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1.
Int J Mol Sci ; 22(3)2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33498911

RESUMO

Artemether, an artemisinin derivative, is used in the management of life-threatening severe malaria. This study aimed to develop an intravenous dosage form of artemether using nanotechnology. Artemether-loaded zein nanoparticles were prepared by modified antisolvent precipitation using sodium caseinate as a stabilizer. Subsequently, the physicochemical properties of the nanoparticles were characterized; the in vitro hemolytic property was examined with red blood cells, while the pharmacokinetic profile was evaluated in Sprague-Dawley rats after intravenous administration. The artemether-loaded zein nanoparticles were found to display good encapsulation efficiency, excellent physical stability and offer an in vitro extended-release property. Interestingly, encapsulation of artemether into zein nanoparticles substantially suppressed hemolysis, a common clinical phenomenon occurring after artemisinin-based antimalarial therapy. Upon intravenous administration, artemether-loaded zein nanoparticles extended the mean residence time of artemether by ~80% in comparison to the free artemether formulation (82.9 ± 15.2 versus 45.6 ± 16.4 min, p < 0.01), suggesting that the nanoparticles may prolong the therapeutic duration and reduce the dosing frequency in a clinical setting. In conclusion, intravenous delivery of artemether by artemether-loaded zein nanoparticles appears to be a promising therapeutic option for severe malaria.


Assuntos
Artemeter/administração & dosagem , Artemeter/farmacocinética , Malária/tratamento farmacológico , Nanopartículas/química , Zeína/química , Administração Intravenosa , Animais , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Artemeter/uso terapêutico , Caseínas/química , Preparações de Ação Retardada , Ratos , Ratos Sprague-Dawley
2.
Clin Biochem ; 89: 70-76, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33453194

RESUMO

BACKGROUND: Hydroxychloroquine is an antimalarial drug that has been prescribed for the treatment of patients with COVID-19 infection. To assist in clinician decision-making, several clinical laboratories have developed and validated measurement procedures in-house based on HPLC or HPLC-MS/MS to measure the mass concentration of hydroxychloroquine in different biological fluids. In these cases, laboratories produce their calibration materials but rarely estimate the measurement uncertainty of their assigned values. Thus, we aimed to show how this uncertainty can be calculated, using the preparation of hydroxychloroquine calibrators in blood-hemolysate-based matrix as an example. METHODS: A bottom-up approach was used to estimate the uncertainty related to the values assigned to end-user calibration materials prepared in-house. First, a specification of the measurand and a measurement equation were proposed. Then, different sources of uncertainty related to the preparation of hydroxychloroquine calibration materials were identified and quantified. Afterwards, the combined uncertainty was calculated using the law for the propagation of uncertainty resulting in the final expanded uncertainty. RESULTS: In this study, the most significant source of uncertainty was that associated with the hydroxychloroquine's reference material mass obtained via balance, while the smallest contribution was from the uncertainty associated with the hydroxychloroquine reference material purity. CONCLUSIONS: A simple procedure to estimate the measurement uncertainty of values assigned to calibration materials is presented here, which would be easy to implement in clinical laboratories. Also, it could be put into practice for other pharmacological quantities measured by in-house HPLC or HPLC-MS/MS procedures commonly used in clinical laboratories.


Assuntos
/sangue , Cromatografia Líquida de Alta Pressão/métodos , Hidroxicloroquina/sangue , Antimaláricos/administração & dosagem , Antimaláricos/sangue , /patologia , Calibragem , Cromatografia Líquida de Alta Pressão/normas , Hemólise , Humanos , Hidroxicloroquina/administração & dosagem , Controle de Qualidade , Padrões de Referência , Incerteza
3.
J Antimicrob Chemother ; 76(3): 753-757, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33338232

RESUMO

INTRODUCTION: Effective treatments are urgently needed to tackle the novel coronavirus disease 2019 (COVID-19). This trial aims to evaluate sofosbuvir and daclatasvir versus standard care for outpatients with mild COVID-19 infection. METHODS: This was a randomized controlled clinical trial in outpatients with mild COVID-19. Patients were randomized into a treatment arm receiving sofosbuvir/daclatasvir plus hydroxychloroquine or a control arm receiving hydroxychloroquine alone. The primary endpoint of the trial was symptom alleviation after 7 days of follow-up. The secondary endpoint of the trial was hospital admission. Fatigue, dyspnoea and loss of appetite were investigated after 1 month of follow-up. This study is registered with the IRCT.ir under registration number IRCT20200403046926N1. RESULTS: Between 8 April 2020 and 19 May 2020, 55 patients were recruited and allocated to either the sofosbuvir/daclatasvir treatment arm (n = 27) or the control arm (n = 28). Baseline characteristics were similar across treatment arms. There was no significant difference in symptoms at Day 7. One patient was admitted to hospital in the sofosbuvir/daclatasvir arm and four in the control arm, but the difference was not significant. After 1 month of follow-up, two patients reported fatigue in the sofosbuvir/daclatasvir arm and 16 in the control arm; P < 0.001. CONCLUSIONS: In this study, sofosbuvir/daclatasvir did not significantly alleviate symptoms after 7 days of treatment compared with control. Although fewer hospitalizations were observed in the sofosbuvir/daclatasvir arm, this was not statistically significant. Sofosbuvir/daclatasvir significantly reduced the number of patients with fatigue and dyspnoea after 1 month. Larger, well-designed trials are warranted.


Assuntos
Assistência Ambulatorial/métodos , Antivirais/administração & dosagem , /tratamento farmacológico , Carbamatos/administração & dosagem , Imidazóis/administração & dosagem , Pirrolidinas/administração & dosagem , Sofosbuvir/administração & dosagem , Valina/análogos & derivados , Adulto , Assistência Ambulatorial/tendências , Antimaláricos/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Hidroxicloroquina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Valina/administração & dosagem
4.
J Ethnopharmacol ; 266: 113424, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33010404

