Sipatrigine (BW 619C89) is a Neuroprotective Agent and a Sodium Channel and Calcium Channel Inhibitor

Sipatrigine is a substituted pyrimidine derived from lamotrigine. It attenuates glutamate release in vitro and in vivo, probably as a result of sodium and calcium channel inhibition. It consistently reduces cortical infarct volume in rodent models of global, permanent focal, and transient focal ischemia (typically 50–60% reduction with maximum effective doses >20 mg/kg). Striatal protection was found in some studies but not others. The drug was effective also in a rat optic nerve model of white matter ischemia, providing complete neuroprotection at the highest concentration (100 μM) used. In monkeys, CNS penetration by sipatrigine was rapid and the steady state brain/plasma ratio was >40. In humans, low doses (< 2 mg/kg, then 1 mg/kg/8 h) were well tolerated. At higher doses a significant incidence of hallucinations and vomiting was observed. These adverse effects were speculated to be due to interactions with muscarinic receptors and 5-HT3 (or sigma) receptors, respectively. Cardiovascular side effects appeared not to be a major concern. In electrophysiological studies, sipatrigine inhibited native neuronal sodium and calcium channels (including L, N, and P/Q type) and recombinant type IIA sodium and N and T type calcium channels, all with similar potency (IC50 in the range 5–16 μM). Inhibitory potency was increased by high action potential firing frequencies and a depolarized resting voltage. These properties may account for its actions in vitro and in animal models but do not exclude possible additional actions in later stages of ischemic damage.