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1.
JAMA ; 328(5): 460-471, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35916842

RESUMO

Importance: Malaria is caused by protozoa parasites of the genus Plasmodium and is diagnosed in approximately 2000 people in the US each year who have returned from visiting regions with endemic malaria. The mortality rate from malaria is approximately 0.3% in the US and 0.26% worldwide. Observations: In the US, most malaria is diagnosed in people who traveled to an endemic region. More than 80% of people diagnosed with malaria in the US acquired the infection in Africa. Of the approximately 2000 people diagnosed with malaria in the US in 2017, an estimated 82.4% were adults and about 78.6% were Black or African American. Among US residents diagnosed with malaria, 71.7% had not taken malaria chemoprophylaxis during travel. In 2017 in the US, P falciparum was the species diagnosed in approximately 79% of patients, whereas P vivax was diagnosed in an estimated 11.2% of patients. In 2017 in the US, severe malaria, defined as vital organ involvement including shock, pulmonary edema, significant bleeding, seizures, impaired consciousness, and laboratory abnormalities such as kidney impairment, acidosis, anemia, or high parasitemia, occurred in approximately 14% of patients, and an estimated 0.3% of those receiving a diagnosis of malaria in the US died. P falciparum has developed resistance to chloroquine in most regions of the world, including Africa. First-line therapy for P falciparum malaria in the US is combination therapy that includes artemisinin. If P falciparum was acquired in a known chloroquine-sensitive region such as Haiti, chloroquine remains an alternative option. When artemisinin-based combination therapies are not available, atovaquone-proguanil or quinine plus clindamycin is used for chloroquine-resistant malaria. P vivax, P ovale, P malariae, and P knowlesi are typically chloroquine sensitive, and treatment with either artemisinin-based combination therapy or chloroquine for regions with chloroquine-susceptible infections for uncomplicated malaria is recommended. For severe malaria, intravenous artesunate is first-line therapy. Treatment of mild malaria due to a chloroquine-resistant parasite consists of a combination therapy that includes artemisinin or chloroquine for chloroquine-sensitive malaria. P vivax and P ovale require additional therapy with an 8-aminoquinoline to eradicate the liver stage. Several options exist for chemoprophylaxis and selection should be based on patient characteristics and preferences. Conclusions and Relevance: Approximately 2000 cases of malaria are diagnosed each year in the US, most commonly in travelers returning from visiting endemic areas. Prevention and treatment of malaria depend on the species and the drug sensitivity of parasites from the region of acquisition. Intravenous artesunate is first-line therapy for severe malaria.


Assuntos
Antimaláricos , Resistência a Medicamentos , Malária , Doença Relacionada a Viagens , Adulto , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Artemisininas/efeitos adversos , Artemisininas/uso terapêutico , Artesunato/efeitos adversos , Artesunato/uso terapêutico , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Humanos , Malária/diagnóstico , Malária/tratamento farmacológico , Malária/epidemiologia , Malária/prevenção & controle , Malária Falciparum/diagnóstico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Viagem/estatística & dados numéricos , Estados Unidos/epidemiologia
2.
Folia Med (Plovdiv) ; 64(1): 169-175, 2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35851897

RESUMO

Stevens-Johnson syndrome (SJS) is a rare medical condition with severe mucocutaneous reaction due to infection or adverse drug reaction. The present case reports the impact of chloroquine-induced SJS on the tooth root development. A 20-year-old Indian male reported to conservative dentistry and endodontics speciality clinic with the chief complaint of food lodgement and sensitivity in maxillary and mandibular posterior teeth. He had a past medical history of severe cutaneous reaction after taking Tab. Lariago (chloroquine) for treatment of malarial fever at the age of 8 years. The acute inflammatory immune response was managed by hospitalization and administration of steroids and anti-inflammatory drugs. Clinical examination revealed dry mucosa, carious teeth with adequate oral hygiene. Panoramic X-ray showed multiple teeth with short roots. A detailed cone beam computed tomographic scan (CBCT) demonstrated a healthy bone trabecular pattern with the absence of any periapical radiolucency. Short, blunt roots with immature apex were seen in many teeth. Based upon the measurement of root to the crown ratio on the CBCT scan and correlating the development status of teeth with the medical history, a diagnosis of short root anomaly (SRA) after chloroquine-induced SJS was made. This is the first report to describe the three-dimensional features of teeth with SRA in a patient with SJS. Diagnostic, restorative, and endodontic implications of SJS are highlighted.


