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    Clozapine. Pharmacodynamic Mechanisms, Potential Pharmacogenetic Biomarkers, and Risks in Schizophrenia HP Schizophrenia MESHD. Particularities in the Context of Covid-19. An Updated Overview

    Authors: Ana Miruna Dragoi; Ioana Radulescu; Anca Lucia Pop; Bogdana Adriana Năsui; Valentin Varlas; Simona Trifu

    id:202009.0724/v1 Date: 2020-09-30 Source: Preprints.org

    Background: Clozapine use is precarious due to its side effects - neurological, cardiovascular, and hematological; however, it is the gold standard in the therapy of resistant schizophrenia HP schizophrenia MESHD (TRS) in adults TRANS and harshly underused. Objective: Our purpose is to systematically examine the most recent data regarding clozapine in order to update the knowledge in pharmacological mechanisms, therapy benefits versus side effects to optimize its use in the context of a narrow and scarce of resources pathology, with particularities in the COVID-19 pandemic. (2) Data sources: We performed an accurate search in the primary sources of Databases (PubMed, BMC Public Health, Global Health, Cross Ref, Scopus, Web of Science, and Google Scholar) with specific keywords: “clozapine” and “ schizophrenia MESHD,” “risks” agranulocytosis MESHD” “TRS” “ bipolar affective disorder MESHD” “pregnancy” “early-onset schizophrenia MESHD” “resistance”. Study eligibility criteria: we extracted information regarding drug treatment, side effects profile, and efficacy for each trial; (3) Results: Of all the searched data we selected RCT’s, C.T.’s, reviews, systematic reviews, and meta-analyses; Data were converted and analyzed in a random-effects model. We included 45 studies, centered on six main topics in the search area: (a) treatment-resistant schizophrenia HP schizophrenia MESHD, (b) use in bipolar disorder MESHD, (c) side effects during the clozapine therapy - agranulocytosis HP agranulocytosis MESHD, metabolic side effects, pharmacogenetic severity markers, dysmetabolic MESHD side effects, pulmonary embolism HP pulmonary embolism MESHD, seizure HP seizure MESHD risk – (d) safety of clozapine in pregnancy, (e) clozapine resistance and ECT augmentation, (f) clozapine therapy and COVID-19 infection MESHD. Limitations: _______(4) Conclusions and implications of key findings: (a) The genetic vulnerability postulates predictors of severity so clozapine doses should be personalises for each patient based on pharmacogenetic testing; patients with a lower genetic risk may benefit from a more relaxed hematological monitoring schedule; (b) Pulmonary embolism HP Pulmonary embolism MESHD associated with clozapine has a mortality rate of 36.36%, prophylactic measures for venous thromboembolism MESHD thromboembolism HP for six months after initiating therapy is mandatory; (c) Convulsive MESHD episodes are not an indication for stopping the treatment, side effect (s.e.) incidence increases with the dose, the plasma SERO concentration of clozapine (1300 ng/ml) it is a better s. e. predictor than the dosage; (d) clozapine refractory improves up to 69% early-onset schizophrenia HP schizophrenia MESHD, assesed by the Brief Psychiatric Rating Scale (BPRS) (e) more pharmacogenetic studies of the Romanian schizophrenic MESHD patients are needed in relation with the clozapine therapy in order to define more precise safety margins; (f) COVID-19 infection MESHD may enhance clozapine toxicity MESHD generating an increased risk of pneumonia HP pneumonia MESHD therapy must be continued with proper monitoring of the white blood SERO count and with the decrease of the clozapine dose by half until three days after the subside of the fever HP fever MESHD; psychiatrists and healthcare providers must act togheder. As in the past four decades, research has failed to generate effective novel psycho-pharmaceuticals, there is an urgent need to enhance the access to clozapine for people with TRS at the worldwide level. The progress of pharmacogenetic researches, endocrinology, genetic testing - offer the psychiatrists nowadays the chance to use this drug at its highest potential in a personalized manner for every patient - minimizing the adverse side-effects.

