tonabersat and Migraine-Disorders

The management of patients with migraine is often unsatisfactory because available acute and preventive therapies are either ineffective or poorly tolerated. The acute treatment of migraine attacks has been limited to the use of analgesics, combinations of analgesics with caffeine, ergotamines, and the triptans. Successful new approaches for the treatment of acute migraine target calcitonin gene-related peptide (CGRP) and serotonin (5-hydroxytryptamine, 5-HT1F) receptors. Other approaches targeting the transient receptor potential vanilloid (TRPV1) receptor, glutamate, GABAA receptors, or a combination of 5-HT1B/1D receptors and neuronal nitric oxide synthesis have been investigated but have not been successful in clinical trials thus far. In migraine prevention, the most promising new approaches are humanised antibodies against CGRP or the CGRP receptor. Non-invasive and invasive neuromodulation approaches also show promise as both acute and preventive therapies, although further studies are needed to define appropriate candidates for these therapies and optimum protocols for their use.

Topics: Antibodies, Monoclonal; Benzamides; Benzopyrans; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Neurotransmitter Agents; Nitric Oxide Synthase Type I; Transcutaneous Electric Nerve Stimulation; TRPV Cation Channels

Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5-hydroxytrypamine (5-HT)(1F) receptor agonists, which are in late-stage development. Nitric oxide antagonists are also in development. New forms of administration of sumatriptan might improve efficacy and reduce side effects. Botulinum toxin A has recently been approved for the prophylaxis of chronic migraine. Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development. The greatest need is for new prophylactic drugs, and it seems likely that such compounds will be developed in the coming decade.

Topics: Benzamides; Benzopyrans; Botulinum Toxins, Type A; Calcitonin Gene-Related Peptide Receptor Antagonists; Drug Design; Drug Therapy; Humans; Migraine Disorders; Nervous System; Nitric Oxide; Serotonin 5-HT1 Receptor Agonists; Sumatriptan

Topics: Administration, Intranasal; Anti-Inflammatory Agents, Non-Steroidal; Benzamides; Benzopyrans; Clinical Trials as Topic; Electric Stimulation Therapy; Foramen Ovale, Patent; Humans; Ketorolac; Migraine Disorders; Neuropharmacology; Transcranial Magnetic Stimulation; Vitamin B 12

Migraine is a neurovascular disorder characterized by recurrent episodic headaches, and is caused by abnormal processing of sensory information due to peripheral and/or central sensitization. The exact pathophysiological mechanism underlying migraine is not fully understood; however, cortical spreading depression (CSD) is thought to provide the basis for migraine aura and may serve as a trigger of migraine pain. CSD depends on neuronal-glial cell communication, which is mediated by intercellular transfer of messengers through connexin-containing gap junctions, as well as messengers released into the extracellular space by non-junctional connexin-containing hemichannels. These processes are believed to be important in peripheral sensitization within the trigeminal ganglion and to lead to central sensitization. The novel benzopyran compound tonabersat binds selectively to a unique site in the brain. In preclinical studies, tonabersat markedly reduced CSD and CSD-associated events and inhibited gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion. Together, these findings suggest that tonabersat should have clinical application in preventing migraine attacks.

Topics: Analgesics; Animals; Benzamides; Benzopyrans; Brain; Cortical Spreading Depression; Gap Junctions; Humans; Migraine Disorders

Migraine is a common, recurrent, primary headache disorder associated with significant morbidity as well as high direct and indirect costs. Despite its impact, only a proportion of migraineurs who meet criteria for prophylactic treatment take preventive medication. Antiepileptic drugs and beta-blockers are among the most used preventive therapies, but their exact mechanisms of action in migraine prophylaxis are unknown. Recent research has pointed to the role of cortical spreading depression in the genesis of migraine aura and pain, with neuronal-glial gap junctions playing a prominent part in cortical spreading depression. Tonabersat is a unique compound with demonstrated activity as a gap-junction inhibitor in animal studies. In preclinical and clinical trials, tonabersat was well tolerated, with no cardiovascular effects; the pharmacokinetic profile suggested its usefulness in the prophylaxis of migraine.

Topics: Analgesics; Animals; Benzamides; Benzopyrans; Brain; Clinical Trials as Topic; Cortical Spreading Depression; Gap Junctions; Guidelines as Topic; Humans; Migraine Disorders

Migraine is a common disabling brain disorder that--considering its clinical and economic impact--is understudied and in need of additional management options. Currently, treatments are classified as preventive or acute-attack therapies, although it is expected that this distinction will become blurred over time. The gap-junction blocker tonabersat, an inducible nitric oxide synthase (NOS) inhibitor and botulinum toxin A are all being investigated in clinical trials as preventive therapies. Device-based approaches using neurostimulation of the occipital nerve have provided promising results, whereas the first study of patent foramen ovale closure for migraine prevention produced disappointing results. Calcitonin gene-related peptide receptor antagonists, vanilloid TRPV1 receptor antagonists and NOS inhibitors are all being investigated in clinical trials for acute migraine. There is much cause for optimism in this area of neurology and considerable benefit awaits our patients.

