The effects of pioglitazone, a PPARγ receptor agonist, on the abuse liability of oxycodone among nondependent opioid users

Aims: Activation of PPARγ by pioglitazone (PIO) has shown some efficacy in attenuating addictive-like responses in laboratory animals. The ability of PIO to alter the effects of opioids in humans has not been characterized in a controlled laboratory setting. The proposed investigation sought to examine the effects of PIO on the subjective, analgesic, physiological and cognitive effects of oxycodone (OXY). Methods: During this investigation, nondependent prescription opioid abusers (N = 17 completers) were maintained for 2-3 weeks on ascending daily doses of PIO (0 mg, 15 mg, 45 mg) prior to completing a laboratory session assessing the aforementioned effects of OXY [using a within-session cumulative dosing procedure (0, 10, and 20 mg, cumulative dose = 30 mg)]. Results: OXY produced typical mu opioid agonist effects: miosis, decreased pain perception, and decreased respiratory rate. OXY also produced dose-dependent increases in positive subjective responses. Yet, ratings such as: drug "liking," "high," and "good drug effect," were not significantly altered as a function of PIO maintenance dose. Discussion: These data suggest that PIO may not be useful for reducing the abuse liability of OXY. These data were obtained with a sample of nondependent opioid users and therefore may not be applicable to dependent populations or to other opioids. Although PIO failed to alter the abuse liability of OXY, the interaction between glia and opioid receptors is not well understood so the possibility remains that medications that interact with glia in other ways may show more promise

The impact of polyphenols on chondrocyte growth and survival: a preliminary report

Background: Imbalances in the functional binding of fibroblast growth factors (FGFs) to their receptors (FGFRs) have consequences for cell proliferation and differentiation that in chondrocytes may lead to degraded cartilage. The toxic, proinflammatory, and oxidative response of cytokines and FGFs can be mitigated by dietary polyphenols. Objective: We explored the possible effects of polyphenols in the management of osteoarticular diseases using a model based on the transduction of a mutated human FGFR3 (G380R) in murine chondrocytes. This mutation is present in most cases of skeletal dysplasia and is responsible for the overexpression of FGFR3 that, in the presence of its ligand, FGF9, results in toxic effects leading to altered cellular growth. Design: Different combinations of dietary polyphenols derived from plant extracts were assayed in FGFR3 (G380R) mutated murine chondrocytes, exploring cell survival, chloride efflux, extracellular matrix (ECM) generation, and grade of activation of mitogen-activated protein kinases. Results: Bioactive compounds from Hibiscus sabdariffa reversed the toxic effects of FGF9 and restored normal growth, suggesting a probable translation to clinical requests in humans. Indeed, these compounds activated the intracellular chloride efflux, increased ECM generation, and stimulated cell proliferation. The inhibition of mitogen-activated protein kinase phosphorylation was interpreted as the main mechanism governing these beneficial effects. Conclusions: These findings support the rationale behind the encouragement of the development of drugs that repress the overexpression of FGFRs and suggest the dietary incorporation of supplementary nutrients in the management of degraded cartilage.The authors are grateful for the constant support provided by the Hospital Universitari de Sant Joan and the Universitat Rovira i Virgili. Salvador Fernández-Arroyo is the recipient of a Sara Borrell grant (CD12/00672) from the Instituto de Salud Carlos III, Madrid, Spain. The authors also thank the Andalusian Regional Government Council of Innovation and Science for the Excellence Project P11-CTS-7625 and Generalitat Valenciana for the project PROMETEO/2012/007. This work was also supported by projects of the Fundación Areces and the Fundación MAGAR

Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009

Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD). Multiple prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes, as well as in non-diabetic individuals. The molecular causes of insulin resistance, i.e. impaired insulin signalling through the phosphoinositol-3 kinase pathway with intact signalling through the mitogen-activated protein kinase pathway, are responsible for the impairment in insulin-stimulated glucose metabolism and contribute to the accelerated rate of CVD in type 2 diabetes patients. The current epidemic of diabetes is being driven by the obesity epidemic, which represents a state of tissue fat overload. Accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis. Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients

<b>Desenvolvimento e Teste Preliminar da Estabilidade de formulações cosméticas acrescidas de extrato comercial de <i>Trichilia catigua</i> Adr. Juss (e) <i>Ptychopetalum olacoides</i> Bentham</b>

<p class="MsoNormal" style="margin: 0cm 0cm 0pt; line-height: normal; text-align: justify; mso-layout-grid-align: none;"> O presente estudo apresenta etapas de desenvolvimento de emulsões cosméticas, contendo 5% do extrato comercial de <i>Trichilia catigua</i> Adr. Juss (e) <i>Ptychopetalum olacoides</i> Bentham. Desenvolveramse 14 formulações-teste e avaliou-se a obtenção de emulsões macroscopicamente estáveis, com valores de viscosidade aparente variados, pH compatível com o da pele e características organolépticas adequadas, por meio dos Testes de Estabilidade Preliminar e Acelerada. Estas formulações foram divididas em dois grupos: um com emulsões fluidas e outro com emulsões mais viscosas. Após análise, oito formulações-teste foram consideradas aptas para serem submetidas ao Teste de Estabilidade Preliminar. Após os ensaios, cinco formulações-teste foram selecionadas para o Teste de Estabilidade Acelerada. Os ensaios foram conduzidos em condições de armazenamento, de luminosidade e de temperatura extremas. Ao final do estudo, duas formulações-teste foram consideradas aprovadas por apresentarem os perfis mais estáveis durante o estudo, sendo ambas, emulsões fluidas constituídas de ceras auto-emulsionantes e 0,3% p/p de um polímero natural, e uma delas adicionada também de 2,0% lecitina de soja. Palavras-chave: estabilidade de emulsões cosméticas; desenvolvimento de emulsões; <i>Trichilia catigua</i> Adr. Juss (e) <i>Ptychopetalum olacoides</i> Bentham</p&gt