Pharmacological characterization of paracetamol: new therapeutic approach to postoperative pain.

Acetaminophen, commonly known as paracetamol, is an active ingredient possessing analgesic and antipyretic activity used widely in medical practice to alleviate acute and chronic pain and to reduce the body temperature when this exceeds physiological values. Paracetamol, conversely to the majority of commonly used analgesic drugs, is not an non-steroidal anti-inflammatory drug (NSAIDs), since it is almost devoid of antiaggregant and anti-inflammatory activity. The most typical paracetamol-based pharmaceutical formulations are those in solid tablet form, in granule form or in the form of suppositories. Moreover, formulations containing paracetamol in the form of a solution for intravenous infusion can also be found on the market. These are formulations indicated for the short-term treatment of pain of medium intensity, in particular of the type experienced following a surgical intervention. Intravenous administration is reserved for cases in which, from a clinical viewpoint, there is the need to treat the pain and/or hyperthermia with urgency or in cases in which it is impossible to implement the other administration methods. Administration of paracetamol by means of methods alternative to traditional ones is still to be explored, no specific applications have been found in the field of analgesic therapy. Acute postoperative pain is a normal response to surgical intervention and is a cause of delayed recovery and discharge after surgery as well as increased risk of wound infection and respiratory/cardiovascular complications. Untreated acute pain leads to reduced patient satisfaction and increased morbidity and mortality and also places a burden on the paient and health system finances. Acute pain that becomes intractable and persists is referred to as chronic postsurgical pain (CPSP). CPSP can have a significant impact on the patient’s quality of life and daily activities, including disturbances of sleep and affective mood In the clinical field, paracetamol is used fundamentally as an antipyretic in the treatment of febrile states and as an analgesic in the treatment of mild and medium pain as postoperative pain. Traditional pharmacological approaches to pain management in the postoperative period include oral or intravenous administration of opioids and oral administration of paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs); nevertheless these approaches are associated with a variety of adverse events. Recently, much attention was focused on spinal administration of paracetamol, in order to overcome the possible hepatotoxicity after oral administration. The administration of injectable solutions by spinal administration generally presents limitations. A first limitation is of the physical type, because the drug is perfused in a defined and confined space in which a limited quantity of solution can be infused. This limit can be overcome using a paracetamol hypersaturated solution. In this regard, our aim has been to verify effect of a new supersaturated aqueous solution of paracetamol (SINTETICO; SIN) at different doses (100-500 μg/it) after spinal administration in an animal model of postoperative pain. Mechanical hyperalgesia was evaluated by mechanical stimuli using the Randall-Selitto analgesimeter for rats. Hyperalgesia was assessed on incision paw 2, 4, 24, 48, 72 h after spinal administration. Data showed that spinal Sintetico administration produced a significant antihyperalgesic effect, in dose and time manner. In particular, the high doses of Sintetico (500 µg) produced a significant analgesic effect until 72 h after surgery. Moreover, knowing the marked analgesic effect of paracetamol following oral administered, and considering the use of this drug as a premedication before surgery, we investigated efficacy of combination of oral and spinal routes of paracetamol and SIN using inactive and active doses (PARA 200 and 500 mg/kg/os and SIN 100 and 500 µg/it/ respectively). Surprisingly, a synergic effect was obtained after oral and intrathecal combination of inactive doses; in fact PARA 200 mg/kg/os and SIN 100 µg/it produced a prolonged analgesic effect up to 24 h after administration. Despite its medical use is consolidated by many years, its mechanism of action is still poorly understood. There are several hypothesis concerning the possible mechanism of action; for this reason we investigated the involvement of cannabinergic (CB1 and CB2), opioidergic (μ and κ receptors) and serotoninergic (5HT3) systems. Our results indicated that in paracetamol-induced analgesdia all these system are involved, confirming data reported in literature. Finally, it is well known that orally high doses of paracetamol could cause perilobular hepatotoxicity, which is the main limit to use this drug, especially in fasting patients before chirurgical surgery. It very poor the knowledge about the possible toxicity of paracetamol after intrathecal administration. We examined if single or repeated spinal Sintetico administration by spinal catheter showed physiological and/or morphological modification of cauda equina or nerve bundles of the lumbosacral spinal cord sections. Both acute (500µg) or repeated (200-500 µg for 7 days) administration of SIN resulted in a mild degree of toxicity with little or no degeneration of nerve fibers and there was no difference between SIN-treated and vehicle-treated rats. Furthermore, we observed macroscopically, whether the administration of Sintetico for 7 days had produced liver toxicity. No significant alteration of margins and sizes was observed in SIN-treated rats respect vehicle group. In conclusion, during this my PhD, we evaluated the pharmacological effects and toxicological profile of a new supersaturated aqueous solution of paracetamol; results obtained confirm the efficacy of this drug in postoperative pain, offering a new therapeutic approach based on spinal route

