Multiple drug-delivery strategies to enhance the pharmacological and toxicological properties of Mefenamic acid.

OBJECTIVE: To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS). METHODS: The in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer. RESULTS: When the PSs were resuspended in water, MefeGAL's, MA's and their mixture's apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44 hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS. CONCLUSIONS: These preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.

The Beneficial Effects of Ultramicronized Palmitoylethanolamide in the Management of Neuropathic Pain and Associated Mood Disorders Induced by Paclitaxel in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of antineoplastic drugs, particularly paclitaxel (PTX). It can affect the quality of patients' lives and increase the risk of developing mood disorders. Although several drugs are recommended, they yielded inconclusive results in clinical trials. The aim of the present work is to investigate whether the palmitoylethanolamide (PEA) would reduce PTX-induced CIPN and associated mood disorders. Moreover, the role PPAR-α and the endocannabinoid system will also be investigated. CIPN was induced by intraperitoneally injection of PTX (8 mg/kg) every other day for a week. PEA, 30 mg/kg, was orally administrated in a bioavailable form (i.e., ultramicronized PEA, um-PEA) one hour after the last PTX injection, for 7 days. In the antagonism experiments, AM281 (1 mg/kg) and GW6471 (2 mg/kg) were administrated 30 min before um-PEA. Our results demonstrated that um-PEA reduced the development of hypersensitivity with the effect being associated with the reduction in spinal and hippocampal pro-inflammatory cytokines, as well as antidepressive and anxiolytic effects. Moreover, the PPAR-α and CB1 receptor antagonists blocked the behavioral and antinociceptive effects of um-PEA. Our findings suggest that um-PEA is a promising adjunct in CIPN and associated mood disorders through the activation of PPAR-α, which influences the endocannabinoid system.

Phaseolus vulgaris extract ameliorates high-fat diet-induced colonic barrier dysfunction and inflammation in mice by regulating peroxisome proliferator-activated receptor expression and butyrate levels.

Obesity is a health concern worldwide, and its onset is multifactorial. In addition to metabolic syndrome, a high-fat diet induces many deleterious downstream effects, such as chronic systemic inflammation, a loss of gut barrier integrity, and gut microbial dysbiosis, with a reduction of many butyrate-producing bacteria. These conditions can be ameliorated by increasing legumes in the daily diet. White and kidney beans (Phaseolus vulgaris L.) and their non-nutritive bioactive component phaseolamin were demonstrated to mitigate several pathological features related to a metabolic syndrome-like condition. The aim of the present study was to investigate the molecular pathways involved in the protective effects on the intestinal and liver environment of a chronic oral treatment with P. vulgaris extract (PHAS) on a murine model of the high-fat diet. Results show that PHAS treatment has an anti-inflammatory effect on the liver, colon, and cecum. This protective effect was mediated by peroxisome proliferator-activated receptor (PPAR)-α and γ. Moreover, we also observed that repeated PHAS treatment was able to restore tight junctions' expression and protective factors of colon and cecum integrity disrupted in HFD mice. This improvement was correlated with a significant increase of butyrate levels in serum and fecal samples compared to the HFD group. These data underline that prolonged treatment with PHAS significantly reduces some pathological features related to the metabolic syndrome-like condition, such as inflammation and intestinal barrier disruption; therefore, PHAS could be a valid tool to be associated with the therapeutic strategy.