Proactive inter-disciplinary CME to improve medication management in the elderly population.

BACKGROUND: The absence of collaboration between health professionals is known to influence prescriptions' quality, also disadvantaging elderly frail patients' polytherapies. OBJECTIVES: This study aims to improve the adherence to medications of elderly patients suffering from multiple diseases through interpersonal continuing medical education (CME). The CME was organized for general practitioners (GPs) by hospital pharmacists (HPs) from a Territorial Pharmaceutical Centre of Piedmont, in collaboration with pharmacists from the Drug Science and Technology Department of the University of Turin, to enhance awareness on the management of chronic therapies and de-prescription. METHODS: Pharmacists set face-to-face lessons for GPs between April 2018 and November 2018, while therapies' reconciliation and delivery of the Illustrated Therapy Schedules (ITS) lasted until September 2019. Polytherapies were evaluated by pharmacists and GPs in terms of appropriateness (number of potentially inappropriate prescriptions - PIPs according to 2019 Beers Criteria) and number of drug-drug interactions (DDIs), using a clinical decision support system (CDSS - NavFarma©) to help health professionals dealing with the process of review, reconciliation and individuation of possible adverse reactions. RESULTS: From the CME organization it emerged that the collaboration between health professionals supported by a CDSS could improve the quality of elderly patients polytherapies. Two-hundred fifteen patients were enrolled by GPs; patients included were aged - results reported as average (sd) - 76.4 (6.3), mostly men (54.9%), number of daily medications per patient was 8.1 (2.4); 2.1 (1.8) DDIs per patient were individuated, 12.9% of which were solved thanks to the CME. Average number of PIPs found was 2.5 (1.4) per patient. CONCLUSIONS: The CME represented a proactive approach by HPs to the management of elderly patients' polytherapies. Moreover, clinicians' engagement is a mean to enhance quality, safety, professionalism and communication in health processes.

Video-oculography eye tracking towards clinical applications: A review.

Most neurological diseases are usually accompanied by a broad spectrum of oculomotor alterations. Being able to record and analyze these different types of eye movements would be a valuable tool to understand the functional integrity of brain structures. Nowadays, video-oculography is the most widely used eye-movements assessing method. This paper presents a study of the existing eye tracking video-oculography techniques and also analyzes the importance of measuring slight head movements for diseases diagnosis. In particular, two types of methods are reviewed and compared, including appearance-based and feature-based methods which are further subdivided into 2D-mapping and 3D model-based approaches. In order to demonstrate the advantages and disadvantages of these different eye tracking methods for disease diagnosis, a series of comparisons are conducted between them, addressing the complexity of the system, the accuracy achieved, the ability to measure head movements and the external conditions for which they have been designed. Lastly, it also highlights the open challenges in this research field and discusses possible future directions.

Cystic "feminine" pancreatic neoplasms in men. Do any clinical alterations correlate with these uncommon entities?

INTRODUCTION: Mucinous cystic neoplasm (MCN) and solid pseudopapillary neoplasm (SPN) of the pancreas are uncommon hormone-related pancreatic tumors (HRPTs) with a clear predominance in young women. This trial aims to investigate the possible association between HRPTs development in males and phenotypic and sex hormone alterations. METHODS: We performed a retrospective analysis of our database between February 1990 and February 2012. Risk factors for sexual dysfunction were considered exclusion criteria. We investigated secondary sexual characteristics development, sex hormone level and overall sexual dysfunction degree according with the International Index of Erectile Function Questionnaire (IIEF). RESULTS: We initially identified 25 patients [(MCN: n = 16 (64%); SPN: n = 9 (36%)]. At follow-up, 5 patients were lost, 8 resulted dead and 3 were excluded according to exclusion criteria. We finally enrolled 9 patients (MCN: n = 5; SPN: n = 4). Puberty occurred within physiological age for 7 patients, whereas it was delayed in 2 cases. Three patients revealed mild to moderate sexual dysfunction, along with low testosterone level in two cases. One patient presented hormonal alteration with a normal IIEF score. DISCUSSION: In this study, the first in literature with similar aim, hormonal and/or sexual dysfunction was present in 4 out of 9 patients affected by HRPT. The rarity of these lesions makes further trials to be needed for reliable conclusions.

A new class of ibuprofen derivatives with reduced gastrotoxicity.

A new series of nonsteroidal antiinflammatory drugs (NSAIDs) obtained by linking ibuprofen to selected furoxan moieties and to related furazans were synthesized and tested for their antiinflammatory, antiaggregatory, and ulcerogenic properties. All the derivatives are endowed with antiinflammatory activity comparable to that of ibuprofen, but, unlike this drug, they display reduced acute gastrotoxicity. The masking of the ibuprofen-free carboxylic group seems to be principally at the basis of this reduced topical irritant action. The two furoxan derivatives 8 and 9 also trigger potent antiaggregatory effects, principally as a consequence of their NO-donor ability.

