Anti-Inflammatory and Antinociceptive Activities of the Essential Oil of Tagetes parryi A. Gray (Asteraceae) and Verbenone.

Tagetes parryi is a plant empirically used to treat gastrointestinal and inflammatory diseases, its essential oil (EOTP) was obtained from the aerial parts, and the composition was elucidated by GC-MS. The in vivo and in vitro anti-inflammatory activities and the antinociceptive activity of EOTP and (1S)-(-)-verbenone (VERB) were assessed. The major compounds identified for EOTP were verbenone (33.39%), dihydrotagetone (26.88%), and tagetone (20.8%). EOTP and VERB diminished the ear oedema induced with TPA by 93.77 % and 81.13 %, respectively. EOTP and VERB decreased inflammation in a 12-O-tetradecanoylphorbol-13-acetate (TPA) chronic model with ED50 = 54.95 mg/kg and 45.24 mg/kg, respectively. EOTP (15 µg/mL) inhibited the in vitro production of the pro-inflammatory mediators NO (67.02%), TNF-α (69.21%), and IL-6 (58.44%) in LPS-stimulated macrophages. In the acetic induced writhing test, EOTP and VERB showed antinociceptive effects with ED50 = 84.93 mg/kg and ED50 = 45.24 mg/kg, respectively. In phase 1 of the formalin test, EOTP and VERB showed no antinociceptive effects, whereas in phase 2, EOTP (ED50 = 35.45 mg/kg) and VERB (ED50 = 24.84 mg/kg) showed antinociceptive effects. The antinociceptive actions of ETOP and VERB were blocked with the co-administration of L-NAME. This study suggests that EOTP and VERB might be used in the treatment of pain and inflammatory problems.

Novel 2-aryl-4-aryloxyquinoline-based fungistatics for Mucor circinelloides. Biological evaluation of activity, QSAR and docking study.

Zygomycetes are ubiquitous saprophytes in natural environments which transform organic matter. Some zygomycetes of gender Mucor have attracted interest in health sector. Due to its ability as opportunistic microorganisms infecting immuno-compromised people and to the few available pharmacological treatments, the mucormycosis is receiving worldwide attention. Concerning to the pharmacological treatments, some triazole-based compounds such as fluconazole are extensively used. Nevertheless, we focused in the quinolines since they are broadly used models for the design and development of new synthetic antifungal agents. In this study, the fungistatic activity on M. circinelloides of various 2-aryl-4-aryloxyquinoline-based compounds was discovered, and in some cases, it resulted better than reference compound fluconazole. These quinoline derivatives were synthesized via the Csp2-O bond formation using diaryliodonium(III) salts chemistry. A QSAR study was carried out to quantitatively correlate the chemical structure of the tested compounds with their biological activity. Also, a docking study to identify a plausible action target of our more active quinolines was carried out. The results highlighted an increased activity with the fluorine- and nitro-containing derivatives. In light of the few mucormycosis pharmacological treatments, herein we present some non-described molecules with excellent in vitro activities and potential use in the mucormycosis treatment.

Evaluation of the neuropharmacological effects of Gardenin A in mice.

This work describes the neuropharmacological (sedative, anxiolytic, antidepressant, and anticonvulsant) actions of Gardenin A (GA) (0.1-25 mg/kg p.o.), a flavonoid found in medicinal plants. The sedative effects of GA were assessed with the pentobarbital-induced sleep test. The anxiolytic actions of GA were evaluated with the elevated plus-maze, the light-dark box test, the exploratory cylinder assay, and the open field test. Motor coordination was evaluated with the rotarod test and the open field test. The antidepressant-like actions of GA were evaluated with the tail suspension test and forced swimming test. The mechanisms of the anxiolytic-like and antidepressant-like effects of GA were assessed using inhibitors of neurotransmission pathways. The anticonvulsant activity of GA was evaluated with the strychnine-induced seizure test. The sedative effects of GA were evident only at a dose of 25 mg/kg, which increased the duration of sleep but did not alter sleep onset. GA showed anxiolytic-like actions with activity comparable to that of clonazepam in all experimental tests. The GABAA receptor antagonist bicuculline reversed the anxiolytic-like effects of GA. Furthermore, GA showed significant antidepressant-like actions in both models with activity comparable to that of fluoxetine. Yohimbine, an α2-adrenoceptor blocker, inhibited the antidepressant-like actions of GA. In addition, GA (1-10 mg/kg) did not affect locomotor coordination in mice and delayed the onset of convulsions. These findings suggest that GA induces anxiolytic-like effects and has anticonvulsant actions by the possible involvement of the GABAergic system. The antidepressant-like actions of GA may be mediated by noradrenergic neurotransmission.

Antidiarrheal, vasorelaxant, and neuropharmacological actions of the diterpene tilifodiolide.