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria is a life-threatening health problem worldwide and treatment remains a major challenge. Natural products from medicinal plants are credible sources for better anti-malarial drugs. AIM OF THE STUDY: This study aimed at assessing the in vitro and in vivo antiplasmodial activities of the hydroethanolic extract of Bridelia atroviridis bark. MATERIALS AND METHODS: The phytochemical characterization of Bridelia atroviridis extract was carried out by High-Performance Liquid Chromatography-Mass spectrometry (HPLC-MS). The cytotoxicity test on Vero cells was carried out using the resazurin-based assay while the in vitro antiplasmodial activity was determined on Plasmodium falciparum (Dd2 strain, chloroquine resistant) using the SYBR green I-based fluorescence assay. The in vivo assay was performed on Plasmodium berghei-infected rats daily treated for 5 days with distilled water (10 mL/kg) for malaria control, 25 mg/kg of chloroquine sulfate for positive control and 50, 100 and 200 mg/kg of B. atroviridis extract for the three test groups. Parasitaemia was daily monitored using 10% giemsa-staining thin blood smears. At the end of the treatment, animals were sacrificed, blood was collected for hematological and biochemical analysis while organs were removed for biochemical and histopathological analyses. RESULTS: The HPLC-MS analysis data of B. atroviridis revealed the presence of bridelionoside D, isomyricitrin, corilagin, myricetin and 5 others compounds not yet identified. Bridelia atroviridis exhibited good in vitro antiplasmodial activity with the IC50 evaluated at 8.08 µg/mL and low cytotoxicity with the median cytotoxic concentration (CC50) higher than 100 µg/mL. B. atroviridis extract significantly reduced the parasitemia (p < 0.05) with an effective dose-50 (ED-50) of 89 mg/kg. B. atroviridis also prevented anemia, leukocytosis and liver and kidneys impairment by decrease of transaminases, ALP, creatinine, uric acid, and triglycerides concentrations. As well, B. atroviridis extract decreased some pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) levels and significantly improved the anti-inflammatory status (P < 0.01) of infected animals marked by a decrease of IL-10 concentration. These results were further confirmed by the improved of antioxidant status and the quasi-normal microarchitecture of the liver, kidneys and spleen in test groups. Overall, the hydroethanolic bark extract of Bridelia atroviridis demonstrated antimalarial property and justified its use in traditional medicine to manage malaria disease.


Assuntos
Antimaláricos/farmacologia , Euphorbiaceae/química , Extratos Vegetais/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/administração & dosagem , Antimaláricos/isolamento & purificação , Chlorocebus aethiops , Cloroquina/farmacologia , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Concentração Inibidora 50 , Malária/tratamento farmacológico , Malária/parasitologia , Masculino , Espectrometria de Massas , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Ratos , Ratos Wistar , Células Vero
5.
J Ethnopharmacol ; 266: 113427, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33022339

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria is caused by infection with some species of Plasmodium parasite which leads to adverse alterations in physical and hematological features of infected persons and ultimately results in death. Antrocaryon micraster is used to treat malaria in Ghanaian traditional medicine. However, there is no scientific validation of its anti-malaria properties. The plant does not also have any chemical fingerprint or standardization parameters. AIM OF THE STUDY: This study sought to evaluate the anti-malaria activity of standardized A. micraster stem bark extract (AMSBE) and its effect on mean survival time (MST) and body weight reduction of Plasmodiumberghei infested mice. And to study the effect of treatment of AMSBE on hematological indices of the P. berghei infested mice in order to partly elucidate its anti-malarial mechanism of action. MATERIALS AND METHODS: Malaria was induced in female ICR mice by infecting them with 0.2 mL of blood (i.p.) containing 1.0 × 107P. berghei-infested RBCs from a donor mouse and leaving them without treatment for 3 days. AMSBE or Lonart (standard control) was then orally administered at 50, 200 and 400 mg/kg or 10 mg/kg once daily for 4 consecutive days. The untreated control received sterile water. Malaria parasitemia reduction, anti-malarial activity, mean change in body weight and MST of the parasitized mice were evaluated. Furthermore, changes in white blood cells (WBCs), red blood cells (RBCs), platelets count, hemoglobin (HGB), hematocrit (HCT) and mean corpuscular volume (MCV) were also determined in the healthy animals before infection as baseline and on days 3, 5 and 8 after infection by employing complete blood count. Standardization of AMSBE was achieved by quantification of its constituents and chemical fingerprint analysis using UHPLC-MS. RESULTS: Administration of AMSBE, standardized to 41.51% saponins and 234.960 ± 0.026 mg/g of GAE phenolics, produced significant (P < 0.05) reduction of parasitemia development, maximum anti-malaria activity of 46.01% (comparable to 32.53% produced by Lonart) and significantly (P < 0.05) increased body weight and MST of P. berghei infected mice compared to the untreated control. Moreover, there were significant (P > 0.05) elevation in WBCs, RBCs, HGB, HCT and platelets in the parasitized-AMSBE (especially at 400 mg/kg p.o.) treated mice compared to their baseline values. Whereas, the non-treated parasitized control recorded significant reduction (P < 0.05) in all the above-mentioned parameters compared to its baseline values. The UHPLC-MS fingerprint of AMSBE revealed four compounds with their retention times, percentage composition in their chromatograms and m/z of the molecular ions and fragments in the spectra. CONCLUSIONS: These results show that A. micraster stem bark possessed significant anti-malaria effect and also has the ability to abolish body weight loss, leucopenia, anemia and thrombocytopenia in P. berghei infected mice leading to prolonged life span. The UHPLC-MS fingerprint developed for AMSBE can be used for rapid authentication and standardization of A. micraster specimens and herbal preparations produced from its hydroethanolic stem bark extract to ensure consistent biological activity. The results justify A. micraster's use as anti-malaria agent.


Assuntos
Anacardiaceae/química , Antimaláricos/farmacologia , Malária/tratamento farmacológico , Extratos Vegetais/farmacologia , Plasmodium berghei/efeitos dos fármacos , Animais , Antimaláricos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Gana , Malária/parasitologia , Medicina Tradicional Africana , Camundongos , Camundongos Endogâmicos ICR , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Casca de Planta , Extratos Vegetais/administração & dosagem
6.
Biosci Trends ; 14(6): 408-414, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33342929

RESUMO

The aim of this study is to assess the efficacy of multiple treatments, especially hydroxychloroquine, used in different disease stages of coronavirus disease 2019 (COVID-19). All consecutive patients with COVID-19 admitted to Shanghai Public Health Clinical Center (Shanghai, China) between January 20, 2020, and April 30, 2020, were enrolled, and their clinical data were retrospectively collected. Binary logistic regression was used to screen the factors associated with disease aggravation, and multivariable analyses with the Cox proportional hazards model were used to estimate the effects of prognostic factors on the improvement time and PCR conversion days in throat swabs and stool swabs. A total of 616 patients, including 50 (8.11%) severe and 18 (2.92%) critical patients, were enrolled in our retrospective cohort study. The early use of hydroxychloroquine was a protective factor associated with disease aggravation (95% CI: 0.040-0.575, p = 0.006). Clinical improvement by 20 days was significantly different between patients with hydroxychloroquine used early and those with hydroxychloroquine not used (p = 0.016, 95% CI: 1.052-1.647). The median time to clinical improvement was 6 days in the hydroxychloroquine used early group, compared with 9 days in the without hydroxychloroquine used group and 8 days in the with hydroxychloroquine not used early group (p < 0.001). Hydroxychloroquine used early was associated with earlier PCR conversion in both throat swabs (HR = 1.558, p = 0.001) and stool swabs (HR = 1.400, p = 0.028). The use of hydroxychloroquine at an early stage is a potential therapeutic strategy for treating patients before irreversible severe respiratory complications occur. The early use of hydroxychloroquine decreased the improvement time and the duration of COVID-19 detection in throat and stool swabs.