Estudo de efeitos dos genes opaque-2, shruken e shrunken-2 durante a germinação do milho

Orientador: William Jose da SilvaDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: Três linhagens isogênicas de milho, cada uma com dois tipos de endospermas: o endosperma normal, do tipo selvagem, condicionado pelo gene dominante, e o endosperma mutante, homozigoto para o alelo recessivo, foram utilizadas para estudar o efeito dos genes opaque-2, shrunken e shrunken-2 durante a germinação. Cada um dos mutantes e os respectivos endospermas normais foram obtidos em uma mesma espiga através da autofecundação de uma planta heterozigota para o loco em questão. Os pesos fresco e seco e quantidade de nitrogênio foram analisados diariamente em endospermas e plântulas durante dez dias de germinação, a '27 GRAUS¿ e no escuro.Nesse período estudou-se também o metabolismo de aminoácidos nos diferentes endospermas e plântulas. Os resultados obtidos indicaram que a quantidade de água absorvida pelos vários endospermas durante a embebição, está relacionada com as características físicas e químicas deste tecido. Os endospermas com maiores quantidades de açúcares, e portanto, com os menores potenciais osmóticos, em ordem decrescente, sh2, sh e o2 apresentaram também os maiores aumentos no peso fresco. A utilização de matéria seca, ou indiretamente de carboidratos, foi semelhante nos mutantes e nos tipos normais. Desse modo, a transferência de matéria seca do endosperma para a plântula parece depender de um sistema genético diferente daquele governado pelos genes que atuam na formação do endosperma. ...Observação: O resumo, na íntegra, poderá ser visualizado no texto completo da tese digitalAbstract: Abstract: Three isogenic inbreads of maize were used to study the effect of the opaque-2 (o2)~ shrunken (sh) and shrunken-2 (sh2) genes during germination. One inbread had two types of endosperm; one homozygote for the 02 gene and the other for the 02 gene. A second line had also two different endosperms: one homozygote for the sh allele and the other for the Sh allele. Finnaly, a third inbread line with also two types of endosperms; one homozygote for the sh2 gene and the other for the allele.Each mutant and his normal endosperm were produced in a same ear of an inbread by self "pollnating of a heterozigote plantfor the pertinent locus. Fresh and dry weight and nitrogen content were analysed daily in both endosperms and seedlings, along ten days, during germination at 270C in the dark. The aminoacid metabolism were an alysed in both endosperms and seedlings. Data showed that the amount of water absorbed by the endosperm during imbibition depends on both physical and chemical characteristics of this tissue. The mutant endosperms with high sugar content and therefore with low osmotic potential, in decreasing order sh2, sh and 02, were also the ones that showed high increases in endosperms fresh weight. ...Note: The complete abstract is available with the full electronic digital thesis or dissertationsMestradoMestre em Ciências Biológica

Ketogal: A Derivative Ketorolac Molecule with Minor Ulcerogenic and Renal Toxicity

