Effects of Curcumin and Its Different Formulations in Preclinical and Clinical Studies of Peripheral Neuropathic and Postoperative Pain: A Comprehensive Review.

Lesion or disease of the somatosensory system leads to the development of neuropathic pain. Peripheral neuropathic pain encompasses damage or injury of the peripheral nervous system. On the other hand, 10-15% of individuals suffer from acute postoperative pain followed by persistent pain after undergoing surgeries. Antidepressants, anticonvulsants, baclofen, and clonidine are used to treat peripheral neuropathy, whereas opioids are used to treat postoperative pain. The negative effects associated with these drugs emphasize the search for alternative therapeutics with better efficacy and fewer side effects. Curcumin, a polyphenol isolated from the roots of Curcuma longa, possesses antibacterial, antioxidant, and anti-inflammatory properties. Furthermore, the low bioavailability and fast metabolism of curcumin have led to the advent of various curcumin formulations. The present review provides a comprehensive analysis on the effects of curcumin and its formulations in preclinical and clinical studies of neuropathic and postoperative pain. Based on the positive outcomes from both preclinical and clinical studies, curcumin holds the promise of mitigating or preventing neuropathic and postoperative pain conditions. However, more clinical studies with improved curcumin formulations are required to involve its use as adjuvant to neuropathic and postoperative drugs.

Topical Capsaicin for the Treatment of Neuropathic Pain.

BACKGROUND: Neuropathic pain (NP) is an egregious problem worldwide. Due to the side-effects of oral drugs, drugs delivered directly to the affected area of pain are preferred. OBJECTIVE: Capsaicin, a chemical compound isolated from chili peppers, is used as an analgesic in topical ointments and dermal patches to alleviate pain. Objective of the study is to review the application and functionality of topical capsaicin in treatment of neuropathic pain. DATA SOURCES: To systematically review capsaicin's functions on NP, we retrieved articles from the PubMed database published in the last ten years. STUDY ELIGIBILITY CRITERIA: The inclusion criteria were capsaicin and the use of capsaicin for the treatment of NP; on the other hand, articles were excluded according to the mentioned criteria such as abstracts, articles written in any language other than English, incomplete articles, and conference papers. PARTICIPANTS AND INTERVENTIONS: Out of 265 articles, 108 articles were selected after filtering through the inclusion and exclusion criteria. The data and knowledge currently existing for capsaicin treatment in NP are summarized. RESULTS: This review indicates that capsaicin effectively improves NP treatment without affecting the motor and large nerve fibres involved in sensory function. Transient receptor potential channel vanilloid type 1 (TRPV1) is the capsaicin receptor expressed in central and peripheral terminals of a sensitive primary nerve cell. Conclusions and implications of key findings: Topical capsaicin has a sensible safety profile and is effective in reducing NP. Therefore, studies over the last decade suggest that capsaicin might be a potential drug for NP treatment.

Traditional uses, phytochemistry, pharmacology, pharmacokinetics and toxicology of the fruit of Tetradium ruticarpum: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Tetradium ruticarpum (FTR) known as Tetradii fructus or Evodiae fructus (Wu-Zhu-Yu in Chinese) is a versatile herbal medicine which has been prescribed in Chinese herbal formulas and recognized in Japanese Kampo. FTR has been clinically used to treat various diseases such as headache, vomit, diarrhea, abdominal pain, dysmenorrhea and pelvic inflammation for thousands of years. AIM OF THE REVIEW: The present paper aimed to provide comprehensive information on the ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics, drug interaction and toxicology of FTR in order to build up a foundation on the mechanism of ethnopharmacological uses as well as to explore the trends and perspectives for further studies. MATERIALS AND METHODS: This review collected the literatures published prior to July 2020 on the phytochemistry, pharmacology, pharmacokinetics and toxicity of FTR. All relevant information on FTR was gathered from worldwide accepted scientific search engines and databases, including Web of Science, PubMed, Elsevier, ACS, ResearchGate, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI). Information was also obtained from local books, PhD. and MSc. Dissertations as well as from Pharmacopeias. RESULTS: FTR has been used as an herbal medicine for centuries in East Asia. A total of 165 chemical compounds have been isolated so far and the main chemical compounds of FTR include alkaloids, terpenoids, flavonoids, phenolic acids, steroids, and phenylpropanoids. Crude extracts, processed products (medicinal slices) and pure components of FTR exhibit a wide range of pharmacological activities such as antitumor, anti-inflammatory, antibacterial, anti-obesity, antioxidant, insecticide, regulating central nervous system (CNS) homeostasis, cardiovascular protection. Furthermore, bioactive components isolated from FTR can induce drug interaction and hepatic injury. CONCLUSIONS: Therapeutic potential of FTR has been demonstrated with the pharmacological effects on cancer, inflammation, cardiovascular diseases, CNS, bacterial infection and obesity. Pharmacological and pharmacokinetic studies of FTR mostly focus on its main active alkaloids. Further in-depth studies on combined medication and processing approaches mechanisms, pharmacological and toxic effects not limited to the alkaloids, and toxic components of FTR should be designed.

