Ralfinamide mesylate

Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat.[Pubmed:18583049]

Pain. 2008 Oct 15;139(2):293-305.

Ralfinamide is analgesic when applied as a single dose in rodent models of stimulus-evoked chronic pain. However, it is unknown whether its chronic application after nerve injury can suppress spontaneous chronic pain, the main symptom driving patients to seek treatment. In this study ralfinamide was administered to rats at doses producing plasma levels similar to those causing analgesia in pain patients. The analgesic effect was tested on autotomy, a behavior of self-mutilation of a denervated paw that models spontaneous neuropathic pain. Sprague-Dawley male rats (N=10-20/group) underwent transection of the sciatic and saphenous nerves unilaterally. Ralfinamide or its vehicle were administered per os for 7 days preoperatively (80 mg/kg; bid), followed by the vehicle or Ralfinamide, until postoperative d42. Autotomy was scored daily until d63. Lasting 'preemptive analgesia' was found in rats treated with ralfinamide preoperatively, expressed by delayed autotomy onset (P=0.009) and reduced scores on d63 (P=0.01). Rats treated with ralfinamide (30 or 60 mg/kg; bid) from the operation till d42, but not preoperatively, also showed delayed autotomy (P=0.05, P=0.006), and reduced autotomy scores lasting till d63 (P=0.02, P=0.01), for the two doses, respectively. Combining ralfinamide treatments for 7 days preoperatively and 42 days postoperatively also resulted in significantly suppressed scores on d42 and d63 (P=0.005, P=0.001, respectively). Suppression of neuropathic pain-related behavior was likely caused by a combination of mechanisms reported for ralfinamide, including inhibition of Na+ and Ca++ currents in Nav1.3, Nav1.7, Nav1.8, and Cav2.2 channels in rat DRG neurons, inhibition of substance P release from spinal cord synaptosomes, NMDA receptor antagonism and neuroprotection.

Effects of ralfinamide, a Na+ channel blocker, on firing properties of nociceptive dorsal root ganglion neurons of adult rats.[Pubmed:17707373]

Exp Neurol. 2007 Nov;208(1):63-72.

Recent studies revealed that ralfinamide, a Na(+) channel blocker, suppressed tetrodotoxin-resistant Na(+) currents in dorsal root ganglion (DRG) neurons and reduced pain reactions in animal models of inflammatory and neuropathic pain. Here, we investigated the effects of ralfinamide on Na(+) currents; firing properties and action potential (AP) parameters in capsaicin-responsive and -unresponsive DRG neurons from adult rats in the presence of TTX (0.5 microM). Ralfinamide inhibited TTX-resistant Na(+) currents in a frequency- and voltage-dependent manner. Small to medium sized neurons exhibited different firing properties during prolonged depolarizing current pulses (600 ms). One group of neurons fired multiple spikes (tonic), while another group fired four or less APs (phasic). In capsaicin-responsive tonic firing neurons, ralfinamide (25 microM) reduced the number of APs from 10.6+/-1.8 to 2.6+/-0.7 APs/600 ms, whereas in capsaicin-unresponsive tonic neurons, the drug did not significantly change firing (8.4+/-0.9 in control to 6.6+/-2.0 APs/600 ms). In capsaicin-responsive phasic neurons, substance P and 4-aminopyridine induced multiple spikes, an effect that was reversed by ralfinamide (25 microM). In addition to effects on firing, ralfinamide increased the threshold, decreased the overshoot, and increased the rate of rise of the AP. To conclude, ralfinamide suppressed afferent hyperexcitability selectively in capsaicin-responsive, presumably nociceptive neurons, but had no measurable effects on firing in CAPS-unresponsive neurons. The action of ralfinamide to selectively inhibit tonic firing in nociceptive neurons very likely contributes to the effectiveness of the drug in reducing inflammatory and neuropathic pain as well as bladder overactivity.

Anti-allodynic effect of NW-1029, a novel Na(+) channel blocker, in experimental animal models of inflammatory and neuropathic pain.[Pubmed:12620593]

Pain. 2003 Mar;102(1-2):17-25.

NW-1029, a benzylamino propanamide derivative, was selected among several molecules of this chemical class on the basis of its affinity for the [(3)H]batracotoxin ligand displacement of the Na(+) channel complex and also on the basis of its voltage and use-dependent inhibitory action on the Na(+) currents of the rat DRG (dorsal root ganglia) sensory neuron. This study evaluated the analgesic activity of NW-1029 in animal models of inflammatory and neuropathic pain (formalin test in mice, complete Freund's adjuvant and chronic constriction injury in rats) as well as in acute pain test (hot-plate and tail-flick in rats). Orally administered NW-1029 dose-dependently reduced cumulative licking time in the early and late phase of the formalin test (ED(50)=10.1 mg/kg in the late phase). In the CFA model, NW-1029 reversed mechanical allodynia (von Frey test) after both i.p. and p.o. administration (ED(50)=0.57 and 0.53 mg/kg), respectively. Similarly, NW-1029 reversed mechanical allodynia in the CCI model after both i.p. and p.o. administration yielding an ED(50) of 0.89 and 0.67 mg/kg, respectively. No effects were observed in the hot-plate and tail-flick tests up to 30 mg/kg p.o. The compound orally administered (0.1-10 mg/kg) was well tolerated, without signs of neurological impairment up to high doses (ED(50)=470 and 245 mg/kg in rat and mice Rotarod test, respectively). These results indicate that NW-1029 has anti-nociceptive properties in models of inflammatory and neuropathic pain.

Ralfinamide mesylate (FCE-26742A mesylate) is an orally available Na+ channel blocker derived from α-aminoamide, with function of suppressing pain.

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