Development and characterization of an amorphous solid dispersion of furosemide in the form of a sublingual bioadhesive film to enhance bioavailability

Administered by an oral route, Furosemide (FUR), a diuretic used in several edematous states and hypertension, presents bioavailability problems, reported as a consequence of an erratic gastrointestinal absorption due to various existing polymorphic forms and low and pH-dependent solubility. A mucoadhesive sublingual fast-dissolving FUR based film has been developed and evaluated in order to optimize the bioavailability of FUR by increasing solubility and guaranteeing a good dissolution reproducibility. The Differential Scanning Calorimetry (DSC) analyses confirmed that the film prepared using the solvent casting method entrapped FUR in the amorphous state. As a solid dispersion, FUR increases its solubility up to 28.36 mg/mL. Drug content, thickness, and weight uniformity of film were also evaluated. The measured Young\ue2\u80\u99s Modulus, yield strength, and relative elongation of break percentage (EB%) allowed for the classification of the drug-loaded film as an elastomer. Mucoadhesive strength tests showed that the force to detach film from mucosa grew exponentially with increasing contact time up to 7667 N/m2. FUR was quickly discharged from the film following a trend well fitted with the Weibull kinetic model. When applied on sublingual mucosa, the new formulation produced a massive drug flux in the systemic compartment. Overall, the proposed sublingual film enhances drug solubility and absorption, allowing for the prediction of a rapid onset of action and reproducible bioavailability in its clinical application

A multianalytical approach to investigate stone biodeterioration at a UNESCO world heritage site: the volcanic rock-hewn churches of Lalibela, Northern Ethiopia.

A multianalytical approach combining Optical Microscopy (OM), Backscattered Variable Pressure Scanning Electron Microscopy + Energy Dispersive X-ray Spectroscopy (VP-BSEM + EDS), Powder X-ray Diffractometry (PXRD), Raman Spectroscopy, and Microbiological techniques has been applied to characterize decay products and processes occurring at the surface of two rockhewn churches (Bete Gyorgis and Bete Amanuel) at the UNESCO’s World Heritage site of Lalibela, Northern Ethiopia. The two churches were carved into volcanic scoria deposits of basaltic composition. In their geological history, the Lalibela volcanic rocks underwent late to post-magmatic hydrothermal alteration together with partial laterization and are therefore characterized by a decay-prone highly vesicular microtexture with late stage to post-magmatic precipitation of secondary mineral phases (calcite–zeolite–smectite). The main objective of the study was to gain a better insight into the weathering products and mechanisms affecting the surface of the stone monuments and to assess the relative contribution of natural “geological” weathering processes versus biological/salt attack in stone decay at this unique heritage site. Results indicate that while the main cause of bulk rock deterioration and structural failure could be related to the stone inherited “geological” features, biological attack by micro- (bacteria) and/or macro- (lichens) organisms is currently responsible for severe stone surface physical and chemical weathering leading to significant weakening of the stone texture and to material loss at the surface of the churches walls. A prompt and careful removal of the biological patinas with the correct biocidal treatment is therefore recommended

Phaseolus vulgaris L. Extract: Alpha-amylase inhibition against metabolic syndrome in mice