The leaves of Bougainvillea spectabilis suppressed inflammation and nociception in vivo through the modulation of glutamatergic, cGMP, and ATP-sensitive K+ channel pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Bougainvillea spectabilis is an ornamental shrub from Nyctaginaceae family, widely used in the traditional medicine in the treatment of pain, inflammation, and ulcer. Some research investigated the analgesic potential of this plant, however, the in-depth analysis of its antinociceptive properties and molecular mechanism(s) are yet to be revealed. PURPOSE OF THE STUDY: This study, therefore, investigated the antinociceptive potential of methanol extract of the leaves of B. spectabilis (MEBS) with possible molecular mechanism(s) of action using several pre-clinical models of acute and chronic pain in mice. MATERIALS AND METHODS: The dry leaf powder of B. spectabilis was macerated with 100% methanol, and then dried crude extract was used for in vivo experiments. Following the acute toxicity test with 500, 1000, and 2000 mg/kg b.w. doses of MEBS, the central antinociceptive activities of the extract (50, 100, and 200 mg/kg b.w.) were evaluated using hot plate and tail immersion tests, whereas the peripheral activities were investigated using acetic acid-induced writhing, formalin-induced licking and oedema, and glutamate-induced licking tests. Moreover, the possible involvements of cGMP and ATP-sensitive K+ channel pathways in the observed antinociceptive activities were also investigated using methylene blue (20 mg/kg b.w.) and glibenclamide (10 mg/kg b.w.), respectively. We also performed GC/MS-MS analysis of MEBS to identify the phyto-constituents and in silico modelling of the major compounds for potential molecular targets. RESULTS: Our results demonstrated that MEBS at 50, 100, and 200 mg/kg b.w. doses were not effective enough to suppress centrally mediated pain in the hot plate and tail immersion models. However, the extract was potent (at 100 and 200 mg/kg b.w. doses) in reducing peripheral nociception in the acetic acid-induced writhing and inflammatory phase of the formalin tests. Further analyses revealed that MEBS could interfere with glutamatergic system, cGMP and ATP-sensitive K+ channel pathways to show its antinociceptive properties. GC/MS-MS analysis revealed 35 different phytochemicals with potent anti-inflammatory and antinociceptive properties including phytol, neophytadiene, 2,4-Di-tert-butylphenol, fucoxanthin, and Vit-E. Prediction analysis showed high intestinal absorptivity and low toxicity profiles of these compounds with capability to interact with glutamatergic system, inhibit JAK/STAT pathway, scavenge nitric oxide and oxygen radicals, and inhibit expression of COX3, tumor necrosis factor, and histamine. CONCLUSION: Taken together, these results suggested the antinociceptive potentials of MEBS which were mediated through the modulation of glutamatergic, cGMP, and ATP-sensitive K+ channel pathways. These also suggested that MEBS could be beneficial in the treatment of complications associated with nociceptive pain.

Mesotherapy: From Historical Notes to Scientific Evidence and Future Prospects.

