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Pacheco G, Lopes ALF, Oliveira APD, Corrêa WDRM, Lima LDB, Souza MHLPD, Teles AS, Nicolau LAD, Medeiros JVR. Comprehensive analysis of gastrointestinal side effects in COVID-19 patients undergoing combined pharmacological treatment with azithromycin and hydroxychloroquine: a systematic review and network meta-analysis. Crit Rev Toxicol 2024; 54:345-358. [PMID: 38860720 DOI: 10.1080/10408444.2024.2348169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 04/22/2024] [Indexed: 06/12/2024]
Abstract
During the COVID-19 pandemic, several drugs were repositioned and combined to quickly find a way to mitigate the effects of the infection. However, the adverse effects of these combinations on the gastrointestinal tract are unknown. We aimed investigate whether Hydroxychloroquine (HD), Azithromycin (AZ), and Ivermectin (IV) used in combination for the treatment of COVID-19, can lead to the development of gastrointestinal disorders. This is a systematic review and network meta-analysis conducted using Stata and Revman software, respectively. The protocol was registered with PROSPERO (CRD42023372802). A search of clinical trials in Cochrane Library databases, Embase, Web of Science, Lilacs, PubMed, Scopus and Clinicaltrials.gov conducted on November 26, 2023. The eligibility of the studies was assessed based on PICO criteria, including trials that compared different treatments and control group. The analysis of the quality of the evidence was carried out according to the GRADE. Six trials involving 1,686 COVID-19 patients were included. No trials on the association of HD or AZ with IV met the inclusion criteria, only studies on the association between HD and AZ were included. Nausea, vomiting, diarrhea, abdominal pain and increased transaminases were related. The symptoms of vomiting and nausea were evaluated through a network meta-analysis, while the symptom of abdominal pain was evaluated through a meta-analysis. No significant associations with these symptoms were observed for HD, AZ, or their combination, compared to control. Low heterogeneity and absence of inconsistency in indirect and direct comparisons were noted. Limitations included small sample sizes, varied drug dosages, and potential publication bias during the pandemic peak. This review unveils that there are no associations between gastrointestinal adverse effects and the combined treatment of HD with AZ in the management of COVID-19, as compared to either the use of a control group or the administration of the drugs individually, on the other hand, highlighting the very low or low certainty of evidence for the evaluated outcomes. To accurately conclude the absence of side effects, further high-quality randomized studies are needed.
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Affiliation(s)
- Gabriella Pacheco
- Medicinal Plants Research Center (NPPM), Post-graduation Program in Pharmacology, Federal University of Piauí, Teresina, PI, Brazil
| | - André Luis Fernandes Lopes
- Biotechnology and Biodiversity Research Center (BIOTEC), Post-graduation Program in Biotechnology, Parnaíba Delta Federal University (UFDPar), Parnaíba, PI, Brazil
| | | | | | - Lucas Daniel Batista Lima
- Biotechnology and Biodiversity Research Center (BIOTEC), Post-graduation Program in Biotechnology, Parnaíba Delta Federal University (UFDPar), Parnaíba, PI, Brazil
| | | | - Ariel Soares Teles
- Biotechnology and Biodiversity Research Center (BIOTEC), Post-graduation Program in Biotechnology, Parnaíba Delta Federal University (UFDPar), Parnaíba, PI, Brazil
- Federal Institute of Maranhão (IFMA), Araioses, MA, Brazil
| | - Lucas Antonio Duarte Nicolau
- Biotechnology and Biodiversity Research Center (BIOTEC), Post-graduation Program in Biotechnology, Parnaíba Delta Federal University (UFDPar), Parnaíba, PI, Brazil
| | - Jand Venes Rolim Medeiros
- Medicinal Plants Research Center (NPPM), Post-graduation Program in Pharmacology, Federal University of Piauí, Teresina, PI, Brazil
- Biotechnology and Biodiversity Research Center (BIOTEC), Post-graduation Program in Biotechnology, Parnaíba Delta Federal University (UFDPar), Parnaíba, PI, Brazil
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Velásquez PA, Hernandez JC, Galeano E, Hincapié-García J, Rugeles MT, Zapata-Builes W. Effectiveness of Drug Repurposing and Natural Products Against SARS-CoV-2: A Comprehensive Review. Clin Pharmacol 2024; 16:1-25. [PMID: 38197085 PMCID: PMC10773251 DOI: 10.2147/cpaa.s429064] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 11/14/2023] [Indexed: 01/11/2024] Open