Assuntos
Síndrome de Stevens-Johnson , Adulto , Criança , Cloroquina/efeitos adversos , Tomografia Computadorizada de Feixe Cônico/métodos , Humanos , Masculino , Síndrome de Stevens-Johnson/diagnóstico por imagem , Síndrome de Stevens-Johnson/etiologia , Ápice Dentário , Raiz Dentária/diagnóstico por imagem , Adulto Jovem
4.
Infect Dis Poverty ; 11(1): 43, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35462549

RESUMO

BACKGROUND: Plasmodium vivax remains the predominant species at the China-Myanmar border, imposing a major challenge to the recent gains in regional malaria elimination. To closely supervise the emerging of drug resistance in this area, we surveyed the variations in genes potentially correlated with drug resistance in P. vivax parasite and the possible drug selection with time. METHODS: A total of 235 P. vivax samples were collected from patients suffering uncomplicated malaria at Yingjiang, Tengchong, and Longling counties, and Nabang port in China, Yunnan province, and Laiza sub-township in Myanmar, from 2008 to 2017. Five potential drug resistance genes were amplified utilizing nested-PCR and analyzed, including pvdhfr, pvdhps, pvmdr1, pvcrt-o, and pvk12. The Pearson's Chi-squared test or Fisher's exact test were applied to determine the statistical frequency differences of mutations between categorical data. RESULTS: The pvdhfr F57I/L, S58R, T61M and S117T/N presented in 40.6%, 56.7%, 40.1%, and 56.0% of the sequenced P. vivax isolates, and these mutations significantly decreased with years. The haplotype formed by these quadruple mutations predominated in Yingjiang, Tengchong, Longling and Nabang. While a mutation H99S/R (56.6%) dominated in Laiza and increased with time. In pvdhps, the A383G prevailed in 69.2% of the samples, which remained the most prevalent haplotype. However, a significant decrease of its occurrence was also noticed over the time. The S382A/C and A553G existed in 8.4% and 30.8% of the isolates, respectively. In pvmdr1, the mutation Y976F occurred at a low frequency in 5/232 (2.2%), while T958M was fixed and F1076L was approaching fixed (72.4%). The K10 insertion was detected at an occurrence of 33.2% in pvcrt-o, whereas there was no significant difference among the sites or over the time. No mutation was identified in pvk12. CONCLUSIONS: Mutations related with resistance to antifolate drugs are prevalent in this area, while their frequencies decrease significantly with time, suggestive of increased susceptibility of P. vivax parasite to antifolate drugs. Resistance to chloroquine (CQ) is possibly emerging. However, since the molecular mechanisms underneath CQ resistance is yet to be better understood, close supervision of clinical drug efficiency and continuous function investigation is urgently needed to alarm drug resistance.


Assuntos
Antimaláricos , Resistência a Medicamentos , Malária Vivax , Plasmodium vivax , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Biomarcadores/análise , Biomarcadores/sangue , China/epidemiologia , Cloroquina/efeitos adversos , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Resistência a Medicamentos/genética , Antagonistas do Ácido Fólico/efeitos adversos , Antagonistas do Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Malária Vivax/tratamento farmacológico , Malária Vivax/genética , Malária Vivax/parasitologia , Mutação , Mianmar/epidemiologia , Plasmodium vivax/genética , Plasmodium vivax/metabolismo , Polimorfismo Genético , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo
6.
Rheumatol Int ; 42(10): 1767-1774, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35430712

RESUMO

COVID-19 raised concern regarding cardiotoxicity and QTc prolongation of hydroxychloroquine (HCQ) and chloroquine (CQ). We examined the frequency and patient factors associated with ECG testing and the detection of prolonged QTc among new HCQ/CQ users in a large academic medical system. 10,248 subjects with a first HCQ/CQ prescription (1/2015-3/2020) were included. We assessed baseline (1 year prior to and including day of initiation of HCQ/CQ through 2 months after initial HCQ/CQ prescription) and follow-up (10 months after the baseline period) patient characteristics and ECGs obtained from electronic health records. Among 8384 female HCQ/CQ new users, ECGs were obtained for 22.3%, 14.3%, and 7.6%, at baseline, follow, and both periods, respectively. Among 1864 male HCQ/CQ new users, ECGs were obtained more frequently at baseline (29.7%), follow-up (18.0%), and both periods (11.3%). Female HCQ/CQ users with a normal QTc at baseline but prolonged QTc (> 470 ms) at follow-up (13.1%) were older at HCQ/CQ initiation [mean 64.7 (SD 16.5) vs. 58.7 (SD 16.9) years, p = 0.004] and more likely to have history of myocardial infarction (41.0% vs. 21.6%, p = 0.0003) compared to those who had normal baseline and follow-up QTc. The frequency of prolonged QTc development was similar (12.4%) among male HCQ/CQ new users (> 450 ms). Prior to COVID-19, ECG testing before and after HCQ/CQ prescription was infrequent, particularly for females who are disproportionately affected by rheumatic diseases and were just as likely to develop prolonged QTc (> 1/10 new users). Prospective studies are needed to guide future management of HCQ/CQ therapy in rheumatic populations.