Assuntos
Antimaláricos/administração & dosagem , Hidroxicloroquina/administração & dosagem , Adulto , Idoso , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
7.
J Med Case Rep ; 14(1): 210, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33138853

RESUMO

BACKGROUND: Since the World Health Organization declared a global pandemic due to the novel coronavirus disease2019, there have been targeted efforts to establish management modalities. Hydroxychloroquine has been suggested as a possible treatment; however, it is associated with multiple adverse reactions. We report a rare case of a patient with acute generalized exanthematous pustulosis with Stevens-Johnson syndrome due to hydroxychloroquine. Acute generalized exanthematous pustulosis is characterized by acute onset of a generalized rash that is pustular and erosive in nature, affecting limbs; trunk; face; and, less often, mucosal membranes. Although rare, it is important to be mindful of this side effect because the diagnosis is often delayed, and the disease has the potential to be life-threatening. CASE PRESENTATION: A 68-year-old American woman presented to our hospital with a painful, rapidly spreading rash. Its morphologic features included erythema multiforme-like lesions with extensive skin sloughing in various regions of the head, neck, and trunk and mucosal involvement. Her Nikolsky sign was negative, and she had no evidence of lesions on areas of skin trauma. Four weeks prior, she had been initiated on hydroxychloroquine for a presumed diagnosis of cutaneous sarcoidosis. Three punch biopsies of the head and neck area revealed subcorneal pustules consistent with acute generalized exanthematous pustulosis. Treatment began with high doses of methylprednisolone, leading to only minimal improvement of existing areas and ongoing spread to new areas. Treatment with intravenous immunoglobulin was initiated, at which point disease stability was achieved. The patient's rash ultimately resolved, as did her cutaneous pain and pruritus. CONCLUSIONS: Among many potential adverse reactions involving hydroxychloroquine, cutaneous side effects are varied and can lead to significant morbidity or even death. The drug is currently being investigated in a multitude of trials for coronavirus disease2019 treatment, prevention, and prophylaxis after exposure to severe acute respiratory syndrome coronavirus 2. Acute generalized exanthematous pustulosis is a rare side effect of hydroxychloroquine, and even fewer cases demonstrate histologic evidence of acute generalized exanthematous pustulosis while clinically presenting with Stevens-Johnson syndrome. Patients who develop Stevens-Johnson syndrome/toxic epidermal necrolysis require best supportive care with aggressive fluid and electrolyte replacement and prevention of further breakdown of the skin barrier. With the potential of widespread hydroxychloroquine use, it is important that providers be aware of its potential severe adverse drug reactions.


Assuntos
Pustulose Exantematosa Aguda Generalizada , Infecções por Coronavirus/epidemiologia , Hidroxicloroquina , Imunoglobulinas Intravenosas/administração & dosagem , Metilprednisolona/administração & dosagem , Pneumonia Viral/epidemiologia , Sarcoidose/tratamento farmacológico , Síndrome de Stevens-Johnson , Pustulose Exantematosa Aguda Generalizada/diagnóstico , Pustulose Exantematosa Aguda Generalizada/etiologia , Pustulose Exantematosa Aguda Generalizada/fisiopatologia , Pustulose Exantematosa Aguda Generalizada/terapia , Idoso , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Biópsia/métodos , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Fatores Imunológicos , Pandemias , Pele/patologia , Dermatopatias/tratamento farmacológico , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/etiologia , Síndrome de Stevens-Johnson/fisiopatologia , Síndrome de Stevens-Johnson/terapia , Resultado do Tratamento
8.
Bol Med Hosp Infant Mex ; 77(5): 242-251, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33064677

RESUMO

Since December 2019, health systems worldwide have faced the pandemic caused by the new severe acute respiratory syndrome coronavirus 2. The pandemic began in China and has spread throughout the world. This new coronavirus has a high transmission capacity and elevated lethality in people over 60 years old and in those with risk factors (obesity, diabetes, and systemic arterial hypertension); those characteristics have a different proportion in each country. At present, there is no specific, effective, and safe treatment to treat this virus. In this review, an analysis is made on the differences in epidemiological aspects of the disease and its presentation in pediatric patients; the poorly-based recommendation for using an empirical combination of antimalarials plus antimicrobials as antiviral treatment; the indication of intravenous steroids; and the possible influence of antihypertensive drugs on the course of the disease.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Fatores Etários , Antimaláricos/administração & dosagem , Antivirais/administração & dosagem , Criança , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Fatores de Risco
9.
Trials ; 21(1): 866, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33081849

