| SO3 is a synthetic small peptide of institute of biotechnology, academy of military medical sciences. The amino acid sequence came from gene cloning of Conns striatus inhibited in South China Sea, with a very similar structure (76%) to SNX-111, a new analgesic drug researched and developed by Neurex Corporation, USA. SNX-111 (USAN: Ziconotide), the synthetic form of a w-conotoxin MVIIA present in Conns magus, is a neurone-specific N-type calcium channel blocker with an analgesic and neuroprotective effect. Intrathecal ziconotide has been recommended for approval by the FDA for the management of chronic pain. Preliminary results of Dr. Dai qiuyun show that SO3 produced powerful antinociception in the mice by intracerebral administration which ED50 is 0.75μg/kg, similar to that of SNX-111. The toxicity of SO3 is lower than that of SNX-111 for LD50 in mice is 13.5mg/kg and 1.56mg/kg, respectively. Measured on rat tail-pressure test by intrathecal administration in this experiment, the analgesic effect of SO3 is compared to SNX-1 1 1 and the dose-dependence and tolerance were determined. The effect of SO3 on Na+, K+ and Ca2+ channel and excitary postsynaptic currents ( EPSC ) in cultured hippocampal neurons is investigated by patch-clamp technique. The results and conclusions are as follows:1 Analgesic Properties1 . 1 Analgesic effect comparison of SO3 and SNX-1 1 1The nociceptive response threshold is measured before treatment and 0.5, 1, 2, 3, 4, 8 hour after treatment. An intrathecal bolus dose of 300ng produces a significant antinociceptive effect (approx. 20% increase in nociceptive threshold compared to saline-treated rats) during 1 to 4 hour, but this effect disappears in 8 hours. 300ng SNX-111 produces the similar effect in 0.5 hour, and this effect remains in 8 hours. The result indicates 300ng S03 is the same analgesic potent to 300ng SNX-111, although SO3 takes effect more slowly and sustains shorter than SNX-111. Neither S03-treated or SNX-1 11 -treated rats areobserved behavioral change in the dose of 300ng.1.2 Dose-dependence of S03100ng SO3 does not produce analgesic effect in 0.5-8 hour after intrathecal injection. lOOOng SO3 takes effect in 0.5 hour, and the nociceptive threshold was increased 46% during 1 to 4 hour, which was very higher than that of 300ng SO3 or SNX-111, but this effect disappeares in 8 hour. The result indicated the analgesic effect of SO3 is dose-dependent in the dose of 300ng-1000ng, but increasing dose does not prolong action period. 1000ng SO3 does not produce apparent behavioral changes, while the research of Omote shows the intermittent shaking symptom appears in the rats with 1000ng SNX-111 intrathecal injection.1.3 Development of tolerance of SO3SO3 and SNX-111 are intrathecally infused continuously for 7 days at a constant-rate of 100ng/h with implanted micro-pump subcutaneously. The nociceptive threshold is measured before operation and 3 to 9 day after operation. SO3 and SNX-111 significantly increase the threshold by 53.7% and 51.1%, respectively , without apparent loss of potency during treatment. The findings show that SO3 and SNX-111 do not develop tolerance after prolonged use, and SO3 produce similar analgesic effect to SNX-111 in condition of continuous infusion. The effects of SO3 and SNX-111 are both reversible completely for the threshold return to control level when drug solutions in micro-pump are used up on post-operation 8 to 9 day.Rats of all groups receiving Saline, SNX-111 or SO3 by continuous infusion loss weight during the 7-day treatment period. Body weights declines apparently during the first 3 to 5 days of treatment and then rise gradually. There is no difference in body weight among groups on any day, indicating that it is the operation but not the drugs result in losing weight. The SNX-111-infused rats show behavioral changes, which consists of intermittent spontaneous shaking , serpentine-like movement of the tail and tremble. SO3 has no significant behavioral effect. The observation indicates SO3 is better tole...
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