Abstract
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a betacoronavirus responsible for the COVID-19 pandemic, causing respiratory disorders, and even death in some individuals, if not appropriately treated in time. To face the pandemic, preventive measures have been taken against contagions and the application of vaccines to prevent severe disease and death cases. For the COVID-19 treatment, antiviral, antiparasitic, anticoagulant and other drugs have been reused due to limited specific medicaments for the disease. Drug repurposing is an emerging strategy with therapies that have already tested safe in humans. One promising alternative for systematic experimental screening of a vast pool of compounds is computational drug repurposing (in silico assay). Using these tools, new uses for approved drugs such as chloroquine, hydroxychloroquine, ivermectin, zidovudine, ribavirin, lamivudine, remdesivir, lopinavir and tenofovir/emtricitabine have been conducted, showing effectiveness in vitro and in silico against SARS-CoV-2 and some of these, also in clinical trials. Additionally, therapeutic options have been sought in natural products (terpenoids, alkaloids, saponins and phenolics) with promising in vitro and in silico results for use in COVID-19 disease. Among these, the most studied are resveratrol, quercetin, hesperidin, curcumin, myricetin and betulinic acid, which were proposed as SARS-CoV-2 inhibitors. Among the drugs reused to control the SARS-CoV2, better results have been observed for remdesivir in hospitalized patients and outpatients. Regarding natural products, resveratrol, curcumin, and quercetin have demonstrated in vitro antiviral activity against SARS-CoV-2 and in vivo, a nebulized formulation has demonstrated to alleviate the respiratory symptoms of COVID-19. This review shows the evidence of drug repurposing efficacy and the potential use of natural products as a treatment for COVID-19. For this, a search was carried out in PubMed, SciELO and ScienceDirect databases for articles about drugs approved or under study and natural compounds recognized for their antiviral activity against SARS-CoV-2.
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Affiliation(s)
- Paula Andrea Velásquez
- Grupo Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín, Colombia
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellín, Colombia
| | - Juan C Hernandez
- Grupo Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín, Colombia
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellín, Colombia
| | - Elkin Galeano
- Grupo Productos Naturales Marinos, Departamento de Farmacia, Facultad de Ciencias Farmacéuticas y Alimentarias, Universidad de Antioquia UdeA, Medellín, Colombia
| | - Jaime Hincapié-García
- Grupo de investigación, Promoción y prevención farmacéutica, Facultad de Ciencias Farmacéuticas y Alimentarias, Universidad de Antioquia UdeA, Medellín, Colombia
| | - María Teresa Rugeles
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellín, Colombia
| | - Wildeman Zapata-Builes
- Grupo Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín, Colombia
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellín, Colombia
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Ceramella J, Iacopetta D, Sinicropi MS, Andreu I, Mariconda A, Saturnino C, Giuzio F, Longo P, Aquaro S, Catalano A. Drugs for COVID-19: An Update. Molecules 2022; 27:8562. [PMID: 36500655 PMCID: PMC9740261 DOI: 10.3390/molecules27238562] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/30/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the seventh known human coronavirus, and it was identified in Wuhan, Hubei province, China, in 2020. It caused the highly contagious disease called coronavirus disease 2019 (COVID-19), declared a global pandemic by the World Health Organization (WHO) on 11 March 2020. A great number of studies in the search of new therapies and vaccines have been carried out in these three long years, producing a series of successes; however, the need for more effective vaccines, therapies and other solutions is still being pursued. This review represents a tracking shot of the current pharmacological therapies used for the treatment of COVID-19.
