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1.
Int J Risk Saf Med ; 32(1): 3-17, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33386817

RESUMO

Coronavirus disease 2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) presenting with pulmonary and extra-pulmonary manifestations. The first case was reported in Wuhan, China in December 2019 and it has rapidly progressed to the form of a pandemic. The presentation is mild in about 80 percent of the cases but the disease can also progress to a severe form of respiratory illness leading to acute respiratory distress syndrome (ARDS) and sometimes multi-organ failure, especially in people with other co-morbidities. Pregnant women also appear to be at a greater risk of acquiring a severe infection due to physiological changes during pregnancy. Many drugs with in vitro activity against the virus or an immunomodulatory effect have been considered for repurposing or have been tried as off-label drugs. The safety data regarding the use of newly approved or off-label or investigational drugs in pregnant women is limited and this poses a great challenge for clinicians. Therefore, it is important to know the utility and safety of the medications to avoid untoward adverse effects on pregnant women and fetuses. In this review, we aim to provide an overview of the approved, off-label, unlicensed, new and some promising pharmacological options for their use in the treatment of COVID-19 and the safety profile in pregnancy in an Indian scenario.


Assuntos
Antivirais/uso terapêutico , Feto/efeitos dos fármacos , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/uso terapêutico , Antivirais/efeitos adversos , Drogas em Investigação , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Índia/epidemiologia , Uso Off-Label , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Gestantes , Esteroides/efeitos adversos , Esteroides/uso terapêutico
2.
Clin Dermatol ; 38(6): 607-612, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33341195

RESUMO

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare, immunologically mediated cutaneous adverse reaction characterized by mucous membrane and epidermal detachment, with a mortality ranging from 15% to 25%. Risk factors for the development of SJS/TEN include immune dysregulation, active malignancy, and genetic predisposition. Medications are the most common cause, particularly antimicrobials, antiepileptics, allopurinol, and nonsteroidal anti-inflammatory medications. Drug-specific CD8 T-cells and natural killer cells are thought to be the major inducers of keratinocyte apoptosis via release of soluble cytotoxic mediators, including Fas ligand, perforin/granzyme, tumor necrosis factor, and granulysin. When SJS/TEN is suspected clinically, appropriate therapy should be instituted without delay. All patients should be managed initially in an intensive care unit or burn unit under a multidisciplinary team of physicians experienced in the care of patients with SJS/TEN. Available data support the use of various pharmacologic agents to halt disease progression and improve outcomes, but no single drug has been found to be superior or beneficial for all patients. Future research should focus on developing a better understanding of the genetic susceptibility and immunopathophysiology of the disease, as well as novel diagnostic and therapeutic targets to improve patient outcomes.


Assuntos
Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/imunologia , Anti-Infecciosos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticonvulsivantes/efeitos adversos , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteína Ligante Fas/metabolismo , Predisposição Genética para Doença , Humanos , Doenças do Sistema Imunitário/complicações , Queratinócitos/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/complicações , Perforina/metabolismo , Fatores de Risco , Síndrome de Stevens-Johnson/genética , Síndrome de Stevens-Johnson/terapia , Fator de Necrose Tumoral alfa/metabolismo
3.
Clin Dermatol ; 38(6): 613-628, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33341196

RESUMO

Drug-induced vasculitis and anticoagulant-related skin reactions are commonly encountered in the inpatient and outpatient settings. The spectrum of clinical presentation is broad and ranges from focal, skin-limited disease, to more extensive cutaneous and soft tissue necrosis, to potentially fatal systemic involvement. The prompt recognition of these adverse events can have a significant impact on patient morbidity and mortality. We highlight the key features of the clinical presentation with an emphasis on primary lesion morphology, distribution, and epidemiology of purpuric drug reactions. The proposed pathophysiology, histologic findings, and therapeutic interventions of these potentially life-threatening diseases are discussed.


Assuntos
Púrpura/induzido quimicamente , Púrpura/diagnóstico , Dermatopatias Vasculares/induzido quimicamente , Dermatopatias Vasculares/diagnóstico , Vasculite/induzido quimicamente , Vasculite/diagnóstico , Anti-Infecciosos/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Anticonvulsivantes/efeitos adversos , Antidiuréticos/efeitos adversos , Antipsicóticos/efeitos adversos , Fatores Biológicos/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Inibidores do Fator Xa/efeitos adversos , Humanos , Púrpura/patologia , Púrpura/terapia , Dermatopatias Vasculares/patologia , Dermatopatias Vasculares/terapia , Vasculite/patologia , Vasculite/terapia
4.
Expert Rev Clin Pharmacol ; 13(11): 1183-1190, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008280