Studies on agents with mixed NO-dependent and calcium channel antagonistic vasodilating activities.

PURPOSE: To obtain new cardiovascular agents with mixed Ca2+-channel antagonistic and NO-donor properties, a series of "hybrid" 1,4-dihydropyridines (1,4-DHPs), bearing NO-donating furoxan moieties on the 3-positioned lateral ester chain were synthesized and pharmacologically characterized. Furazan analogues were also prepared and investigated for control purposes, because they are unable to release NO. METHODS: Synthesis of the models was achieved by a modified Hantzsch approach. All of the final furoxan 1,4-DHPs were assessed for their ability to produce nitrite in the presence of a large excess of cysteine by the Griess reaction. Vasodilating activity was evaluated on rat aorta and expressed as EC50 and EC50MB values, obtained in the absence and in the presence of methylene blue (MB) respectively, a well-known guanylate cyclase inhibitor. Affinities to 1,4-DHP receptor on Ca2+-channels, expressed as IC50 values, were determined through displacement experiments of [3H]-nitrendipine on rat cortex homogenates. RESULTS: Some hybrid compounds (derivatives 15a, 15b, 16a, and 16b) displayed vasodilating activity depending predominantly on their Ca2+-channel blocker properties. By contrast, some others (derivatives 17a, 17b, and 21) behaved as well-balanced hybrids with mixed Ca2+-channel blocking and NO-dependent vasodilating activities. CONCLUSION: This work demonstrates the possibility of obtaining well-balanced hybrids endowed with mixed NO-donor and Ca2+-channel blocker properties using appropriate 1,4-DHP and furoxan moieties. A procedure for the individual evaluation of the NO-dependent vasodilator component and that due to Ca2+-channel blocking is proposed.

Nicorandil analogues containing NO-donor furoxans and related furazans.

The synthesis and in vitro vasodilating properties of hybrid compounds in which furoxan (1,2,5-oxadiazole 2-oxide) moieties, endowed with different NO-donor properties, were substituted for the nitroxy function of Nicorandil are reported. The corresponding cyanoguanidine analogues are also considered. This approach has led to a series of vasorelaxing compounds devoid of affinity for K(ATP) channels, whose activity is prevalently due to their ability to activate sGC, at the concentrations of the experiments. Related furazan (1,2,5-oxadiazole) derivatives, unable to release nitric oxide were also prepared and studied for control. The amide analogues of Nicorandil display feeble vasorelaxing action not involving the activation of K+ channels, while in the guanidine analogues, this mechanism seems to underlie this action.

Antisecretory and gastroprotective activities of compounds endowed with H2 antagonistic and nitric oxide (NO) donor properties.

In spite of the well recognized gastric antisecretory activity, the gastroprotective potential of histamine H2 receptor antagonists is controversial. Most clinical studies in fact indicate that these drugs do not substantially protect the gastric mucosa from aggressive factors. Nitric oxide (NO) has been recently recognized as a fundamental mediator in gastric defence mechanisms, due to its ability to increase gastric mucosal blood flow and mucus production and to inhibit neutrophils adherence to endothelial cells. The aim of this study was to investigate the gastroprotective and H2 receptor antagonistic activity of a series of lamtidine analogues which contain different NO-releasing moieties (furoxan, nitroxy and nitrosothiol). These compounds were tested, in comparison with related H2 antagonists devoid of NO-donor structures, in different H2 receptor assays and in the conscious rat against 0.6 N HCl-induced gastric lesions. All the compounds tested were able to antagonize histamine-mediated responses at cardiac and gastric H2 receptors; however, furoxan and nitroxy derivatives were 10-fold less potent than the analogues devoid of NO-donor properties. By contrast, NO-donor compounds were more active than reference H2 antagonists as gastroprotective agents against mucosal injury induced by 0.6 N HCl. Among the different NO-donor moieties, the furoxan group conferred to the H2 antagonist molecule the highest gastroprotective potential; this finding closely correlates with the characteristics of NO release. In conclusions, lamtidine-analogue H2 antagonists combined with NO-donor moieties are endowed with gastric antisecretory and protective activity and could be the prototypes of a new class of anti-ulcer drugs. Finally, the furoxan NO donor group seems to be the most favourable among the different moieties tested.

New 1,4-dihydropyridines conjugated to furoxanyl moieties, endowed with both nitric oxide-like and calcium channel antagonist vasodilator activities.