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Affiliation(s)
- Jessica Ceramella
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, 87036 Rende, Italy
| | - Domenico Iacopetta
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, 87036 Rende, Italy
| | - Maria Stefania Sinicropi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, 87036 Rende, Italy
| | - Inmaculada Andreu
- Departamento de Química, Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain
- Unidad Mixta de Investigación UPV-IIS La Fe, Hospital Universitari i Politècnic La Fe, Avenida de Fernando Abril Martorell 106, 46026 Valencia, Spain
| | | | - Carmela Saturnino
- Department of Science, University of Basilicata, 85100 Potenza, Italy
| | - Federica Giuzio
- Department of Science, University of Basilicata, 85100 Potenza, Italy
| | - Pasquale Longo
- Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy
| | - Stefano Aquaro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, 87036 Rende, Italy
| | - Alessia Catalano
- Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70126 Bari, Italy
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Safety of Short-Term Treatments with Oral Chloroquine and Hydroxychloroquine in Patients with and without COVID-19: A Systematic Review. Pharmaceuticals (Basel) 2022; 15:ph15050634. [PMID: 35631460 PMCID: PMC9144263 DOI: 10.3390/ph15050634] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/27/2022] [Accepted: 05/13/2022] [Indexed: 01/09/2023] Open
Abstract
Chloroquine (CQ) and hydroxychloroquine (HCQ) have recently become the focus of global attention as possible treatments for Coronavirus Disease 2019 (COVID-19). The current systematic review aims to assess their safety in short treatments (≤14 days), whether used alone or in combination with other drugs. Following the PRISMA and SWiM recommendations, a search was conducted using four health databases for all relevant English-, Chinese-, and Spanish-language studies from inception through 30 July 2021. Patients treated for any condition and with any comparator were included. The outcomes of interest were early drug adverse effects and their frequency. A total of 254 articles met the inclusion criteria, including case and case-control reports as well as cross-sectional, cohort, and randomised studies. The results were summarised either qualitatively in table or narrative form or, when possible (99 studies), quantitatively in terms of adverse event frequencies. Quality evaluation was conducted using the CARE, STROBE, and JADAD tools. This systematic review showed that safety depended on drug indication. In COVID-19 patients, cardiac adverse effects, such as corrected QT interval prolongation, were relatively frequent (0–27.3% and up to 33% if combined with azithromycin), though the risk of torsade de pointes was low. Compared to non-COVID-19 patients, COVID-19 patients experienced a higher frequency of cardiac adverse effects regardless of the regimen used. Dermatological adverse effects affected 0–10% of patients with autoimmune diseases and COVID-19. A broad spectrum of neuropsychiatric adverse effects affected patients treated with CQ for malaria with variable frequencies and some cases were reported in COVID-19 patients. Gastrointestinal adverse effects occurred regardless of drug indication affecting 0–50% of patients. In conclusion, CQ and HCQ are two safe drugs widely used in the treatment of malaria and autoimmune diseases. However, recent findings on their cardiac and neuropsychiatric adverse effects should be considered if these drugs were to be proposed as antivirals again.
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Bajpai J, Pradhan A, Verma AK, Kant S. Use of hydroxychloroquine and azithromycin combination to treat the COVID-19 infection. World J Exp Med 2022; 12:44-52. [PMID: 35765514 PMCID: PMC9168786 DOI: 10.5493/wjem.v12.i3.44] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 01/24/2022] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) infection is unequivocally the worst crisis in recent decades, which is caused by a severe acute respiratory virus 2. Currently, there is no effective therapy for the COVID-19 infection. Different countries have different guidelines for treating COVID-19 in the absence of an approved therapy for COVID-19. Therefore, there is an imminent need to identify effective treatments, and several clinical trials have been conducted worldwide. Both hydroxychloroquine [HCQS], chloroquine, and azithromycin (AZ) have been widely used for management based on in vitro studies favoring antiviral effects against the COVID-19 virus. However, there is evidence both in favor and against the use of hydroxychloroquine and azithromycin (HCQS+AZ) combination therapy to manage the COVID-19 infection. The combination of hydroxychloroquine and azithromycin was significantly associated with increased adverse events. However, the inference of these findings was from observational studies. Therefore, large randomized trials are imperative to show the future path for the use of HCQS+AZ combination therapy. However, owing to the ban on HCQS use in COVID-19, this may no longer be essential. This review is on the pharmacology, trials, regimens, and side effects of hydroxychloroquine and azithromycin combination therapy.