RESUMO

INTRODUCTION: Patients with moderate to severe COVID-19 infection require specific drugs to prevent the morbidity and mortality. Hydroxychloroquine (HCQ) has shown some promise in the management of COVID 19. Minocycline, because of its anticytokine and other useful properties can be an ideal candidate for combining with HCQ. AREAS COVERED: Here we review the need and mechanisms and reasons for combining HCQ and minocycline moderate to severe COVID-19 infection. We also reviewed the advantages, potential safety concerns and precautions to be taken, while combining HCQ and minocycline. EXPERT OPINION: Combining HCQ and minocycline offers many advantages in the management of moderate to severe COVID-19 infection. Both drugs are cheaper, widely available and long-term safety data and contraindications are well known. We do not recommend this combination for prophylaxis or use in asymptomatic or mild disease patients as this can lead to unnecessary safety concerns. Additive antimicrobial and anticytokine effects of both drugs may reduce the morbidity and mortality among patients with COVID-19 and may act as a cheaper alternative to the costlier drugs, however, thorough clinical research is warranted. We call upon public and private healthcare bodies to come up with large well-designed clinical studies for generating evidence-based recommendations.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Minociclina/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/efeitos adversos , Infecções por Coronavirus/fisiopatologia , Quimioterapia Combinada , Humanos , Hidroxicloroquina/efeitos adversos , Minociclina/efeitos adversos , Pandemias , Pneumonia Viral/fisiopatologia , Índice de Gravidade de Doença
5.
J Interferon Cytokine Res ; 40(10): 469-471, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32881593

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has recently emerged as a global health threat. To address this health emergency, various therapeutic approaches are currently under investigation. There is limited evidence on the effectiveness of hydroxychloroquine (HCQ) and chloroquine (CQ) as COVID-19 therapies, and thus World Health Organization (WHO) mentioned that "Current data shows that this drug does not reduce deaths among hospitalized COVID-19 patients, nor help people with mild or moderate disease." CQ and HCQ are typically used for the treatment of malaria but have been recognized for certain beneficial effects in COVID-19 patients based on some clinical outcomes from the clinical treatment of COVID-19. A standard dose of HCQ has been proven effective and less toxic than CQ in COVID-19 patients; however, a comprehensive understanding of a patient's clinical condition is necessary. Based on several hospital findings, the Food and Drug Administration (FDA) has officially cancelled the emergency use authorization for HCQ and CQ for treating hospitalized COVID-19 patients on June 15, 2020. In this review, we highlight both pros and cons of the clinical use of CQ and HCQ in COVID-19 patients.


Assuntos
Anti-Infecciosos/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Cloroquina/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Fatores Imunológicos/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Anti-Infecciosos/efeitos adversos , Azitromicina/uso terapêutico , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/patogenicidade , Cloroquina/efeitos adversos , Ensaios Clínicos como Assunto , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Sinergismo Farmacológico , Humanos , Hidroxicloroquina/efeitos adversos , Fatores Imunológicos/efeitos adversos , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Resultado do Tratamento
6.
Cochrane Database Syst Rev ; 9: CD013628, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32936947

RESUMO

BACKGROUND: COVID-19 infection poses a serious risk to patients and - due to its contagious nature - to those healthcare workers (HCWs) treating them. The risks of transmission of infection are greater when a patient is undergoing an aerosol-generating procedure (AGP). Not all those with COVID-19 infection are symptomatic, or suspected of harbouring the infection. If a patient who is not known to have or suspected of having COVID-19 infection is to undergo an AGP, it would nonetheless be sensible to minimise the risk to those HCWs treating them. If the mouth and nose of an individual undergoing an AGP are irrigated with antimicrobial solutions, this may be a simple and safe method of reducing the risk of any covert infection being passed to HCWs through droplet transmission or direct contact. Alternatively, the use of antimicrobial solutions by the HCW may decrease the chance of them acquiring COVID-19 infection. However, the use of such antimicrobial solutions may be associated with harms related to the toxicity of the solutions themselves or alterations in the natural microbial flora of the mouth or nose. OBJECTIVES: To assess the benefits and harms of antimicrobial mouthwashes and nasal sprays administered to HCWs and/or patients when undertaking AGPs on patients without suspected or confirmed COVID-19 infection. SEARCH METHODS: Information Specialists from Cochrane ENT and Cochrane Oral Health searched the Central Register of Controlled Trials (CENTRAL 2020, Issue 6); Ovid MEDLINE; Ovid Embase and additional sources for published and unpublished trials. The date of the search was 1 June 2020.  SELECTION CRITERIA: This is a question that urgently requires evidence, however at the present time we did not anticipate finding many completed RCTs. We therefore planned to include the following types of studies: randomised controlled trials (RCTs); quasi-RCTs; non-randomised controlled trials; prospective cohort studies; retrospective cohort studies; cross-sectional studies; controlled before-and-after studies. We set no minimum duration for the studies.   We sought studies comparing any antimicrobial mouthwash and/or nasal spray (alone or in combination) at any concentration, delivered to the patient or HCW before and/or after an AGP. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Our primary outcomes were: 1) incidence of symptomatic or test-positive COVID-19 infection in HCWs or patients; 2) significant adverse event: anosmia (or disturbance in sense of smell). Our secondary outcomes were: 3) COVID-19 viral content of aerosol (when present); 4) change in COVID-19 viral load at site(s) of irrigation; 5) other adverse events: changes in microbiome in oral cavity, nasal cavity, oro- or nasopharynx; 6) other adverse events: allergy, irritation/burning of nasal, oral or oropharyngeal mucosa (e.g. erosions, ulcers, bleeding), long-term staining of mucous membranes or teeth, accidental ingestion. We planned to use GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We found no completed studies to include in this review.   AUTHORS' CONCLUSIONS: We identified no studies for inclusion in this review, nor any ongoing studies. The absence of completed studies is not surprising given the relatively recent emergence of COVID-19 infection. However, we are disappointed that this important clinical question is not being addressed by ongoing studies.


