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 (IC025 ), and the proportional reporting ratio. We identified 1683 individual case safety reports recorded as "abuse, dependence and withdrawal" involving SGAPs, mainly quetiapine (n = 1089) and olanzapine (n = 209). The disproportional reporting indicators highlighted an association between "Drug abuse and dependence", and quetiapine, olanzapine and ziprasidone, as indicated by the IC025 (2.263, 0.259 and 1.051, respectively) and proportional reporting ratio values (3.929, 1.020 and 1.334, respectively). The abuse/misuse potential is confirmed for quetiapine and olanzapine and highlighted for the first time for ziprasidone. Physicians should consider these risks when prescribing these antipsychotics, especially to patients with history of drug abuse.

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. Eligible patients were adults with chronic non-cancer pain who consented to participate. RESULTS: In total, 414 patients (62.4% women; mean age: 58.00 years ± 16.00) were included. The prescribed opioids were mainly weak opioids (73.2%; paracetamol/tramadol: 35%). Strong opioids (32.6%) included oxycodone (11.95%), fentanyl (9%) and morphine (9%). The median morphine milligram equivalent (MME) was 40 mg/day (IQR25-75 : 20-80). The POMI score (0 to 6) was ≥4 in 16% of patients who were younger (P < .01), more urban (P = .03), with higher pain visual analogue scale (VAS) score (P < .01) and MME (P < .01), and treated more frequently with strong opioids (P = .04). In multivariate analysis, age (ORfor 10y : 0.68 (95% CI: 0.56-0.82, P < .0001)), VAS (OR2units : 1.78 (95% CI: 1.26-2.40, P = .0008)), and MME (>100 mg, OR: 2.65 (95% CI: 1.14-4.41, P = .0194)) were significantly associated with POMI scores ≥4. CONCLUSIONS: The high proportion of patients with high POMI scores underlines the interest of prescription opioid misuse screening in community pharmacies, in order to help these patients and refer them to pain specialists, if needed.

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. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.

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. Concurrently, we find that, although proton sensing in the acidic pocket is not required for channel function, it does contribute to both activation and desensitization. Furthermore, protonation-mimicking mutations of acidic residues in the palm induce a dramatic acceleration of desensitization followed by the appearance of a sustained current. In summary, this work describes the roles of potential pH sensors in two extracellular domains, and it proposes a model of acidification-induced conformational changes occurring in the acidic pocket of ASIC1a.

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. STUDY DESIGN: This is a before-and-after retrospective cohort study at a university referral hospital. In March 2014, the threshold for defining active labor changed from 4 to >6 cm and arrest of first-stage labor from lack of cervical change despite regular contractions after 3 hours of oxytocin administration with amniotomy and epidural anesthesia to no change after 4 hours of adequate or 6 hours of inadequate contractions in women with an epidural. The definition of second-stage arrest of labor changed simultaneously from lack of progress for 3 hours with adequate contractions in women with epidural anesthesia to no progress for ≥4 hours in nulliparas or 3 hours in multiparas with an epidural. We compared maternal and neonatal outcomes over two 1 year periods: from March 2013 to February 2014 (before, preguideline) and from June 2014 to May 2015 (after, postguideline). We included all women with singleton pregnancies at ≥37 weeks' gestation, in vertex presentation, in spontaneous or induced labor, and with epidural anesthesia. We excluded women with an elective or previous cesarean delivery and those with obstetric or fetal complications. RESULTS: This study included 3283 and 3068 women in the before and after periods, respectively. The groups had similar general and obstetric characteristics. The global cesarean delivery rate decreased significantly from 9.4% in the preguideline to 6.9% in the postguideline period (odds ratio, 0.71; 95% confidence interval, 0.59-0.85; P < .01). The cesarean delivery rate for arrest of first-stage labor fell by half, from 1.8% to 0.9% (odds ratio, 0.51; 95% confidence interval, 0.31-0.81; P < .01) but was significant only among nulliparous women. The cesarean delivery rate for second-stage arrest of labor decreased but not significantly between periods (1.3% vs 1.0%; odds ratio, 0.73; 95% confidence interval, 0.44-1.22; P = .2), and the cesarean delivery rate for failure of induction remained similar (3.7% vs 3.5%; odds ratio, 1.06; 95% confidence interval, 0.06-13.24; P = .88). The median duration of labor before cesarean delivery also became significantly longer among nulliparous women during the later period. Maternal and neonatal outcomes did not differ between the 2 periods, except that the rate of 1 minute Apgar score <7 fell significantly in the later period (8.4% vs 6.9%; odds ratio, 0.80; 95% confidence interval, 0.66-0.97; P = .02). CONCLUSION: The modification of our protocol by implementing the new consensus recommendations was associated with a reduction of the rate of primary cesarean delivery performed for arrest of labor with no apparent increase in immediate adverse neonatal outcomes in nulliparous women at term with singleton pregnancies in vertex presentation and with epidural anesthesia. Further studies are needed to assess the long-term maternal and neonatal safety of these policies.