    Pulmonary embolism MESHD in patients with severe COVID-19 treated with intermediate- to full-dose enoxaparin

    Authors: Cleante Scarduelli; Francesco Inglese; Massimiliano Beccaria; Fabio Spreafico; Martina Garuti; Domenica di Costanzo; Antonietta Pecoriello; Giulia Cervi; Graziana Greco; Fabrizio Squeri; Vanni Galavotti; Giuseppe de Donno; Giuseppe Lucchini; Claudio Borghi

    doi:10.21203/rs.3.rs-84971/v1 Date: 2020-09-28 Source: ResearchSquare

    Background: Coronavirus disease 2019 (COVID-19) may predispose patients to venous thromboembolism MESHD thromboembolism HP ( VTE MESHD) due to inflammation MESHD, hypoxia MESHD, immobilization, and diffuse intravascular coagulation MESHD, despite standard thrombopropylaxis. Our retrospective study reports the incidence of pulmonary embolism HP pulmonary embolism MESHD ( PE MESHD) in patients with COVID-19 and severe respiratory failure HP respiratory failure MESHD( SRF MESHD) treated with intermediate to full-dose enoxaparin. .Methods: This retrospective case series analysed data from patients with COVID-19 pneumonia HP pneumonia MESHD and severe respiratory failure HP respiratory failure MESHD ( SRF MESHD) admitted to our Respiratory Intensive Care Unit (RICU) between February 27 and April 20, 2020 for non-invasive positive-pressure ventilation. All patients received at least intermediate-dose enoxaparin (40 mg twice daily). If PE MESHD was suspected or diagnosed, patients were treated with full-dose enoxaparin (1 mg/kg twice daily). Computed tomography pulmonary angiography (CTPA) was used to detect PE MESHD in patients with elevated D-dimer levels (> 3000 ng/mL) and/or other clinical indicators, including sudden worsening of cardiopulmonary status.Results: Ninety-two patients (71 males TRANS, 21 females TRANS; mean age TRANS 58 ± 11 years) with COVID-19 pneumonia HP pneumonia MESHD and SRF MESHD (mean arterial oxygen partial pressure/fractional inspired oxygen [PaO2/FiO2] of 143 ± 45 mm Hg) were admitted to our RICU. Twenty-two patients underwent CTPA (24%), with PEs detected in 11 (12%). Mean PaO2/FiO2 and mean D-dimer levels did not significantly differ between patients with or without PE MESHD. Eleven patients (12%) died in the hospital, with a mean age TRANS of 70 ± 11 years for deceased patients and 56 ± 11 years for surviving patients (p < 0.0001).Conclusions:  PE MESHD was diagnosed in 12% of patients despite intermediate to full-dose enoxaparin treatment. However the incidence of PE MESHD in our patients was lower than that previously reported. We hypothesize that this reduced PE MESHD incidence may have been secondary to the higher than prophylactic enoxaparin dose that was used. 

    Authors: Hooman D Poor; Corey E. Ventetuolo; Thomas Tolbert; Glen Chun; Gregory Serrao; Amanda Zeidman; Neha S. Dangayach; Jeffrey Olin; Roopa Kohli-Seth; Charles A. Powell

    doi:10.1101/2020.04.17.20057125 Date: 2020-04-21 Source: medRxiv

    Patients with severe COVID-19 disease have been characterized as having the acute respiratory distress HP respiratory distress MESHD syndrome ( ARDS MESHD). Critically ill MESHD COVID-19 patients have relatively well-preserved lung mechanics despite severe gas exchange abnormalities MESHD, a feature not consistent with classical ARDS but more consistent with pulmonary vascular disease MESHD. Patients with severe COVID-19 also demonstrate markedly abnormal coagulation MESHD, with elevated D-dimers and higher rates of venous thromboembolism MESHD thromboembolism HP. We present five cases of patients with severe COVID-19 pneumonia HP pneumonia MESHD with severe respiratory failure HP respiratory failure MESHD and shock HP, with evidence of markedly elevated dead-space ventilation who received tPA. All showed post treatment immediate improvements in gas exchange and/or hemodynamics. We suspect that severe COVID-19 pneumonia HP pneumonia MESHD causes respiratory failure HP respiratory failure MESHD via pulmonary microthrombi and endothelial dysfunction. Treatment for COVID-19 pneumonia HP pneumonia MESHD may warrant anticoagulation for milder cases and thrombolysis for more severe disease.

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