Intradermal therapy, known as mesotherapy, is a technique used to inject a drug into the surface layer of the skin. In particular, it involves the use of a short needle to deposit the drug in the dermis. The intradermal microdeposit modulates the drug's kinetics, slowing absorption and prolonging the local mechanism of action. It is successfully applied in the treatment of some forms of localized pain syndromes and other local clinical conditions. It could be suggested when a systemic drug-sparing effect is useful, when other therapies have failed (or cannot be used), and when it can synergize with other pharmacological or nonpharmacological therapies. Despite the lack of randomized clinical trials in some fields of application, a general consensus is also reached in nonpharmacological mechanism of action, the technique execution modalities, the scientific rationale to apply it in some indications, and the usefulness of the informed consent. The Italian Mesotherapy Society proposes this position paper to apply intradermal therapy based on scientific evidence and no longer on personal bias.

Pharmacokinetics of Sativex® in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders.

The phytocannabinoid-based medicine Sativex® is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathologies, including human-like pathological conditions. With the purpose of assessing different dosing paradigms for using Sativex in Veterinary Medicine, we investigated its pharmacokinetics when administered to naïve dogs via sublingual delivery. In the single dose arm of the study, adult Beagle dogs were treated with 3 consecutive sprays of Sativex, and blood samples were collected at 12 intervals up to 24 h later. In the multiple dose arm of the study, Beagle dogs received 3 sprays daily for 14 days, and blood samples were collected for 24 h post final dose. Blood was used to obtain plasma samples and to determine the levels of cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC) and its metabolite 11-hydroxy-Δ9-THC. Maximal plasma concentrations of both Δ9-THC (Cmax = 18.5 ng/mL) and CBD (Cmax = 10.5 ng/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (Δ9-THC: Cmax = 24.5 ng/mL; CBD: Cmax = 15.2 ng/mL). 11hydroxy-Δ9-THC, which is mainly formed in the liver from Δ9-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and Δ9-THC was detected following repeated exposure, with maximum plasma concentrations for both cannabinoids being achieved following multiple dose. Neurological status, body temperature, respiratory rate and some hemodynamic parameters were also recorded in both conditions, but in general, no changes were observed. In conclusion, this study demonstrates that single or multiple dose sublingual administration of Sativex to naïve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1-2 h and suggested progressive accumulation after the multiple dose treatment.

Physicochemical characterization, released profile, and antinociceptive activity of diphenhydraminium ibuprofenate supported on mesoporous silica.

The thermal, physical, and morphological properties of diphenhydraminium ibuprofenate ([DIP][IBU]) adsorbed onto mesoporous silica (SiO2-60 Šand SiO2-90 Å) from solution were determined. The thermal, physical, and morphological properties of [DIP][IBU] supported on silica were determined. The adsorption of [DIP][IBU] on the pores and surface of silica was proven by N2 adsorption/desorption isotherms. Additionally, release profiles were determined for all systems, and the antinociceptive activity of neat [DIP][IBU] and [DIP][IBU] supported on silica were determined. The interaction of [DIP][IBU] and silica was dependent on pore size, with the formation of a [DIP][IBU] monolayer on SiO2-60 and a multilayer on SiO2-90. The release profile was sustained and slow and dependent on the pore size of the silica, in which the smaller the pore size, the faster the release. The nociceptive evaluation showed that [DIP][IBU] presents a greater (99.21 ±â€¯0.85%) antinociceptive effect than the ibuprofen (46 ±â€¯4.3%). Additionally, [DIP][IBU] on SiO2-60 (90 ±â€¯5.8%) had a greater antinociceptive effect than on SiO2-90 (73 ±â€¯13.2%), which indicates that in vivo tests are in accordance with the in vitro experiments.

Pharmacokinetic study of eight bioactive components following oral administration of Zhiqiao Gancao decoction and observation of its clinical efficacy.