Salvia tiliifolia is used in folk medicine as a relaxant agent and for the treatment of diarrhea and neurodegenerative diseases. Tilifodiolide (TFD) is a diterpene obtained from this plant. The purpose of this work was to evaluate the antidiarrheal, vasorelaxant, and neuropharmacological actions of TFD. These effects were selected based on the folk medicinal use of S. tiliifolia. The antidiarrheal activity of 1-50 mg/kg p.o. TFD was assessed with the castor oil related tests. The vasorelaxant effect of TFD (0.9-298 µM) was performed with smooth muscle tissues from rats, and its mechanism of action was evaluated using different inhibitors. The sedative, anxiolytic, and antidepressant effects of 1-100 mg/kg TFD were assessed. The possible mechanisms of action of the anxiolytic and antidepressant effects of TFD were evaluated using inhibitors. TFD exhibited antidiarrheal (ED50 = 10.62 mg/kg) and vasorelaxant (EC50 = 48 ± 3.51 µM) effects. The coadministration of TFD with N(ω)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), reverted the vasorelaxant action showed by TFD alone. TFD exerted anxiolytic actions (ED50 = 20 mg/kg) in the cylinder exploratory test, whereas TFD (50 mg/kg) showed antidepressant actions in the tail suspension test by 44%. The pretreatment with 2 mg/kg flumazenil partially reverted the anxiolytic actions of TFD, whereas the pretreatment with 1 mg/kg yohimbine abolished the antidepressant effects of TFD. In summary, TFD exerted antidiarrheal activity by decreasing the intestinal fluid accumulation and vasorelaxant effects mediated by nitric oxide and cyclic guanosine monophosphate. TFD showed anxiolytic and antidepressant effects by the partial involvement of gamma-Aminobutyric acid (GABA) receptors and the possible participation of α2-adrenoreceptors, respectively.

Anti-inflammatory and diuretic effects of the diterpene ent-dihydrotucumanoic acid.

Gymnosperma glutinosum (Spreng) Less (Asteraceae) is a shrub used in traditional medicine for the treatment of inflammatory and renal diseases. The ent-dihydrotucumanoic acid (DTA) is a diterpene obtained from G. glutinosum. This study evaluated the antioxidant, genotoxic, and diuretic properties of DTA, as well as its in vitro and in vivo anti-inflammatory actions. The antioxidant actions of DTA were assessed with the 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), ferric reducing antioxidant power (FRAP), and 2,2'-diphenyl-1-picrylhydrazyl (DPPH) assays, the genotoxic action was assessed with the comet assay, and the diuretic effects of DTA were assessed using metabolic cages. The anti-inflammatory actions were evaluated using primary murine peritoneal macrophages stimulated with LPS and the λ-carrageenan-induced hind paw edema test. DTA lacked antioxidant (IC50 > 25,000 µg/mL) activity in the ABTS, FRAP, and DPPH assays. DTA at 500-1,000 µg/mL showed moderate genotoxicity. In LPS-stimulated macrophages, DTA showed IC50 values of 74.85 µg/mL (TNF-α) and 58.12 µg/mL (NO), whereas the maximum inhibition of IL-6 (24%) and IL-1ß (36%) was recorded at 200 µg/mL. DTA induced in vivo anti-inflammatory effects with ED50 = 124.3 mg/kg. The in vitro anti-inflammatory activity of DTA seems to be associated with the decrease in the release of TNF-α and NO. DTA promoted the excretion of urine (ED50 = 86.9 mg/kg), Na+ (ED50 = 66.7 mg/kg), and K+ (ED50 = 8.6 mg/kg). The coadministration of DTA with L-NAME decreased the urinary excretion shown by DTA alone. Therefore, the diuretic activity is probably associated with the participation of nitric oxide synthase. In conclusion, DTA exerted anti-inflammatory and diuretic effects, but lacked antioxidant effects.

Participation of ATP-sensitive K+ channels and µ-opioid receptors in the antinociceptive synergism of the paracetamol-tapentadol co-administration in the formalin-induced pain assay in mice.

Preclinical Research & Development The purpose of this study was to assess the interaction and mechanisms of action of the paracetamol-tapentadol combination in the formalin-induced pain model in mice. Paracetamol (56.23-562.3 mg/kg, i.p.) or tapentadol (1-10 mg/kg, i.p.) were administered 15 min prior the intraplantar injection of formalin. The ED50 value of each drug was determined through the dose-response curves. The ED50 values were used to calculate the combinations in three fixed proportions (1:1, 1:3, and 3:1). Naloxone (1 and 5 mg/kg, i.p.), L-NAME (3 mg/kg, i.p.), or glibenclamide (10 mg/kg, i.p.) were administered before the combination of drugs to evaluate the antinociceptive mechanisms of action. The results showed that the combination 1:1 and paracetamol3-tapenadol1 ratios produced additive effects, whereas the paracetamol1-tapentadol3 proportion showed an antinociceptive synergistic interaction. Moreover, naloxone and glibenclamide reversed the antinociceptive activity of the paracetamol-tapentadol mixture. Our results indicate that the paracetamol-tapentadol combination produces an antinociceptive synergistic interaction with the possible participation of ATP-sensitive K+ channels and µ-opioid receptors in the second phase of the formalin-induced pain model in mice.

