Novel Co-crystal of Pentoxifylline and Protocatechuic Acid Relieves Allodynia in Rat Models of Peripheral Neuropathic Pain and CRPS by Alleviating Local Tissue Hypoxia.

Local tissue ischemic hypoxia is a peripheral process that can be targeted with topical treatment to alleviate pain under chronic pain conditions such as complex regional pain syndrome (CRPS) and peripheral neuropathic pain. We recently reported three novel salts and a co-crystal composed of vasoactive agents and antioxidant nutraceuticals, all of which produced potent topical anti-allodynic effects in the chronic postischemic pain (CPIP) rat model of CRPS. One of the products, pentx-pca, is a co-crystal synthesized from pentoxifylline (pentx) and protocatechuic acid (pca). Pentx-pca exhibited potent topical anti-allodynic effects in CPIP and rats with chronic constriction injury of the sciatic nerve exceeding effects produced individually by pentx and pca. We hypothesized that the anti-allodynic effects of pentx-pca in CPIP rats were due to its impact on local tissue oxygenation and subsequent oxygen-dependent mitochondrial respiration. Percutaneous tissue oxygen saturation (SaO2) measurements taken from the hind paw of the CPIP rats revealed that anti-allodynic doses of topical pentx-pca increased local tissue SaO2. Moreover, assessment of the oxygen-dependent mitochondrial function using a triphenyl tetrazolium chloride assay revealed that mitochondrial dysfunction significantly declined in the plantar muscle collected from CPIP rats topically treated with anti-allodynic doses of pentx-pca as compared to vehicle-treated CPIP rats. Furthermore, time-dependent resolution of plantar muscle mitochondrial dysfunction, that occurred in the CPIP rats at 6-week post procedure, paralleled the loss of the anti-allodynic response to topical treatment with pentx-pca. Our results indicated that pentx-pca produced potent anti-allodynic effects in the CPIP rat model of CRPS by alleviating peripheral tissue ischemia/hypoxia and downstream hypoxia-driven mitochondrial dysfunction.

The effect of a topical combination of clonidine and pentoxifylline on post-traumatic neuropathic pain patients: study protocol for a randomized, double-blind placebo-controlled trial.

BACKGROUND: First-line pharmacotherapy for neuropathic pain entails the use of systemic antidepressants and anticonvulsants. These drugs are not optimally effective and poorly tolerated, especially for older patients with comorbid conditions. Given the high number of such patients, there is a need for a greater repertoire of safer and more effective analgesics. Clonidine and pentoxifylline are vasodilator agents that work synergistically to enhance tissue perfusion and oxygenation. The topical administration of these drugs, individually and in combination, has shown anti-nociceptive properties in rodent models of neuropathic pain. A topically-administered combination of clonidine and pentoxifylline also effectively reduced the intensity of both spontaneous and evoked pain in healthy volunteers with experimentally-induced neuropathic pain. The next step in advancing this formulation to clinical use is the undertaking of a phase II clinical study to assess its efficacy and safety in neuropathic pain patients. METHODS/DESIGN: This is a study protocol for a randomized, double-blind, placebo-controlled, phase II clinical trial with a cross-over design. It is a single-centered, 5-week study that will enroll a total of 32 patients with post-traumatic peripheral neuropathic pain. Patients will be treated topically with either a combination of clonidine and pentoxifylline or placebo for a period of 2 weeks each, in randomly assigned order across patients, with an intervening washout period of 1 week. The primary outcome measures of the study are the intensity of spontaneous pain recorded daily in a pain diary with a visual analog scale, and the degree of mechanical allodynia evoked by a brush stimulus. The secondary outcome measures of the study include scores of pain relief and change in the area of punctate hyperalgesia. This trial has been prospectively registered with ClinicalTrials.gov on November 1, 2017. ClinicalTrials.gov Identifier: NCT03342950 . DISCUSSION: The analgesic use of topical treatment with clonidine and pentoxifylline in combination has not been investigated in post-traumatic neuropathic pain. This study could generate the first evidence for the efficacy and safety of the formulation in alleviating pain in patients with neuropathic pain. Furthermore, this trial will provide objective grounds for the investigation of other agents that enhance tissue oxygenation in the topical treatment of peripheral neuropathic pain. TRIAL REGISTRATION: This trial has been registered with ClinicalTrials.gov owned by NIH's US National Library of Medicine. ClinicalTrials.gov NCT03342950 . Registered on November 1, 2017 (trial was prospectively registered). PROTOCOL VERSION AND IDENTIFIERS: This is protocol version 5, dated June 2018. McGill University Health Center (MUHC) Reaseach Ethics Board (REB) identification number: TTNP 2018-3906.

Drug-Nutraceutical Co-Crystal and Salts for Making New and Improved Bi-Functional Analgesics.

The discovery and development of effective analgesics is greatly lagging behind the steadily rising prevalence of chronic pain. Currently prescribed analgesics for chronic pain are lacking in efficacy mainly due to their narrowly-targeted mechanism of action. Driving neuronal hyperexcitability that underlies symptoms of chronic pain are multiple non-neuronal processes, among which are tissue hypoxia and oxidative stress. Here we demonstrate the design, synthesis, and activity of new multi-component bi-functional analgesic crystalline solids, co-crystals, and salts, based on pairing of vasodilatory anti-hypoxic drugs pentoxifylline, clonidine and linsidomine with antioxidant nutraceuticals protocatechuic acid, α-lipoic acid, and caffeic acid. After validation, chemical and structural characterization of these novel salts and co-crystals, topical formulations of the products were tested in a rat model of complex regional pain syndrome. Analgesic effects achieved with the salts and co-crystal exceeded the efficacy and/or potency of constituent compounds indicating that more effective, advanced analgesics can readily be developed by careful pairing of compounds that simultaneously target multiple neural and non-neural processes driving chronic pain.