Assuntos
Anti-Infecciosos/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/transmissão , Pessoal de Saúde , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Antissépticos Bucais/administração & dosagem , Sprays Nasais , Pneumonia Viral/transmissão , Administração Intranasal , Microbiologia do Ar , Anti-Infecciosos/efeitos adversos , Infecções Assintomáticas/terapia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Humanos , Boca/virologia , Antissépticos Bucais/efeitos adversos , Nariz/virologia , Doenças Profissionais/etiologia , Doenças Profissionais/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia
7.
Cochrane Database Syst Rev ; 9: CD013627, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32936948

RESUMO

BACKGROUND: COVID-19 infection poses a serious risk to patients and - due to its contagious nature - to those healthcare workers (HCWs) treating them. If the mouth and nose of patients with infection are irrigated with antimicrobial solutions, this may help the patients by killing any coronavirus present at those sites. It may also reduce the risk of the active infection being passed to HCWs through droplet transmission or direct contact. However, the use of such antimicrobial solutions may be associated with harms related to the toxicity of the solutions themselves or alterations in the natural microbial flora of the mouth or nose. OBJECTIVES: To assess the benefits and harms of antimicrobial mouthwashes and nasal sprays administered to patients with suspected or confirmed COVID-19 infection to both the patients and the HCWs caring for them. SEARCH METHODS: Information Specialists from Cochrane ENT and Cochrane Oral Health searched the Central Register of Controlled Trials (CENTRAL 2020, Issue 6); Ovid MEDLINE; Ovid Embase and additional sources for published and unpublished trials. The date of the search was 1 June 2020.  SELECTION CRITERIA: This is a question that urgently requires evidence, however at the present time we did not anticipate finding many completed RCTs. We therefore planned to include the following types of studies: randomised controlled trials (RCTs); quasi-RCTs; non-randomised controlled trials; prospective cohort studies; retrospective cohort studies; cross-sectional studies; controlled before-and-after studies. We set no minimum duration for the studies.   We sought studies comparing antimicrobial mouthwash and/or nasal spray (alone or in combination) at any concentration, delivered with any frequency or dosage to suspected/confirmed COVID-19 patients. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Our primary outcomes were: 1) RECOVERY* (www.recoverytrial.net) outcomes in patients (mortality; hospitalisation status; use of ventilation; use of renal dialysis or haemofiltration); 2) incidence of symptomatic or test-positive COVID-19 infection in HCWs; 3) significant adverse event: anosmia (or disturbance in sense of smell). Our secondary outcomes were: 4) change in COVID-19 viral load in patients; 5) COVID-19 viral content of aerosol (when present); 6) other adverse events: changes in microbiome in oral cavity, nasal cavity, oro- or nasopharynx; 7) other adverse events: allergy, irritation/burning of nasal, oral or oropharyngeal mucosa (e.g. erosions, ulcers, bleeding), long-term staining of mucous membranes or teeth, accidental ingestion. We planned to use GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We found no completed studies to include in this review. We identified 16 ongoing studies (including 14 RCTs), which aim to enrol nearly 1250 participants. The interventions included in these trials are ArtemiC (artemisinin, curcumin, frankincense and vitamin C), Citrox (a bioflavonoid), cetylpyridinium chloride, chlorhexidine, chlorine dioxide, essential oils, hydrogen peroxide, hypertonic saline, Kerecis spray (omega 3 viruxide - containing neem oil and St John's wort), neem extract, nitric oxide releasing solution, povidone iodine and saline with baby shampoo.  AUTHORS' CONCLUSIONS: We identified no studies for inclusion in this review. This is not surprising given the relatively recent emergence of COVID-19 infection. It is promising that the question posed in this review is being addressed by a number of RCTs and other studies. We are concerned that few of the ongoing studies specifically state that they will evaluate adverse events such as changes in the sense of smell or to the oral and nasal microbiota, and any consequences thereof. Very few interventions have large and dramatic effect sizes. If a positive treatment effect is demonstrated when studies are available for inclusion in this review, it may not be large. In these circumstances in particular it may be a challenge to weigh up the benefits against the harms if the latter are of uncertain frequency and severity.


