Anti-inflammatory, antinociceptive, and vasorelaxant effects of a new pyrazole compound 5-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)-1H-tetrazole: role of NO/cGMP pathway and calcium channels.

Molecular modification of compounds remains important strategy towards the discovery of new drugs. In this sense, this study presents a new pyrazole derivative 5-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)-1H-tetrazole (LQFM039) and evaluated the anti-inflammatory, analgesic, and vasorelaxant effects of this compound as well the mechanisms of action involved in the pharmacological effects. For this, mice were orally treated with LQFM039 (17.5, 35, or 70 mg/kg) prior acetic acid-induced abdominal writhing, formalin, tail flick, and carrageenan-induced paw edema protocols. In addition, vascular reactivity protocols were made with aortic rings contraction with phenylephrine and stimulated with graded concentrations of LQFM039. Abdominal writhing and licking time in both neurogenic and inflammatory phases of formalin were reduced with LQFM039 without altering latency to nociceptive response in the tail flick test. Carrageenan-induced paw edema showed that LQFM039 reduces edema and cell migration. In addition, the mechanism of action of LQFM039 involves NO/cGMP pathway and calcium channels, since this new pyrazole derivate elicited concentration-dependent relaxation attenuated by Nω-nitro-l-arginine methyl ester and 1H-[1,2,4] oxadiazolo [4,3-alpha]quinoxalin-1-one, and blockade of CaCl2-induced contraction. Altogether, our finding suggests anti-inflammatory, antinociceptive, and vasorelaxant effect of this new pyrazole derivative with involvement of NO/cGMP pathway and calcium channels.

Acute toxicity, antinociceptive, and anti-inflammatory activities of the orally administered crotamine in mice.

Crotamine is a polypeptide toxin isolated from rattlesnake venom. Although several studies have been developed identifying many biological effects of isolated crotamine, none of them evaluated its acute toxicity, antinociceptive, and anti-inflammatory activities through oral administration. All in vivo experiments from this study were performed in mice. The up-and-down procedure and hippocratic screening were carried out to evaluate possible pharmacological and toxic effects. Antinociceptive and anti-inflammatory activities of this toxin were evaluated using acetic acid-induced abdominal writhing, formalin-induced pain assays, croton oil-induced ear edema, and carrageenan-induced pleurisy. Crotamine did not cause lethality or signs of intoxication up to the maximum dose tested (10.88 mg/kg). The number of contortions was reduced significantly by 34, 57, and 74% at the oral doses of 0.08, 0.16, and 0.32 mg/kg, respectively. At the dose of 0.16 mg/kg, crotamine decreases pain time-reactivity at neurogenic phase by 45% and at inflammatory phase by 60%. Also, crotamine elicited antiedematogenic activity through the attenuation of the croton oil-induced ear edema by 77%. In the carrageenan-induced pleurisy, the leukocyte, neutrophil, and mononuclear cell migration to the lesion site were reduced by 52%, 46%, and 59%, respectively. Altogether, crotamine demonstrated in vivo antinociceptive and anti-inflammatory effect through acute oral administration, generating an anti-migratory mechanism of action at non-toxic doses.

Food-Effect on (-) - Hydroxycitric Acid Absorption After Oral Administration of Garcinia cambogia Extract Formulation: a Phase I, Randomized, Cross-Over Study.

Garcinia cambogia extract (GCE)/(-) - hydroxycitric acid (HCA) has been identified as a potential antiobesity agent. However, controversial clinical trial results have been published on its biological effect and poor pharmacokinetic (PK) information increases its dubious efficacy. The aim of this study was to determine the main PK parameters of GCE/HCA in healthy women, and to evaluate food effects on HCA absorption. Healthy women ages 21-41 years with body mass index (BMI; kg/m2) 20.29-25.82 participated in a phase I, open-label, randomized, single-dose, cross-over study. In the fasted- and fed-conditions subjects received 1500/750 mg of GCE/HCA under 8 h of fasting. In the fed-period was given a high calorie breakfast (~600 calories) after dosing. Plasma HCA concentrations were substantially reduced in fed-state. Peak plasma concentration (Cmax) and area under the curve of time-concentration (AUC0-10h) were 3-fold and 2-fold lower (p < 0.001, 0.01) in fed-condition, respectively. Higher volume of distribution (Vd/F) and clearance (Cl/F) were achieved in fed state, probably due to the lower fraction (F) of HCA absorbed induced by food effect. Large inter-individual variations were observed for the main pharmacokinetics parameters in both periods. These findings suggest that HCA might suffer an active absorption uptake and intense adsorption on food.

Anti-nociceptive and anti-inflammatory activities of 4-[(1-phenyl-1H-pyrazol-4-yl) methyl] 1-piperazine carboxylic acid ethyl ester: A new piperazine derivative.