Topics: Analgesics; Animals; Benzamides; Benzopyrans; Botulinum Toxins, Type A; Calcitonin Gene-Related Peptide; Clinical Trials as Topic; Electric Stimulation Therapy; Humans; Migraine Disorders; Neuromuscular Agents; TRPV Cation Channels

Topics: Benzamides; Benzopyrans; Calcitonin Gene-Related Peptide; Drug Therapy, Combination; Ergotamine; Global Health; Humans; Incidence; Indans; Migraine Disorders; Piperazines; Prevalence; Prospective Studies; Quinazolines; Randomized Controlled Trials as Topic; Spiro Compounds; Sumatriptan; Treatment Outcome; United States; Vasoconstrictor Agents; Vasodilator Agents

Tonabersat is a novel putative migraine prophylactic agent with an unique stereospecific binding site in the brain. Tonabersat has been shown, in animal models, to inhibit experimentally induced cortical spreading depression, the likely underlying mechanism for migraine aura, and cerebrovascular responses to trigeminal nerve stimulation. The aim was to study the potential for tonabersat as a migraine preventive. A randomized, double-blind, placebo-controlled, multicentre, parallel group study recruited patients with migraine with and without aura experiencing between two and six migraine attacks per month. After a 1-month baseline they received tonabersat 20 mg daily for 2 weeks and 40 mg daily for a further 10 weeks. The primary end-point was the change in mean number of migraine headache days between the third month and the baseline period in the intention-to-treat population comparing the placebo (n = 65) and tonabersat (n = 58) groups. At the primary end-point there was a 1.0-day (95% confidence interval -0.33, 2.39; P = 0.14) difference in reduction in migraine days between tonabersat and placebo. There were 10 secondary efficacy end-points, of which two were statistically significant. In month 3 of treatment, the responder rate, defined as a 50% reduction in migraine attacks, was 62% for tonabersat and 45% for placebo (P < 0.05), and the rescue medication use was reduced in the tonabersat group compared with placebo by 1.8 days (P = 0.02). Placebo responses were particularly high for all end-points. At least one treatment-emergent adverse event was reported in the tonabersat group in 61% of patients compared with 51% in the placebo group; none was worrisome. Placebo responses were unexpectedly high in this trial, complicating straightforward interpretation of the study results. The good tolerability and promising efficacy results support further exploration of higher doses of tonabersat in larger controlled trials.

Topics: Adolescent; Adult; Benzamides; Benzopyrans; Cortical Spreading Depression; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Young Adult

The ability of tonabersat to relieve the symptoms of migraine attacks with or without aura was evaluated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients received 20 or 40 mg of tonabersat, or 50 mg of sumatriptan (positive control), or placebo at the onset of a moderate or severe attack. Headache intensity, relief and recurrence were recorded for 24 h after dosing. On the basis of primary or secondary efficacy measures, tonabersat did not provide a clinically or statistically significant advantage over placebo. Tonabersat generally was well tolerated and had no effect on vital signs, electrocardiogram recordings or laboratory values. The lack of efficacy may be a function of the slow absorption of tonabersat. As a consequence of slow absorption, daily administration of tonabersat as prophylaxis for migraine attacks is under investigation in ongoing studies.

Topics: Adult; Analgesics; Benzamides; Benzopyrans; Double-Blind Method; Female; Humans; Male; Migraine Disorders; Safety; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

Topics: Adult; Analgesics; Benzamides; Benzopyrans; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Migraine Disorders

The need for experimental migraine models increases as therapeutic options widen. In the present study, we investigated SB-220453 for efficacy in the glyceryltrinitrate (GTN) human experimental migraine model. SB-220453 is a novel benzopyran compound, which in animal models inhibits neurogenic inflammation, blocks propagation of spreading depression and inhibits trigeminal nerve ganglion stimulation-induced carotid vasodilatation. We included 15 patients with migraine without aura in a randomized double-blind crossover study. SB-220453 40 mg or placebo was followed by a 20-min GTN infusion. Headache, scored 0-10, was registered for 12 h, and fulfillment of International Headache Society (IHS) criteria was recorded until 24 h. Four subjects had a hypotensive episode after SB-220453 plus GTN but none after GTN alone. The reaction was unexpected, since animal models and previous human studies had shown no vascular or sympaticolytic activity with SB-220453. The study was terminated prematurely due to this interaction. GTN was consistent in producing headache and migraine that resembled the patients' usual spontaneous migraine. Nine patients had GTN on both study days. Peak headache score showed a trend towards reduction after SB-220453 compared with placebo (median 4 vs. 7, P = 0.15). However, no reduction was seen in the number of subjects experiencing delayed headache (8 vs. 8), number of subjects reporting migraine (6 vs. 8), migraine attacks fulfilling IHS criteria 1.1 or 1.7 (6 vs. 7) or IHS 1.1 alone (4 vs. 5). SB-220453 had no significant pre-emptive anti-migraine activity compared with placebo in this human model of migraine. Interaction between SB-220453 and GTN was discovered. This is important for the future development of the compound and underlines the usefulness of experimental migraine models.