Assuntos
Anti-Infecciosos/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/terapia , Pessoal de Saúde , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Antissépticos Bucais/administração & dosagem , Sprays Nasais , Pneumonia Viral/terapia , Anti-Infecciosos/efeitos adversos , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Humanos , Boca/virologia , Antissépticos Bucais/efeitos adversos , Nariz/virologia , Doenças Profissionais/etiologia , Doenças Profissionais/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Irrigação Terapêutica
8.
Cochrane Database Syst Rev ; 9: CD013626, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32936949

RESUMO

BACKGROUND: COVID-19 infection poses a serious risk to patients and - due to its contagious nature - to those healthcare workers (HCWs) treating them. If the mouth and nose of HCWs are irrigated with antimicrobial solutions, this may help reduce the risk of active infection being passed from infected patients to HCWs through droplet transmission or direct contact. However, the use of such antimicrobial solutions may be associated with harms related to the toxicity of the solutions themselves, or alterations in the natural microbial flora of the mouth or nose. Understanding these possible side effects is particularly important when the HCWs are otherwise fit and well. OBJECTIVES: To assess the benefits and harms of antimicrobial mouthwashes and nasal sprays used by healthcare workers (HCWs) to protect themselves when treating patients with suspected or confirmed COVID-19 infection. SEARCH METHODS: Information Specialists from Cochrane ENT and Cochrane Oral Health searched the Central Register of Controlled Trials (CENTRAL 2020, Issue 6); Ovid MEDLINE; Ovid Embase and additional sources for published and unpublished trials. The date of the search was 1 June 2020.  SELECTION CRITERIA: This is a question that urgently requires evidence, however at the present time we did not anticipate finding many completed randomised controlled trials (RCTs). We therefore planned to include the following types of studies: RCTs; quasi-RCTs; non-randomised controlled trials; prospective cohort studies; retrospective cohort studies; cross-sectional studies; controlled before-and-after studies. We set no minimum duration for the studies.   We sought studies comparing any antimicrobial mouthwash and/or nasal spray (alone or in combination) at any concentration, delivered to HCWs, with or without the same intervention being given to the patients with COVID-19. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Our primary outcomes were: 1) incidence of symptomatic or test-positive COVID-19 infection in HCWs; 2) significant adverse event: anosmia (or disturbance in sense of smell). Our secondary outcomes were: 3) viral content of aerosol, when present (if intervention administered to patients); 4) other adverse events: changes in microbiome in oral cavity, nasal cavity, oro- or nasopharynx; 5) other adverse events: allergy, irritation/burning of nasal, oral or oropharyngeal mucosa (e.g. erosions, ulcers, bleeding), long-term staining of mucous membranes or teeth, accidental ingestion. We planned to use GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We found no completed studies to include in this review. We identified three ongoing studies (including two RCTs), which aim to enrol nearly 700 participants. The interventions included in these trials are povidone iodine, nitric oxide and GLS-1200 oral spray (the constituent of this spray is unclear and may not be antimicrobial in nature).   AUTHORS' CONCLUSIONS: We identified no studies for inclusion in this review. This is not surprising given the relatively recent emergence of COVID-19 infection. It is promising that the question posed in this review is being addressed by two RCTs and a non-randomised study. We are concerned that only one of the ongoing studies specifically states that it will evaluate adverse events and it is not clear if this will include changes in the sense of smell or to the oral and nasal microbiota, and any consequences thereof. Very few interventions have large and dramatic effect sizes. If a positive treatment effect is demonstrated when studies are available for inclusion in this review, it may not be large. In these circumstances in particular, where those receiving the intervention are otherwise fit and well, it may be a challenge to weigh up the benefits against the harms if the latter are of uncertain frequency and severity.


Assuntos
Anti-Infecciosos/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/transmissão , Pessoal de Saúde , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Antissépticos Bucais/administração & dosagem , Sprays Nasais , Pneumonia Viral/transmissão , Anti-Infecciosos/efeitos adversos , Infecções por Coronavirus/prevenção & controle , Humanos , Boca/virologia , Antissépticos Bucais/efeitos adversos , Nariz/virologia , Doenças Profissionais/etiologia , Doenças Profissionais/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Irrigação Terapêutica
10.
Int J Antimicrob Agents ; 56(4): 106142, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32853675