Assuntos
COVID-19 , Hidroxicloroquina , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Cloroquina/efeitos adversos , Eletrocardiografia , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Masculino , Prevalência , SARS-CoV-2 , Centros de Atenção Terciária
7.
Int J Infect Dis ; 118: 224-229, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35227869

RESUMO

OBJECTIVES: Our study aimed to assess the statistical relationship between the use of chloroquine phosphate or hydroxychloroquine plus azithromycin (CQ/HCQ + AZ) and virological recovery, disease worsening, and death among out- and inpatients with COVID-19 in Burkina Faso. METHODS AND DESIGNS: This was a retrospective observational study that compared outcomes in terms of time to recovery, worsening, and death in patients who received CQ/HCQ + AZ and those who did not using a multivariable Cox or Poisson model before and after propensity matching. RESULTS: Of the 863 patients included in the study, about 50% (432/863) were home-based follow-up patients and 50% were inpatients. Of these, 83.3% (746/863) received at least 1 dose of CQ/HCQ + AZ and 13.7% (118/863) did not. There were no significant differences in associated time to recovery for patients receiving any CQ/HCQ + AZ (adjusted HR 1.44; 95% CI 0.76-2.71). Similarly, there was no significant association between CQ/HCQ + AZ use and worsening (adjusted IRR 0.80; 95% CI 0.50-1.50). However, compared with the untreated group, the treated group had a lower risk of death (adjusted HR 0.20; 95% CI 0.10-0.44). CONCLUSIONS: The study provided valuable additional information on the use of CQ/HCQ in patients with COVID-19 and did not show any harmful outcomes of CQ/HCQ + AZ treatment.


Assuntos
COVID-19 , Hidroxicloroquina , Antivirais/uso terapêutico , Azitromicina/efeitos adversos , Burkina Faso/epidemiologia , COVID-19/tratamento farmacológico , Cloroquina/efeitos adversos , Humanos , Hidroxicloroquina/uso terapêutico , Pacientes Internados , Pacientes Ambulatoriais , SARS-CoV-2
8.
Medicine (Baltimore) ; 101(11)2022 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35356915

RESUMO

BACKGROUND: Chloroquine and hydroxychloroquine are 2 medications used to treat some systemic diseases. OBJECTIVE: The aim of this scoping review was to assess the occurrence of oral pigmentation induced by chloroquine or hydroxychloroquine and to understand the pathogenic mechanism behind this phenomenon. METHODS: The review was performed according to the list of PRISMA SrC recommendations and the JBI Manual for Evidence Synthesis for Scoping Reviews. MEDLINE (PubMed), Scopus, EMBASE, SciELO, Web of Science, Lilacs, and LIVIVO were primary sources, and "gray literature" was searched in OpenThesis and Open Access Thesis and Dissertations (OATD). Studies that screened the occurrence of oral pigmentation associated to the use of chloroquine or hydroxychloroquine were considered eligible. No restrictions of year and language of publication were applied. Study selection and data extraction were performed by 2 independent reviewers. The risk of bias was assessed through the JBI tool, depending on the design of the selected studies. RESULTS: The initial search resulted in 2238 studies, of which 19 were eligible. Sixteen studies were case reports, 2 had case-control design and 1 was cross-sectional. Throughout the studies, 44 cases of oral pigmentation were reported. The hard palate was the anatomic region most affected with pigmentation (66%). According to the case reports, most of the lesions (44%) were bluish-gray. The minimum time from the beginning of treatment (chloroquine or hydroxychloroquine) to the occurrence of pigmentation was 6 months. The mean treatment time with the medications was 4.9 years, and the mean drug dosage was 244 mg. Most of the studies (63.1%) had low risk of bias (high methodological quality). CONCLUSIONS: The outcomes of this study suggest that hyperpigmentation depend on drug dosage and treatment length. Hyperpigmentation was detected after a long period of treatment with chloroquine or hydroxychloroquine.


Assuntos
Hidroxicloroquina , Hiperpigmentação , Cloroquina/efeitos adversos , Estudos Transversais , Humanos , Hidroxicloroquina/uso terapêutico , Hiperpigmentação/tratamento farmacológico , Pigmentação
9.
N Engl J Med ; 386(13): 1244-1253, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35353962