RESUMO

OBJECTIVES: 1. To compare the safety and efficacy of Hydroxychloroquine with Ribavirin and standard treatment in patients with non-severe COVID-19 infection 2. To compare the safety and efficacy of standard treatment, Lopinavir-ritonavir with Ribavarin, and Hydroxychloroquine with Ribavirin in patients with severe COVID-19 infection TRIAL DESIGN: The study is an Open label, Parallel arm design, stratified randomised controlled trial. Patients will be categorised as non-severe or severe based on predefined criteria. Those who satisfy all inclusion criteria and no exclusion criteria in the respective categories, will be randomly assigned to one of the three treatment groups in a ratio of 1:1 in the non-severe category and 1:1:1 in the severe category. PARTICIPANTS: The trial will be undertaken in a tertiary care center of the country where both Covid and non-Covid patients are getting treated. All patients who are confirmed positive and admitted will be screened for the eligibility criteria and will be enrolled in the study after a written informed consent. Patients will be categorised as non-severe or severe based on predefined criteria. INCLUSION CRITERIA (ALL REQUIRED): 1. Age ≥18 years at time of participation in the study 2. Laboratory (RT-PCR) confirmed infection with SARS-CoV-2 3. Symptomatic (severe or non-severe) Covid-19 disease 4. Willingness of study participant to accept randomization to any assigned treatment arm EXCLUSION CRITERIA: 1. Use of medications that are contraindicated with Lopinavir/Ritonavir, Hydroxychloroquine/Chloroquine, or Ribavirin and that cannot be replaced or stopped 2. Patient already on antiretroviral therapy with Lopinavir-Ritonavir based regimen or on Hydroxychloroquine/Chloroquine or on Ribavirin 3. Any known contraindication to test drugs such as retinopathy and QT prolongation 4. Known allergic reaction or inability to take orally of Lopinavir-ritonavir, Hydroxychloroquine/ Chloroquine, Ribavarin 5. Pregnant or breastfeeding females 6. Receipt of any experimental treatment for 2019-nCoV (off-label, compassionate use, or trial related) within 30 days prior to participation in the present study or want to participate after enrolment INTERVENTION AND COMPARATOR: Two therapeutic interventions for non-severe category and three for severe category as described below NON-SEVERE TREATMENT ARMS (NS-GROUP): Treatment Arm Drug A Standard Treatment (STNS) B Hydroxychloroquine 400 mg twice on first day followed by 400 mg per oral daily for 10 days + Ribavirin (1.2 g orally as a loading dose followed by 600mg orally every 12 hours) for 10 days + Standard Treatment (STNS) Standard Treatment for non-severe cases (STNS): Strict Isolation, Standard Precautions (Hand hygiene, Cough Etiquette, Wear surgical mask), Hydration, Proper Nutrition, Supportive Pharmacotherapy (Antipyretic, Antiallergic, Cough Suppressant), Treatment of Comorbid Diseases, Oseltamivir (75 mg BD) for patients who are tested positive for H1N1. SEVERE GROUP TREATMENT ARMS (S-GROUP): Treatment Arm Drug A Standard Treatment (STs) B Hydroxychloroquine 400mg BD on day1 followed by 400 mg once daily + Ribavirin (1.2 g orally as a loading dose followed by 600mg orally every 12 hours) for 10 days + Standard Treatment (STs) C Lopinavir(200mg) + Ritonavir (50mg) two tablets twice daily+ Ribavirin (1.2g orally as a loading dose followed by 600mg orally every 12 hours) for 10 days + Standard Treatment (STs)6 Standard Treatment for severe patients (STs): Strict Isolation, Standard Precautions (Hand hygiene, Cough Etiquette, Wear surgical mask), Fluid Therapy, Supportive Pharmacotherapy (Antipyretic, Antiallergic, Cough Suppressant), Oxygen supplementation (As required), Invasive ventilation (As required), Antibiotic agents for other associated infections (according to 2019 ATS/IDSA guidelines for non-ICU and ICU patients), Vasopressor support, Renal-replacement therapy, Treatment of Comorbid Diseases, Oseltamivir (75 mg BD) for patients who are tested positive for H1N1. MAIN OUTCOMES: Primary endpoints: (1) Time to Clinical recovery (TTCR) defined as the time (in hours) from initiation of study treatment (active or placebo) until normalisation of fever, respiratory rate, oxygen saturation, and alleviation of cough, sustained for at least 72 hours. (2) Time to SARS-CoV-2 RT-PCR negative in upper respiratory tract specimen, time to laboratory recovery of each organ involvement. Secondary Endpoints: All causes mortality, Frequency of respiratory progression (defined as SPO2≤ 94% on room air or PaO2/FiO2 <300mmHg and requirement for supplemental oxygen or more advanced ventilator support), time to defervescence (in those with fever at enrolment), frequency of requirement for supplemental oxygen or non-invasive ventilation, frequency of requirement for mechanical ventilation, frequency of serious adverse events as per DAIDS table grade of severity. Outcomes are monitored for 28 days from the time of enrolment into the study OR until the patient is discharged or death whichever is longer. RANDOMIZATION: The randomization will be done using a secured central computer-based randomization using a secure website using a central, computer-based randomisation program in a ratio of 1:1 in the non-severe category and 1:1:1 in the severe category. BLINDING (MASKING): This is an open labelled study i.e. Study assigned treatment will be known to the research team, the investigators and participants. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Since it is an exploratory trial as COVID-19 being a new disease, all patients who came under the purview of the inclusion criteria within the study period (5 months duration of the recruitment period of the total 6 months duration of the study i.e. from the month of June, 2020 to October 2020) and who have consented for the study will be included. TRIAL STATUS: Protocol version:1.0 Recruitment start: June 3rd, 2020 (Ongoing) Recruitment finish (expected): October 31st, 2020 TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI): CTRI/2020/06/025575 . Registration on 03 June 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Ribavirina/uso terapêutico , Administração Oral , Adulto , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Antivirais/administração & dosagem , Betacoronavirus/genética , Protocolos Clínicos , Terapia Combinada , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Índia/epidemiologia , Consentimento Livre e Esclarecido , Lopinavir/administração & dosagem , Lopinavir/uso terapêutico , Masculino , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Ribavirina/administração & dosagem , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Segurança , Fatores de Tempo , Resultado do Tratamento
10.
J Pharmacol Sci ; 144(3): 95-101, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32921396

RESUMO

Patients living with HIV in malarial endemic regions may experience clinically significant drug interaction between antiretroviral and antimalarial drugs. Effects of nevirapine (NVP), efavirenz (EFV) and lopinavir/ritonavir (LPVr) on lumefantrine (LM) therapeutic concentrations and toxicity were evaluated. In a four-arm parallel study design, the blood samples of 40 participants, treated with artemether/lumefantrine (AL), were analysed. Lumefantrine Cmax was increased by 32% (p = 0.012) and 325% (p < 0.0001) in the NVP and LPVr arms respectively but decreased by 62% (p < 0.0001) in the EFV-arm. AUC of LM was, respectively, increased by 50% (p = 0.27) and 328% (p < 0.0001) in the NVP and LPVr arms but decreased in the EFV-arm by 30% (p = 0.019). Median day 7 LM concentration was less than 280 ng/mL in EFV-arm (239 ng/mL) but higher in control (290 ng/mL), NVP (369 ng/mL, p = 0.004) and LPVr (1331 ng/mL, p < 0.0001) arms. There were no clinically relevant toxicities nor adverse events in both control and test arms. Artemether/lumefantrine is safe and effective for treatment of malaria in PLWHA taking NVP and LPVr based ART regimen but not EFV-based regimen.