Assessment of the antinociceptive and ulcerogenic activity of the tapentadol-diclofenac combination in rodents.

Preclinical Research & Development The objective of the present study was to evaluate the tapentadol-diclofenac combination in three dose-ratios in the mouse acetic acid-induced visceral pain and their ulcerogenic activity on the stomachal mucous. Dose-response curves were generated for tapentadol, diclofenac, and their combination in the acetic acid-induced writhing test in mice. Moreover, the stomachs of animals were surgically removal and gastrointestinal ulcerogenic action of the combination was assessed. The isobolographic analysis, interaction index, and ANOVA were used to analyze the data. The isobolographic analysis and interaction index showed a similar antinociceptive activity for the three combinations of the analgesic mixture. Moreover, tapentadol and the proportions 1:1 or 3:1 of the analgesic combination caused a mild gastrointestinal damage. These data indicate that the systemic co-administration of tapentadol and diclofenac produced a synergistic interaction in the acetic acid-induced visceral pain test with an acceptable gastric damage profile in mice.

Bacterial resistance and failure of clinical cure could be produced by oxidative stress in patients with diabetes or cardiovascular diseases during fluoroquinolone therapy.

Fluoroquinolone agents are used widely for the treatment of infectious diseases which are a common cause of deaths around the world. The level of oxidative stress in patients taking fluoroquinolone antibiotics has not been considered a factor to reduce the clinical efficacy of this kind of drugs. Patients with diabetes and/or cardiovascular diseases present abnormal levels of oxidative stress in the blood stream. In this regards, our hypothesis supposes that patients with diabetes and/or cardiovascular disease suffering a bacterial disease could experience a therapeutic failure and bacterial resistance when treated with fluoroquinolones. The crucial mechanism could be an inefficient blood distribution of the drug via red blood cell dysfunction induced by oxidative stress that might reduce the pharmacokinetic-pharmacodinamic ratios. In this way, we review the scientific information to support our hypothesis alongside possible implications. Additionally, this work exhibits the urgent need of studies considering these conditions for quinolone agents.

Isobolographic Analysis of the Interaction Between Tapentadol and Ketorolac in a Mouse Model of Visceral Pain.

Preclinical Research The aim of this experimental assay was to assess the antinociceptive interaction between tapentadol and ketorolac in the acetic acid-induced writhing model in mice. Tapentadol (5.62-31.6 mg/kg ip) or ketorolac (5.62-31.6 mg/kg ip) were administered 15 min before the acetic acid administration. The ED50 values of the individual drugs were determined and different proportions (tapentadol-ketorolac in 1:1, 3:1, and 1:3) were assayed in combination in the writhing test. Isobolographic analysis and the interaction index demonstrated an antinociceptive synergistic interaction between tapentadol and ketorolac in all combination. Thus, the experimental ED50 values were lower when compared with their theoretical ED50 values. These data suggest that the tapentadol-ketorolac combination produces an antinociceptive synergistic interaction in the mouse acetic acid-induced writhing model. Drug Dev Res 77 : 187-191, 2016. © 2016 Wiley Periodicals, Inc.

Hypoxia-inducible factor-1α (HIF-1α) protein diminishes sodium glucose transport 1 (SGLT1) and SGLT2 protein expression in renal epithelial tubular cells (LLC-PK1) under hypoxia.

In this work, we demonstrated the regulation of glucose transporters by hypoxia inducible factor-1α (HIF-1α) activation in renal epithelial cells. LLC-PK1 monolayers were incubated for 1, 3, 6, or 12 h with 0% or 5% O2 or 300 µm cobalt (CoCl2). We evaluated the effects of hypoxia on the mRNA and protein expression of HIF-1α and of the glucose transporters SGLT1, SGLT2, and GLUT1. The data showed an increase in HIF-1α mRNA and protein expression under the three evaluated conditions (p < 0.05 versus t = 0). An increase in GLUT1 mRNA (12 h) and protein expression (at 3, 6, and 12 h) was observed (p < 0.05 versus t = 0). SGLT1 and SGLT2 mRNA and protein expression decreased under the three evaluated conditions (p < 0.05 versus t = 0). In conclusion, our results suggest a clear decrease in the expression of the glucose transporters SGLT1 and SGLT2 under hypoxic conditions which implies a possible correlation with increased expression of HIF-1α.