RESUMO

This longitudinal, prospective cohort study aimed to assess risk of QTc interval prolongation and its predicting factors in subjects treated with combinations containing hydroxychloroquine (HCQ) for COVID-19. Moderate-to-severe QTc prolongation during therapy was defined as a QTc interval >470 ms in men or >480 ms in women. Patients were treated under strict cardiac supervision. A total of 105 adults were included [56% male; median (IQR) age 69 (57-79) years]. All patients received therapy with HCQ in combination with azithromycin (AZM), and 95 (90%) also with lopinavir/ritonavir (LPV/r). Concomitant medications classified as having risk of developing torsades de pointes (TdP) were simultaneously used in 81 patients (77%). Moderate-to-severe QTc prolongation was observed in 14 patients (13%), mostly at Days 3-5 from baseline, with 6 (6%) developing severe prolongation (>500 ms). There was no evidence of TdP arrhythmia or TdP-associated death. Adding LPV/r to HCQ+AZM did not significantly prolong the QTc interval. Multivariable Cox regression revealed that comedications with known risk of TdP (HR = 11.28, 95% CI 1.08-117.41), higher neutrophil-to-lymphocyte (NLR) ratio (HR = 1.10, 95% CI 1.03-1.18 per unit increase) and higher serum hs-cardiac troponin I (HR = 4.09, 95% CI 1.36-12.2 per unit increase) were major contributors to moderate-to-severe QTc prolongation. In this closely screened and monitored cohort, no complications derived from QTc prolongation were observed during pharmacological therapy containing HCQ for COVID-19. Evidence of myocardial injury with elevated troponin and strong inflammatory response, specifically higher NLR, are conditions requiring careful QTc interval monitoring.


Assuntos
Anti-Infecciosos/administração & dosagem , Azitromicina/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Lopinavir/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Ritonavir/administração & dosagem , Idoso , Anti-Infecciosos/efeitos adversos , Azitromicina/efeitos adversos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Biomarcadores/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Progressão da Doença , Combinação de Medicamentos , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Unidades de Terapia Intensiva , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/fisiopatologia , Lopinavir/efeitos adversos , Linfócitos/patologia , Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Neutrófilos/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Ritonavir/efeitos adversos , Resultado do Tratamento , Troponina I/sangue
11.
PLoS Med ; 17(8): e1003203, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822347

RESUMO

BACKGROUND: Artemisinin resistance is threatening malaria control. We aimed to develop and test a human model of artemisinin-resistant (ART-R) Plasmodium falciparum to evaluate the efficacy of drugs against ART-R malaria. METHODS AND FINDINGS: We conducted 2 sequential phase 1, single-centre, open-label clinical trials at Q-Pharm, Brisbane, Australia, using the induced blood-stage malaria (IBSM) model, whereby healthy participants are intravenously inoculated with blood-stage parasites. In a pilot study, participants were inoculated (Day 0) with approximately 2,800 viable P. falciparum ART-R parasites. In a comparative study, participants were randomised to receive approximately 2,800 viable P. falciparum ART-R (Day 0) or artemisinin-sensitive (ART-S) parasites (Day 1). In both studies, participants were administered a single approximately 2 mg/kg oral dose of artesunate (AS; Day 9). Primary outcomes were safety, ART-R parasite infectivity, and parasite clearance. In the pilot study, 2 participants were enrolled between April 27, 2017, and September 12, 2017, and included in final analyses (males n = 2 [100%], mean age = 26 years [range, 23-28 years]). In the comparative study, 25 participants were enrolled between October 26, 2017, and October 18, 2018, of whom 22 were inoculated and included in final analyses (ART-R infected participants: males n = 7 [53.8%], median age = 22 years [range, 18-40 years]; ART-S infected participants: males n = 5 [55.6%], median age = 28 years [range, 22-35 years]). In both studies, all participants inoculated with ART-R parasites became parasitaemic. A total of 36 adverse events were reported in the pilot study and 277 in the comparative study. Common adverse events in both studies included headache, pyrexia, myalgia, nausea, and chills; none were serious. Seven participants experienced transient severe falls in white cell counts and/or elevations in liver transaminase levels which were considered related to malaria. Additionally, 2 participants developed ventricular extrasystoles that were attributed to unmasking of a predisposition to benign fever-induced tachyarrhythmia. In the comparative study, parasite clearance half-life after AS was significantly longer for ART-R infected participants (n = 13, 6.5 hours; 95% confidence interval [CI] 6.3-6.7 hours) compared with ART-S infected participants (n = 9, 3.2 hours; 95% CI 3.0-3.3 hours; p < 0.001). The main limitation of this study was that the ART-R and ART-S parasite strains did not share the same genetic background. CONCLUSIONS: We developed the first (to our knowledge) human model of ART-R malaria. The delayed clearance profile of ART-R parasites after AS aligns with field study observations. Although based on a relatively small sample size, results indicate that this model can be safely used to assess new drugs against ART-R P. falciparum. TRIAL REGISTRATION: The studies were registered with the Australian New Zealand Clinical Trials Registry: ACTRN12617000244303 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372357) and ACTRN12617001394336 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373637).