Assuntos
Antirretrovirais/efeitos adversos , Antimaláricos/efeitos adversos , Combinação Arteméter e Lumefantrina/efeitos adversos , Benzoxazinas/efeitos adversos , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Malária/tratamento farmacológico , Nevirapina/efeitos adversos , Adulto , Alquinos , Antirretrovirais/administração & dosagem , Antirretrovirais/sangue , Antimaláricos/administração & dosagem , Antimaláricos/sangue , Combinação Arteméter e Lumefantrina/administração & dosagem , Combinação Arteméter e Lumefantrina/sangue , Benzoxazinas/administração & dosagem , Benzoxazinas/sangue , Ciclopropanos , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/complicações , Humanos , Lopinavir , Malária/complicações , Masculino , Pessoa de Meia-Idade , Nevirapina/administração & dosagem , Nevirapina/sangue , Nigéria , Ritonavir , Resultado do Tratamento , Adulto Jovem
11.
Eur J Drug Metab Pharmacokinet ; 45(6): 703-713, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32968954

RESUMO

BACKGROUND AND OBJECTIVE: In the absence of characterization on pharmacokinetics and reference concentrations for hydroxychloroquine in COVID-19 patients, the dose and treatment duration for hydrochloroquine are currently empirical, mainly based on in vitro data, and may vary across national guidelines and clinical study protocols. The aim of this paper is to describe the pharmacokinetics of hydroxychloroquine in COVID-19 patients, considered to be a key step toward its dosing optimization. METHODS: We have developed a population pharmacokinetic model for hydroxychloroquine in COVID-19 patients using prospectively collected pharmacokinetic data from patients either enrolled in a clinical trial or treated with hydroxychloroquine as part of standard of care in two tertiary Belgian hospitals. RESULTS: The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination. The estimated parameter values were 9.3/h, 860.8 L, and 15.7 L/h for the absorption rate constant, the central compartment volume, and the clearance, respectively. The bioavailability factor was fixed to 0.74 based on previously published models. Model validations by bootstraps, prediction corrected visual predictive checks, and normalized prediction distribution errors gave satisfactory results. Simulations were performed to compare the exposure obtained with alternative dosing regimens. CONCLUSION: The developed models provide useful insight for the dosing optimization of hydroxychloroquine in COVID-19 patients. The present results should be used in conjunction with exposure-efficacy and exposure-safety data to inform optimal dosing of hydroxychloroquine in COVID-19.


Assuntos
Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/farmacocinética , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Disponibilidade Biológica , Infecções por Coronavirus/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/metabolismo , Adulto Jovem
12.
Cochrane Database Syst Rev ; 9: CD010458, 2020 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-32892362

RESUMO

BACKGROUND: Plasmodium vivax malaria has a persistent liver stage that causes relapse of the disease and continued P vivax transmission. Primaquine (PQ) is used to clear the liver stage of the parasite, but treatment is required for 14 days. Primaquine also causes haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Tafenoquine (TQ) is a new alternative to PQ with a longer half-life and can be used as a single-dose treatment. OBJECTIVES: To assess the effects of tafenoquine 300 mg (single dose) on preventing P vivax relapse. SEARCH METHODS: We searched the following up to 3 June 2020: the Cochrane Infectious Diseases Group Specialized Register; CENTRAL; MEDLINE; Embase; and three other databases. We also searched the WHO International Clinical Trial Registry Platform and the metaRegister of Controlled Trials for ongoing trials using "tafenoquine" and "malaria" as search terms up to 3 June 2020. SELECTION CRITERIA: Randomized controlled trials (RCTs) that gave TQ to prevent relapse in people with P vivax malaria. We planned to include trials irrespective of whether participants had been screened for G6PD enzyme deficiency. DATA COLLECTION AND ANALYSIS: All review authors independently extracted data and assessed risk of bias. As true relapse and reinfection are difficult to differentiate in people living in endemic areas, studies report "recurrences" of infection as a proxy for relapse. We carried out meta-analysis where appropriate, and gave estimates as risk ratios (RR) with 95% confidence intervals (CI). We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Three individually randomized RCTs met our inclusion criteria, all in endemic areas, and thus reporting recurrence. Trials compared TQ with PQ or placebo, and all participants received chloroquine (CQ) to treat the asexual infection). In all trials, pregnant and G6PD-deficient people were excluded. Tafenoquine 300 mg single dose versus no treatment for relapse prevention Two trials assessed this comparison. TQ 300 mg single dose reduces P vivax recurrences compared to no antihypnozoite treatment during a six-month follow-up, but there is moderate uncertainty around effect size (RR 0.32, 95% CI 0.12 to 0.88; 2 trials, 504 participants; moderate-certainty evidence). In people with normal G6PD status, there is probably little or no difference in any type of adverse events (2 trials, 504 participants; moderate-certainty evidence). However, we are uncertain if TQ causes more serious adverse events (2 trials, 504 participants; very low-certainty evidence). Both RCTs reported a total of 23 serious adverse events in TQ groups (One RCT reported 21 events) and a majority (15 events) were a drop in haemoglobin level by > 3g/dl (or >30% reduction from baseline). Tafenoquine 300 mg single dose versus primaquine 15 mg/day for 14 days for relapse prevention Three trials assessed this comparison. There is probably little or no difference between TQ and PQ in preventing recurrences (proxy measure for relapse) up to six months of follow-up (RR 1.04, 95% CI 0.8 to 1.34; 3 trials, 747 participants; moderate-certainty evidence). In people with normal G6PD status, there is probably little or no difference in any type of adverse events (3 trials, 747 participants; moderate-certainty evidence). We are uncertain if TQ can cause more serious adverse events compared to PQ (3 trials, 747 participants; very low-certainty evidence). Two trials had higher point estimates against TQ while the other showed the reverse. Most commonly reported serious adverse event in TQ group was a decline in haemoglobin level (19 out of 29 events). Some other serious adverse events, though observed in the TQ group, are unlikely to be caused by it (Hepatitis E infection, limb abscess, pneumonia, menorrhagia). AUTHORS' CONCLUSIONS: TQ 300 mg single dose prevents relapses after clinically parasitologically confirmed P vivax malaria compared to no antihypnozoite treatment, and with no difference detected in studies comparing it to PQ to date. However, the inability to differentiate a true relapse from a recurrence in the available studies may affect these estimates. The drug is untested in children and in people with G6PD deficiency. Single-dose treatment is an important practical advantage compared to using PQ for the same purpose without an overall increase in adverse events in non-pregnant, non-G6PD-deficient adults.


