Effect of low versus high dialysate sodium concentration on blood pressure and endothelial-derived vasoregulators during hemodialysis: a randomized crossover study.

Background: Intradialytic hypertension affects ∼15% of hemodialysis patients and is associated with increased morbidity and mortality. While intradialytic hypertension is associated with increases in endothelin 1 relative to nitric oxide (NO), the cause of these imbalances is unknown. In vitro evidence suggests that altering plasma sodium levels could affect endothelial-derived vasoregulators and blood pressure (BP).

Development of apixaban: a novel anticoagulant for prevention of stroke in patients with atrial fibrillation.

The factor Xa inhibitor apixaban is one of the novel anticoagulants to emerge as alternatives to long-standing standards of care that include low-molecular-weight heparin and warfarin. The development of apixaban reflects a strategy to optimize the clinical pharmacology profile, dosing posology, trial designs, and statistical analyses across multiple indications, and to seek alignment with global health authorities. The primary objective of dose selection was to maintain balance between efficacy and bleeding risk.

Ipilimumab administration for advanced melanoma in patients with pre-existing Hepatitis B or C infection: a multicenter, retrospective case series.

Ipilimumab is a fully human, monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma. Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis. Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection, there is a paucity of data on the safety of ipilimumab administration to that patient population.

Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies.

Background: This report provides a survival update at a follow-up of >5 years (5.5-6 years) for patients with advanced melanoma who previously received ipilimumab in phase II clinical trials. Safety and efficacy data following ipilimumab retreatment are also reported.

Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events.

Background: Dapagliflozin reduces hyperglycaemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion.

Objectives: This study determined the overall safety profile of dapagliflozin in T2DM.

Methods: Safety of dapagliflozin in pooled analyses of phase IIb/III studies was evaluated.

Symptoms of nicotine toxicity in subjects achieving high cotinine levels during nicotine replacement therapy.

Introduction: Nicotine replacement therapy (NRT) aids smoking reduction and cessation. Although NRT is effective and safe, some smokers may achieve high nicotine levels. The purpose of this study was to determine the incidence and severity of nicotine-related adverse events in subjects with levels of cotinine, a metabolite of nicotine, that increased by >50% compared with baseline smoking in controlled clinical trials of NRT.

Efficacy of a non-updated, Matrix-C-based equine influenza subunit-tetanus vaccine following Florida sublineage clade 2 challenge.

Assessing the ability of current equine influenza vaccines to provide cross-protection against emerging strains is important. Horses not vaccinated previously and seronegative for equine influenza based on haemagglutination inhibition (HI) assay were assigned at random to vaccinated (n=7) or non-vaccinated (control, n=5) groups. Vaccination was performed twice four weeks apart with a 1 ml influenza subunit (A/eq/Prague/1/56, A/eq/Newmarket/1/93, A/eq/Newmarket/2/93), tetanus toxoid vaccine with Matrix-C adjuvant (EquilisPrequenza Te).

Enabled clinical use of an HIV-1 attachment inhibitor through drug delivery.

The clinical advancement of HIV-1 attachment inhibitors was hindered initially by poor bioavailability. Attempts to identify improved candidates revealed that solubility and dissolution-rate-limited absorption are barriers to achieving adequate antiviral plasma levels. This was mitigated by forming nanosized drugs or by creating stabilised amorphous drug-polymer composites.

Efficacy of adjunctive aripiprazole in patients with major depressive disorder whose symptoms worsened with antidepressant monotherapy.

Introduction: Efficacy of depression treatments, including adjunctive antipsychotic treatment, has not been explored for patients with worsening symptoms after antidepressant therapy (ADT).

Methods: This post-hoc analysis utilized pooled data from 3 similarly designed, randomized, double-blind, placebo-controlled trials that assessed the efficacy, safety, and tolerability of adjunctive aripiprazole in patients with major depressive disorder with inadequate response to ADT. The studies had 2 phases: an 8-week prospective ADT phase and 6-week adjunctive (aripiprazole or placebo) treatment phase.

Rate of hypoglycemia in patients with type 2 diabetes receiving metformin plus saxagliptin versus metformin plus sulfonylurea: a retrospective observational cohort study using administrative claims data.

Objectives: Hypoglycemia is a limiting factor in the management of diabetes. Studies comparing oral antidiabetic medications are needed to identify treatment options that can help clinicians and patients minimize their associated hypoglycemia risk. The purpose of this study was to compare hypoglycemia rates in patients with type 2 diabetes on metformin who initiated treatment with saxagliptin versus sulfonylurea (SU).

Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study.

Objective: Dapagliflozin is a highly selective, orally active inhibitor of renal sodium-glucose cotransporter 2 that reduces hyperglycemia by increasing urinary glucose excretion. The goal of this study was to evaluate dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise.

Methods: In this Phase III, multicenter, parallel-group, double-blind study, drug-naive patients with glycosylated hemoglobin (HbA1c) levels ≥7.

The landscape of clinical trials in nephrology: a systematic review of Clinicaltrials.gov.

