Myrna Déciga-Campos

Antinociceptive effect of extracts and compounds from Hofmeisteria schaffneri

ETHNOPHARMACOLOGICAL RELEVANCE Hofmeisteria schaffneri (Asteraceae) is a medicinal plant widely commercialized in the most important Markets of Mexico City for the treatment of gastro-intestinal complaints and skin afflictions. AIM OF THE STUDY The main goals of this study were to establish the potential acute toxicity and the antinociceptive activity in animal models of several preparations and compounds from Hofmeisteria schaffneri. MATERIALS AND METHODS The aqueous and organic extracts as well as the essential oil of Hofmeisteria schaffneri were prepared by infusion, maceration and hydrodistillation, respectively. Investigation of the acute toxicity was accomplished by the Lorke method. The antinociceptive effect was assessed using the writhing and the hot plate tests. Natural compounds were isolated by standard phytochemical procedures. In addition, a few thymol esters were prepared by chemical synthesis. The stability of natural and synthetic esters was qualitatively analyzed by measuring their susceptibility to hydrolysis by pig liver estearase and mouse plasma at 37 degrees C. RESULTS The LD(50) for each preparation tested was higher than 5000 mg/kg revealing that they were not toxic to mice after exposure for short space of time. On the other hand, the extracts showed significant antinociceptive effect when tested in the hot plate model. The most active natural product as antinociceptive agent was hofmeisterin III (1) which also was the most stable in the stability study. Its pharmacological effect seems to be partially mediated by an opioid mechanism since naloxone inhibits its action. Using compound 1 as a lead molecule, several synthetic thymol esters were prepared and only compounds 13, 15 and 17 were antinoceptive at the dose of 1 mg/kg. CONCLUSIONS The present investigation provided evidence of the efficacy of several preparations of Hofmeisteria schaffneri as antinociceptive agents. The most active preparation was the essential oil which contained large amount of hofmeisterin III (1) and other thymol derivatives. Some novel synthetic analogs of hofmeisterin III with antinociceptive properties were discovered. The nature of the ester chain of these analogs did not have a clear impact on the antinociceptive activity. The phyto-preparations analyzed in this study were not toxic to mice according to the Lorkes test; therefore considering their long term use of the plant they might be secure for human consumption.

Co-administration of rofecoxib and tramadol results in additive or sub-additive interaction during arthritic nociception in rat

Over the decades, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. In order to assess a possible antinociceptive interactions, the antinociceptive effects of rofecoxib p.o., a preferential inhibitor of cyclooxygenase-2, and tramadol-hydrochloride p.o., an atypical opioid analgesic, administered either separately or in combination, were determined using a rat model of arthritic pain. The data were interpreted using the surface of synergistic interaction (SSI) analysis and an isobolographic analysis to establish the nature of the interaction. The SSI was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Female rats received orally rofecoxib alone (1.0, 1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg), tramadol alone (1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg) or 12 different combinations of rofecoxib plus tramadol. Five combinations exhibited various degrees of sub-additive (i.e. less than the sum of the effects produced by the each drug alone) antinociceptive effects (3.2 mg/kg tramadol with 7.8 mg/kg rofecoxib; 5.6 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib; 10.0 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib), whereas the other 7 combinations showed additive antinociceptive effects (i.e. the sum of the effects produced by each agent alone). Three combination of rofecoxib+tramadol (10.0+5.6, 10.0+10.0, and 17.8+5.6 mg/kg respectively) presented high sub-additive interactions (P<0.002: Q=9.5). The combination rofecoxib (17.8 mg/kg)+tramadol (10.0 mg/kg) caused gastric injuries less severe than those observed with indomethacin, but more severe than those obtained with rofecoxib or tramadol in single administration. The antinociceptive interaction of rofecoxib and tramadol suggests that combinations with these drugs may have no clinical utility in pain therapy.

QSAR Study on the Antinociceptive Activity of Some Morphinans

Quantitative structure–activity relationship studies were performed to describe and predict the antinociceptive activity of 31 morphinan derivatives reported by the US Drug Evaluation Committee in 2005 and 2006. From these, three data sets were constructed and several models were calculated following the multiple linear regression and Leave‐One‐Out Cross‐Validation (LOO‐CV) tests. In general, these models achieved good descriptive power (approximately 92%) as well as predictive power (approximately 76%), but were unable to predict an external validation set of morphinan derivatives. When artificial neural networks were applied to these models, an improvement of the predictive and external validation values was obtained. It was observed that the results of the NN models are significantly better that those obtained by multiple linear regression. In spite that the problem under investigation can be handled adequately by a linear model, a neural network does bring slight improvements in the predictive power.

The Antinociceptive Effects of Tramadol and/or Gabapentin on Rat Neuropathic Pain Induced by a Chronic Constriction Injury

Preclinical Research

The Effect of Gabapentin and Tramadol in Cancer Pain Induced by Glioma Cell in Rat Femur

Preclinical Research

N-(2-morpholin-4-yl-ethyl)−2-(1naphthyloxy)acetamide inhibits the chronic constriction injury-generated hyperalgesia via the antagonism of sigma-1 receptors

&NA; The most used therapeutic treatment to relieve neuropathic pain is that of neuromodulators such as anti‐epileptics or anti‐depressants; however, there are alternatives that may be potentially useful. The sigma‐1 receptor is a therapeutic target that has shown favorable results at preclinical levels. The aim of this study was to evaluate the anti‐hyperalgesic effect of N‐(2‐morpholin‐4‐yl‐ethyl)‐2‐(1‐naphthyloxy) acetamide (NMIN) in a chronic constriction injury model (CCI) and compare it both a sigma‐1 antagonist (BD‐1063) and also Gabapentin, as well as determine its possible role as an antagonist of sigma‐1 receptors. The anti‐hyperalgesic effects of Gabapentin (10.0, 17.8, 31.6, 56.2 and 100 mg/kg, s.c.), BD‐1063 (5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg, s.c.) and NMIN (31.6, 10.0, 316 mg/kg and 562 mg/kg, s.c.) were determined after single‐doses, using the von Frey test in the CCI model. NMIN had the same efficacy as BD‐1063, but both show less efficacy than Gabapentin. In an analysis of pharmacological potency, the ED50 were compared with it being found that BD‐1063 is the most potent drug, followed by Gabapentin and NMIN. The anti‐hyperalgesic effect of NMIN on CCI rats was reversed by (+)‐pentazocine (s.c. route) and by PRE‐084 (i.t. route), both sigma‐1 agonists. Furthermore, NMIN reversed the hyperalgesic effect of PRE‐084 in naïve rats. These results suggest that NMIN has an anti‐hyperalgesic effect on the CCI model, and that one of its mechanisms of action is as a sigma‐1 antagonist, being a significant role the blocking of these receptors at the spinal level.

Antinociceptive and Antihyperalgesic Activity of a Traditional Maya Herbal Preparation Composed of Pouteria Campechiana, Chrysophyllum Cainito, Citrus Limonum, and Annona Muricata

Preclinical Research