Topics: Adult; Benzamides; Benzopyrans; Cross-Over Studies; Double-Blind Method; Drug Interactions; Female; Humans; Male; Middle Aged; Migraine Disorders; Nitroglycerin; Statistics, Nonparametric

Sensitization and activation of trigeminal neurons are implicated in the underlying pathology of migraine, acute sinusitis, and allergic rhinitis. Cell bodies of trigeminal neurons that provide sensory innervation of the dura and nasal mucosa reside in the trigeminal ganglion in association with satellite glial cells where they communicate via gap junctions. Gap junctions, channels formed by connexins, modulate the excitability state of both neurons and glia under pathological conditions. Tonabersat, a compound being tested as an antimigraine drug, is thought to block gap junction activity.. To investigate the cellular events within trigeminal ganglia that may account for the significant comorbidity of migraine and rhinosinusitis and determine the effect of tonabersat on neuron-satellite glia communication.. Sprague Dawley rats injected with True Blue were used to localize neuronal cell bodies in the ganglion and study neuron-glia signaling via gap junctions in the trigeminal ganglion. Dye coupling studies were conducted under basal conditions and in response to tumor necrosis factor-alpha injection into the whisker pad and/or capsaicin injection into the eyebrow. Changes in connexin 26 and active p38 levels were determined by immunohistochemistry. In addition, the effect of tonabersat prior to chemical stimulation on gap junction activity and expression of connexins and active p38 was investigated.. Injection of tumor necrosis factor-alpha, a cytokine implicated in the pathology of acute sinusitis and allergic rhinitis, into the V2 region was shown to lower the amount of capsaicin required to stimulate neurons located in the V1 region of the ganglion. While injection of tumor necrosis factor-alpha into the whisker pad or capsaicin injection into the eyebrow alone did not cause increased dye movement, the combination of both stimuli greatly increased neuron-satellite glia communication via gap junctions in both V1 and V2 regions. The change in gap junction activity was accompanied by increased expression of connexin 26 and active p38 levels in both neurons and satellite glia in V1 and V2 regions. Pretreatment with tonabersat inhibited gap junction communication between neurons and satellite glia and blocked the increase in connexin 26 and active p38 levels in response to injection of both tumor necrosis factor-alpha (V2) and capsaicin (V1).. We propose that increased levels of tumor necrosis factor-alpha, as reported during acute sinusitis and allergic rhinitis, reduces the amount of capsaicin necessary to stimulate V1 neurons that leads to cellular changes in both V1 and V2 regions. The cellular events observed in this study may help to explain, in part, the significant comorbidity reported with migraine and rhinosinusitis. In addition, we have provided evidence to suggest that tonabersat can prevent increased neuron-satellite glia signaling and, thus, may be useful in the treatment of migraine, acute sinusitis, and allergic rhinitis.

Topics: Animals; Benzamides; Benzopyrans; Connexin 26; Connexins; Gap Junctions; Immunohistochemistry; Male; Migraine Disorders; Neurons; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Sprague-Dawley; Rhinitis, Allergic, Seasonal; Satellite Cells, Perineuronal; Signal Transduction; Sinusitis; Trigeminal Ganglion; Tumor Necrosis Factor-alpha

Topics: Benzamides; Benzopyrans; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Humans; Migraine Disorders

Migraine headache is proposed to be mediated by nitric oxide (NO). Suitable mechanisms for eliciting increases in brain NO concentration in migraineurs have not yet been identified, although, animal models highlight cortical spreading depression (CSD) as a potential candidate. These studies have focused on CSD-associated NO release at highly acute time points (min-hours) and have not employed markers of NO metabolism with direct clinical application e.g. cGMP. The current study evaluated changes in plasma cGMP concentrations 3 h, 24 h and 3 days post-CSD and compared these to cortical and brainstem cGMP concentrations at 3 days. Moreover, this study also examined the effect of sumatriptan, a clinically effective antimigraine agent, and tonabersat (SB-220453) a potential novel antimigraine agent, on any observed changes in cGMP. Following pre-treatment with vehicle (n=3), sumatriptan (300 microg kg(-1) i.v, n=3) or tonabersat (SB-220453 10 mg kg(-1) i.p., n=3), CSD was evoked in anaesthetised rats by a 6-min KCl application to the parietal cortex. In the vehicle-treated group a median of eight depolarisations, were observed. Sumatriptan had no effect on the number of depolarisations, whereas tonabersat significantly reduced the number of events (median=2). No depolarisation events were observed throughout the recording period in the sham group. Following KCl application plasma cGMP concentrations were reduced up to 24 h post-CSD, but not significantly different from sham animals at 3 days. CSD in vehicle-treated animals produced a highly significant elevation in cGMP concentration in the brain stem 3 days after application of KCl. cGMP concentration increased 2.3-fold from 68+/-8 fmol/mg in sham animals (n=3) to 158+/-28 fmol/mg in the vehicle group. This increase in brain stem cGMP was abolished by tonabersat pre-treatment but not by sumatriptan.