Assuntos
Anti-Infecciosos/uso terapêutico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/sangue , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/metabolismo , Adolescente , Adulto , Animais , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/farmacologia , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Artemisininas/efeitos adversos , Artemisininas/farmacologia , Artesunato/efeitos adversos , Artesunato/farmacologia , Artesunato/uso terapêutico , Austrália/epidemiologia , Feminino , Cefaleia/induzido quimicamente , Voluntários Saudáveis , Humanos , Malária Falciparum/epidemiologia , Masculino , Náusea/induzido quimicamente , Parasitos/metabolismo , Projetos Piloto , Adulto Jovem
12.
Vascul Pharmacol ; 133-134: 106779, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32814163

RESUMO

Atherosclerosis is a very common macrovascular complication in type 2 diabetes mellitus, and cardiovascular disease is the primary cause of death in diabetes patients. Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are a newly identified class of drugs targeting the renal proximal tubules to increase glucose excretion. Large-scale clinical trials have confirmed the cardiovascular protective effects of SGLT inhibitors in patients with diabetes diagnosed with or at a higher risk of atherosclerotic cardiovascular disease. In addition to its direct effect on glycemic control, the function of SGLT-2i in the alleviation of volume load, renal protection, and reduction of inflammation plays an essential role in its therapeutic effect on atherosclerosis. SGLT-2i are known to decrease the levels of inflammatory factors in circulation and in arteries in situ, inhibit foam cell formation and macrophage infiltration, and sustain plaque stability, ultimately blocking the development and progression of atherosclerosis.


Assuntos
Anti-Infecciosos/uso terapêutico , Artérias/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inflamação/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Anti-Infecciosos/efeitos adversos , Artérias/metabolismo , Artérias/patologia , Aterosclerose/diagnóstico , Aterosclerose/metabolismo , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Humanos , Inflamação/diagnóstico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Placa Aterosclerótica , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
13.
Lancet Gastroenterol Hepatol ; 5(9): 862-874, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32818465

RESUMO

Drug-induced liver injury (DILI) is a rare, unpredictable, and potentially serious adverse reaction. It is induced by many drugs, herbs, and dietary supplements and represents a diagnostic challenge to clinicians. Older people (aged 65 years and older) are often polymedicated, and their declining physiological function affects drug pharmacokinetics. There is no consistent evidence that age is a general risk factor for DILI; however, age might be a risk factor with specific medications, with antimicrobials and cardiovascular drugs being the most likely medications to cause DILI in older people. Ageing influences DILI phenotypes, making cholestatic damage and chronic DILI more likely. In older people with DILI, comorbidities act as confounding causes and account for higher mortality unrelated to the liver. There are no specific therapies for DILI and supportive measures are still the mainstay of management. This Review highlights current advances and gaps in DILI epidemiology, mechanisms, and diagnosis that are pertinent to older individuals.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Colestase/induzido quimicamente , Suplementos Nutricionais/efeitos adversos , Plantas Medicinais/efeitos adversos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anti-Infecciosos/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/terapia , Comorbidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Farmacocinética , Fenótipo , Polimedicação , Fatores de Risco
14.
Circ Arrhythm Electrophysiol ; 13(8): e008627, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32654514

RESUMO

BACKGROUND: During acute infections, the risk of malignant ventricular arrhythmias is increased, partly because of a higher propensity to develop QTc prolongation. Although it is generally believed that QTc changes almost exclusively result from concomitant treatment with QT-prolonging antimicrobials, direct effects of inflammatory cytokines on ventricular repolarization are increasingly recognized. We hypothesized that systemic inflammation per se can significantly prolong QTc during acute infections, via cytokine-mediated changes in K+ channel expression. METHODS: We evaluated (1) the frequency of QTc prolongation and its association with inflammatory markers, in patients with different types of acute infections, during active disease and remission; (2) the prevalence of acute infections in a cohort of consecutive patients with Torsades de Pointes; (3) the relationship between K+ channel mRNA levels in ventricles and peripheral blood mononuclear cells and their changes in patients with acute infection over time. RESULTS: In patients with acute infections, regardless of concomitant QT-prolonging antimicrobial treatments, QTc was significantly prolonged but rapidly normalized in parallel to CRP (C-reactive protein) and cytokine level reduction. Consistently in the Torsades de Pointes cohort, concomitant acute infections were highly prevalent (30%), despite only a minority (25%) of these cases were treated with QT-prolonging antimicrobials. KCNJ2 K+ channel expression in peripheral blood mononuclear cell, which strongly correlated to that in ventricles, inversely associated to CRP and IL (interleukin)-1 changes in acute infection patients. CONCLUSIONS: During acute infections, systemic inflammation rapidly induces cytokine-mediated ventricular electrical remodeling and significant QTc prolongation, regardless concomitant antimicrobial therapy. Although transient, these changes may significantly increase the risk of life-threatening ventricular arrhythmia in these patients. It is timely and warranted to transpose these findings to the current coronavirus disease 2019 (COVID-19) pandemic, in which both increased amounts of circulating cytokines and cardiac arrhythmias are demonstrated along with a frequent concomitant treatment with several QT-prolonging drugs. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Doenças Transmissíveis/metabolismo , Citocinas/metabolismo , Parada Cardíaca/metabolismo , Frequência Cardíaca , Ventrículos do Coração/metabolismo , Inflamação/metabolismo , Leucócitos Mononucleares/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Torsades de Pointes/metabolismo , Potenciais de Ação , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Infecciosos/efeitos adversos , Doenças Transmissíveis/tratamento farmacológico , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/fisiopatologia , Feminino , Parada Cardíaca/epidemiologia , Parada Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Inflamação/epidemiologia , Inflamação/fisiopatologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Canais de Potássio Corretores do Fluxo de Internalização/genética , Prevalência , Fatores de Risco , Transdução de Sinais , Fatores de Tempo , Torsades de Pointes/epidemiologia , Torsades de Pointes/fisiopatologia , Adulto Jovem
15.
Heart Rhythm ; 17(11): 1960-1966, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32621881