RESUMO

BACKGROUND: In most of the Americas, the recommended treatment to prevent relapse of Plasmodium vivax malaria is primaquine at a total dose of 3.5 mg per kilogram of body weight, despite evidence of only moderate efficacy. METHODS: In this trial conducted in Brazil, we evaluated three primaquine regimens to prevent relapse of P. vivax malaria in children at least 5 years of age and in adults with microscopy-confirmed P. vivax monoinfection. All the patients received directly observed chloroquine for 3 days (total dose, 25 mg per kilogram). Group 1 received a total primaquine dose of 3.5 mg per kilogram (0.5 mg per kilogram per day) over 7 days with unobserved administration; group 2 received the same regimen as group 1 but with observed administration; and group 3 received a total primaquine dose of 7.0 mg per kilogram over 14 days (also 0.5 mg per kilogram per day) with observed administration. We monitored the patients for 168 days. RESULTS: We enrolled 63 patients in group 1, 96 in group 2, and 95 in group 3. The median age of the patients was 22.4 years (range, 5.4 to 79.8). By day 28, three P. vivax recurrences were observed: 2 in group 1 and 1 in group 2. By day 168, a total of 70 recurrences had occurred: 24 in group 1, 34 in group 2, and 12 in group 3. No serious adverse events were noted. On day 168, the percentage of patients without recurrence was 58% (95% confidence interval [CI], 44 to 70) in group 1, 59% (95% CI, 47 to 69) in group 2, and 86% (95% CI, 76 to 92) in group 3. Survival analysis showed a difference in the day 168 recurrence-free percentage of 27 percentage points (97.5% CI, 10 to 44; P<0.001) between group 1 and group 3 and a difference of 27 percentage points (97.5% CI, 12 to 42; P<0.001) between group 2 and group 3. CONCLUSIONS: The administration of primaquine at a total dose of 7.0 mg per kilogram had higher efficacy in preventing relapse of P. vivax malaria than a total dose of 3.5 mg per kilogram through day 168. (Supported by the U.S. Agency for International Development; ClinicalTrials.gov number, NCT03610399.).


Assuntos
Antimaláricos , Cloroquina , Malária Vivax , Primaquina , Adolescente , Adulto , Idoso , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Brasil , Criança , Pré-Escolar , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Terapia Diretamente Observada , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Malária Vivax/tratamento farmacológico , Malária Vivax/prevenção & controle , Pessoa de Meia-Idade , Primaquina/administração & dosagem , Primaquina/efeitos adversos , Primaquina/uso terapêutico , Recidiva , Prevenção Secundária , Adulto Jovem
10.
Am J Trop Med Hyg ; 106(3): 831-840, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35008062

RESUMO

Plasmodium vivax malaria elimination requires radical cure with chloroquine/primaquine. However, primaquine causes hemolysis in glucose-6-phosphate dehydrogenase-deficient (G6PDd) individuals. Between February 2016 and July 2017 in Odisha State, India, a prospective, observational, active pharmacovigilance study assessed the hematologic safety of directly observed 25 mg/kg chloroquine over 3 days plus primaquine 0.25 mg/kg/day for 14 days in 100 P. vivax patients (≥ 1 year old) with hemoglobin (Hb) ≥ 7 g/dL. Pretreatment G6PDd screening was not done, but patients were advised on hemolysis signs and symptoms using a visual aid. For evaluable patients, the mean absolute change in Hb between day 0 and day 7 was -0.62 g/dL (95% confidence interval [CI]: -0.93, -0.31) for males (N = 53) versus -0.24 g/dL (95%CI: -0.59, 0.10) for females (N = 45; P = 0.034). Hemoglobin declines ≥ 3 g/dL occurred in 5/99 (5.1%) patients (three males, two females); none had concurrent clinical symptoms of hemolysis. Based on G6PD qualitative testing after study completion, three had a G6PD-normal phenotype, one female was confirmed by genotyping as G6PDd heterozygous, and one male had an unknown phenotype. A G6PDd prevalence survey was conducted between August 2017 and March 2018 in the same region using qualitative G6PD testing, confirmed by genotyping. G6PDd prevalence was 12.0% (14/117) in tribal versus 3.1% (16/509) in nontribal populations, with G6PD Orissa identified in 29/30 (96.7%) of G6PDd samples. Following chloroquine/primaquine, notable Hb declines were observed in this population that were not recognized by patients based on clinical signs and symptoms.


Assuntos
Antimaláricos , Deficiência de Glucosefosfato Desidrogenase , Malária Vivax , Antimaláricos/efeitos adversos , Cloroquina/efeitos adversos , Feminino , Deficiência de Glucosefosfato Desidrogenase/genética , Hemoglobinas , Hemólise , Humanos , Malária Vivax/epidemiologia , Masculino , Farmacovigilância , Plasmodium vivax , Primaquina/efeitos adversos , Estudos Prospectivos
11.
Eur J Clin Pharmacol ; 78(5): 733-753, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35088108