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Affiliation(s)
- Jyoti Bajpai
- Department of Respiratory Medicine, King George's Medical University, Lukcnow, Lucknow 226003, Uttar Pradesh, India
| | - Akshyaya Pradhan
- Department of Cardiology, King George's Medical University, Lukcnow, Lucknow 226003, Uttar Pradesh, India
| | - Ajay Kumar Verma
- Department of Respiratory Medicine, King George's Medical University, Lukcnow, Lucknow 226003, Uttar Pradesh, India
| | - Surya Kant
- Department of Respiratory Medicine, King George Medical University, Lucknow 226003, Uttar Pradesh, India
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Deng J, Zhou F, Heybati K, Ali S, Zuo QK, Hou W, Dhivagaran T, Ramaraju HB, Chang O, Wong CY, Silver Z. Efficacy of chloroquine and hydroxychloroquine for the treatment of hospitalized COVID-19 patients: a meta-analysis. Future Virol 2021; 17:10.2217/fvl-2021-0119. [PMID: 34887938 PMCID: PMC8647998 DOI: 10.2217/fvl-2021-0119] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 11/11/2021] [Indexed: 02/06/2023]
Abstract
Aims: To evaluate the efficacy and safety of hydroxychloroquine/chloroquine, with or without azithromycin, in treating hospitalized COVID-19 patients. Materials & methods: Data from randomized and observational studies were included in a random-effects meta-analysis. Primary outcomes included time to negative conversion of SARS-CoV-2 tests, length of stay, mortality, incidence of mechanical ventilation, time to normalization of body temperature, incidence of adverse events and incidence of QT prolongations. Results: Fifty-one studies (n = 61,221) were included. Hydroxychloroquine/chloroquine showed no efficacy in all primary efficacy outcomes, but was associated with increased odds of QT prolongations. Conclusion: Due to a lack of efficacy and increased odds of cardiac adverse events, hydroxychloroquine/chloroquine should not be used for treating hospitalized COVID-19 patients.
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Affiliation(s)
- Jiawen Deng
- Faculty of Health Sciences, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada
| | - Fangwen Zhou
- Faculty of Health Sciences, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada
| | - Kiyan Heybati
- Faculty of Health Sciences, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada
- Mayo Clinic Alix School of Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA
| | - Saif Ali
- Faculty of Health Sciences, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada
| | - Qi Kang Zuo
- Department of Anesthesiology, Rutgers, New Jersey Medical School, 185 S Orange Ave, Newark, NJ 07103, USA
- Faculty of Science, McGill University, 845 Sherbrooke St W, Montreal, QC, H3A 0G5, Canada
| | - Wenteng Hou
- Faculty of Health Sciences, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada
| | - Thanansayan Dhivagaran
- Faculty of Health Sciences, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada
- Integrated Biomedical Engineering & Health Sciences Program (iBioMed), McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada
| | | | - Oswin Chang
- Faculty of Health Sciences, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada
| | - Chi Yi Wong
- Faculty of Health Sciences, McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada
| | - Zachary Silver
- Faculty of Science, Carleton University, 1125 Colonel By Dr, Ottawa, ON, K1S 5B6, Canada
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Di Castelnuovo A, Costanzo S, Cassone A, Cauda R, De Gaetano G, Iacoviello L. Hydroxychloroquine and mortality in COVID-19 patients: a systematic review and a meta-analysis of observational studies and randomized controlled trials. Pathog Glob Health 2021; 115:456-466. [PMID: 34128772 PMCID: PMC8220439 DOI: 10.1080/20477724.2021.1936818] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Background: Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19, but its association with mortality is unclear. We reviewed published literature for evidence of an association between HCQ (with or without azithromycin (AZM)) and total mortality in COVID-19 patients.Methods: Articles were retrieved until April 29th, 2021 by searching in seven databases. Data were combined using the general-variance-based method.Results: A total of 25 cohort studies (N=41,339 patients) and 11 randomized clinical trials (RCTs; N=8,709) were found. The use of HCQ was not associated with mortality in meta-analysis of RCTs (pooled risk ratio (PRR): 1.08, 95%CI: 0.97-1.20; I2=0%), but it was associated with 20% lower mortality risk (PRR=0.80, 95%CI: 0.69-0.93; I2=80%) in pooling of cohort studies. The negative association with mortality was mainly apparent by pooling cohort studies that used lower doses of HCQ (≤400 mg/day; PRR=0.69, 95%CI: 0.57-0.87). Use of HCQ+AZM (11 studies) was associated with 25% non-statistically significant lower mortality risk (PPR=0.75; 0.51-1.10; P=0.15). Use of HCQ was not associated with severe adverse events (PRR=1.12, 95%CI: 0.88-1.44; I2=0%).Conclusions: HCQ use was not associated with mortality in COVID-19 patients in pooling results from RCTs (high level of certainty of evidence), but it was associated with 20% mortality reduction when findings from observational studies were combined (low level of certainty of evidence). The reduction of mortality was mainly apparent in observational studies where lower doses of HCQ were used. These findings might help disentangling the debate on HCQ use in COVID-19.