RESUMO

BACKGROUND: There is limited data regarding the electrophysiological abnormalities and arrhythmias in children with COVID-19, including those associated with treatment using potentially proarrhythmic hydroxychloroquine (HCQ) and azithromycin (AZN). OBJECTIVES: To describe the electrophysiologic findings and arrhythmias associated with pediatric COVID-19 and its treatment. METHODS: A single-center retrospective chart review was undertaken and included all patients with (1) symptoms of COVID-19 and (2) PCR-positive nasopharyngeal swabs for SARS-CoV-2 who were placed on continuous telemetry for the duration of their hospitalization during March through May, 2020. RESULTS: Thirty-six patients were included in the study. Significant arrhythmias were found in 6 (nonsustained ventricular tachycardia in 5 and sustained atrial tachycardia in 1). All were self-resolving and half prompted prophylactic antiarrhythmic therapy. Patients with significant arrhythmias were likely to have noncardiac comorbidities (4/6), but these were not more common than in patients without arrhythmias (20/30, P = 1). The use of HCQ was associated with statistically significant QTc prolongation (413 ± 19 ms vs 425 ± 16 ms, P =.005). QTc was not statistically different in patients with and without arrhythmias (425 ± 15 ms vs 425 ± 15 ms, P = 1). CONCLUSIONS: In pediatric patients with PCR-positive active COVID-19 infection, significant arrhythmias are infrequent, but are more common than expected in a general pediatric population. Comorbidities are not more common in patients with arrhythmias than in patients without arrhythmias. COVID-19 treatment using HCQ is associated with QTc prolongation but was not associated with arrhythmias in pediatric patients.


Assuntos
Arritmias Cardíacas , Azitromicina , Infecções por Coronavirus , Eletrocardiografia , Hidroxicloroquina , Síndrome do QT Longo , Pandemias , Pneumonia Viral , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/efeitos adversos , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiologia , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Betacoronavirus/isolamento & purificação , Criança , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Eletrocardiografia/métodos , Eletrocardiografia/estatística & dados numéricos , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Incidência , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Masculino , Cidade de Nova Iorque/epidemiologia , Avaliação de Processos e Resultados em Cuidados de Saúde , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Estudos Retrospectivos , Fatores de Risco
16.
Cardiol Young ; 30(10): 1482-1485, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32686633

RESUMO

INTRODUCTION AND AIM: Hydroxychloroquine alone or in combination with azithromycin has been increasingly used for patients with coronavirus disease 2019, in both children and adults. Drugs are generally well tolerated in clinical practice; however, both can cause corrected QT prolongation. We aimed to report our experience of QT interval evaluation associated with the use of hydroxychloroquine with concurrent azithromycin among children testing positive for coronavirus disease 2019. METHODS: Our single-centre; retrospective, study evaluated children with coronavirus disease 2019 disease admitted to the Pediatric Department at Sancaktepe Training and Research Hospital Istanbul, Turkey from 10 March, 2020 to 10 April, 2020. The data including demographics, clinical symptoms, co-morbid diseases, laboratory, radiological findings as well as electrocardiographs of the patients were obtained from our records. Electrocardiograms were evaluated before, one day after and at the termination of the treatment. RESULTS: 21 patients aged 9 to 18 years were evaluated. The median age was 170 months (range 112-214), 51.1% of them were girls and 48.9% were boys. Their laboratory results did not reveal any abnormalities. None of them needed intensive care. We did not detect QT prolongation during or at the termination of the treatment. CONCLUSION: We did not detect QT prolongation during or at the termination of the treatment in our patients due to the fact that they were not severely affected by the disease. Patients were treated in our inpatient clinic and none of them required intensive care. Laboratory results were also insignificant. Furthermore, they did not need other medications.