RESUMO

PURPOSE: The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has affected millions all over the world and has been declared pandemic, as of 11 March 2020. In addition to the ongoing research and development of vaccines, there is still a dire need for safe and effective drugs for the control and treatment against the SARS-CoV-2 virus infection. Numerous repurposed drugs are under clinical investigations whose reported adverse events can raise worries about their safety. The aim of this review is to illuminate the associated adverse events related to the drugs used in a real COVID-19 setting along with their relevant mechanism(s). METHOD: Through a literature search conducted on PubMed and Google Scholar database, various adverse events suspected to be induced by eight drugs, including dexamethasone, hydroxychloroquine, chloroquine, remdesivir, favipiravir, lopinavir/ritonavir, ivermectin, and tocilizumab, administered in COVID-19 patients in clinical practice and studies were identified in 30 case reports, 3 case series, and 10 randomized clinical trials. RESULTS: Mild, moderate, or severe adverse events of numerous repurposed and investigational drugs caused by various factors and mechanisms were observed. Gastrointestinal side effects such as nausea, abdominal cramps, diarrhea, and vomiting were the most frequently followed by cardiovascular, cutaneous, and hepatic adverse events. Few other rare adverse drug reactions were also observed. CONCLUSION: In light of their ineffectiveness against COVID-19 as evident in large clinical studies, drugs including hydroxychloroquine, lopinavir/ritonavir, and ivermectin should neither be used routinely nor in clinical studies. While lack of sufficient data, it creates doubt regarding the reliability of chloroquine and favipiravir use in COVID-19 patients. Hence, these two drugs can only be used in clinical studies. In contrast, ample well-conducted studies have approved the use of remdesivir, tocilizumab, and dexamethasone under certain conditions in COVID-19 patients. Consequently, it is significant to establish a strong surveillance system in order to monitor the proper safety and toxicity profile of the potential anti-COVID-19 drugs with good clinical outcomes.


Assuntos
COVID-19 , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , Cloroquina/efeitos adversos , Dexametasona/efeitos adversos , Humanos , Hidroxicloroquina/efeitos adversos , Ivermectina/uso terapêutico , Lopinavir/efeitos adversos , Reprodutibilidade dos Testes , Ritonavir/farmacologia , SARS-CoV-2
12.
Lupus ; 31(2): 238-245, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35041536

RESUMO

OBJECTIVE: To estimate the risk ratio (RR) of thromboembolic events in chloroquine and hydroxychloroquine users compared to non-users. METHODS: We systematically reviewed randomized controlled trials (RCTs), using MEDLINE and EMBASE databases from inception to the present, reporting thromboembolic events in chloroquine and hydroxychloroquine users compared to non-users. Four authors independently screened all the records obtained through our search strategy and later revised the selected full-text articles for eligibility, according to our inclusion criteria. The same four authors independently extracted relevant data through a customized data collection form while two other authors assessed the quality of the included RCTs using the Cochrane risk-of-bias tool (Version 2.0). All the disagreements were resolved through discussions among the authors. We calculated the risk ratio (RR) and its respective standard error of developing thromboembolic events in hydroxychloroquine users and non-users for each individual study and pooled the results using a random effects model meta-analysis. We assessed Heterogeneity using the Tau2 and I2, and publication bias using funnel plotting and Egger's regression. The protocol for this systematic review is registered at the PROSPERO database (CRD42021247902). RESULTS: Thirteen RCTs met our eligibility criteria and were included in our analysis (2663 patients). We found that hydroxychloroquine-no study on chloroquine was found-reduced the risk of thromboembolic events by 49% (RR 0.51[IC 95% 0.31-0.84]) with a medium heterogeneity (I2 = 67% and T2 = 0.4948). We did find some asymmetry in the inspection of the funnel plot, which was ruled out through an Egger's regression (p-value = 0.1025). CONCLUSION: Our data reinforce the idea that hydroxychloroquine reduces the risk of thromboembolic events.


Assuntos
Hidroxicloroquina , Lúpus Eritematoso Sistêmico , Cloroquina/efeitos adversos , Humanos , Hidroxicloroquina/efeitos adversos
13.
Br J Pharmacol ; 179(11): 2631-2646, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34837219

RESUMO

BACKGROUND AND PURPOSE: Hydroxychloroquine, chloroquine and azithromycin are three drugs that were proposed to treat coronavirus disease 2019 (COVID-19). While concern already existed around their proarrhythmic potential, there are little data regarding how altered physiological states encountered in patients such as febrile state, electrolyte imbalances or acidosis might change their risk profiles. EXPERIMENTAL APPROACH: Potency of human ether-à-go-go related gene (hERG) block was measured using high-throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell-derived cardiomyocytes from multiple individuals. KEY RESULTS: Chloroquine and hydroxychloroquine blocked hERG with IC50 of 1.47 ± 0.07 and 3.78 ± 0.17 µM, respectively, indicating proarrhythmic risk at concentrations effective against severe acute respiratory syndrome-coronovirus-2 (SARS-CoV-2) in vitro. Hypokalaemia and hypermagnesaemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs, whereas increased temperature decreased potency of chloroquine and hydroxychloroquine against hERG but increased potency for azithromycin. In silico simulations demonstrated that proarrhythmic risk was increased by female sex, hypokalaemia and heart failure and identified specific genetic backgrounds associated with emergence of arrhythmia. CONCLUSION AND IMPLICATIONS: Our study demonstrates how proarrhythmic risk can be exacerbated by metabolic changes and pre-existing disease. More broadly, the study acts as a blueprint for how high-throughput in vitro screening, combined with in silico simulations, can help guide both preclinical screening and clinical management of patients in relation to drugs with potential to prolong repolarisation.