Assuntos
Aminoquinolinas/administração & dosagem , Antimaláricos/administração & dosagem , Malária Vivax/tratamento farmacológico , Primaquina/administração & dosagem , Prevenção Secundária , Adulto , Aminoquinolinas/efeitos adversos , Antimaláricos/efeitos adversos , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Esquema de Medicação , Deficiência de Glucosefosfato Desidrogenase/complicações , Humanos , Parasitemia/tratamento farmacológico , Placebos , Primaquina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva
13.
Cien Saude Colet ; 25(9): 3517-3554, 2020 Sep.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32876256

RESUMO

This work aimed to evaluate the effects of drug therapies for coronavirus infections. Rapid systematic review with search in the MEDLINE, EMBASE, Cochrane, BVS, Global Index Medicus, Medrix, bioRxiv, Clinicaltrials.gov and International Clinical Trials Registry Platform databases. Thirty-six studies evaluating alternative drugs against SARS, SARS-CoV-2 and MERS were included. Most of the included studies were conducted in China with an observational design for the treatment of COVID-19. The most studied treatments were with antimalarials and antivirals. In antimalarial, the meta-analysis of two studies with 180 participants did not identify the benefit of hydroxychloroquine concerning the negative viral load via real-time polymerase chain reaction, and the use of antivirals compared to standard care was similar regarding outcomes. The available scientific evidence is preliminary and of low methodological quality, which suggests caution when interpreting its results. Research that evaluates comparative efficacy in randomized, controlled clinical trials, with adequate follow-up time and with the methods properly disclosed and subject to scientific peer review is required. A periodic update of this review is recommended.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Antimaláricos/administração & dosagem , Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Pandemias , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/isolamento & purificação , Síndrome Respiratória Aguda Grave/virologia
14.
J Bras Nefrol ; 42(2 suppl 1): 49-50, 2020 Aug 26.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32877501

RESUMO

Chloroquine and hydroxychloroquine have shown promising preliminary results and have been discussed as therapeutic options for patients with Covid-19. Despite the lack of robust evidence demonstrating the benefits and justifying the use of one of these drugs, the final decision is the responsibility of the attending physician and should be individualized and shared, whenever possible. This position statement recommends dosage adjustment for these drugs in the context of renal impairment.


Assuntos
Antimaláricos/administração & dosagem , Cloroquina/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Insuficiência Renal , Brasil , Humanos , Nefrologia , Pandemias , Sociedades Médicas
15.
PLoS Med ; 17(8): e1003214, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822362

RESUMO

BACKGROUND: Seasonal malaria chemoprevention (SMC) is now widely deployed in the Sahel, including several countries that are major contributors to the global burden of malaria. Consequently, it is important to understand whether SMC continues to provide a high level of protection and how SMC might be improved. SMC was evaluated using data from a large, household-randomised trial in Houndé, Burkina Faso and Bougouni, Mali. METHODS AND FINDINGS: The parent trial evaluated monthly SMC plus either azithromycin (AZ) or placebo, administered as directly observed therapy 4 times per year between August and November (2014-2016). In July 2014, 19,578 children aged 3-59 months were randomised by household to study group. Children who remained within the age range 3-59 months in August each year, plus children born into study households or who moved into the study area, received study drugs in 2015 and 2016. These analyses focus on the approximately 10,000 children (5,000 per country) under observation each year in the SMC plus placebo group. Despite high coverage and high adherence to SMC, the incidence of hospitalisations or deaths due to malaria and uncomplicated clinical malaria remained high in the study areas (overall incidence rates 12.5 [95% confidence interval (CI): 11.2, 14.1] and 871.1 [95% CI: 852.3, 890.6] cases per 1,000 person-years, respectively) and peaked in July each year, before SMC delivery began in August. The incidence rate ratio comparing SMC within the past 28 days with SMC more than 35 days ago-adjusted for age, country, and household clustering-was 0.13 (95% CI: 0.08, 0.20), P < 0.001 for malaria hospitalisations and deaths from malaria and 0.21 (95% CI 0.20, 0.23), P < 0.001 for uncomplicated malaria, indicating protective efficacy of 87.4% (95% CI: 79.6%, 92.2%) and 78.3% (95% CI: 76.8%, 79.6%), respectively. The prevalence of malaria parasitaemia at weekly surveys during the rainy season and at the end of the transmission season was several times higher in children who missed the SMC course preceding the survey contact, and the smallest prevalence ratio observed was 2.98 (95% CI: 1.95, 4.54), P < 0.001. The frequency of molecular markers of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance did not increase markedly over the study period either amongst study children or amongst school-age children resident in the study areas. After 3 years of SMC deployment, the day 28 PCR-unadjusted adequate clinical and parasitological response rate of the SP + AQ regimen in children with asymptomatic malaria was 98.3% (95% CI: 88.6%, 99.8%) in Burkina Faso and 96.1% (95% CI: 91.5%, 98.2%) in Mali. Key limitations of this study are the potential overdiagnosis of uncomplicated malaria by rapid diagnostic tests and the potential for residual confounding from factors related to adherence to the monthly SMC schedule. CONCLUSION: Despite strong evidence that SMC is providing a high level of protection, the burden of malaria remains substantial in the 2 study areas. These results emphasise the need for continuing support of SMC programmes. A fifth monthly SMC course is needed to adequately cover the whole transmission season in the study areas and in settings with similar epidemiology. TRIAL REGISTRATION: The AZ-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT02211729.


Assuntos
Antimaláricos/administração & dosagem , Características da Família , Malária/epidemiologia , Malária/prevenção & controle , Estações do Ano , Burkina Faso/epidemiologia , Quimioprevenção/métodos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Humanos , Lactente , Malária/sangue , Masculino , Mali/epidemiologia
16.
Cochrane Database Syst Rev ; 8: CD012656, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32816320