To examine the effects of the alpha-amylase inhibitor isoform 1 called phaseolamin, a standardized extract from white kidney beans (Phaseolus vulgaris L) was tested against the hallmarks of metabolic syndrome. The efficacy of a per os repeated treatment with P. vulgaris extract (500 mg/kg) was compared with metformin (100 mg/kg) and atorvastatin (10 mg/kg) in a model of metabolic syndrome evoked by prolonged high fat diet (HFD; week 1 to week 19) in C57BL/6 mice. Bean extract and compounds administration started after metabolic syndrome establishment (week 11). P. vulgaris extract reduced the body weight overtime, as well as effectively lowered glycaemia, triglycerides, and cholesterol. On week 19, bean extract normalized the HFD-evoked tolerance to glucose and insulin. According to the phytochemical characterization, it inhibited the alpha-amylase activity. Animals treated with the extract were rescued from motor impairments and nociceptive threshold alterations induced by HFD. Specific organs analysis revealed that P. vulgaris extract decreased hepatic steatosis and lipid peroxidation in liver. It protected the heart from HFD oxidative alterations increasing the expression of the detoxifying enzymes catalase and glutathione reductase, and normalizing NADH dehydrogenase level. The histological analysis of aorta showed a protection about the development of fatty streaks in the muscular layers. In conclusion, a prolonged treatment with the standardized extract of P. vulgaris significantly reduced several pathological features related to a metabolic syndrome-like condition; a multifactorial approach that candidates this vegetal product as a possible therapeutic option against metabolic syndrome

A multianalytical approach to investigate stone biodeterioration at a UNESCO world heritage site: the volcanic rock-hewn churches of Lalibela, Northern Ethiopia.

A multianalytical approach combining Optical Microscopy (OM), Backscattered Variable Pressure Scanning Electron Microscopy + Energy Dispersive X-ray Spectroscopy (VP-BSEM + EDS), Powder X-ray Diffractometry (PXRD), Raman Spectroscopy, and Microbiological techniques has been applied to characterize decay products and processes occurring at the surface of two rockhewn churches (Bete Gyorgis and Bete Amanuel) at the UNESCO’s World Heritage site of Lalibela, Northern Ethiopia. The two churches were carved into volcanic scoria deposits of basaltic composition. In their geological history, the Lalibela volcanic rocks underwent late to post-magmatic hydrothermal alteration together with partial laterization and are therefore characterized by a decay-prone highly vesicular microtexture with late stage to post-magmatic precipitation of secondary mineral phases (calcite–zeolite–smectite). The main objective of the study was to gain a better insight into the weathering products and mechanisms affecting the surface of the stone monuments and to assess the relative contribution of natural “geological” weathering processes versus biological/salt attack in stone decay at this unique heritage site. Results indicate that while the main cause of bulk rock deterioration and structural failure could be related to the stone inherited “geological” features, biological attack by micro- (bacteria) and/or macro- (lichens) organisms is currently responsible for severe stone surface physical and chemical weathering leading to significant weakening of the stone texture and to material loss at the surface of the churches walls. A prompt and careful removal of the biological patinas with the correct biocidal treatment is therefore recommended

Theory of Room Temperature Ferromagnet V(TCNE)_x (1.5 < x < 2): Role of Hidden Flat Bands

Theoretical studies on the possible origin of room temperature ferromagnetism (ferromagnetic once crystallized) in the molecular transition metal complex, V(TCNE)_x (1.5<x<2) have been carried out. For this family, there have been no definite understanding of crystal structure so far because of sample quality, though the effective valence of V is known to be close to +2. Proposing a new crystal structure for the stoichiometric case of x=2, where the valence of each TCNE molecule is -1 and resistivity shows insulating behavior, exchange interaction among d-electrons on adjacent V atoms has been estimated based on the cluster with 3 vanadium atoms and one TCNE molecule. It turns out that Hund's coupling among d orbitals within the same V atoms and antiferromagnetic coupling between d oribitals and LUMO of TCNE (bridging V atoms) due to hybridization result in overall ferromagnetism (to be precise, ferrimagnetism). This view based on localized electrons is supplemented by the band picture, which indicates the existence of a flat band expected to lead to ferromagnetism as well consistent with the localized view. The off-stoichiometric cases (x<2), which still show ferromagnetism but semiconducting transport properties, have been analyzed as due to Anderson localization.Comment: Accepted for publication in J. Phys. Soc. Jpn. Vol.79 (2010), No. 3 (March issue), in press; 6 pages, 8 figure

Can we ‘seize’ the gut microbiota to treat epilepsy?

