KT-2962

Ergot alkaloids have been the mainstay of acute migraine therapy for most of the 20th century. They have been supplanted by sumatriptan-like drugs ('triptans'), which, while keeping some of the ergotś mechanisms of action, show improved safety profiles due to their increased receptor selectivity. However, triptans are still far from being perfect drugs: they can constrict human coronary arteries at therapeutic doses and, therefore, are contra-indicated in the presence of cardiovascular disease. Another problem with these agents is recurrence of moderate-to-severe pain within 24 h of initial headache relief. While mechanism-driven drug design has led to the development of various novel, albeit still imperfect, acute antimigraine medications, only a few new prophylactic agents have been made available to migraine clinicians. The efficacy of most, if not all of them has been discovered serendipitously. This is probably due to the fact that, while the pathophysiology of a migraine attack is now reasonably understood, the mechanisms leading to an attack are still mostly unknown. This update analyses the profile of some antimigraine drugs in clinical trials, their mode of action and their potential advantages or drawbacks over already available agents.

The purpose of the current study was to compare the efficacy of two structurally unrelated thromboxane A (TXA ) receptor antagonists, KT2-962 and daltroban (BM 13.505), in a dog model of myocardial ischemia/reperfusion injury. Pentobarbital-anesthetized dogs were subjected to left circumflex coronary artery occlusion for 90 minutes followed by 5 hours of reperfusion. Vehicle, KT2-962 (10 mg/kg), or daltroban (10 mg/kg) were administered as intravenous boluses 10 minutes before coronary occlusion. Systemic hemodynamics were measured throughout the experiments and regional myocardial blood flow was measured by the radioactive microsphere technique. At the end of the reperfusion period, myocardial infarct size was quantified by staining with triphenyltetrazolium chloride. Neither KT2-962 nor daltroban significantly altered heart rate, mean arterial blood pressure, or regional myocardial blood flow. The content of myeloperoxidase activity in the ischemic/reperfused tissue, an index of neutrophil infiltration, was not significantly different among the three treatment groups. However, administration of KT2-962, but not daltroban, significantly reduced the incidence of ventricular fibrillation during the ischemic period and significantly reduced myocardial infarct size expressed as a percentage of the risk region (approximately 40%). Subsequent in-vitro assays using electron spin resonance spectroscopy demonstrated that KT2-962 inhibited the formation of hydroxyl radicals, whereas daltroban had no effect. These results suggest that the beneficial effects of KT2-962 may be due to its direct free radical scavenging properties rather than its ability to block TXA receptors.(2) (2) (2)