Ketorolac is a powerful non-steroidal anti-inflammatory drug (NSAID), with a great analgesic activity, present on the Italian market since 1991. Despite the excellent therapeutic activity, the chronic use of ketorolac has long been limited owing to the high incidence of gastrointestinal and kidney side events. In our previous study, we demonstrated that ketorolac–galactose conjugate (ketogal), synthesized and tested in a single-dose study, was able to reduce ulcerogenicity, while preserving the high pharmacological efficacy of its parent drug. In this paper, in order to verify the suitability of this compound, for repeated administration, ex vivo experiments on naïve mice were performed. Mice were treated for 5 or 7 days with the highest doses of two drugs (ketorolac 10 mg/kg and ketogal 16.3 mg/kg), and the expression of both gastric COX-1 and PGsyn was evaluated. Results showed that oral ketorolac treatment significantly reduced both enzymes; surprisingly, oral treatment with ketogal did not produce significant variation in the expression of the two constitutive enzymes. Moreover, histological experiments on stomach and kidneys clearly indicated that repeated administration of ketogal induced lower toxicity than ketorolac. At same time, in vivo results clearly showed that both ketorolac and ketogal had a similar therapeutic activity in a model of inflammation and in pain perception. These effects were accompanied by the reduction of enzyme expression such as COX-2 and iNOS, and by the modulation of levels of nuclear NF-kB and cytosolic IkB-a in the inflamed paws. These very encouraging results demonstrate for the first time that ketogal could represent a valid and novel therapeutic alternative to the ketorolac and might pave the way for clinical studies

Gender studies: Knowledge transfer betweeen Europe and Latin America

In this paper we present the proyect (GENDERCIT) "Gender and Citizenship" coordinated for the University Pablo de Olavide and funded by the People Programme of European Union, IRSES, one of Marie Curie actions, Seventh Frame work Programme (FP7/ 2007 2013/under grantagreement 318960). Its main objective is to create an international scientific network to promote interdisciplinary studies, original and innovative. Since this proyect will study and analyze gender realtions in various countries in Europe and Latin America, focussing to four areas: a) Citizenship Equality of social and political rights; b) violenc of gender; c) education; e) migration. The transfer of knowledge between Euorope (Spain, Portugal, France and Italy) an Latin America (Argentina and Mexico), was done through academic stays, jointn training and research on the subject. Through the following pages analyze the need for gender studies in different areas, and present the design of our project and the results obtained so far seeking to strengthen the network of researches that is developing internationally. Moreover we intend to promote gender studies min contexts where patriarchy mis still deeply rooted in society, and in areas where gender inequalities are still very presentEn este artículo presentamos el proyecto GENDERCIT (Género y Ciudadanía) coordinado por la Universidad Pablo de Olavide y financiado por el Programa People de la Unión Europea, IRSES, una de las acciones del Marie Curie, séptimo programa marco (FP7/2007-2013/under grantagreement 318960) Su objetivo principal es crear una red científica internacional para impulsar estudios de género interdisciplinares, originales e innovadores. Desde este proyecto se estudian y analizan las relaciones de género en diversos países de Europa y América Latina, centándonos en cuatro ámbitos a)Ciudadanía. Igualdad de derechos sociales y políticos b);violencia de género; c) educación; d) migraciones. La transferencia de conocimiento entre Europa (España, Portugal, Francia e Italia) y América Latina (Argentina y Méjico), se realiza a través de estancias académicas, investigaciones conjuntas y formación sobre la temática A través de las siguientes páginas analizamos la necesidad realizar estudios género en distintos ámbitos y presentamos el diseño de nuestro proyecto y los resultados obtenidos hasta momento, buscando potenciar la red de investigadoras/es que se está desarrollando a nivel internacional . Por otro lado, pretendemos impulsar estudios de género en aquellos contextos donde el el patriarcado está aún muy arraigado en la sociedad, y en aquellos ámbitos donde las desigualdades de género siguen estando muy presente

Intervención educativa familiar y terapia sistémica en la adicción adolescente a Internet

