Disease relevance of BW 619C89

• The neuroprotective efficacy of BW619C89 has been evaluated using the middle cerebral artery occlusion model of focal cerebral ischemia in the Fischer 344 rat [1].
• Neuroprotection by agents that block glutamate release in vitro may be due to sodium channel blockade in vivo, but some agents (619C89) exhibit neurological effects similar to NMDA antagonists in stroke [2].
• BW619C89 did not induce significant arterial hypotension, except when it was administered by rapid bolus administration [3].
• 5. In conclusion, the pharmacokinetics of 619C89 are independent of dose in acute stroke patients [4].
• These results confirm the neuroprotective effects of 619C89 in temporary focal ischemia [5].

Psychiatry related information on BW 619C89

• Neuropsychiatric effects (reduced consciousness, agitation, confusion, visual perceptual disturbance, or frank hallucinations) occurred in 16 of 21 patients receiving sipatrigine and in no placebo patients [6].

High impact information on BW 619C89

• When administered intravenously to Fischer 344 rats 5 minutes after permanent middle cerebral artery occlusion, BW619C89 produced marked reductions of both total (cortex and basal ganglia) and cortical infarct volumes [1].
• RESULTS: In the in vitro studies, BW619C89 inhibited veratrine- (but not potassium-) evoked release of both endogenous glutamate and aspartate from rat cerebral cortex slices with IC50 values of approximately 5 microM [1].
• CONCLUSIONS: These results suggest that glutamate release inhibitors such as BW619C89 may provide an alternative to excitatory amino acid receptor antagonists in the treatment of focal cerebral ischemia and stroke [1].
• In the endothelin-1 (ET-1) model of middle cerebral artery occlusion (MCAo) in conscious rats, both AM-36 (6 mg/kg i.p.) and sipatrigine (10 mg/kg i.p.) 30 min post-MCAo significantly reduced cortical, but not striatal infarct volume [7].
• Effects of extracellular pH on the interaction of sipatrigine and lamotrigine with high-voltage-activated (HVA) calcium channels in dissociated neurones of rat cortex [8].

Biological context of BW 619C89

• The number of action potentials produced in response to a depolarizing current pulse in the recorded neurons was reduced by sipatrigine (EC(50) 4.5 microM) [9].
• In the presence of 20 microM BW619C89, activation kinetics were significantly faster [10].
• Dose-response curves revealed that 619C89 have an approximately 8 microM binding site [11].
• The amplitude of excitatory postsynaptic potentials (EPSPs), recorded following stimulation of the corticostriatal pathway, was depressed by sipatrigine (EC(50) 2 microM) [9].
• 4. Average AUC for 341C90 was 270% and that for 78C90 was 62% of the AUC for 619C89 [4].

Anatomical context of BW 619C89

• BW619C89 at doses of 20 and 30 mg/kg also significantly reduced noncortical (basal ganglia) infarct volumes, demonstrating that a proportion of this tissue also appears to be salvageable [1].
• METHODS: In the studies reported here, the effect of BW619C89 [4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine] on neurotransmitter release (endogenous amino acids, gamma-aminobutyric acid, and acetylcholine) from slices of rat brain cerebral cortex in vitro has been determined [1].
• In the cell line expressing type IIA Na+ channels, 619C89 caused a reversible inhibition of Na+ currents in a concentration- and voltage-dependent manner [12].
• At a concentration affording near complete protection (100 microM), BW619C89 had no significant effect on the optic nerve compound action potential [13].
• BW619C89 did not induce the 72 kD heat shock protein in cingulate gyrus or retrosplenial cortex as did MK801, suggesting that BW619C89 does not injure neurons in these regions as do N-methyl-D-aspartate antagonists [3].

Associations of BW 619C89 with other chemical compounds

• Drugs such as Ifenprodil, Cerestat and Selfotel, that have failed in clinical trials, were found to have very low therapeutic ratios of < or = 1, whereas compounds with more tolerable clinical side-effect profiles were found to have higher therapeutic ratios (2, 10 and 10 for Sipatrigine, Remacemide and sPBN, respectively) [14].

Gene context of BW 619C89

• The neuroprotective agent sipatrigine (10 microM) inhibited both hTREK-1 (73.3+/-4.4%) and hTRAAK (45.1+/-11.2%) in a reversible, voltage-independent manner [15].

Analytical, diagnostic and therapeutic context of BW 619C89

• These findings suggest that BW619C89 has long-lasting cerebroprotective effects with advantageous functional consequences after single oral administration in a rodent model of stroke [16].
• Administration of 50 mg/kg of 619C89 30 and 60 min after the onset of ischemia reduced cortical infarction volume (P < 0.05), but there was no effect when the drug was given 5 min after reperfusion [5].
• METHODS: Patients within 12 h of clinically diagnosed stroke were randomized to placebo or sipatrigine at total doses of 10, 18, 27, or 36 mg/kg by continuous intravenous infusion over 65 h [6].
• Although associated with cardiovascular effects in animal models in vivo, there is no published information concerning the effects of sipatrigine on cardiac ion currents and action potentials (AP) [17].

References