Zhiqiao Gancao (ZQGC) decoction is widely used in China due to its therapeutic effect on lumbar disc herniation (LDH). In this study, we compared the clinical therapeutic effects among oral ZQGC decoction treatment, bed rest, and oral anti-inflammatory drug celecoxib treatment using visual analog scale, Oswestry Disability Index, and MacNab scores. The results showed that ZQGC decoction can significantly improve the symptoms of patients with LDH. A selective, sensitive, and rapid ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of eight bioactive components in rat plasma. The plasma samples were extracted by simple protein precipitation with methanol. The protonated analytes were quantitated simultaneously in positive and negative ion modes by multiple reaction monitoring with a mass spectrometer. The calibration curve of eight components in plasma showed good linearity (r > .996) and the extraction recovery was 81.19% ± 2.15% - 100.39 ± 3.36 (relative standard deviation: 1.21%-10.70%). The accuracy of all the lower limit of quantitation values was quantified within 80%-120%, and the precision was less than 15%. This validated method was successfully applied to the pharmacokinetics study in rat plasma after ZQGC decoction oral treatment. Our research can provide experimental basis for the rational clinical application of ZQGC decoction in the treatment of LDH.

Mucoadhesive thin films for the simultaneous delivery of microbicide and anti-inflammatory drugs in the treatment of periodontal diseases.

There is an unmet clinical need for new products to address the high percentage of the populous who present with periodontal diseases. Drug dose retention at the point of application would facilitate sustained release and more efficacious treatments. The aim of this study was to evaluate mucoadhesive polymeric thin films for simultaneous in situ delivery chlorhexidine and anti-inflammatory and analgesic drugs. Mucoadhesive thin films were prepared using a polymer mixture containing chlorhexidine (25 mg) ± diclofenac sodium (10 and 50 mg), and lidocaine hydrochloride (10 mg) or betamethasone dipropionate (10 and 50 mg). The films were assessed for in vitro drug release and localised tissue delivery, followed by determination of modulated prostaglandin E2 (PGE2) levels in ex vivo tissue and cytotoxicity using a HaCaT keratinocyte cell line. Antibacterial activity of the chlorhexidine/diclofenac film was determined against planktonic and biofilm bacteria associated with periodontal disease and dental plaque. Chlorhexidine release was consistently low (up to 10% of initial loading) from all films, whereas the release of diclofenac, betamethasone and lidocaine exceeded 50% within 30 min. The 50 mg betamethasone film released up to 4-fold more than the 10 mg film. Statistically significant reduction of PGE2 was observed in ex vivo porcine gingival tissue for films containing chlorhexidine with or without diclofenac, and betamethasone. No cytotoxicity was observed for any film, apart from 50 mg betamethasone at 24 h. Films loaded with chlorhexidine and diclofenac were inhibitory against relevant test bacteria. Between 3 and 6 log10 reductions in bacterial cell recovery was observed after biofilm exposure to the chlorhexidine films irrespective of the presence of the anti-inflammatory or anaesthetic. This work demonstrated that thin film formulations have the potential to simultaneously counter key causative factors in periodontal diseases, namely associated bacteria biofilm and chronic local inflammation.

Discovery of Nonpungent Transient Receptor Potential Vanilloid 1 (TRPV1) Agonist as Strong Topical Analgesic.

Paradoxically, some TRPV1 agonists are, at the organismal level, both nonpungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, nonpungent vanilloid. Potent analgesic activity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accumulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.

Pharmacokinetics and pharmacodynamics of mitragynine, the principle alkaloid of Mitragyna speciosa: present knowledge and future directions in perspective of pain.

Mitragyna speciosa, commonly known as Ketum or Biak in Malaysia and Kratom in Thailand, is a native plant to Southeast Asia and has various pharmacological benefits. Mitragynine (MG) is the principal alkaloid found in the leaves of Mitragyna speciosa and has been reported to be responsible for the plant's therapeutic actions. Traditionally, local communities use Kratom preparations for relief from different types of pain. The potential analgesic effects of MG using rodent models have been reported in literatures. We have reviewed the published analgesic and pharmacokinetic studies and all of these findings showed the routes of drug administration, doses employed, and type of vehicles used to solubilize the drug, varied considerably; hence this posted difficulties in predicting the drug's pharmacokinetic-response relationship. A rational approach is warranted for accurate prediction of dose-response relationship; as this is essential for the development of MG as an alternative medicinal drug for pain management. PKPD modeling would serve as a better method to understand the dose-response relationship in future MG preclinical and clinical studies.

Study of the in vitro metabolic profile of a new α2-adrenergic agonist in rat and human liver microsomes by using liquid chromatography-multiple-stage mass spectrometry and nuclear magnetic resonance.

