Sequential immunotherapy: towards cures for autoimmunity.

Despite major progress in the treatment of autoimmune diseases in the past two decades, most therapies do not cure disease and can be associated with increased risk of infection through broad suppression of the immune system. However, advances in understanding the causes of autoimmune disease and clinical data from novel therapeutic modalities such as chimeric antigen receptor T cell therapies provide evidence that it may be possible to re-establish immune homeostasis and, potentially, prolong remission or even cure autoimmune diseases. Here, we propose a 'sequential immunotherapy' framework for immune system modulation to help achieve this ambitious goal.

Calcium regulates acid-sensing ion channel 3 activation by competing with protons in the channel pore and at an allosteric binding site.

The extracellular Ca concentration changes locally under certain physiological and pathological conditions. Such variations affect the function of ion channels of the nervous system and consequently also neuronal signalling. We investigated here the mechanisms by which Ca controls the activity of acid-sensing ion channel (ASIC) 3.

Ten-year trends in hospitalizations related to cocaine abuse in France.

In France, the abuse/misuse of psychoactive substances, including cocaine, is monitored via spontaneous notifications, and under-reporting is its main limitation. Therefore, the French national hospital discharge database (Programme de Médicalisation des Systèmes d'information [PMSI]) was used to identify all hospital stays possibly due to complications related to cocaine use. The objective was to determine the main trends in the rate of cocaine-related hospitalizations from 2010 to 2019 by age category and by areas.

Abuse and misuse of second-generation antipsychotics: An analysis using VigiBase, the World Health Organisation pharmacovigilance database.

The study aim was to assess the abuse/misuse potential of second-generation antipsychotics (SGAPs) using VigiBase data. We extracted individual case safety reports of "Drug abuse, dependence and withdrawal" involving SGAPs up to June 2018. We assessed disproportionate reporting by calculating the information component, considering the lower end of the 95% credibility interval for the information component (IC ), and the proportional reporting ratio.

Management of Pregabalin Use Disorder: A Case Series.

Pregabalin is indicated for the treatment of partial epilepsy, generalized anxiety disorder, and neuropathic pain. The first reports on pregabalin use disorder have been published in Europe in 2010 and notified to the French Addictovigilance Network (FAN) in 2011. The management of pregabalin use disorder is challenging due to the risks associated with the abrupt withdrawal and lack of guidelines.

Opioid misuse in community pharmacy patients with chronic non-cancer pain.

Aims: Community pharmacists could contribute to identify people misusing prescription opioids, which may be associated with hospitalizations, substance use disorders and death. This study investigated prescription opioid misuse in community pharmacy patients and the factors potentially associated with high Prescription Opioid Misuse Index (POMI) scores.

Methods: In this cross-sectional study, pharmacy students asked patients with opioid prescriptions to fill in a questionnaire (including the POMI) in community pharmacies in a French region, in April 2019.

and Functional Redundancy in Erythropoiesis.

Several studies have established the crucial role of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway in hematopoietic cell proliferation and differentiation. MEK1 and MEK2 phosphorylate and activate ERK1 and ERK2. However, whether MEK1 and MEK2 differentially regulate these processes is unknown.

Bacterial infections in people who inject psychoactive substances: An observational study in a French university hospital.

Aim Of The Study: To describe bacterial infections in injection drug users (IDUs) hospitalized at Montpellier University Hospital, France, and to identify factors that might influence the development of local or systemic infections.

Methods: This cross-sectional observational monocentric study prospectively included bacterial infections in IDUs hospitalized at Montpellier University Hospital between 2012 and 2018. Types of infection (local or systemic) were described and compared to identify specific features (injection practices).

Soluble guanylate cyclase stimulators for the treatment of hypertension: Discovery of MK-2947.

The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential.

The fatigue-induced alteration in postural control is larger in hypobaric than in normobaric hypoxia.

To test the hypothesis that postural control would be more affected by plantar flexors fatigue during acute exposure in hypobaric (HH) than in normobaric (NH) hypoxia or normobaric normoxia (NN). Twelve young male adults performed in a random order three experimental sessions (in HH and NH (FO 0.139) at an altitude of 2950 m, and in NN at 500 m) composed of a bipedal postural control with eyes open on a posturographic platform before and after a plantar flexors fatiguing protocol.

Mutations in the palm domain disrupt modulation of acid-sensing ion channel 1a currents by neuropeptides.

Modulation by neuropeptides enhances several functions of acid-sensing ion channels (ASICs), such as pain sensation and acid-induced neuronal injury. The acid-induced opening of ASICs is transient, because of a rapid desensitization. Neuropeptides containing an Arg-Phe-amide motif affect ASIC desensitization and allow continuous activity of ASICs.

Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment.

Context: The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause early-onset severe obesity.

Methods: Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1, and LEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants.

Impact of recommended changes in labor management for prevention of the primary cesarean delivery.

Background: The dramatic rise in cesarean delivery rates worldwide in recent decades, without evidence of a concomitant decrease in cerebral palsy rates, has raised concerns about its potential negative consequences for maternal and infant health. In 2014, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine jointly published an Obstetric Care Consensus for safe prevention of the primary cesarean delivery.

Objective: We sought to assess whether modification of our protocol to implement these recommendations helped to decrease our primary cesarean delivery rate safely.

Improvement of hERG-ROMK index of spirocyclic ROMK inhibitors through scaffold optimization and incorporation of novel pharmacophores.

SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone.

Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating.

Acid-sensing ion channels (ASICs) are proton-activated Na channels expressed in the nervous system, where they are involved in learning, fear behaviors, neurodegeneration, and pain sensation. In this work, we study the role in pH sensing of two regions of the ectodomain enriched in acidic residues: the acidic pocket, which faces the outside of the protein and is the binding site of several animal toxins, and the palm, a central channel domain. Using voltage clamp fluorometry, we find that the acidic pocket undergoes conformational changes during both activation and desensitization.

Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold.

Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles.

Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure.

ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties.

The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartter's Syndrome Type II Phenotype.

The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs.

Differentiation of ROMK potency from hERG potency in the phenacetyl piperazine series through heterocycle incorporation.

Following the discovery of small molecule acyl piperazine ROMK inhibitors and their initial preclinical validation as a novel diuretic agent, our group set out to discover new ROMK inhibitors with reduced risk for QT effects, suitable for further pharmacological experiments in additional species. Several strategies for decreasing hERG affinity while maintaining ROMK inhibition were investigated and are described herein. The most promising candidate, derived from the newly discovered 4-N-heteroaryl acetyl series, improved functional hERG/ROMK ratio by >10× over the previous lead.

Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation.

A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.