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. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.

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. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors.

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. In vivo evaluation demonstrated comparable diuretic effects in rat with no detectable QT effects at the doses evaluated in an in vivo dog model.

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. This new series also retained comparable ROMK potency compared to earlier leads.

Acute hemodynamic and renal effects of glucagon-like peptide 1 analog and dipeptidyl peptidase-4 inhibitor in rats.

BACKGROUND: Glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP4) inhibitors are a newer class of antidiabetics named as incretin-based therapy. In addition to the homeostatic control of glucose, the incretin-based therapy has shown beneficial effects on the cardiovascular system in preclinical and clinical studies. However, there is limited information on their renal effects. To this end, we assessed the acute hemodynamic and renal effects of a GLP-1 analog, Liraglutide, and a DPP4 inhibitor, MK-0626. METHODS: Experiments were performed in anesthetized male Sprague-Dawley rats. Three ascending doses of Liraglutide (3, 9, and 27 nmol/kg/h) or MK-0626 (1 mg/kg) with or without GLP-1 peptide (2.4, 4.8, or 9.6 pmol/kg/min) were administered. Blood pressure (BP) and heart rate (HR) were recorded from an indwelling catheter. Glomerular filtration rate (GFR) and renal blood flow (RBF) were assessed by inulin and para-aminohippurate clearance, respectively. Renal excretory function was assessed in metabolic studies. RESULTS: Both Liraglutide and MK-0626 plus GLP-1 evoked significant diuretic and natriuretic responses and increased GFR. MK-0626 alone increased RBF. Liraglutide at 27 nmol//kg/h and MK-0626 plus GLP-1 at 9.6 pmol/kg/min also increased HR, whereas BP was not affected. CONCLUSION: The results of the present study demonstrated that a GLP-1 analog and a DPP4 inhibitor may have beneficial effects on renal sodium and water handling. Additionally, the DPP4 inhibitor, MK-0626, favorably affects renal hemodynamics by increasing RBF. However, exceedingly high levels of GLP-1 receptor agonists may adversely affect the cardiovascular system in acute setting, as demonstrated by an acute increase in HR.

Pharmacologic inhibition of the renal outer medullary potassium channel causes diuresis and natriuresis in the absence of kaliuresis.

The renal outer medullary potassium (ROMK) channel, which is located at the apical membrane of epithelial cells lining the thick ascending loop of Henle and cortical collecting duct, plays an important role in kidney physiology by regulating salt reabsorption. Loss-of-function mutations in the human ROMK channel are associated with antenatal type II Bartter's syndrome, an autosomal recessive life-threatening salt-wasting disorder with mild hypokalemia. Similar observations have been reported from studies with ROMK knockout mice and rats. It is noteworthy that heterozygous carriers of Kir1.1 mutations associated with antenatal Bartter's syndrome have reduced blood pressure and a decreased risk of developing hypertension by age 60. Although selective ROMK inhibitors would be expected to represent a new class of diuretics, this hypothesis has not been pharmacologically tested. Compound A [5-(2-(4-(2-(4-(1H-tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one)], a potent ROMK inhibitor with appropriate selectivity and characteristics for in vivo testing, has been identified. Compound A accesses the channel through the cytoplasmic side and binds to residues lining the pore within the transmembrane region below the selectivity filter. In normotensive rats and dogs, short-term oral administration of compound A caused concentration-dependent diuresis and natriuresis that were comparable to hydrochlorothiazide. Unlike hydrochlorothiazide, however, compound A did not cause any significant urinary potassium losses or changes in plasma electrolyte levels. These data indicate that pharmacologic inhibition of ROMK has the potential for affording diuretic/natriuretic efficacy similar to that of clinically used diuretics but without the dose-limiting hypokalemia associated with the use of loop and thiazide-like diuretics.

Molecular determinants of desensitization in an ENaC/degenerin channel.

Epithelial Na(+) channel (ENaC)/degenerin family members are involved in mechanosensation, blood pressure control, pain sensation, and the expression of fear. Several of these channel types display a form of desensitization that allows the channel to limit Na(+) influx during prolonged stimulation. We used site-directed mutagenesis and chemical modification, functional analysis, and molecular dynamics simulations to investigate the role of the lower palm domain of the acid-sensing ion channel 1, a member of the ENaC/degenerin family. The lower palm domains of this trimeric channel are arranged around a central vestibule, at ∼20 Šabove the plasma membrane and are covalently linked to the transmembrane channel parts. We show that the lower palm domains approach one another during desensitization. Residues in the palm co-determine the pH dependence of desensitization, its kinetics, and the stability of the desensitized state. Mutations of palm residues impair desensitization by preventing the closing movement of the palm. Overexpression of desensitization-impaired channel mutants in central neurons allowed--in contrast to overexpression of wild type--a sustained signaling response to rapid pH fluctuations. We identify and describe here the function of an important regulatory domain that most likely has a conserved role in ENaC/degenerin channels.