A potent synthetic α2-adrenergic agonist called PT-31, (3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione), was recently detected as a potential drug to be used as an adjuvant drug to treat chronic pain. The excellent pharmacological property of PT-31 highlights the importance in elucidating its metabolism, which could provide valuable information about its metabolite profile for further pharmacokinetics studies and additionally to estimate the impact of its metabolites on the efficacy, safety and elimination of PT-31. In this work, the study of the in vitro metabolism of PT-31 was initially carried out by using a liquid chromatography coupled to ion trap multiple-stage mass spectrometer (LC-IT-MSn) and a hybrid triple quadrupole/linear ion trap mass spectrometer (LC-QTrap). The production of at least three unknown oxidative metabolites was observed. Structural identification of the unknown metabolites was carried out by combination of LC-MS experiments, including selected reaction monitoring (SRM) and multi-stage full scan experiments. Further analysis of 1H-NMR led to the structural confirmation of the major metabolite. The results indicated that PT-31 was metabolized by a hydroxylation reaction in the imidazolidine-2,4-dione ring in rat and human liver microsomes, producing the metabolite 3-(2-chloro-6-fluorobenzyl)-5-hydroxyimidazolidine-2,4-dione in rat liver microsomes. A carbon hydroxylation onto the benzyl ring, produced two other minor metabolites of the PT-31 in rat liver microsomes.

Neoline is the active ingredient of processed aconite root against murine peripheral neuropathic pain model, and its pharmacokinetics in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Processed aconite root (PA), the root of Aconitum carmichaeli (Ranunculaceae), is a crude drug used in traditional Chinese or Japanese kampo medicine to treat pain associated with coldness. In our previous study, PA and its active ingredient, neoline, alleviated oxaliplatin-induced peripheral neuropathy in mice. AIM OF THE STUDY: The present study investigated the effects of PA on a murine peripheral neuropathy model induced by intraperitoneal injection of paclitaxel and partial ligation of the sciatic nerve (Seltzer model), and identified its active ingredients. MATERIALS AND METHODS: PA powder (1 g/kg/day) was orally administered, and either neoline or benzoylmesaconine (10 mg/kg/day) was subcutaneously injected into the murine model. Mechanical hyperalgesia was evaluated via the von Frey filament method. PA extract was orally administered to rats; blood samples were chronologically collected, and the plasma concentrations of Aconitum alkaloids were measured. The contents of Aconitum alkaloids in commercial PA products were also measured. RESULTS: PA extract and neoline significantly attenuated the mechanical hyperalgesia induced by either paclitaxel or partial ligation of the sciatic nerve in mice. In the plasma samples of rats treated with PA extract, higher concentrations of benzoylmesaconine and neoline were apparent among Aconitum alkaloids. The contents of benzoylmesaconine and neoline varied among PA products with different processing procedures. Subcutaneous injection of benzoylmesaconine did not attenuate the hyperalgesia induced by each paclitaxel, partial ligation of the sciatic nerve, or oxaliplatin in mice. CONCLUSIONS: The present results indicate that PA and its active ingredient, neoline, are promising agents for the alleviation of neuropathic pain. Neoline can be used as a marker compound to determine the quality of the PA products for the treatment of neuropathic pain.

A three-pronged formulation approach to improve oral bioavailability and therapeutic efficacy of two lipophilic drugs with gastric lability.