ABSTRACTThis article addresses the theoretical fundaments of systemic family therapy to promote an appropriate use of the Internet in the adolescent user. The study of the concept of Internet addiction and especially the different risk profiles shows the need to look deeply into the family dynamics behind many cases of addiction. This work is based on a literature review that has followed a double standard: we have selected the latest publications taking into account the main sections of this article (Internet addiction, prior profile and pathology in teenagers and systemic family therapy). In this sense the literature review indicates different research works that propose family therapy as an intervention strategy in the treatment of addiction along with other therapies such as cognitive-behavioral. As a result, an educational response in the family will be able to strengthen the usual dynamics through an active approach to problems and a model of fluent communication between all components of family system. In this case, enjoying the use of online games in family will lead to generate shared goals, respect common rules, facilitate the involvement of the family and establish stronger and closer bonds: an adaptive and shared use of online game instead of avoiding it. An empirical research about the preventive and therapeutic efficacy of this theoretical proposal is not the aim of this paper.RESUMEN El presente artículo trata sobre los fundamentos teóricos de la terapia familiar sistémica para favorecer un uso adecuado de Internet en el usuario adolescente. El estudio del concepto de adicción a la red así como especialmente de los diferentes perfiles de riesgo muestra la necesidad de profundizar en el conocimiento de la dinámica familiar que está detrás de muchos casos de adicciones. Este trabajo consiste en un estudio bibliográfico en el que se ha seguido un doble criterio: se apoya tanto en las publicaciones más recientes como en la adecuación a los principales apartados de este artículo (concepto de adicción a Internet, perfil previo y patología en adolescentes y la terapia familiar sistémica). En este sentido la revisión bibliográfica señala diferentes investigaciones en las que la terapia familiar se propone como estrategia de intervención en el tratamiento de la adicción junto con otro tipo de terapias como la cognitivo-conductual. Como resultado una respuesta educativa desde el ámbito familiar fortalecerá la dinámica habitual a través de una actitud activa ante los problemas y de un modelo de comunicación fluido entre todos los componentes del sistema familiar. En este caso un uso de los juegos virtuales en familia permitirá generar metas compartidas, respetar normas comunes, así como facilitar la implicación de la familia y establecer lazos afectivos más fuertes y estrechos: un uso adaptativo y compartido del juego online en lugar de su evitación. No es objeto de este trabajo el estudio empírico de la eficacia preventiva y terapéutica de esta propuesta teórica.ABSTRACTThis article addresses the theoretical fundaments of systemic family therapy to promote an appropriate use of the Internet in the adolescent user. The study of the concept of Internet addiction and especially the different risk profiles shows the need to look deeply into the family dynamics behind many cases of addiction. This work is based on a literature review that has followed a double standard: we have selected the latest publications taking into account the main sections of this article (Internet addiction, prior profile and pathology in teenagers and systemic family therapy). In this sense the literature review indicates different research works that propose family therapy as an intervention strategy in the treatment of addiction along with other therapies such as cognitive-behavioral. As a result, an educational response in the family will be able to strengthen the usual dynamics through an active approach to problems and a model of fluent communication between all components of family system. In this case, enjoying the use of online games in family will lead to generate shared goals, respect common rules, facilitate the involvement of the family and establish stronger and closer bonds: an adaptive and shared use of online game instead of avoiding it. An empirical research about the preventive and therapeutic efficacy of this theoretical proposal is not the aim of this paper

Gut-brain axis: Role of lipids in the regulation of inflammation, pain and CNS diseases

The human gut is a composite anaerobic environment with a large, diverse and dynamic enteric microbiota, represented by more than 100 trillion microorganisms, including at least 1000 distinct species. The discovery that a different microbial composition can influence behavior and cognition, and in turn the nervous system can indirectly influence enteric microbiota composition, has significantly contributed to establish the well-accepted concept of gut-brain axis. This hypothesis is supported by several evidence showing mutual mechanisms, which involve the vague nerve, the immune system, the hypothalamic-pituitary-adrenal (HPA) axis modulation and the bacteria-derived metabolites. Many studies have focused on delineating a role for this axis in health and disease, ranging from stress-related disorders such as depression, anxiety and irritable bowel syndrome (IBS) to neurodevelopmental disorders, such as autism, and to neurodegenerative diseases, such as Parkinson Disease, Alzheimer Disease etc. Based on this background, and considering the relevance of alteration of the symbiotic state between host and microbiota, this review focuses on the role and the involvement of bioactive lipids, such as the N-acylethanolamine (NAE) family whose main members are N-arachidonoylethanolamine (AEA), palmitoylethanolamide (PEA) and oleoilethanolamide (OEA), and short chain fatty acids (SCFAs), such as butyrate, belonging to a large group of bioactive lipids able to modulate peripheral and central pathologic processes. It is well established their effective role in inflammation, acute and chronic pain, obesity and central nervous system diseases. It has been shown a possible correlation between these lipids and gut microbiota through different mechanisms. Indeed, systemic administration of specific bacteria can reduce abdominal pain through the involvement of cannabinoid receptor 1 in rat; on the other hand, PEA reduces inflammation markers in a murine model of inflammatory bowel disease (IBD), and butyrate, producted by gut microbiota, is effective in reducing inflammation and pain in irritable bowel syndrome and IBD animal models. In this review, we underline the relationship among inflammation, pain, microbiota and the different lipids, focusing on a possible involvement of NAEs and SCFAs in the gut-brain axis and their role in central nervous system diseases.    