Assuntos
Azitromicina , Infecções por Coronavirus/tratamento farmacológico , Eletrocardiografia/métodos , Hidroxicloroquina , Síndrome do QT Longo , Pneumonia Viral/tratamento farmacológico , Adolescente , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/efeitos adversos , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Criança , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/prevenção & controle , Masculino , Avaliação de Processos e Resultados em Cuidados de Saúde , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Estudos Retrospectivos , Turquia/epidemiologia
18.
Int J Clin Pharmacol Ther ; 58(9): 511-517, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32567546

RESUMO

A 66-year-old male patient presented with fever, headache, mental status changes, and nuchal rigidity with a lumbar puncture revealing neutropenic pleocytosis, and a presumptive diagnosis of bacterial meningitis was made. A careful history revealed that symptoms started within hours of starting oral trimethoprim-sulfamethoxazole. Additional history uncovered a nearly identical episode 1 year earlier after 1 dose of trimethoprim-sulfamethoxazole. All microbiologic diagnostic testing for meningitis was negative and all antimicrobials were discontinued. The patient had resolution of symptoms by 96 hours after last dose of trimethoprim-sulfamethoxazole and went on to full recovery. Based on history, clinical course, and a score of 7 on the Naranjo scale, he was diagnosed with recurrent trimethoprim-sulfamethoxazole-induced aseptic meningitis (TSIAM). This case illustrates the profound importance of thorough medication history and medication reconciliation.


Assuntos
Meningite Asséptica , Idoso , Anti-Infecciosos/efeitos adversos , Humanos , Masculino , Meningite Asséptica/induzido quimicamente , Meningite Asséptica/diagnóstico , Combinação Trimetoprima e Sulfametoxazol/efeitos adversos
19.
Clin Pharmacol Ther ; 108(5): 1090-1097, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32588427

RESUMO

Association between Hydroxychloroquine (HCQ) and Azithromycin (AZT) is under evaluation for patients with lower respiratory tract infection (LRTI) caused by the Severe Acute Respiratory Syndrome (SARS-CoV-2). Both drugs have a known torsadogenic potential, but sparse data are available concerning QT prolongation induced by this association. Our objective was to assess for COVID-19 LRTI variations of QT interval under HCQ/AZT in patients hospitalized, and to compare manual versus automated QT measurements. Before therapy initiation, a baseline 12 lead-ECG was electronically sent to our cardiology department for automated and manual QT analysis (Bazett and Fridericia's correction), repeated 2 days after initiation. According to our institutional protocol (Pasteur University Hospital), HCQ/AZT was initiated only if baseline QTc ≤ 480ms and potassium level> 4.0 mmol/L. From March 24th to April 20th 2020, 73 patients were included (mean age 62 ± 14 years, male 67%). Two patients out of 73 (2.7%) were not eligible for drug initiation (QTc ≥ 500 ms). Baseline average automated QTc was 415 ± 29 ms and lengthened to 438 ± 40 ms after 48 hours of combined therapy. The treatment had to be stopped because of significant QTc prolongation in two out of 71 patients (2.8%). No drug-induced life-threatening arrhythmia, nor death was observed. Automated QTc measurements revealed accurate in comparison with manual QTc measurements. In this specific population of inpatients with COVID-19 LRTI, HCQ/AZT could not be initiated or had to be interrupted in less than 6% of the cases.


Assuntos
Azitromicina , Infecções por Coronavirus , Monitoramento de Medicamentos , Eletrocardiografia/métodos , Hidroxicloroquina , Síndrome do QT Longo , Pandemias , Pneumonia Viral/tratamento farmacológico , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/farmacocinética , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Azitromicina/farmacocinética , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Precisão da Medição Dimensional , Monitoramento de Medicamentos/instrumentação , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/normas , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/farmacocinética , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Pneumonia Viral/diagnóstico , Pneumonia Viral/fisiopatologia , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/prevenção & controle
20.
Ann Am Thorac Soc ; 17(8): 1008-1015, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32425051

RESUMO

Coronavirus disease (COVID-19) is a potentially fatal illness with no proven therapy beyond excellent supportive care. Treatments are urgently sought. Adaptations to traditional trial logistics and design to allow rapid implementation, evaluation of trials within a global trials context, flexible interim monitoring, and access outside traditional research hospitals (even in settings where formal placebos are unavailable) may be helpful. Thoughtful adaptations to traditional trial designs, especially within the global context of related studies, may also foster collaborative relationships among government, community, and the research enterprise. Here, we describe the protocol for a pragmatic, active comparator trial in as many as 300 patients comparing two current "off-label" treatments for COVID-19-hydroxychloroquine and azithromycin-in academic and nonacademic hospitals in Utah. We developed the trial in response to local pressures for widespread, indiscriminate off-label use of these medications. We used a hybrid Bayesian-frequentist design for interim monitoring to allow rapid, contextual assessment of the available evidence. We also developed an inference grid for interpreting the range of possible results from this trial within the context of parallel trials and prepared for a network meta-analysis of the resulting data. This trial was prospectively registered (ClinicalTrials.gov Identifier: NCT04329832) before enrollment of the first patient.Clinical trial registered with www.clinicaltrials.gov (NCT04329832).


Assuntos
Azitromicina , Infecções por Coronavirus , Hidroxicloroquina , Pandemias , Pneumonia Viral , Adulto , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/efeitos adversos , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Masculino , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Utah
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