The aim of present study was to co-administer curcumin (CRM) liquisolid pellets and coated duloxetine hydrochloride (DXH) pellets in rats to treat neuropathic pain (NP) associated with chronic constriction injury (CCI). To formulate liquisolid pellets of CRM, it was first dissolved in Tween-80 and then adsorbed on the porous surface of MCC PH102 and Syloid XDP that were used as carrier and coating materials, respectively. Central composite design was used to optimize the liquisolid formulation. The results of powder X-ray diffraction studies, differential scanning calorimetry, and scanning electron microscopy showed complete solubility of drug in Tween-80 followed by its complete adsorption on the porous surface of Syloid XDP and MCC PH102. Both DXH and liquisolid CRM powders were converted into pellets using extrusion-spheronization. DXH pellets were further coated with Eudragit S100 to bypass the gastric pH. About 32.31-fold increase in dissolution rate of CRM present in liquisolid formulation was observed as compared to its unprocessed form. Similarly, the dissolution profile in 0.1 N HCl for Eudragit S100-coated DXH showed complete protection of drug for 2 h and complete release after its introduction in buffer medium (0.2 M phosphate buffer pH 6.8). he pharmacokinetic studies carried out on rats revealed 7.3-fold increase in bioavailability of CRM present in liquisolid pellets and 4.1-fold increase in bioavailability of DXH present in coated pellets was observed as compared to their unprocessed pellets. This increase in bioavailability of drugs caused significant amelioration of CCI-induced pain in rats as compared to their unprocessed forms. The histological sections showed better improvement in regeneration of nerve fibers in rats.

Ketamine-induced hypnosis and neuroplasticity in mice is associated with disrupted p-MEK/p-ERK sequential activation and sustained upregulation of survival p-FADD in brain cortex: Involvement of GABAA receptor.

Ketamine (KET) is an antidepressant and hypnotic drug acting as an antagonist at excitatory NMDA glutamate receptors. The working hypothesis postulated that KET-induced sleep in mice results in dysregulation of mitogen-activated protein kinases (MAPK) MEK-ERK sequential phosphorylation and upregulation of survival p-FADD and other neuroplastic markers in brain. Low (5-15 mg/kg) and high (150 mg/kg) doses of KET on target proteins were assessed by Western immunoblot in mouse brain cortex. During the time course of KET (150 mg/kg)-induced sleep (up to 50 min) p-MEK was increased (up to +79%) and p-ERK decreased (up to -46%) indicating disruption of MEK to ERK signal. Subhypnotic KET (5-15 mg/kg) also revealed uncoupling of p-MEK (+13-81%) to p-ERK (unchanged content). KET did not alter contraregulatory MAPK mechanisms such as inactivated p-MEK1 (ERK dampening) and phosphatases MKP1/2/3 (ERK dephosphorylation). As other relevant findings, KET (5, 15 and 150 mg/kg) upregulated p-FADD in a dose-dependent manner, and for the hypnotic dose the effect paralleled the time course of sleep which resulted in increased p-FADD/FADD ratios. KET (150 mg/kg) also increased NF-κΒ and PSD-95 neuroplastic markers. Flumazenil (a neutral allosteric antagonist at GABAA receptor) prolonged KET sleep and blocked p-MEK upregulation, indicating the involvement of this receptor as a negative modulator. SL-327 (a MEK inhibitor) augmented KET sleep, further indicating the relevance of reduced p-ERK1/2 in KET-induced hypnosis. These findings suggest that hypnotic and subhypnotic doses of KET inducing uncoupling of p-MEK to p-ERK signal and regulation of p-ERK (downregulation) and p-FADD (upregulation) may participate in the expression of some of its adverse effects (e.g. amnesia, dissociative effects).

Analgesic effect of mineral cream containing natural spa minerals for use on the skin.

Previous studies have shown that dissolved substances in some natural hot springs have analgesic/anti-nociceptive and anti-inflammatory actions. However, the mechanisms underlying how such dissolved substances exert these actions are not fully understood. In the present study on mice, we examined the analgesic/anti-nociceptive and anti-inflammatory properties of a mineral cream containing natural hot spring ingredients. The anti-nociceptive effects of the mineral cream were assessed by using the von Frey test. Application of the mineral cream to the hind paw of mice produced a significant anti-nociceptive effect compared to control. The anti-nociceptive effects of the mineral cream were also assessed following the injection of complete Freund's adjuvant (CFA) into the hind paws of mice after pre-treatment for one or four weeks with the mineral cream. Histological experiments with light microscopy showed that the mineral cream did not reduce inflammation caused by the CFA treatment. In addition, the mineral cream did not inhibit oxidative stress as evidenced by increased levels of oxidative metabolites (d-ROMs) and biological anti-oxidant potential (BAP). These results suggest that the mineral cream does not exert a protective effect against inflammation, and that the constituents of the mineral cream may produce their anti-nociceptive effects transdermally via different mechanisms including the nervous system.

