Abstract
Acidic environments, such as in inflamed tissues, favor the charged form of local anesthetics (LA). Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin (CAP) triggers opening of the TRPV1 receptor pore, its combination with LAs could result in better uptake and improved anesthesia. We tested the above hypothesis and report here for the first time the analgesia effect of a two-drug combination (LA and CAP) on an inflamed tissue. First, CAP solubility increased up to 20 times with hydroxypropyl-beta-cyclodextrin (HP-β-CD), as shown by the phase solubility study. The resulting complex (HP-β-CD-CAP) showed 1:1 stoichiometry and high association constant, according to phase-solubility diagrams and isothermal titration calorimetry data. The inclusion complex formation was also confirmed and characterized by differential scanning calorimetry (DSC), X-ray diffraction, and 1H-NMR. The freeze-dried complex showed physicochemical stability for at least 12 months. To test in vivo performance, we used a pain model based on mouse paw edema. Results showed that 2% mepivacaine injection failed to anesthetize mice inflamed paw, but its combination with complexed CAP resulted in pain control up to 45 min. These promising results encourages deeper research of CAP as an adjuvant for anesthesia in inflamed tissues and cyclodextrin as a solubilizing agent for targeting molecules in drug delivery.
Highlights
The presence of inflammation decreases the efficiency of local anesthetic (LA) agents in clinical procedures [1]
Since inflammation demands a higher amount of LA, the patient stands at risk of systemic toxicity, especially to the nervous and cardiovascular systems [2]
Capsaicin (C18H27NO3, 95% purity, 305.4 molecular weight) was obtained from Cayman Chemical Co. (Cayman Chemical Co., Ann Arbor, MI, USA); mepivacaine hydrochloride (C15H22N2O, 99% purity, 246.35 molecular weight) was donated by Cristália. (Cristália Produtos Químicos Farmacêuticos Ltda, Itapira, São Paulo, Brazil); hydroxypropyl-β-cyclodextrin, acetonitrile (HPLC grade), and sodium acetate were purchased from Sigma-Aldrich
Summary
The presence of inflammation decreases the efficiency of local anesthetic (LA) agents in clinical procedures [1]. New strategies that provide local anesthesia under inflammation are highly desirable. The reduced efficacy of LA under inflammation has been explained by a variety of hypothetical mechanisms, such as peripheral vasodilatation (increment in LA clearance), increased excitability of nerves, and pH reduction in the inflamed tissue [3,4]. No single mechanism could fully explain the failure of LA in such conditions, the reduced pH in the tissue is the most accepted one [5]. Since the charged LA species poorly permeate the neuron cells, a necessary step to further bind the block site in the voltage-dependent sodium channel, low pH could provoke LA failure [7,8]
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