Assuntos
Acidose , COVID-19 , Hipopotassemia , Células-Tronco Pluripotentes Induzidas , Acidose/induzido quimicamente , Acidose/tratamento farmacológico , Azitromicina/efeitos adversos , COVID-19/tratamento farmacológico , Cloroquina/efeitos adversos , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Hipopotassemia/induzido quimicamente , SARS-CoV-2
14.
Syst Rev ; 10(1): 294, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34736537

RESUMO

BACKGROUND: Despite the expectations regarding the effectiveness of chloroquine (CQ) and hydroxychloroquine (HCQ) for coronavirus disease (COVID-19) management, concerns about their adverse events have remained. OBJECTIVES: The objective of this systematic review was to evaluate the safety of CQ and HCQ from malarial and non-malarial randomized clinical trials (RCTs). METHODS: The primary outcomes were the frequencies of serious adverse events (SAEs), retinopathy, and cardiac complications. Search strategies were applied to MEDLINE, EMBASE, LILACS, CENTRAL, Scopus, and Trip databases. We used a random-effects model to pool results across studies and Peto's one-step odds ratio (OR) for event rates below 1%. Both-armed zero-event studies were excluded from the meta-analyses. We used the Grading of Recommendations Assessment, Development, and Evaluation system to evaluate the certainty of evidence. RESULTS: One hundred and six RCTs were included. We found no significant difference between CQ/HCQ and control (placebo or non-CQ/HCQ) in the frequency of SAEs (OR: 0.98, 95% confidence interval [CI]: 0.76-1.26, 33 trials, 15,942 participants, moderate certainty of evidence). However, there was a moderate certainty of evidence that CQ/HCQ increases the incidence of cardiac complications (RR: 1.62, 95% CI: 1.10-2.38, 16 trials, 9908 participants). No clear relationship was observed between CQ/HCQ and retinopathy (OR: 1.63, 95% CI: - 0.4-6.57, 5 trials, 344 participants, very low certainty of evidence). CONCLUSIONS: CQ and HCQ probably do not increase SAEs, with low frequency of these adverse events on malarial and non-malarial conditions. However, they may increase cardiac complications especially in patients with COVID-19. No clear effect of their use on the incidence of retinopathy was observed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020177818.


Assuntos
COVID-19 , Hidroxicloroquina , COVID-19/tratamento farmacológico , Cloroquina/efeitos adversos , Humanos , Hidroxicloroquina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2
15.
Eur Rev Med Pharmacol Sci ; 25(19): 6003-6012, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34661260

RESUMO

OBJECTIVE: The present study aims to identify potential safety signals of chloroquine (CQ) and hydroxychloroquine (HCQ), over the period preceding their repurpose as COVID-19 treatment options, through the analysis of safety data retrieved from the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database. MATERIALS AND METHODS: We performed a disproportionality analysis of FAERS data between the first quarter of 2004 and December 2019 using the OpenVigil2.1-MedDRA software. Disproportionality was quantified using the reporting odds ratio (ROR) and its 95% confidence interval (CIs). The reported mortality of CQ and HCQ was also investigated. RESULTS: The dataset contained 6,635,356 reports. Comparison of the RORs revealed significant differences between CQ and HCQ for the following adverse events: cardiomyopathy, cardiac arrhythmias, retinal disorders, corneal disorders, hearing disorders, headache, hepatic disorders, severe cutaneous reactions, musculoskeletal disorders, and cytopenia. Only CQ was associated with psychotic disorders, suicide, self-injury, convulsions, peripheral neuropathy, and decreased appetite. In multivariable logistic regression, death was more frequently associated with CQ use, advanced age, male sex, co-reported suicide and self-injury, cardiomyopathy, cardiac arrhythmias, and decreased appetite. CONCLUSIONS: Our results confirm previously published evidence and suggest that HCQ has a safer clinical profile compared to CQ, and thus could serve as the drug of choice for future therapeutic purposes.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Cloroquina/efeitos adversos , Hidroxicloroquina/efeitos adversos , United States Food and Drug Administration , COVID-19/tratamento farmacológico , Intervalos de Confiança , Bases de Dados Factuais , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Farmacovigilância , Suicídio , Estados Unidos
16.
Arthritis Rheumatol ; 73(12): 2151-2160, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34697918