Impairment of several immune functions and redox state in blood cells of Alzheimer's disease patients. Relevant role of neutrophils in oxidative stress

Since aging is considered the most risk factor for sporadic Alzheimer’s Disease (AD), the age-related impairment of the immune system (immunosenescence), based on a chronic oxidative-inflammatory stress situation, could play a key role in the development and progression of AD. Although AD is accompanied by systemic disturbance, reflecting the damage in the brain, the changes in immune response and redox-state in different types of blood cells in AD patients have been scarcely studied. The aim was to analyze the variations in several immune functions and oxidative-inflammatory stress and damage parameters in both isolated peripheral neutrophils and mononuclear blood cells, as well as in whole blood cells, from patients diagnosed with mild (mAD) and severe AD, and of age-matched controls (elderly healthy subjects) as well as of adult controls. The cognitive decline of all subjects was determined by Mini-Mental State Examination (MMSE) test (mAD stage was established at 20 ≤ MMSE ≤ 23 score; AD stage at 27 MMSE). The results showed an impairment of the immune functions of human peripheral blood neutrophils and mononuclear cells of mAD and AD patients in relation to healthy elderly subjects, who showed the typical immunosenescence in comparison with the adult individuals. However, several alterations were only observed in severe AD patients (lower chemotaxis, lipopolysaccharide lymphoproliferation, and interleukin (IL)-10 release; higher basal proliferation, tumor necrosis factor (TNF)-α release, and IL-10/TNF-α ratio), others only in mAD subjects (higher adherence), meanwhile others appeared in both mAD and AD patients (lower phytohemaglutinin lymphoproliferation and higher IL-6 release). This impairment of immune functions could be mediated by: (1) the higher oxidative stress and damage also observed in blood cells from mAD and AD patients and in isolated neutrophils [lower glutathione (GSH) levels, high oxidized glutathione (GSSG)/GSH ratio, and GSSG and malondialdehyde contents], and (2) the higher release of basal pro-inflammatory cytokines (IL-6 and TNF-α) found in AD patients. Because the immune system parameters studied are markers of health and rate of aging, our results supported an accelerated immunosenescence in AD patients

Gut microbiota composition and butyrate production in children affected by non-IgE-mediated cow’s milk allergy

Cow’s milk allergy (CMA) is one of the earliest and most common food allergy and can be elicited by both IgE- or non-IgE-mediated mechanism. We previously described dysbiosis in children with IgE-mediated CMA and the effect of dietary treatment with extensively hydrolyzed casein formula (EHCF) alone or in combination with the probiotic Lactobacillus rhamnosus GG (LGG). On the contrary, the gut microbiota in non-IgE-mediated CMA remains uncharacterized. In this study we evaluated gut microbiota composition and fecal butyrate levels in children affected by non-IgE-mediated CMA. We found a gut microbiota dysbiosis in non-IgE-mediated CMA, driven by an enrichment of Bacteroides and Alistipes. Comparing these results with those previously obtained in children with IgE-mediated CMA, we demonstrated overlapping signatures in the gut microbiota dysbiosis of non-IgE-mediated and IgE-mediated CMA children, characterized by a progressive increase in Bacteroides from healthy to IgE-mediated CMA patients. EHCF containg LGG was more strongly associated with an effect on dysbiosis and on butyrate production if compared to what observed in children treated with EHCF alone. If longitudinal cohort studies in children with CMA will confirm these results, gut microbiota dysbiosis could be a relevant target for innovative therapeutic strategies in children with non-IgE-mediated CMA

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