Topics: Analgesics; Animals; Benzamides; Benzopyrans; Brain Stem; Cerebral Cortex; Cortical Spreading Depression; Cyclic GMP; Male; Migraine Disorders; Nitric Oxide; Nitric Oxide Synthase; Potassium Chloride; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sumatriptan; Vasoconstrictor Agents

Profound nitric oxide release associated with cortical spreading depression (SD), has been implicated in stroke, traumatic brain injury and migraine pathophysiology. SB-220453 represents a mechanistically novel, well-tolerated class of compounds which may have therapeutic potential in the treatment of conditions associated with neuronal hyperexcitability and inflammation. The aim of the present study was to investigate the effects of SB-220453 on the nitric oxide (NO) release associated with SD in the anaesthetized cat. In vehicle treated animals, KCl application for 6 min to the cortical suface produced repeated changes in extracellular direct current field potential with associated NO release. This activity was sustained for a median duration of 55 min (25-75% range, 32-59 min) and 59 min (25-75% range, 34-59 min), respectively. SB-220453 (1, 3 and 10 mg/kg i.p.) produced a dose-related inhibition of this activity and at the highest dose tested, the median duration of changes in extracellular field potential and NO release were reduced to 4 min (25-75% range, 4-5 min) and 5 min (25-75% range, 5-5 min), respectively. No effect was observed on basal systemic haemodynamic parameters or resting cerebral laser Doppler blood flux at any of the doses of SB-220453 tested. SB-220453 therefore represents a novel compound to assess the potential benefit of inhibiting SD associated nitric oxide release in neurological disease.

Topics: Analgesics; Anesthetics, Inhalation; Animals; Benzamides; Benzopyrans; Blood Pressure; Cats; Cerebral Cortex; Cortical Spreading Depression; Halothane; Heart Rate; Male; Migraine Disorders; Nitric Oxide

Transient cortical depolarization is implicated in the pathology of migraine. SB-220453 is a potent anti-convulsant which inhibits neurogenic inflammation and cortical spreading depression (SD)-evoked nitric oxide release via a novel but unknown mechanism. This study further investigates the effects of SB-220453 on generation and propagation of repetitive SD in the anaesthetized cat. Vehicle or SB-220453 1, 3 or 10 mg/kg was administered intraperitoneally 90 min prior to induction of SD in the suprasylvian gyrus (SG). Changes in d.c. potential were recorded in the SG and the adjacent marginal gyrus (MG). In vehicle-treated animals (n = 7), a brief exposure (6 min) to KCl induced a median (25-75% range) number of five (four to six) and three (two to four) depolarizations over a duration of 55 min (32-59 min) and 51 min (34-58 min) in the SG and MG, respectively. SB-220453 produced dose-related inhibition of the number of events and period of repetitive SD activity. SB-220453 also reduced SD-induced repetitive pial vasodilatation but had no effect on resting haemodynamics. However, when SD events were observed in the presence of SB-220453, it had no effect on metabolic coupling. These results show that SB-220453 produces marked inhibition of repetitive SD in the anaesthetized cat. SB-220453 may therefore have therapeutic potential in treatment of SD-like activity in migraine.

Topics: Analgesics; Animals; Anticonvulsants; Benzamides; Benzopyrans; Cats; Cortical Spreading Depression; Drug Evaluation, Preclinical; Hemodynamics; Male; Membrane Potentials; Meningeal Arteries; Migraine Disorders; Nitric Oxide; Pia Mater; Potassium Chloride; Vasodilation

Optimisation of novel cis- and trans-4-(substituted-amido)benzopyran-3-ol derivatives has led to the identification of SB-220453 20 with an in vivo pre-clinical CNS profile predictive of potential antimigraine activity.

Topics: Animals; Benzamides; Benzopyrans; Dose-Response Relationship, Drug; Methylcellulose; Mice; Migraine Disorders; Rats; Seizures; Sumatriptan; Temperature; Time Factors