Influence of the formulation components on the properties of the system SLN-dextran hydrogel for the modified release of drugs

A system composed by solid lipid nanoparticles (SLN) entrapped into a chemical hydrogel of dextran was recently proposed for the controlled release of lipophilic drugs in oral formulations. This study reports now an extension of such study focused on the investigation of how the nature and the amount of the formulation components are able to modify the properties of the system. In particular the concentration of the two surfactants used for the nanosuspension stabilization, the nature of the lipid phase used for the nanoparticles preparation, as well as the concentration and the derivatization degree of the polymer employed for the gel preparation were investigated. The effects of these variables on the physicochemical properties of the nanoparticles and/or on the release profiles of the model drug (S)-(+)-2-(4-isobutylphenyl)-propionic acid (ibuprofen) were reported and discussed. Rheological experiments on samples of SLN, dextran hydrogel, and SLN-dextran hydrogel were also performed.     

Calpain activity contributes to the control of SNAP-25 levels in neurons

Calpains are a family of calcium-dependent proteases with abundant expression in the CNS, and potent in cleaving some synaptic components. Assessment of calpain activity by its fluorescent substrate, Boc-Leu-Met-CMAC, revealed that cultured neurons display a significant level of constitutive enzyme activity. Notably, calpain activity differs in distinct neuronal populations, with a significantly higher level of activity in GABAergic cells. Using selectively-enriched cultures of fast-spiking GABAergic interneurons, we show that calpain activity partially contributes to the post-translational down regulation of SNAP-25, a calpain substrate, in differentiated GABA cells. In addition, we demonstrate that SNAP-25 is cleaved by calpain in response to acute seizures induced by intraperitoneal kainate injection in vivo. These data indicate that calpains in neurons are active even at physiological calcium concentrations and that different levels of calpain activation in selected neuron subtypes may contribute to the pattern of synaptic protein expression.     

Benzodiazepine-induced chemotaxis is impaired in monocytes from patients with generalized anxiety disorder

Peripheral benzodiazepine receptors (PBR) modulate chemotaxis and cytokine production of monocytes and lymphocytes. Since PBR are decreased in animal models of stress and in patients with anxiety disorders, in the present study we analyze the ability of monocytes obtained from patients suffering from generalized anxiety to migrate towards chemoattracting benzodiazepines. In these patients, the benzodiazepine-induced chemotaxis is completely abolished, while the response to the control chemoattractant formyl-leu-met-phe is still maintained. The chemotaxis responses are not restored after pharmacological treatment of the pathology. The decreased chemotactic response could be linked to a decreased number of PBR receptors present on monocytes of generalized anxiety disorder patients.     

Effects of tramadol and its enantiomers on Concanavalin-A induced-proliferation and NK activity of mouse splenocytes: involvement of serotonin

The centrally acting analgesic drug tramadol is a 1:1 racemic mixture of two enantiomers, with different pharmacological properties. The (-)-tramadol preferentially inhibits noradrenaline uptake, whereas the (+)-tramadol inhibits serotonin uptake and binds to opioid receptors. Since tramadol has been shown to stimulate some immune responses in mice, in the present work we analyzed the effects of its enantiomers on the same parameters, with the aim to better characterize the mechanisms involved in such action of tramadol. The acute administration of 20 and 40 mg/kg of racemic tramadol and of 10 and 20 mg/kg of (+)-tramadol induced a significant and comparable stimulation of Concanavalin-A (Con-A) induced proliferation and of Natural Killer (NK) activity of splenocytes. On the contrary, the (-)-tramadol was devoid of any effect. The pretreatment with the serotoninergic antagonist metergoline (3.0 mg/kg) completely blocked the effects of both tramadol and (+)-tramadol. We suggest that the enhancement of the serotoninergic tone could be at the basis of the stimulatory effects exerted by tramadol on Con-A induced lymphoproliferation and NK activity.     

Plasmazellen in Ohrpolypen

Ohne Zusammenfassung     

The concept of recovery in major depression

BACKGROUND: There is increasing literature on the unsatisfactory degree of remission that current therapeutic strategies yield in unipolar depression. The aims of this review were to survey the available literature on residual symptoms of depression, to introduce new targets for therapy and to outline a more stringent definition of recovery. METHOD: Studies were identified by using MEDLINE (English language articles published from 1967 to June 2006; keywords: recovery, remission, residual symptoms, sequential treatment, drugs and psychotherapy, related to depressive disorder and depression) and a manual search of the literature and Index Medicus for the years 1960-2006. RESULTS: Most patients report residual symptoms despite apparently successful treatment. Residual symptoms upon remission have a strong prognostic value. There appears to be a relationship between residual and prodromal symptomatology. The concept of recovery should involve psychological well-being. CONCLUSIONS: Appraisal of subclinical symptomatology in depression has important implications for pathophysiological models of disease and relapse prevention. New therapeutic strategies for improving the level of remission, such as treatment on residual symptoms that progress to become prodromes of relapse, may yield more lasting benefits.     