The gut-microbiota, the complex intestinal microbial ecosystem essential to health, is an emerging concept in medicine. Several studies demonstrate a microbiota-gut-brain bidirectional connection via neural, endocrine, metabolic and immune pathways. Accordingly, the gut microbiota has a crucial role in modulating intestinal permeability, to alter local/peripheral immune responses and in production of essential metabolites and neurotransmitters. Its alterations may consequently influence all these pathways that contribute to neuronal hyper-excitability and mirrored neuroinflammation in epilepsy and similarly other neurological conditions. Indeed, pre- and clinical studies support the role of the microbiome in pathogenesis, seizure modulation and responses to treatment in epilepsy. Up to now, researchers have focussed attention above all on the brain to develop antiepileptic treatments, but considering the microbiome, could extend our possibilities for developing novel therapies in the future. We provide here a comprehensive overview of the available data on the potential role of gut microbiota in the physiopathology and therapy of epilepsy and the supposed underlying mechanisms

Do patients’ information needs decrease over the course of radiotherapy?

PURPOSE: We aimed to investigate if cancer patients’ information needs decrease during radiotherapy and if so, which patient, consultation and radiation oncologist characteristics are associated with a decrease in information needs over time. METHODS: In this longitudinal study, patients (n = 104) completed a baseline questionnaire a week before the initial radiotherapy consultation, immediately following this initial consultation, and 1 week prior to the first follow-up visit, which took place on average 3–5 weeks after the initial visit. Besides information needs, measured by the Information Preference for Radiotherapy Patients scale, the questionnaire assessed patient, consultation and radiation oncologist characteristics. RESULTS: Information needs decreased over time, but remained at a high level. Being religious, being male, having low health literacy and higher perceived involvement during the consultation were all statistically significantly associated to a decrease in information needs on specific domains (e.g. procedures or side effects). CONCLUSIONS: Cancer patients’ information needs decline between the initial consultation and the first follow-up visit, but remain high. It is therefore advised to investigate the patients’ information needs at every radiotherapy visit and not rely on giving information just once. Furthermore, radiation oncologists should check if the information given at first consultation is understood and remembered. By those means, tailored information giving becomes possible

Characterization of New TRPM8 Modulators in Pain Perception

Background: Transient Receptor Potential Melastatin-8 (TRPM8) is a non-selective cation channel activated by cold temperature and by cooling agents. Several studies have proved that this channel is involved in pain perception. Although some studies indicate that TRPM8 inhibition is necessary to reduce acute and chronic pain, it is also reported that TRPM8 activation produces analgesia. These conflicting results could be explained by extracellular Ca2+-dependent desensitization that is induced by an excessive activation. Likely, this effect is due to phosphatidylinositol 4,5-bisphosphate (PIP2) depletion that leads to modification of TRPM8 channel activity, shifting voltage dependence towards more positive potentials. This phenomenon needs further evaluation and confirmation that would allow us to understand better the role of this channel and to develop new therapeutic strategies for controlling pain. Experimental approach: To understand the role of TRPM8 in pain perception, we tested two specific TRPM8-modulating compounds, an antagonist (IGM-18) and an agonist (IGM-5), in either acute or chronic animal pain models using male Sprague-Dawley rats or CD1 mice, after systemic or topical routes of administration. Results: IGM-18 and IGM-5 were fully characterized in vivo. The wet-dog shake test and the body temperature measurements highlighted the antagonist activity of IGM-18 on TRPM8 channels. Moreover, IGM-18 exerted an analgesic effect on formalin-induced orofacial pain and chronic constriction injury-induced neuropathic pain, demonstrating the involvement of TRPM8 channels in these two pain models. Finally, the results were consistent with TRPM8 downregulation by agonist IGM-5, due to its excessive activation. Conclusions: TRPM8 channels are strongly involved in pain modulation, and their selective antagonist is able to reduce both acute and chronic pain

Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy

We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-\u3baB, I\u3ba-B\u3b1, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy

Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy

We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-κB, Iκ-Bα, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy