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Abstract Details

Analgesic Nutraceutical Salts and Co-crystals of Pentoxifylline, Clonidine and Linsidomine for the Topical Treatment of Complex Regional Pain Syndrome-1
Pain
S52 - From Bench to Bedside with Novel Treatments for Pain (4:30 PM-4:42 PM)
006

CRPS-1 is a chronic pain condition of the limbs that follows sugery, trauma or minor injuries. CRPS-1 affected limbs exhibit peripheral tissue ischemia/hypoxia and oxidative stress. Current analgesics for CRPS-1 have poor efficacy and a myriad of systemic side effects. 

Clonidine, linsidomine and pentoxifylline are drugs that enhance microvascular flow by modulating sympathetic vasoconstriction and nitric oxide mediated vasodilation. α-lipoic acid, caffeic acid and protocatechuic acid are antioxidant nutraceuticals that scavenge reactive oxygen species and alleviate oxidative stress.

This is study is aimed at developing effective topical analgesics for the treatment of complex regional pain syndrome-1 (CRPS-1). We synthesized multi-component co-crystals and salts  to target microvascular dysfunction-induced tissue ischemia/hypoxia and oxidative stress, and produce analgesia.

Nutraceutical salts/co-crystals of clonidine, linsidomine and pentoxifylline were synthesized mechanochemically using liquid-assisted grinding and products validated with crystallographic and spectroscopic techniques. The chronic post-ischemic pain (CPIP) model of CRPS-1 was generated by inducing 3-hour long ischemia of the rat hind paw followed by reperfusion. Ointment formulation of the salts/co-crystals, using a polyethylene-glycol-base system, was prepared and applied on the hind paws of CPIP rats. The baseline and post-treatment levels of mechanical allodynia in the rats were measured by an up-down paw withdrawal threshold procedure using von Frey filaments.

The mechanochemical reactions between clonidine and α-lipoic acid, linsidomine and caffeic acid, and pentoxifylline and protocatechuic acid successfully produced novel salts and co-crystals. The topical application of the salts clonidine-lipoate and linsidomine-caffeate, and the co-crystal pentoxifylline-protocatechuic acid, dose-dependently relieved mechanical allodynia in CPIP rats for up to 2 hours post-application. A comparison of the dose-response curves of the salts/co-crystal with their parent drugs indicated a significant improvement in anti-allodynic potency and/or efficacy. 

Our results show that topical formulations that simultaneously target tissue ischemia/hypoxia and oxidative stress can effectively relieve mechanical allodynia in CRPS-1.

Authors/Disclosures
Oli Abate Fulas, MD, PhD (Neurology Residency Program, University of Toronto)
PRESENTER
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