candesartan and PD123,319, respectively), AChE inhibitor (donepezil), and antioxidant melatonin was studied on memory, CBF, and biochemical parameters.. Ang II caused spatial memory impairment by affecting acquisition, consolidation, and recall in the MWM test along with a significant reduction in CBF. Ang II significantly reduced ACh level and caused oxidative stress in the rat brain 1 h post-injection. No significant change was observed in BDNF, AChE, and ATP level. Candesartan and donepezil prevented Ang II-induced memory impairment, reduction in CBF and ACh level. However, PD123,319 and melatonin failed to prevent Ang II-induced memory impairment but improved CBF partially.. This study suggests that Ang II, via the AT1 receptor, affects spatial memory formation, CBF, and ACh level while AT2 receptor has no significant role.

Topics: Acetylcholine; Acetylcholinesterase; Adenosine Triphosphate; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Brain-Derived Neurotrophic Factor; Cerebrovascular Circulation; Cholinesterase Inhibitors; Donepezil; Hippocampus; Imidazoles; Indans; Male; Melatonin; Memory; Oxidative Stress; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Synaptic Transmission; Tetrazoles

An increase in coronary perfusion pressure leads to increased cardiac contractility, a phenomenon known as the Gregg effect. Exogenous endothelin (ET)-1 exerts a positive inotropic effect; however, the role of endogenous ET-1 in the contractile response to elevated load is unknown. We characterized here the role of ETA and ETB receptors in regulation of contractility in isolated, perfused mouse hearts subjected to increased coronary flow. Elevation of coronary flow from 2 to 5 ml/min resulted in 80 +/- 10% increase in contractile force (P < 0.001). BQ-788 (ETB receptor antagonist) augmented the load-induced contractile response by 35% (P < 0.05), whereas bosentan (ETA/B receptor antagonist) and BQ-123 (ETA receptor antagonist) attenuated it by 34% and 56%, respectively (P < 0.05). CV-11974 (ANG II type 1 receptor antagonist) did not modify the increase in contractility. These results show that endogenous ET-1 is a key mediator of the Gregg effect in mouse hearts. Moreover, ET-1 has a dual role in the regulation of cardiac contractility: ETA receptor-mediated increase in contractile force is suppressed by ETB receptors.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bosentan; Coronary Circulation; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Heart Rate; In Vitro Techniques; Male; Mice; Myocardial Contraction; Oligopeptides; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sulfonamides; Tetrazoles