Medication reviews focusing on deprescribing can reduce potentially inappropriate medication; however, evidence regarding the effects on health-related outcomes is scares. In a real-life, quality improvement project, we aimed to investigate how a general practitioner-led medication review intervention with focus on deprescribing affected health-related outcomes. We performed a before-after intervention study including care home residents and community-dwelling patients affiliated with a large Danish general practice. The primary outcomes were changes in self-reported health status, general condition, and functional level from baseline to 3-4 months follow-up. Of 105 included patients, 87 completed follow-up. From baseline to follow-up, 255 medication changes were made, of which 83% were deprescribing. Mean self-reported health status increased from 7.3 to 7.9 (0.6 [95% CI: 0.2 to 0.9]); the proportion of patients with general condition rated as “average or above” was stable (74.7% to 80.5% (5.7% [95% CI: -3.4 to 14.9]); and the proportion of patients with functional level “without any disability” was stable (58.6% to 54.0% (-4.6% [95% CI: -10.1 to 1.0]). In conclusion, this general practitioner-led medication review intervention led to deprescribing and increased self-reported health status without deterioration of general condition or functional level in real-life primary care patients.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by elevated pulmonary pressure, right ventricular failure (RVF) and ultimately death. Aggressive treatment of RVF is considered the most important therapeutic strategy. In this study, betaine injection was prepared and characterized by various techniques. The therapeutic efficacy of gavage (I.G.), nebulized inhalation (Inh.) and intravenous (I.V.) injections was evaluated comprehensively in terms of pharmacokinetics, tissue distribution and pharmacodynamics using three different methods of administration. The results of pharmacokinetic demonstrated that Inh. betaine injection significantly prolonged the half-life of the drug, increased its internal circulation time and increased Inh. administration significantly improved the pharmacokinetics of betaine compared to I.G. and I.V. administration. Combined with biodistribution experiments verified that betaine formulation could accumulate in lung tissue via Inh. The results of pharmacodynamic further confirmed that right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP) and right ventricular hypertrophy index (RVHI) were increased in the model group and that betaine prepared by Inh. was able to suppress this increase to levels similar to those observed in the control group. Consequently, Inh. administration would be a promising strategy for the treatment of PAH-induced RVF.

Transient receptor potential vanilloid type-1 (TRPV1) channels play key roles in chronic pain conditions and are modulated by different inflammatory mediators to elicit heat sensitisation. Bradykinin is a 9-amino acid peptide chain that promotes inflammation. The aim of present study is to investigate how bradykinin and prostaglandin receptors (EP3 and EP4) modulate the sensitisation of TRPV1-mediated responses. Calcium imaging studies of rat dorsal root ganglion (DRG) neurons were employed to investigate the desensitizing responses of TRPV1 ion channels by capsaicin, and the re-sensitization of TRPV1 by bradykinin, then to explore the role EP3 and EP4 receptors in mediating these bradykinin-dependent effects. Immunocytochemistry was used to study the co-expression and distribution of EP4, TRPV1, COX-1 and B2 in rat DRG neurons. Desensitization was seen upon repeated capsaicin application, we show that bradykinin-mediated sensitization of capsaicin-evoked calcium responses in rat DRG neurons occurs is dependent on COX-1 activity, and utilises a pathway that invovles EP4 but not EP3 receptors. The present study provides evidence for a novel signalling pathway through which bradykinin can regulate the TRPV1 ion channel function via the EP4 but not EP3 receptors and provides the anatomical basis for this regulation

Dementia is an umbrella term for a broad group of age-associated neurodegenerative diseases. It is estimated that dementia affects 50 million people worldwide and that Alzheimer’s disease (AD) is responsible for up to 75% of cases. Small extracellular senile plaques composed of filamentous aggregates of amyloid β (Aβ) protein tend to bind to neuronal receptors, affecting cholinergic, serotonergic, dopaminergic, and noradrenergic neurotransmission, leading to neuroinflammation, among other pathophysiologic processes, and subsequent neuronal death, followed by dementia. The amyloid cascade hypothesis points to a pathological process in the cleavage of the amyloid precursor protein (APP), resulting in pathological Aβ. There is a close relationship between the pathologies that lead to dementia and depression. It is estimated that depression is prevalent in up to 90% of individuals diagnosed with Parkinson’s disease, with varying severity, and in 20 to 30% of cases of Alzheimer’s disease. The hypothalamic pituitary adrenal (HPA) axis is the great intermediary between the pathophysiological mechanisms in neurodegenerative diseases and depression. This review discusses the role of Aβ protein in the pathophysiological mechanisms of dementia and depression, considering the HPA axis, neuroinflammation, oxidative stress, signaling pathways, and neurotransmission.

The objective of this study was to develop a population pharmacokinetic-pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different compositions of microparticle formulations called LIQ865. Population pharmacokinetic-pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modeling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for bupivacaine clearance at higher doses. Bupivacaine clearance and the transit rate constant describing the slow absorption process both decreased with increasing doses following a power function with a shared covariate effect of dose on the two parameters. The pharmacokinetic-pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine, and the biphasic absorption seen for several local anesthetics.

Alzheimer’s disease (AD) is a neurodegenerative disorder that primarily manifests itself by progressive memory loss and cognitive decline, thus significantly affecting memory functions and quality of life. The canonical amyloid-β hypothesis, while significant, has faced setbacks, highlighting the need to adopt a broader perspective considering the intricate interplay of diverse pathological pathways for effective AD treatments. Sex differences in AD offer valuable insights into a better understanding of its pathophysiology. Fluctuation of the levels of ovarian sex hormones during perimenopause is associated with changes in glucose metabolism, as a possible window of opportunity to further understand the roles of sex steroid hormones and their associated receptors in the pathophysiology of AD. We review these dimensions, emphasizing the potential of estrogen receptors (ER) to reveal mitochondrial functions in the search for further research and therapeutic strategies for AD pharmacotherapy. Understanding and addressing the intricate interactions of mitochondrial dysfunction and estrogen receptors potentially pave the way for more effective approaches to AD therapy.