Remote preconditioning in normal and hypertrophic rat hearts

Background  

The aim of our study was to investigate whether remote preconditioning (RPC) improves myocardial function after ischemia/reperfusion injury in both normal and hypertrophic isolated rat hearts. This is the first time in world literature that cardioprotection by RPC in hypertrophic myocardium is investigated.     

Crystalline Nanosuspensions as Potential Toxicology and Clinical Oral Formulations for BCS II/IV Compounds

Nanosuspensions, formulations based on the reduction of the active pharmaceutical ingredient (API) particle size in the sub-micron range and most typically around 100–200 nm, represent a valuable option for formulators to facilitate oral absorption of Biopharmaceutics Classification System class II and IV compounds. Their ability to increase the API dissolution rate and subsequent absorption and thus oral bioavailability has been demonstrated in preclinical and clinical settings. This review summarizes the current experience in the biopharmaceutic field with the use of nanosuspensions as oral delivery formulations. The principles behind nanosuspensions as well as the in vitro and in silico evaluation are discussed, while examples are presented highlighting both successes as well as limitations in their application as either toxicology or clinical formulations.Key words: bioavailability enhancement, nanocrystals, nanoparticles, nanosizing, nanosuspensions     

HIV controllers: a multifactorial phenotype of spontaneous viral suppression

A small minority of HIV-infected individuals, known as HIV controllers, is able to exert long-term control over HIV replication in the absence of treatment. Increasing evidence suggests that the adaptive immune system plays a critical role in this control but also that a combination of several host and/or viral factors, rather than a single cause, leads to this rare phenotype. Here, we review recent advances in the study of these remarkable individuals. We summarize the epidemiology and clinical characteristics of HIV controllers, and subsequently describe contributing roles of host genetic factors, innate and adaptive immune responses, and viral factors to this phenotype. We emphasize distinctive characteristics of HIV-specific CD4 T cell responses and of CD4 T cell subpopulations that are frequently found in HIV controllers. We discuss major controversies in the field and the relevance of the study of HIV controllers for the development of novel therapeutic strategies and vaccines.     

The role of the non-smoker in enforcing smoke-free laws

Compliance with laws making certain environments smoke free has focused mainly on smokers' behavior, while the role of non-smokers has scarcely been investigated. Our cross-sectional study interviewed 4043 adults (2037 smokers and 2006 non-smokers) in the general population of Greece during April 2009. Non-smokers reported that they would actively work for compliance with the law. The non-smokers were older, more educated (odds ratio, OR 1.4), and were more likely to be annoyed by the smell of environmental tobacco smoke (OR 2.4) or report that it irritates their eyes (OR 1.8). Policymakers should evaluate how non-smokers could actively support smoke-free laws through reporting of violations using media campaigns that inform them of their rights, and other measures.     

Therapeutic strategies for chemotherapy-induced neutropenia in patients with solid tumors

Introduction: Chemotherapy-induced neutropenia (CIN) is a common adverse event during treatment of cancer patients, associated with increased morbidity, mortality, health care costs and impairment of patients’ quality of life which necessitate dose reductions.

Areas covered: A computerized systematic literature search was performed through Medline, PubMed, Google Scholar and the Cochrane Library to identify peer reviewed publications relevant to CIN, pathophysiology and epidemiology, patient risk-assessment and existing treatment approaches. Additionally, emerging issues such as alternative therapeutic options and implications in elderly care were addressed.

Expert opinion: Although CIN represents a common adverse event in the management of patients with solid tumors, the heterogeneity in clinical practice across different settings underlines the need to improve existing tools for accurate patient classification. Moreover, the definition of the optimal implementation of out-patient treatment and the use of colony-stimulating factor as add-on treatment together with antibiotics should be further investigated in order to accumulate more solid data. Finally, physician education is required to ensure that scientific knowledge is implemented in the daily clinical practice.     

Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration with Zolpidem

Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms. The purpose of this work was to develop and evaluate a novel, physiologically based oral cavity model for projection and mechanistic analysis of the clinical pharmacokinetics of intraoral formulations. The GastroPlus™ Oral Cavity Compartmental Absorption and Transit (OCCAT™) model was used to simulate the plasma concentration versus time profiles and the fraction and rate of intraoral drug transit/absorption for Intermezzo® sublingual tablets (zolpidem tartrate). The model was evaluated by the goodness-of-fit between simulated and observed concentrations and the deviation of key PK parameters (e.g., C_max, T_max, and AUC). In addition, a sensitivity analysis was conducted to demonstrate the interplay and impact of key modeling parameters on the fraction absorbed via oral mucosa (F_{a_IO}). The OCCAT™ model captured the observed pharmacokinetics for Intermezzo® sublingual tablets (R² > 0.9). The predicted deviations (%) for C_max, AUC_0–inf, AUC_0–20 min, and T_max were 5.7, 28.0, 11.8, and 28.6%, respectively, indicating good prediction accuracy. The model also estimated ~18% of total drug was absorbed via the IO route. Furthermore, the sensitivity analysis indicated that the F_{a_IO} was not only associated with drug diffusivity and unbound fraction in epithelium tissue (f_ut) but also depended on the physicochemical properties of compounds for IO delivery (e.g., solubility and logD_pH = 7.4). The novel physiologically based IO absorption OCCAT™ model showed satisfactory performance and will be helpful to guide development of future intraoral formulations.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9727-7) contains supplementary material, which is available to authorized users.KEY WORDS: diffusivity, intraoral delivery, oral cavity compartmental absorption and transit (OCCAT™) model, unbound fraction in epithelium tissue, zolpidem     

Left atrial remodelling contributes to the progression of asymptomatic left ventricular systolic dysfunction to chronic symptomatic heart failure

Systolic heart failure (HF) is a progressive disorder that often begins with asymptomatic left ventricular (LV) systolic dysfunction and culminates in symptoms from fluid overload and poor end-organ perfusion. The progression to symptomatic HF is accompanied by marked activation of neurohormonal and cytokine systems, as well as a series of adaptive LV anatomical and functional changes, collectively referred to as LV remodelling. However, the mechanisms underlying symptom appearance have not been delineated and the weight of experimental and clinical evidence suggests that the development of symptomatic HF occurs independently of the haemodynamic status of the patient. The left atrium is a muscular chamber strategically located between the left ventricle and the pulmonary circulation with important mechanical function (modulation of LV filling), which is closely coupled with its endocrine (atrial natriuretic peptide synthesis and secretion) and regulatory (contribution to the control of sympathetic activity and vasopressin release) functions. In this narrative review we provide evidence supporting the concept that left atrial dilation and systolic dysfunction (left atrial remodelling) contributes to the progression of asymptomatic LV dysfunction to chronic symptomatic systolic HF as it is a prerequisite for the development of the pulmonary congestion and marked neuronhormoral activity that characterize the symptomatic state.     

Renal artery thrombosis caused by stent fracture in a single kidney patient.

PURPOSE: To report a case of incomplete expansion, fracture, and thrombosis of a stent in the renal artery. CASE REPORT: A 47-year-old man with right renal artery occlusion underwent direct stenting of the left renal artery using a balloon-expandable stent. Completion angiography showed satisfactory patency of the vessel although the stent was not fully expanded in its central segment. The patient received 5000 units of heparin during the procedure, but no additional anticoagulant or antiplatelet therapy in the peri/postinterventional period. Twenty-five days later, he presented with acute renal insufficiency and uncontrolled hypertension. Angiography revealed in-stent thrombosis and collateral flow in the distal segment of the left renal artery. He underwent an aortorenal bypass, which salvaged the kidney. The stent, after removal from the vessel, was fractured and not completely expanded. CONCLUSIONS: Incomplete expansion and fracture of the stent associated with insufficient antiplatelet therapy produced in-stent thrombosis. Collateral flow prevented kidney necrosis.