A Double-Blind Study of SB-220453 (Tonerbasat) in the Glyceryltrinitrate (GTN) Model of Migraine

Abstract

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.

Future drugs for migraine

“…A new approach for this problem is to study drugs reducing trigeminal nerve stimulation, like tonabersat, a gap-junction blocker of the trigeminal nerve that does not exert vasoconstrictive properties [13].…”

Antimigraine drugs: new frontiers

“…A trial investigated the efficacy of SB-220453 in the glyceryltrinitrate (GTN) human experimental migraine model [11]. The study reported, ''15 patients with migraine without aura entered a randomized, double-blind, crossover study with 40 mg or placebo followed by a 20-min GTN infusion.…”

Tonabersat: A Cortical Spreading Depression Inhibitor as Potential Pharmacologic Prophylaxis in Migraine with Aura

“…Cortical spreading depression (CSD) is a neurophysiologic phenomenon that since its discovery by Leão, has been amply investigated and is now widely recognized as the neurophysiologic substrate of migraine aura [1]. SB-220453 (now known as tonabersat) is a benzoylamino-benzopyran compound that has shown the ability to inhibit CSD in animal models of migraine [2]. Great interest has developed with regard to the possibility that pharmacologic CSD inhibition may prevent migraine headache attacks, although in a human model of migraine, tonabersat failed as a preemptive antimigraine agent in a double-blind study [2].…”

“…SB-220453 (now known as tonabersat) is a benzoylamino-benzopyran compound that has shown the ability to inhibit CSD in animal models of migraine [2]. Great interest has developed with regard to the possibility that pharmacologic CSD inhibition may prevent migraine headache attacks, although in a human model of migraine, tonabersat failed as a preemptive antimigraine agent in a double-blind study [2]. For prophylaxis, however, commonly prescribed migraine preventatives such as topiramate, valproate, propranolol, and amitriptyline all were recently found to inhibit CSD in a dose-dependent fashion when administered chronically and on a daily basis in rats, suggesting that CSD can provide a common therapeutic target for migraine prophylactic drugs [3].…”