A Simulated Stomach Duodenum Model Predicting the Effect of Fluid Volume and Prandial Gastric Flow Patterns on Nifedipine Pharmacokinetics From Cosolvent-Based Capsules

Nifedipine is a Biopharmaceutics Classification System class II drug displaying large variability in absorption even when administered as immediate-release soft gelatin capsules of a cosolvent formulation. This in vitro study sought to understand the reasons behind variability in nifedipine absorption, how it can be minimized, and if it can be predicted using in vitro models. A dynamic in vitro simulated stomach duodenum model was used to explore drug concentration–time profiles of nifedipine soft gelatin capsules under conditions simulating how patients take their medicines. Specifically, the effect of prandial gastric emptying patterns and fluid volume administration (250 mL vs. 50 mL water) were investigated. Significant supersaturation of nifedipine was observed. While administration of large and small water volumes gave rise to a similar C_max and area under the curve (AUC_∞), the coefficient of variation in AUC was 4.8% and 49%, respectively, which can be attributed to differences in precipitation kinetics. Fasting and fed gastric emptying patterns also gave rise to a similar AUC; however, C_max was significantly lower in the fed state. These trends are consistent with previously published in vivo results in healthy volunteers. The simulated stomach duodenum provides a good discriminative screening tool for predicting trends in drug concentration profiles of Biopharmaceutics Classification System class II drugs.     

Standard immunosuppressive therapy of immune-mediated glomerular diseases

Glomerulonephritis (GN) accounts for 10%–20% of the total incident cases of end stage renal disease (ESRD), and is the third most common cause of ESRD after diabetes and hypertension in western countries. The pathogenesis of glomerulonephritis is prevalently immune mediated: humoral and cell-mediated immunity are involved, although the rationale for an etiological treatment is still lacking. In the last forty years, empirical treatment based upon the use of corticosteroids and/or immunosuppressive drugs have obtained excellent results in improving survival of both the patient and the kidney. Almost 95% of children affected by minimal change disease (MCD) achieve remission of proteinuria within 4 to 8 weeks of prednisone administration. In adults with focal segmental glomerulosclerosis (FSGS), prednisone induces complete or partial remission in the majority of patients, but a longer period of steroid treatment or the combination of calcineurin inhibitors or cytotoxic drugs can be needed. A percentage of 65%–70% of patients with idiopathic membranous nephropathy (MN) reach complete or partial remission with a 6-month course of therapy alternating glucocorticoids with alkylating agents. Glucocorticoids plus cyclophosphamide, and, on occasion, plasmapheresis are effective in 70%–90% of patients with ANCA-associated vasculitis (AAV). Fifty percent of responders relapse within the 3–5 years and currently, the mortality of AAV at 1 year exceeds 15%.This article is aimed to analyze the risk-to-benefit balance of steroids and conventional immunosuppressive regimens, focusing, for a sake of brevity, on idiopathic nephrotic syndrome (INS) and ANCA associated vasculitis.     

Are all forms of feature binding disturbed in schizophrenia? Evidence from a central vs. peripheral distinction in working memory

In this study we investigated central and peripheral feature binding in a group of 24 high pre-morbid IQ patients with schizophrenia and 24 healthy controls. In particular, participants were asked to remember specific single (e.g., word, colour) or multiple features (e.g., coloured words) of experimental items with central (coloured word) vs. peripheral (a coloured frame) attributes in a working memory binding task. Performance of the patients was significantly inferior to that of controls, especially when required to remember the peripheral combination of multiple features. Results suggest that patients with schizophrenia may have difficulties in unitizing peripheral features in working memory.     

Granular Computing Techniques for Classification and Semantic Characterization of Structured Data

We propose a system able to synthesize automatically a classification model and a set of interpretable decision rules defined over a set of symbols, corresponding to frequent substructures of the input dataset. Given a preprocessing procedure which maps every input element into a fully labeled graph, the system solves the classification problem in the graph domain. The extracted rules are then able to characterize semantically the classes of the problem at hand. The structured data that we consider in this paper are images coming from classification datasets: they represent an effective proving ground for studying the ability of the system to extract interpretable classification rules. For this particular input domain, the preprocessing procedure is based on a flexible segmentation algorithm whose behavior is defined by a set of parameters. The core inference engine uses a parametric graph edit dissimilarity measure. A genetic algorithm is in charge of selecting suitable values for the parameters, in order to synthesize a classification model based on interpretable rules which maximize the generalization capability of the model. Decision rules are defined over a set of information granules in the graph domain, identified by a frequent substructures miner. We compare the system with two other state-of-the-art graph classifiers, evidencing both its main strengths and limits.     

The Role of Topiramate in the Management of Cocaine Addiction: A Possible Therapeutic Option

Topiramate (TPM) is an antiepileptic drug able to play a role in both neurological and psychiatric disorders. TPM facilitates gamma-aminobutyric acid (GABA) transmission and inhibits glutamatergic transmission (i.e. AMPA/kainate receptors).Several studies reported that the modulation of GABAergic and glutamatergic synaptic transmission may reduce cocaine reinforcement. Therefore, TPM could be used in the management of cocaine dependence.     

Chronic Oral Anticoagulation and Clinical Outcome in Hospitalized COVID-19 Patients

Cardiovascular Drugs and Therapy - The clinical course of COVID-19 may be complicated by acute respiratory distress syndrome (ARDS) and thromboembolic events, which are associated with high risk of...     

Evolution of metabolic and functional derangements of pancreatic islets in phosphate depletion.

Phosphate depletion (PD) causes a rise in basal level of cytosolic calcium ([Ca2+]i) of pancreatic islets, a decrease in their basal and stimulated ATP content, a reduction in the maximum velocity (Vmax) of Ca2+ adenosine triphosphatase (ATPase) and Na(+)-K+ ATPase, impaired glucose-induced calcium signal and decreased glucose-induced insulin secretion. The sequence of events that lead to these derangements during the evolution of PD are not defined. The present study examined this issue by measuring the metabolic and functional profile of pancreatic islets weekly during the evolution of PD over a period of 6 weeks, and whether phosphate repletion reverses these abnormalities. The results show that initial abnormalities are a rise in Vmax of Ca2+ ATPase and modest rise in basal [Ca2+]i. This was followed by a fall in basal and stimulated ATP content. With the fall in ATP content, the Vmax of Ca2+ ATPase and Na(+)-K+ ATPase decreases and the rise in [Ca2+]i becomes more pronounced. A decrease in glucose-induced insulin secretion becomes evident with the fall in ATP, the decrease in glucose-induced calcium signal, and/or delta[Ca2+]i/basal[Ca2+]i. All functional and metabolic derangements of the pancreatic islets returned to normal after phosphate repletion. Taken together, our data are consistent with the notion that PD is associated with an initial increase in calcium influx into the islets. This is followed by modest but significant rise in [Ca2+]i which, in turn, would inhibit mitochondrial oxidation and ATP generation leading to a decrease in ATP content. The latter compromises the activity of Ca2+ ATPase and Na(+)-K+ ATPase which are involved, directly or indirectly, in calcium extrusion out of the islets. The increased influx of calcium combined with decreased calcium extrusion is followed by a further rise in basal levels of [Ca2+]i. This sequence of events continues until a steady state is reached and is characterized by reduced basal and stimulated ATP content, reduced Vmax of Ca2+ ATPase and Na(+)-K+ ATPase and elevated basal level of [Ca2+]i. Phosphate repletion reverses all these abnormalities.