A series of 4-phenyl-1,4-dihydropyridines substituted at the ortho and meta positions of the phenyl ring with NO-donating furoxan moieties and their non-NO-releasing furazan analogues were synthesized and pharmacologically characterized. The vasodilator activities of these compounds were evaluated on rat aorta and expressed as EC50 values or as EC50iGC values when obtained in the presence of inhibitors of guanylate cyclase methylene blue (MB) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Affinities to 1, 4-DHP receptors on Ca2+ channels, expressed as IC50 values, were determined through displacement experiments of [3H]nitrendipine on rat cortex homogenates. A linear correlation between IC50 and EC50 values was found for compounds unable to release NO. EC50calcd values for derivatives containing NO-donor moieties, expression of the Ca2+-blocking component of their vasodilator activity, were interpolated on this linear regression. They showed a good correspondence with EC50iGC values determined in the presence of soluble guanylate cyclase inhibitors. Analysis of EC50iGC/EC50 ratios provided a useful tool to distinguish well-balanced hybrids from derivatives biased toward Ca2+-blocking or NO-dependent vasodilator activity. A detrimental effect on affinity to the 1, 4-DHP receptor, due to substitution at the ortho and meta positions of the 4-phenyl ring, was observed. SAR to explain this effect is proposed.

SAR studies on H2 antagonists containing alkylamino substituted 1,2, 5-thiadiazole 1-oxide moieties.

A number of ranitidine analogues in which the diamino-1,2,5-thiadiazole 1-oxide substructure bearing alkyl chains of different length is present as the urea equivalent group, were synthesised and studied for their lipophilic and H2 antagonist properties. Derivatives which displayed a logP < or = 3 behaved as competitive antagonists of histamine at H2 receptors present on guinea pig right atrium. The remaining more lipophilic members of the series showed an insurmountable antagonism not completely reversible after prolonged washing. A binding study suggested that an increase in the length of alkyl chain gave rise to hydrophobic interactions with the receptor which were responsible for the apparent irreversible H2 antagonism shown by the higher homologues of the series.

Water soluble furoxan derivatives as NO prodrugs.

The synthesis, characterization, NO donor properties, and in vitro vasodilating activity of a series of water soluble furoxans (5-14a,b) are described. All of the compounds released NO when treated with a large excess of cysteine under physiological conditions (pH 7.4; 37 degrees C). The amount of NO produced after 1 h of incubation was evaluated by detecting nitrites, via the Griess reaction. Derivatives 5b, 7b, and 14b were able to release nitric oxide also in the absence of the thiol cofactor. The initial rates of NO release were determined at different concentrations, using a spectrophotometric technique based on the NO-induced oxidation of oxyhemoglobin (HbO2) to methemoglobin (MetHb). The initial rates of NO release were linearly dependent on the concentrations of the single compounds. The vasodilating potency (EC50) of all the derivatives was assessed on rat aortic strips precontracted with noradrenaline. Correlation between potency and initial NO release rate is discussed.

Studies on agents with mixed NO-dependent vasodilating and beta-blocking activities.

PURPOSE: A series of derivatives having a propranolol-like moiety linked to NO-donor furoxan substructures were synthesized. The main objective of this investigation was to obtain agents with mixed NO-dependent vasodilating and beta-blocking activities. METHODS: Most of the target compounds were synthesized from the appropriate furoxans bearing XCH2CH2NH2 (X = O, S, SO2) chains at the 4 position of the ring, using Al(C2H5)3 in methylene chloride solution and (+/-)2,3-epoxypropyl 1-naphtyl ether. Two of the final products (X = CONH) were obtained by coupling the appropriate furoxancarboxylic acids with N-[2-hydroxy-3-(1-naphthoxy)propyl]-ethylenediamine. beta 1- and beta 2-blocking activities were examined on isolated guinea pig right atria and on guinea pig trachea respectively. Vasodilating properties were assessed on endothelium denuded strips of rat aorta. RESULTS: Some derivatives behave as well balanced "hybrids" displaying NO-dependent vasodilating and beta-blocking properties in the same concentration range. Some others display either prevalent beta-blocking or vasodilating activity. Generally speaking hybrid formation lowers the affinity for beta-receptors, in particular for beta 2-type, to give an increase in beta 1/beta 2 selectivity. CONCLUSIONS: The furoxan system is a flexible tool in designing analogues of propranolol whose NO-donating and beta-blocking properties are modulated over a wide range.

The cyano-NNO-azoxy function in the design of an irreversible label for alpha 1 adrenoreceptors.

A potential alpha 1-adrenergic irreversible antagonist 6, containing the cyano-NNO-azoxy function was synthesized and tested. The effects of norepinephrine on rat thoracic aorta were irreversibly blocked by this compound at the concentration of 1 x 10(-5) M after 60 minutes. Binding studies showed that 6, at 1 x 10(-6) M, did not modify the KD of Prazosin and caused a 30% decrease of the Bmax. Substitution in 6 of the bis (2-chloroethyl)amino moiety for the cyano-NNO-azoxy function afforded 7 which behaves as an irreversible antagonist able to change KD of Prazosin without influencing Bmax.