RESUMO

Hydroxychloroquine (HCQ) and chloroquine (CQ) are well-established medications used in treating systemic lupus erythematosus and rheumatoid arthritis, as well as skin conditions such as cutaneous lupus erythematosus. In rare cases, arrhythmias and conduction system abnormalities, as well as cardiomyopathy, have been reported in association with HCQ/CQ use. Recently, however, the corrected QT interval (QTc)-prolonging potential of these medications, and risk of torsade de pointes (TdP) in particular, have been highlighted in the setting of their experimental use for COVID-19 infection. This report was undertaken to summarize the current understanding of HCQ/CQ cardiac toxicity, describe QTc prolongation and TdP risks, and discuss areas of priority for future research. A working group of experts across rheumatology, cardiology, and dermatology performed a nonsystematic literature review and offered a consensus-based expert opinion. Current data clearly indicate that HCQ and CQ are invaluable medications in the management of rheumatic and dermatologic diseases, but they are associated with QTc prolongation by directly affecting cardiac repolarization. Prescribing clinicians should be cognizant of this small effect, especially in patients taking additional medications that prolong the QTc interval. Long-term use of HCQ/CQ may lead to a cardiomyopathy associated with arrhythmias and heart failure. Risk and benefit assessment should be considered prior to initiation of any medication, and both initial and ongoing risk-benefit assessments are important with regard to prescription of HCQ/CQ. While cardiac toxicity related to HCQ/CQ treatment of rheumatic diseases is rarely reported, it can be fatal. Awareness of the potential adverse cardiac effects of HCQ and CQ can increase the safe use of these medications. There is a clear need for additional research to allow better understanding of the cardiovascular risk and safety profile of these therapies used in the management of rheumatic and cutaneous diseases.


Assuntos
Antimaláricos/uso terapêutico , COVID-19/tratamento farmacológico , Cardiotoxicidade/etiologia , Cloroquina/uso terapêutico , Hidroxicloroquina/uso terapêutico , Antimaláricos/efeitos adversos , Cloroquina/efeitos adversos , Humanos , Hidroxicloroquina/efeitos adversos
17.
Sci Rep ; 11(1): 19998, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620963

RESUMO

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.


Assuntos
Antivirais/metabolismo , COVID-19/tratamento farmacológico , Descoberta de Drogas , SARS-CoV-2/efeitos dos fármacos , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/metabolismo , Adenina/farmacologia , Adenosina/efeitos adversos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Alanina/efeitos adversos , Alanina/análogos & derivados , Alanina/metabolismo , Alanina/farmacologia , Amidas/efeitos adversos , Amidas/metabolismo , Amidas/farmacologia , Antivirais/efeitos adversos , Antivirais/farmacologia , COVID-19/metabolismo , Cloroquina/efeitos adversos , Cloroquina/análogos & derivados , Cloroquina/metabolismo , Cloroquina/farmacologia , Desenho de Fármacos , Humanos , Redes e Vias Metabólicas , Simulação de Acoplamento Molecular , Nitrocompostos/efeitos adversos , Nitrocompostos/metabolismo , Nitrocompostos/farmacologia , Pirazinas/efeitos adversos , Pirazinas/metabolismo , Pirazinas/farmacologia , Pirrolidinas/efeitos adversos , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Ribavirina/efeitos adversos , Ribavirina/metabolismo , Ribavirina/farmacologia , SARS-CoV-2/metabolismo , Tiazóis/efeitos adversos , Tiazóis/metabolismo , Tiazóis/farmacologia
18.
J Clin Lab Anal ; 35(9): e23923, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34390043

RESUMO

BACKGROUND: The dynamic alteration and comparative study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding pattern during treatment are limited. This study explores the potential risk factors influencing prolonged viral shedding in COVID-19. METHODS: A total of 126 COVID-19 patients were enrolled in this retrospective longitudinal study. A multivariate logistic regression analysis was carried out to estimate the potential risk factors. RESULTS: 38.1% (48/126) cases presented prolonged respiratory tract viral shedding, and 30 (23.8%) cases presented prolonged rectal swab viral shedding. Obesity (OR, 3.31; 95% CI, 1.08-10.09), positive rectal swab (OR, 3.43; 95% CI, 1.53-7.7), treatment by lopinavir/ritonavir with chloroquine phosphate (OR, 2.5; 95% CI, 1.04-6.03), the interval from onset to antiviral treatment more than 7 days (OR, 2.26; 95% CI, 1.04-4.93), lower CD4+ T cell (OR, 0.92; 95% CI, 0.86-0.99) and higher NK cells (OR, 1.11; 95% CI, 1.02-1.20) were significantly associated with prolonged respiratory tract viral shedding. CD3-CD56+ NK cells (OR, 0.87; 95% CI, 0.76-0.99) were related with prolonged fecal shedding. CONCLUSIONS: Obesity, delayed antiviral treatment, and positive SARS-CoV-2 for stool were independent risk factors for prolonged SARS-CoV-2 RNA shedding of the respiratory tract. A combination of LPV/r and abidol as the initial antiviral regimen was effective in shortening the duration of viral shedding compared with LPV/r combined with chloroquine phosphate. CD4+ T cell and NK cells were significantly associated with prolonged viral shedding, and further studies are to be warranted to determine the mechanism of immunomodulatory response in virus clearance.