Piperazine compounds possess anti-infective, anti-carcinogenic, anxiolytic, hypotensive, anti-hypertensive and vasorelaxant properties and are attractive candidates for the development of new analgesic and anti-inflammatory drugs. This study investigates the anti-nociceptive and anti-inflammatory effects of piperazine derivative 4-[(1-phenyl-1H-pyrazol-4-yl) methyl]1-piperazine carboxylic acid ethyl ester (LQFM-008) and the involvement of the serotonergic pathway. In the formalin test, treatments with LQFM-008 (15 and 30mg/kg p.o.) reduced the licking time in both neurogenic and inflammatory phases of this test. In the tail flick and hot plate tests, LQFM008 treatment (15 and 30mg/kg p.o.) increased latency to thermal stimulus, suggesting the involvement of central mechanisms in the anti-nociceptive effect of LQFM-008. In the carrageenan-induced paw edema test, LQFM-008 (p.o.) at the doses of 15 and 30mg/kg reduced the edema at all tested time points, while the dose of 7.5mg/kg reduced the edema only for the first hour. LQFM-008 (30mg/kg p.o.) reduced both cell migration and protein exudation in the carrageenan-induced pleurisy test. Furthermore, pre-treatment with NAN-190 (0.6mg/kgi.p.) and PCPA (100mg/kgi.p.) antagonized the anti-nociceptive effect of LQFM-008 in both phases of the formalin test. Our data suggest that LQFM-008 possesses anti-inflammatory and anti-nociceptive effects mediated through the serotonergic pathway.

Involvement of the NO/cGMP/KATP pathway in the antinociceptive effect of the new pyrazole 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021).

The pyrazol compounds are known to possess antipyretic, analgesic and anti-inflammatory activities. This study was conducted to investigate the peripheral antinociceptive effect of the pyrazole compound 5-(1-(3-Fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021) and involvement of opioid receptors and of the NO/cGMP/K(ATP) pathway. The oral treatments in mice with LQFM-021 (17, 75 or 300 mg/kg) decreased the number of writhing. In the formalin test, the treatments with LQFM-021 at doses of 15, 30 and 60 mg/kg reduced the licking time at both neurogenic and inflammatory phases of this test. The treatment of the animals with LQFM-021 (30 mg/kg) did not have antinociceptive effects in the tail-flick and hot plate tests. Furthermore, pre-treatment with naloxone (3 mg/kg i.p.), L-name (10 mg/kg i.p.), ODQ (10 mg/kg i.p.) or glibenclamide (3 mg/kg i.p.) antagonized the antinociceptive effect of LQFM-021 in both phases of the formalin test. In addition, it was also demonstrated that the treatments of mice with LQFM-021(15, 30 and 60 mg/kg) did not compromise the motor activity of the animals in the chimney test. Only the highest dose used in the antinociceptive study promoted changes in the open field test and pentobarbital-induced sleep test, thus ruling out possible false positive effects on nociception tests. Our data suggest that the peripheral antinociception effects of the LQFM-021 were mediated through the peripheral opioid receptors with activation of the NO/cGMP/KATP pathway.

Hypotensive and vasorelaxant effects of (E) - methyl isoeugenol: a naturally occurring food flavour.

Application of naturally occurring (E) - methyl isoeugenol (MIE) as food flavour has been widely accepted despite the growing concerns over cardiovascular issue. Hence, we sought to investigate hypotensive property of MIE and the involvement of central and/or peripheral mechanism (s). Variation in mean arterial pressure (MAP), heart rate (HR), systolic blood pressure (SBP), baroreflex sensitivity of normotensive rats and vascular reactivity were recorded. MIE (1.11, 2.25 or 4.50mg/kg, iv) elicited dose-related decrease in MAP (-16.9±1.13; -19.0±4.18 or -27.2±3.65mmHg, respectively) and an increase in HR (17.4±1.79; 24.4±5.11 or 29.9±6.62 bmp, respectively). MIE 25 or 50mg/kg (p.o) reduced the SBP (-13.6±4.18 or -16.6±5.60mmHg, respectively) without altering baroreflex sensitivity. The hypotensive effect of MIE remained unaltered by WAY100635 (antagonist of 5-HT1A) and L-NAME (NO synthase inhibitor). Intracerebroventricular injection of MIE did not change MAP. MIE elicited endothelium independent vasorelaxation (endothelium-intact vessels, Emax 92.5±1.75%; Endothelium-denuded vessels, Emax 91.4±2.79%). MIE blocked CaCl2 or BAY K8644 (L-type voltage gated calcium channel activator)-induced vascular contractions. Our findings showed evidence of hypotensive and vasorelaxation effects of MIE with involvement of calcium channel.