Lactase persistence and bitter taste response: instrumental variables and mendelian randomization in epidemiologic studies of dietary factors and cancer risk

Consumption of dairy products seems to increase the risk of cancer at several sites, while intake of cruciferous vegetables could have protective effects. However, these dietary intakes are subject to measurement error, and associations with cancer could be due to confounders. Mendelian randomization has been suggested as a way to overcome confounding by exploiting the random allocation of alleles from parents to offspring. In mid-2006, the authors conducted a study of allele frequencies for the lactase (LCT) and taste receptor, type 2, member 38 (TAS2R38) genes, including 634 volunteers recruited (1992-1998) from the Italian branch of the European Prospective Investigation into Cancer and Nutrition. The authors hypothesized that there would be a lower milk intake among carriers of the LCT CC genotype and a different intake of cruciferous vegetables among carriers of the TAS2R38 variant. Overall, the frequency of the LCT T allele was higher in northern Italy than in southern Italy. Food intake was associated with gene variants. An association was evident for ice cream and LCT variants (p = 0.004); less so for milk intake. In addition, the TAS2R38 variant showed a geographic gradient and an association with cruciferous vegetable intake. These results suggest that the LCT and TAS2R38 variants are good candidates for Mendelian randomization studies of cancer and other health outcomes.     

FOLFOXIRI-Bevacizumab or FOLFOX-Panitumumab in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer: A Propensity Score-Based Analysis

BackgroundDoublets plus anti‐epidermal growth factor receptors (EGFRs) are the preferred upfront option for patients with left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). Initial therapy with FOLFOXIRI‐bevacizumab is superior to doublets plus bevacizumab independently from primary tumor sidedness and RAS/BRAF status. No randomized comparison between FOLFOXIRI‐bevacizumab versus doublets plus anti‐EGFRs is available in left‐sided RAS/BRAF wild‐type mCRC.Materials and MethodsWe selected patients with left‐sided RAS and BRAF wild‐type mCRC treated with first‐line FOLFOX‐panitumumab or FOLFOXIRI‐bevacizumab in five randomized trials: Valentino, TRIBE, TRIBE2, STEAM, and CHARTA. A propensity score‐based analysis was performed to compare FOLFOXIRI‐bevacizumab with FOLFOX‐panitumumab.ResultsA total of 185 patients received FOLFOX‐panitumumab and 132 received FOLFOXIRI‐bevacizumab. Median progression‐free survival (PFS) and median overall survival (OS) were 13.3 and 33.1 months in the FOLFOXIRI‐bevacizumab group compared with 11.4 and 30.3 months in the FOLFOX‐panitumumab group (propensity score‐adjusted hazard ratio (HR) for PFS, 0.82; 95% confidence interval (CI), 0.64–1.04; p = .11; propensity score‐adjusted HR for OS, 0.80; 95% CI, 0.59–1.08; p = .14). No significant differences in overall response rate and disease control rate were observed. A statistically nonsignificant difference in favor of FOLFOXIRI‐bevacizumab was observed for OS after secondary resection of metastases. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group, with specific regard to grade 3 and 4 neutropenia (48% vs. 26%, adjusted p = .001).ConclusionAlthough randomized comparison is lacking, both FOLFOXIRI‐bevacizumab and FOLFOX‐panitumumab are valuable treatment options in left‐sided RAS/BRAF wild‐type mCRC.Implications for PracticeA propensity score‐based analysis of five trials was performed to compare FOLFOX‐panitumumab versus FOLFOXIRI‐bevacizumab in left‐sided RAS/BRAF wild‐type metastatic colorectal cancer (mCRC). No significant differences were observed, but FOLFOXIRI‐bevacizumab achieved numerically superior survival outcomes versus FOLFOX‐panitumumab. Chemotherapy‐related adverse events were more frequent in the FOLFOXIRI‐bevacizumab group. These observations suggest that although doublet chemotherapy plus anti‐EGFRs remains the preferred treatment in patients with left‐sided RAS/BRAF wild‐type mCRC, FOLFOXIRI‐bevacizumab is a valuable option able to provide similar, if not better, outcomes at the price of a moderate increase in toxicity and may be adopted based on patients’ preference and potential impact on quality of life.