RESUMO

BACKGROUND: Plasmodium vivax liver stages (hypnozoites) may cause relapses, prolonging morbidity, and impeding malaria control and elimination. The World Health Organization (WHO) recommends three schedules for primaquine: 0.25 mg/kg/day (standard), or 0.5 mg/kg/day (high standard) for 14 days, or 0.75 mg/kg once weekly for eight weeks, all of which can be difficult to complete. Since primaquine can cause haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, clinicians may be reluctant to prescribe primaquine without G6PD testing, and recommendations when G6PD status is unknown must be based on an assessment of the risks and benefits of prescribing primaquine. Alternative safe and efficacious regimens are needed. OBJECTIVES: To assess the efficacy and safety of alternative primaquine regimens for radical cure of P vivax malaria compared to the standard or high-standard 14-day courses. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); LILACS (BIREME); WHO International Clinical Trials Registry Platform and ClinicalTrials.gov up to 2 September 2019, and checked the reference lists of all identified studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) of adults and children with P vivax malaria using either chloroquine or artemisinin-based combination therapy plus primaquine at a total adult dose of at least 210 mg, compared with the WHO-recommended regimens of 0.25 or 0.5 mg/kg/day for 14 days. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality, and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data. We grouped efficacy data according to length of follow-up, partner drug, and trial location. We analysed safety data where included. MAIN RESULTS: 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days There may be little or no difference in P vivax recurrences at six to seven months when using the same total dose (210 mg adult dose) over seven days compared to 14 days (RR 0.96, 95% CI 0.66 to 1.39; 4 RCTs, 1211 participants; low-certainty evidence). No serious adverse events were reported. We do not know if there is any difference in the number of adverse events resulting in discontinuation of primaquine (RR 1.04, 95% CI 0.15 to 7.38; 5 RCTs, 1427 participants) or in the frequency of anaemia (RR 3.00, 95% CI 0.12 to 72.91, 1 RCT, 240 participants) between the shorter and longer regimens (very low-certainty evidence). Three trials excluded people with G6PD deficiency; two did not provide this information. Pregnant and lactating women were either excluded or no details were provided. High-standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days There may be little or no difference in P vivax recurrences at six months with 0.5 mg/kg/day primaquine for 14 days compared to 0.25 mg/kg/day for 14 days (RR 0.84 (95% CI 0.49 to 1.43; 2 RCTs, 677 participants, low-certainty evidence). No serious adverse events were reported. We do not know whether there is a difference in adverse events resulting in discontinuation of treatment with the high-standard dosage (RR 4.19, 95% CI 0.90 to 19.60; 1 RCT, 778 participants, very low-certainty evidence). People with G6PD deficiency and pregnant or lactating women were excluded. 0.75 mg/kg/week for eight weeks versus high-standard 0.5 mg/kg/day for 14 days We do not know whether weekly primaquine increases or decreases recurrences of P vivax compared to high-standard 0.5 mg/kg/day for 14 days, at 11 months' follow-up (RR 3.18, 95% CI 0.37 to 27.60; 1 RCT, 122 participants; very low-certainty evidence). No serious adverse events and no episodes of anaemia were reported. G6PD-deficient patients were not randomized but included in the weekly primaquine group (only one patient detected). 1 mg/kg/day for seven days versus high standard 0.5 mg/kg/day for 14 days There is probably little or no difference in P vivax recurrences at 12 months between 1.0 mg/kg/day primaquine for seven days and the high-standard 0.5 mg/kg/day for 14 days (RR 1.03, 95% CI 0.82 to 1.30; 2 RCTs, 2526 participants; moderate-certainty evidence). There may be moderate to large increase in serious adverse events in the 1.0 mg/kg/day primaquine for seven days compared with the high-standard 0.5 mg/kg/day for 14 days, during 42 days follow-up (RR 12.03, 95% CI 1.57 to 92.30; 1 RCT, 1872 participants, low-certainty evidence). We do not know if there is a difference between 1.0 mg/kg/day primaquine for seven days and high-standard 0.5 mg/kg/day for 14 days in adverse events that resulted in discontinuation of treatment (RR 2.50, 95% CI 0.49 to 12.87; 1 RCT, 2526 participants, very low-certainty evidence), nor if there is difference in frequency of anaemia by 42 days (RR 0.93, 95% CI 0.62 to 1.41; 2 RCTs, 2440 participants, very low-certainty evidence). People with G6PD deficiency were excluded. Other regimens Two RCTs evaluated other rarely-used doses of primaquine, one of which had very high loss to follow-up. Adverse events were not reported. People with G6PD deficiency and pregnant or lactating women were excluded. AUTHORS' CONCLUSIONS: Trials available to date do not detect a difference in recurrence between the following regimens: 1) 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days; 2) high-standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days; 3) 0.75 mg/kg/week for eight weeks versus high-standard 0.5 mg/kg/day for 14 days; 4) 1 mg/kg/day for seven days versus high-standard 0.5 mg/kg/day for 14 days. There were no differences detected in adverse events for Comparisons 1, 2 or 3, but there may be more serious adverse events with the high seven-day course in Comparison 4. The shorter regimen of 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days may suit G6PD-normal patients. Further research will help increase the certainty of the findings and applicability in different settings.


Assuntos
Antimaláricos/uso terapêutico , Malária Vivax/tratamento farmacológico , Primaquina/uso terapêutico , Adulto , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Criança , Esquema de Medicação , Glucosefosfato Desidrogenase , Humanos , Malária Vivax/enzimologia , Primaquina/administração & dosagem , Primaquina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Prevenção Secundária
17.
PLoS One ; 15(8): e0237831, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817707

RESUMO

INTRODUCTION: Coronavirus disease 2019 (COVID-19) can lead to respiratory failure due to severe immune response. Treatment targeting this immune response might be beneficial but there is limited evidence on its efficacy. The aim of this study was to determine if early treatment of patients with COVID-19 pneumonia with tocilizumab and/or steroids was associated with better outcome. METHODS: This observational single-center study included patients with COVID-19 pneumonia who were not intubated and received either standard of care (SOC, controls) or SOC plus early (within 3 days from hospital admission) anti-inflammatory treatment. SOC consisted of hydroxychloroquine 400mg bid plus, in those admitted before March 24th, also darunavir/ritonavir. Anti-inflammatory treatment consisted of either tocilizumab (8mg/kg intravenously or 162mg subcutaneously) or methylprednisolone 1 mg/kg for 5 days or both. Failure was defined as intubation or death, and the endpoints were failure-free survival (primary endpoint) and overall survival (secondary) at day 30. Difference between the groups was estimated as Hazard Ratio by a propensity score weighted Cox regression analysis (HROW). RESULTS: Overall, 196 adults were included in the analyses. They were mainly male (67.4%), with comorbidities (78.1%) and severe COVID-19 pneumonia (83.7%). Median age was 67.9 years (range, 30-100) and median PaO2/FiO2 200 mmHg (IQR 133-289). Among them, 130 received early anti-inflammatory treatment with: tocilizumab (n = 29, 22.3%), methylprednisolone (n = 45, 34.6%), or both (n = 56, 43.1%). The adjusted failure-free survival among tocilizumab/methylprednisolone/SOC treated patients vs. SOC was 80.8% (95%CI, 72.8-86.7) vs. 64.1% (95%CI, 51.3-74.0), HROW 0.48, 95%CI, 0.23-0.99; p = 0.049. The overall survival among tocilizumab/methylprednisolone/SOC patients vs. SOC was 85.9% (95%CI, 80.7-92.6) vs. 71.9% (95%CI, 46-73), HROW 0.41, 95%CI: 0.19-0.89, p = 0.025. CONCLUSION: Early adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Metilprednisolona/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/virologia , Darunavir/uso terapêutico , Feminino , Seguimentos , Inibidores da Protease de HIV/uso terapêutico , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Ritonavir/uso terapêutico , Resultado do Tratamento
18.
PLoS Med ; 17(8): e1003227, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797101