Assuntos
COVID-19/virologia , Fezes/virologia , SARS-CoV-2/fisiologia , Eliminação de Partículas Virais/fisiologia , Adulto , Animais , Antivirais/administração & dosagem , Contagem de Linfócito CD4 , COVID-19/epidemiologia , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Cloroquina/análogos & derivados , Feminino , Humanos , Células Matadoras Naturais , Estudos Longitudinais , Lopinavir/administração & dosagem , Lynx , Masculino , Obesidade/epidemiologia , Sistema Respiratório/virologia , Estudos Retrospectivos , Fatores de Risco , Ritonavir/administração & dosagem , Fatores de Tempo , Eliminação de Partículas Virais/efeitos dos fármacos
19.
PLoS One ; 16(8): e0256035, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34398893

RESUMO

BACKGROUND: Chloroquine was promoted as a COVID-19 therapeutic early in the pandemic. Most countries have since discontinued the use of chloroquine due to lack of evidence of any benefit and the risk of severe adverse events. The primary aim of this study was to examine if administering chloroquine during COVID-19 imposed an increased risk of ischemic heart injury or heart failure. METHODS: Medical records, laboratory findings, and electrocardiograms of patients with COVID-19 who were treated with 500 mg chloroquine phosphate daily and controls not treated with chloroquine were reviewed retrospectively. Controls were matched in age and severity of disease. RESULTS: We included 20 patients receiving chloroquine (500 mg twice daily) for an average of five days, and 40 controls. The groups were comparable regarding demographics and biochemical analyses including C-reactive protein, thrombocytes, and creatinine. There were no statistically significant differences in cardiac biomarkers or in electrocardiograms. Median troponin T was 10,8 ng/L in the study group and 17.9 ng/L in the control group, whereas median NT-proBNP was 399 ng/L in patients receiving chloroquine and 349 ng/L in the controls. CONCLUSIONS: We found no increased risk of ischemic heart injury or heart failure as a result of administering chloroquine. However, the use of chloroquine to treat COVID-19 outside of clinical trials is not recommended, considering the lack of evidence of its effectiveness, as well as the elevated risk of fatal arrythmias.


Assuntos
Antivirais/efeitos adversos , Biomarcadores/análise , Cloroquina/análogos & derivados , Insuficiência Cardíaca/etiologia , Traumatismos Cardíacos/etiologia , Idoso , Antivirais/uso terapêutico , Proteína C-Reativa/análise , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Estudos de Casos e Controles , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Creatinina/análise , Eletrocardiografia , Feminino , Insuficiência Cardíaca/metabolismo , Traumatismos Cardíacos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/análise , Fragmentos de Peptídeos/análise , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Troponina T/análise
20.
Travel Med Infect Dis ; 43: 102135, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34265436

RESUMO

OBJECTIVE: To synthesize findings from systematic reviews and meta-analyses on the efficacy and safety of chloroquine (CQ) and hydroxychloroquine (HCQ) with or without Azithromycin for treating COVID-19, and to update the evidence using a meta-analysis. METHODS: A comprehensive search was carried out in electronic databases for systematic reviews, meta-analyses and experimental studies which investigated the efficacy and safety of CQ, HCQ with or without Azithromycin to treat COVID-19. Findings from the reviews were synthesised using tables and forest plots and the quality effect model was used for the updated meta-analysis. The main outcomes were mortality, the need for intensive care services, disease exacerbation, viral clearance and occurrence of adverse events. RESULTS: Thirteen reviews with 40 primary studies were included. Two meta-analyses reported a high risk of mortality, with ORs of 2.2 and 3.0, and the two others found no association between HCQ and mortality. Findings from two meta-analyses showed that HCQ with Azithromycin increased the risk of mortality, with similar ORs of 2.5. The updated meta-analysis of experimental studies showed that the drugs were not effective in reducing mortality (RR 1.1, 95%CI 1.0-1.3, I2 = 0.0%), need for intensive care services (OR 1.1, 95%CI 0.9-1.4, I2 = 0.0%), virological cure (OR 1.5, 95%CI 0.5-4.4, I2 = 39.6%) or disease exacerbation (OR 1.2, 95%CI 0.3-5.9, I2 = 31.9%) but increased the odds of adverse events (OR 12,3, 95%CI 2.5-59.9, I2 = 76.6%). CONCLUSION: There is conclusive evidence that CQ and HCQ, with or without Azithromycin are not effective in treating COVID-19 or its exacerbation. REGISTRATION: PROSPERO: CRD42020191353.


Assuntos
COVID-19 , Hidroxicloroquina , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Cloroquina/efeitos adversos , Humanos , Hidroxicloroquina/efeitos adversos , SARS-CoV-2 , Revisões Sistemáticas como Assunto , Resultado do Tratamento
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