Challenges in listeriosis cluster and outbreak investigations, Province of Quebec, 1997-2011.

OBJECTIVES: Public health authorities place a high priority on investigating listeriosis outbreaks, and these epidemiological investigations remain challenging. Some approaches have been described in the literature to address these challenges. This review of listeriosis clusters and outbreaks investigated in the Province of Quebec (Quebec) highlights investigative approaches that contributed to identifying the source of these outbreaks. MATERIALS: The Laboratoire de Santé Publique du Québec (LSPQ) implemented pulsed-field gel electrophoresis (PFGE) molecular subtyping in 1997 to identify Listeria monocytogenes clusters among isolates from invasive listeriosis cases identified throughout Quebec. A cluster was defined as three cases or more with the same or similar PFGE profiles (≤3 band difference) occurring over a 4-month period. An investigation was initiated if the epidemiologic indicators suggested a common source. Listeriosis data from LSPQ's database were reviewed to identify and describe clusters detected from 1997 to 2011, including those that led to an outbreak investigation. Epidemiological reports prepared following each outbreak were also reviewed. RESULTS: Eleven clusters were identified in the province by LSPQ between 1997 and 2011. Outbreak investigations were initiated for six clusters, four of which involved more than 10 cases. Factors that contributed to identifying the source for three of these outbreaks highlighted the value of (1) making all stakeholders (food safety and inspection services, public health authorities, and laboratories) aware of any ongoing investigation and sharing relevant information even if the source is not yet identified; (2) promptly collecting food samples identified and considered as possible vehicles of infection identified during the interview of a Listeria case; (3) collecting food items and/or environmental samples in locations reported in common by cases in the same cluster. CONCLUSIONS: Multiple approaches should be considered when investigating L. monocytogenes clusters. Networks to facilitate continuous exchange of human and food data between public health and food safety partners should be encouraged.

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. This framework encompasses three steps: controlling inflammation; resetting the immune system through elimination of pathogenic immune memory cells; and promoting and maintaining immune homeostasis via immune regulatory agents and tissue repair. We discuss existing drugs and those in development for each of the three steps. We also highlight the importance of causal human biology in identifying and prioritizing novel immunotherapeutic strategies as well as informing their application in specific patient subsets, enabling precision medicine approaches that have the potential to transform clinical care.

Discovery of a novel sub-class of ROMK channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one.

A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents.

Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain L-2-hydroxy acid oxidase.

Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.

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. Relevant PMSI data were extracted using the International Classification of Diseases (10th edition). In France, hospitalizations for cocaine-related complications increased by fourfold (2461 in 2010, 9843 in 2019, +300%). This increase was similar in men and women and was observed in each age category. Patients were mainly men (75% in 2010 and in 2019), with a median age of 38.5 and 35.2 years for men and women, respectively, in 2019. Cocaine poisoning in pediatric patients (0-9 years) concerned less than 10 patients in 2010 and 21 patients in 2019. PMSI data analysis shows an overall increase of cocaine-related hospitalizations in France from 2010 to 2019 that can be linked in part to an increasing recreational use. The increase of pediatric cases of cocaine poisoning suggests a trivialization of cocaine consumption.

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. In this retrospective observational study, the management of pregabalin use disorder was analyzed in eight cases reported to the addictovigilance center of Montpellier, France, between 2019 and 2020. Most of these patients had a history of illicit psychoactive substance use. During the withdrawal period, patients experienced mainly psychiatric problems, nervous system symptoms, general disorders, and gastrointestinal symptoms. Multiple strategies were proposed for these patients to manage pregabalin withdrawal, such as hospitalization and pregabalin gradual dose reduction with or without adjuvant medications. Two patients relapsed and the others were lost to follow up. Although other reports of pregabalin use disorder have been published, recommendations or guidelines for its management are not yet available. The current case series and the previous reports suggest that the use of adjunctive therapy may be useful to limit the risk of convulsions and anxiety.

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

The extracellular Ca2+ 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 Ca2+ controls the activity of acid-sensing ion channel (ASIC) 3. ASICs are neuronal, H+-gated Na+ channels involved in several physiological and pathological processes, including the expression of fear, learning, pain sensation and neurodegeneration after ischaemic stroke. It was previously shown that Ca2+ negatively modulates the ASIC pH dependence. While protons are default activators of ASIC3, this channel can also be activated at pH7.4 by the removal of the extracellular Ca2+. Two previous studies concluded that low pH opens ASIC3 by displacing Ca2+ ions that block the channel pore at physiological pH. We show here that an acidic residue, distant from the pore, together with pore residues, controls the modulation of ASIC3 by Ca2+. Our study identifies a new regulatory site in ASIC3 and demonstrates that ASIC3 activation involves an allosteric mechanism together with Ca2+ unbinding from the channel pore. We provide a molecular analysis of a regulatory mechanism found in many ion channels.