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Affiliation(s)
| | - Simona Costanzo
- Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli (IS), Italy
| | - Antonio Cassone
- Polo Della Genomica, Genetica E Biologia, Università Di Siena, Siena, Italy
| | - Roberto Cauda
- Fondazione Policlinico Universitario A. Gemelli IRCCS Università Cattolica S. Cuore Roma, Italy
| | - Giovanni De Gaetano
- Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli (IS), Italy
| | - Licia Iacoviello
- Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli (IS), Italy
- Research Centre in Epidemiology and Preventive Medicine (EPIMED), Department of Medicine and Surgery, University of Insubria, Varese, Italy
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da Silva JC, Félix VB, Leão SABF, Trindade-Filho EM, Scorza FA. New Brazilian variant of the SARS-CoV-2 (P1/Gamma) of COVID-19 in Alagoas state. Braz J Infect Dis 2021; 25:101588. [PMID: 34102147 PMCID: PMC8133383 DOI: 10.1016/j.bjid.2021.101588] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/29/2021] [Accepted: 05/05/2021] [Indexed: 02/09/2023] Open
Abstract
Since the beginning of 2020, health authorities have been monitoring the cases of Coronavirus Disease 2019 (COVID-19), which has grown every day in Brazil and around the world, becoming pandemic. The new coronavirus, also called SARS-CoV-2 by scientists spreads rapidly, causing fear, deaths, and threats for the economy of several countries. This work aimed to describe the clinical characterization of the first cases of a new Brazilian variant of SARS-CoV-2 (P1) in the State of Alagoas, which occurred on February 16th, 2021. Two cases are described: first, a person infected in Amazonas State, where the new variant P1 was first described, who migrated to Alagoas State, and second, a case of probable community transmission within Alagoas, since the patient had no history of recent travel. In both confirmed cases the symptoms were mild. Further studies are necessary to better understand the clinical behavior of P1 SARS-CoV-2 variant and also the associated sequelae in the context of COVID-19.
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Affiliation(s)
- José Claudio da Silva
- Centro Universitário CESMAC, Maceió, Alagoas, Brasil; Laboratório de Neurociência e comportamento, Núcleo de Ciências Biológicas, Universidade Estadual de Ciências da Saúde de Alagoas (NUCIB-UNCISAL), Maceió, AL, Brasil; Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo (EPM/UNIFESP), Escola Paulista de Medicina, São Paulo, SP, Brasil.
| | - Valtuir Barbosa Félix
- Centro Universitário CESMAC, Maceió, Alagoas, Brasil; Universidade Federal de Alagoas (HUPAA/UFAL/EBSERH), Divisão de apoio e diagnóstico terapêutico do Hospital Universitário, Maceió, AL, Brasil
| | | | - Euclides Maurício Trindade-Filho
- Centro Universitário CESMAC, Maceió, Alagoas, Brasil; Laboratório de Neurociência e comportamento, Núcleo de Ciências Biológicas, Universidade Estadual de Ciências da Saúde de Alagoas (NUCIB-UNCISAL), Maceió, AL, Brasil
| | - Fulvio Alexandre Scorza
- Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo (EPM/UNIFESP), Escola Paulista de Medicina, São Paulo, SP, Brasil
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