RESUMO

BACKGROUND: Malaria eradication remains the long-term vision of the World Health Organization (WHO). However, whether malaria elimination is feasible in areas of stable transmission in sub-Saharan Africa with currently available tools remains a subject of debate. This study aimed to evaluate a multiphased malaria elimination project to interrupt Plasmodium falciparum malaria transmission in a rural district of southern Mozambique. METHODS AND FINDINGS: A before-after study was conducted between 2015 and 2018 in the district of Magude, with 48,448 residents living in 10,965 households. Building on an enhanced surveillance system, two rounds of mass drug administrations (MDAs) per year over two years (phase I, August 2015-2017), followed by one year of reactive focal mass drug administrations (rfMDAs) (phase II, September 2017-June 2018) were deployed with annual indoor residual spraying (IRS), programmatically distributed long-lasting insecticidal nets (LLINs), and standard case management. The four MDA rounds covered 58%-72% of the population, and annual IRS reported coverage was >70%. Yearly parasite surveys and routine surveillance data were used to monitor the primary outcomes of the study-malaria prevalence and incidence-at baseline and annually since the onset of the project. Parasite prevalence by rapid diagnostic test (RDT) declined from 9.1% (95% confidence interval [CI] 7.0-11.8) in May 2015 to 2.6% (95% CI 2.0-3.4), representing a 71.3% (95% CI 71.1-71.4, p < 0.001) reduction after phase I, and to 1.4% (95% CI 0.9-2.2) after phase II. This represented an 84.7% (95% CI 81.4-87.4, p < 0.001) overall reduction in all-age prevalence. Case incidence fell from 195 to 75 cases per 1,000 during phase I (61.5% reduction) and to 67 per 1,000 during phase II (65.6% overall reduction). Interrupted time series (ITS) analysis was used to estimate the level and trend change in malaria cases associated with the set of project interventions and the number of cases averted. Phase I interventions were associated with a significant immediate reduction in cases of 69.1% (95% CI 57.5-77.6, p < 0.001). Phase II interventions were not associated with a level or trend change. An estimated 76.7% of expected cases were averted throughout the project (38,369 cases averted of 50,005 expected). One malaria-associated inpatient death was observed during the study period. There were 277 mild adverse events (AEs) recorded through the passive pharmacovigilance system during the four MDA rounds. One serious adverse event (SAE) that resulted in death was potentially related to the drug. The study was limited by the incomplete coverage of interventions, the quality of the routine and cross-sectional data collected, and the restricted accuracy of ITS analysis with a short pre-intervention period. CONCLUSION: In this study, we observed that the interventions deployed during the Magude project fell short of interrupting P. falciparum transmission with the coverages achieved. While new tools and strategies may be required to eventually achieve malaria elimination in stable transmission areas of sub-Saharan Africa, this project showed that innovative mixes of interventions can achieve large reductions in disease burden, a necessary step in the pathway towards elimination. TRIAL REGISTRATION: ClinicalTrials.gov NCT02914145.


Assuntos
Antimaláricos/administração & dosagem , Controle de Infecções/métodos , Malária Falciparum/prevenção & controle , Malária Falciparum/transmissão , Controle de Mosquitos/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Controle de Infecções/tendências , Malária Falciparum/epidemiologia , Masculino , Pessoa de Meia-Idade , Controle de Mosquitos/tendências , Moçambique , Adulto Jovem
19.
Malawi Med J ; 32(1): 45-51, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32733659

RESUMO

Background: Intermittent presumptive treatment in pregnancy (IPTp) of malaria using sulfadoxine-pyrimethamine (SP) was introduced in Nigeria in 2005 to reduce the burden of malaria in pregnancy. By 2013, 23% of reproductive aged women surveyed received SP for malaria prevention in their last pregnancy of the past 5 years. This paper highlights geographic and socio-economic variations and inequities in accessing and using SP for malaria prophylaxis in pregnancy in Nigeria, as well as client-related and service delivery determinants. Methods: Secondary data from 2013 Nigeria demographic and health survey (DHS) was used. Sample of 38,948 eligible women were selected for interview using stratified three-stage cluster design. Data obtained from the individual recode dataset was used for descriptive and logistic regression analysis of factors associated with SP use in pregnancy was performed. Independent variables were age, media exposure, region, place of residence, wealth index, place of antenatal care (ANC) attendance and number of visits. Results: Women in the upper three wealth quintiles were 1.33 - 1.80 times more likely to receive SP than the poorest (CI: 1.15-1.56; 1.41-1.97; 1.49-2.17). Women who received ANC from public health facilities were twice as likely (inverse of OR 0.68) to use SP in pregnancy than those who used private facilities (CI: 0.60-0.76). Those who attended at least 4 ANC visits were 1.46 times more likely to get SP prophylaxis (CI: 1.31-1.63). Using the unadjusted odds ratio, women residing in rural areas were 0.86 times less likely to use SP compared to those in urban areas. Conclusions: Inequities in access to and use of SP for malaria prophylaxis in pregnancy exist across sub-population groups in Nigeria. Targeted interventions on the least covered are needed to reduce existing inequities and scale-up IPTp of malaria.


Assuntos
Antimaláricos/administração & dosagem , Acesso aos Serviços de Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde , Malária/prevenção & controle , Complicações Parasitárias na Gravidez/prevenção & controle , Cuidado Pré-Natal/estatística & dados numéricos , Pirimetamina/administração & dosagem , Sulfadoxina/administração & dosagem , Adolescente , Adulto , Antimaláricos/uso terapêutico , Combinação de Medicamentos , Feminino , Pesquisas sobre Serviços de Saúde , Humanos , Pessoa de Meia-Idade , Nigéria , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológico , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , Adulto Jovem
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