Formulation Optimization and In-vitro and In-vivo Evaluation of Lornoxicam Ethosomal Gels with Penetration Enhancers.

BACKGROUND: Ethosomes, a novel type of percutaneous drug delivery carrier with a lipid bilayer structure, penetrate the skin barrier due to their deformability and malleability, and presence of ethanol that fluidizes lipids in the skin. In order to further enhance the delivery of drugs through the skin, penetration enhancers are widely used. OBJECTIVE: The objective of this work was to develop an optimized formulation of lornoxicam ethosomal gels, investigate skin permeability with the addition of penetration enhancers, and evaluate the invivo pharmacodynamics of these formulations. METHODS: Lornoxicam ethosomes were prepared by the ethanol injection method and optimized using the orthogonal design method. Lornoxicam ethosomal gels with enhancers were prepared and optimized using in-vitro transdermal delivery experiments. Experiments on lornoxicam ethosomal gels containing various enhancers such as azone, menthol, lauryl alcohol, and oleic acid were conducted using vertical Franz diffusion cells to measure the percutaneous permeability of the different formulations. Furthermore, the in-vivo analgesic effects of the optimized lornoxicam ethosomal gels were examined using the hot-plate and acetic acid-induced writhing tests. Anti-inflammatory activity was investigated using the dimethylbenzene-induced mouse ear swelling method. RESULTS: The results showed that compared to other formulations, the optimized lornoxicam ethosomal gels with 5 % menthol significantly increased transdermal penetration. Meanwhile, the optimized lornoxicam ethosomal gels showed remarkably anti-nociceptive and anti-inflammatory activity compared with the plain lornoxicam gels. CONCLUSION: These results suggest that the optimized ethosomal gel formulated in this study is a promising lornoxicam carrier in transdermal delivery systems to enhance anti-nociceptive and antiinflammatory efficiency.

Discovery of aminocyclohexene analogues as selective and orally bioavailable hNav1.7 inhibitors for analgesia.

hNav1.7 receives a lot of attention owing to its attractive mechanism of action in pain processing pathway. We have previously reported our design of a novel series of tetrahydropyridine analogues towards hNav1.7 selective inhibitors. Herein, we disclose further efforts to the optimization of hit compound (-)-6, which led to the identification of aminocyclohexene analogues (-)-9 and (-)-17 with good potency, high selectivity, and minimal CYP inhibition. Both compounds (-)-9 and (-)-17 demonstrated improved pharmacokinetic profiles in rats, and robust efficacy in rat formalin-induced nociception and spinal nerve ligation (SNL) models.

Hypnosis closed loop TCI systems in outpatient surgery. / Sistemas de TCI en circuito cerrado para la hipnosis en cirugía ambulatoria.

OBJECTIVE: Determine the influence of general anaesthesia with closed-loop systems in the results of outpatient varicose vein surgery. PATIENTS AND METHODS: Retrospective observational study including data from 270 outpatients between 2014 and 2015. The patients were divided into 2 groups according to the type of general anaesthesia used. The CL Group included patients who received propofol in closed-loop guided by BIS and remifentanil using TCI, and the C Group received non-closed-loop anaesthesia. Age, sex, surgical time, discharge time and failure of outpatient surgery were recorded. Quantitative data were checked for normal distribution by the method of Kolmogorov-Smirnov-Lilliefors. Differences between groups were analysed by a Student-t-test or Mann-Whitney-Wilcoxon test, depending on their distribution. Categorical data were analysed by a Chi-squared test. We used Kaplan-Meier estimator and the effect size (calculated by Cohen's d) to study the discharge time. Statistical analysis was performed using R 3.2.3 binary for Mac OS X 10.9. RESULTS: There were no significant differences in age, sex and surgical time and failure of outpatient surgery. Discharge time was different in both groups: 200 (100) vs. 180 (82.5) minutes, C Group and CL Group, respectively (data are median and interquartile rank); P=.005. CONCLUSION: The use of closed-loop devices for the hypnotic component of anaesthesia hastens discharge time. However, for this effect to be clinically significant, some improvements still need to be made in our outpatient surgery units.