Background: Well-designed trials are of paramount importance in improving the delivery of care to patients with kidney disease. However, it remains unknown whether contemporary clinical trials within nephrology are of sufficient quality and quantity to meet this need.

Study Design: Systematic review.

Peri-dialytic hypertension and hypotension: another U-shaped BP-outcome association.

Park et al. performed a retrospective analysis of a large hemodialysis cohort to describe the relationship between pre- to postdialysis changes in BP and mortality. Their study demonstrated adverse outcomes associated both with large decreases and with any increase in blood pressure pre- to postdialysis.

Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study.

Background: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy.

Patients And Methods: In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34).

Evolution of end points for cancer immunotherapy trials.

The effect of cancer immunotherapies is on the immune system and not directly on the tumour. The kinetics of immunotherapy are characterised by a cellular immune response followed by potential changes in tumour burden or patient survival. To adequately investigate immunotherapies in clinical trials, a new development paradigm including reconsideration of established end points addressing this biology is needed.

Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.

Objective: To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD).

Design: Randomized, double-blind, placebo-controlled,24-week phase 2 study.

Setting: Global, multicenter trial.

Model-based projections of the population-level impact of hepatitis A vaccination in Mexico.

There are indications of a shift in the pattern of hepatitis A (HAV) in Mexico from high to intermediate endemicity, progressively increasing the mean age of infection and the proportion of cases which are symptomatic. This study estimated the potential impact of universal infant HAV vaccination in Mexico with two doses of Havrix™ at 12 and 18 mo of age on all HAV infections and symptomatic HAV infections. We developed a dynamic transmission model that accounts for changes in demography and HAV epidemiology.

Butyrylcholinesterase genotype and gender influence Alzheimer's disease phenotype.

Retrospective data are presented to support a spectrum of early Alzheimer's disease (AD) along a continuum defined by gender and genotype. The putative neurodegenerative mechanisms driving distinct phenotypes at each end of the spectrum are glial hypoactivity associated with early failure of synaptic cholinergic neurotransmission and glial overactivation associated with loss of neural network connectivity due to accelerated age-related breakdown of myelin. In early AD, male butyrylcholinesterase K-variant carriers with one or two apolipoprotein ɛ4 alleles have prominent medial temporal atrophy, synaptic failure, cognitive decline, and accumulation of aggregated beta-amyloid peptide.

Efficacy and safety of saxagliptin combination therapy in US patients with type 2 diabetes.

Background: The mechanism of action of dipeptidyl peptidase-4 inhibitors, such as saxagliptin, makes them suitable for combination therapy in type 2 diabetes mellitus (T2DM). Genetic, cultural, and environmental differences in individuals from different regions of the world may result in differences in treatment response to oral antidiabetic drugs (OADs). This post-hoc subanalysis assessed the efficacy and safety of saxagliptin as add-on therapy to metformin, glyburide, or a thiazolidinedione in patients with inadequately controlled T2DM in the United States.

Long-term safety and tolerability of open-label aripiprazole augmentation of antidepressant therapy in major depressive disorder.

Background: Effective management of major depressive disorder often includes the long-term use of multiple medications, and the longer-term utility and safety of adjunctive aripiprazole has not been evaluated in a controlled setting.

Patients And Methods: Patients (n = 706) completing one of two 14-week double-blind studies of aripiprazole augmentation, as well as de novo patients (n = 296) nonresponsive to current antidepressant therapy, were enrolled in this open-label study. Patients received open-label aripiprazole for up to 52 weeks.

Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans.

Glucose is freely filtered in the glomeruli before being almost entirely reabsorbed into circulation from the proximal renal tubules. The sodium-glucose cotransporter 2 (SGLT2), present in the S1 segment of the proximal tubule, is responsible for the majority of glucose reabsorption. SGLT2 inhibitors reduce glucose reabsorption and increase urinary glucose excretion.

Good clinical practice regulatory inspections: Lessons for Indian investigator sites.

Regulatory inspections are important to evaluate the integrity of the data submitted to health authorities (HAs), protect patient safety, and assess adequacy of site/sponsor quality systems to achieve the same. Inspections generally occur after submission of data for marketing approval of an investigational drug. In recent years, there has been a significant increase in number of inspections by different HAs, including in India.

Social connectivity in those 24 months or less postsurgery.

Purpose: This purpose of this study is to characterize the prevalence of social isolation and determine the impact of influencing factors in a sample of adults with ostomies.

Subjects And Settings: Five hundred sixty adults with an ostomy, residing in North America and the United Kingdom, less than 24 months postsurgery, participated in the study.

Methods: Data were extracted from the Ostomy Comprehensive Health and Life Assessment (Hollister Incorporated, Libertyville, Illinois) electronic database.

Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy.

Identification of cytotoxic T-lymphocyte antigen-4 (CTLA-4) as a key negative regulator of T-cell activity led to development of the fully human, monoclonal antibody ipilimumab to block CTLA-4 and potentiate antitumor T-cell responses. Animal studies first provided insight into the ability of an anti-CTLA-4 antibody to cause tumor regression, particularly in combination regimens. Early clinical studies defined ipilimumab pharmacokinetics and possibilities for combinability.