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1.
Molecules ; 28(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36677903

RESUMO

Synergistic drug combinations have demonstrated effective therapeutic effects in cancer treatment. Deep learning methods accelerate identification of novel drug combinations by reducing the search space. However, potential adverse drug-drug interactions (DDIs), which may increase the risks for combination therapy, cannot be detected by existing computational synergy prediction methods. We propose DEML, an ensemble-based multi-task neural network, for the simultaneous optimization of five synergy regression prediction tasks, synergy classification, and DDI classification tasks. DEML uses chemical and transcriptomics information as inputs. DEML adapts the novel hybrid ensemble layer structure to construct higher order representation using different perspectives. The task-specific fusion layer of DEML joins representations for each task using a gating mechanism. For the Loewe synergy prediction task, DEML overperforms the state-of-the-art synergy prediction method with an improvement of 7.8% and 13.2% for the root mean squared error and the R2 correlation coefficient. Owing to soft parameter sharing and ensemble learning, DEML alleviates the multi-task learning 'seesaw effect' problem and shows no performance loss on other tasks. DEML has a superior ability to predict drug pairs with high confidence and less adverse DDIs. DEML provides a promising way to guideline novel combination therapy strategies for cancer treatment.


Assuntos
Perfilação da Expressão Gênica , Redes Neurais de Computação , Interações Medicamentosas , Terapia Combinada , Combinação de Medicamentos
4.
Nat Commun ; 14(1): 402, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36697413

RESUMO

Children recovering from severe malarial anaemia (SMA) remain at high risk of readmission and death after discharge from hospital. However, a recent trial found that post-discharge malaria chemoprevention (PDMC) with dihydroartemisinin-piperaquine reduces this risk. We developed a mathematical model describing the daily incidence of uncomplicated and severe malaria requiring readmission among 0-5-year old children after hospitalised SMA. We fitted the model to a multicentre clinical PDMC trial using Bayesian methods and modelled the potential impact of PDMC across malaria-endemic African countries. In the 20 highest-burden countries, we estimate that only 2-5 children need to be given PDMC to prevent one hospitalised malaria episode, and less than 100 to prevent one death. If all hospitalised SMA cases access PDMC in moderate-to-high transmission areas, 38,600 (range 16,900-88,400) malaria-associated readmissions could be prevented annually, depending on access to hospital care. We estimate that recurrent SMA post-discharge constitutes 19% of all SMA episodes in moderate-to-high transmission settings.


Assuntos
Anemia , Antimaláricos , Malária , Humanos , Criança , Lactente , Recém-Nascido , Pré-Escolar , Antimaláricos/uso terapêutico , Assistência ao Convalescente , Teorema de Bayes , Combinação de Medicamentos , Alta do Paciente , Malária/complicações , Malária/epidemiologia , Malária/prevenção & controle , África/epidemiologia , Anemia/complicações , Anemia/epidemiologia , Anemia/prevenção & controle , Quimioprevenção/métodos
5.
Stroke ; 54(2): 407-414, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36689592

RESUMO

Current projections are that the already overwhelming burden of strokes and atherosclerotic cardiovascular diseases in low- and middle-income countries (LMICs) will continue to rise over the coming decades as the prevalence of traditional vascular risk factors burgeon in these countries. Cardiovascular polypills containing combinations of antihypertensive(s), a statin, with or without aspirin or folic acid in the form of a single pill, represent a viable strategy for both primary and secondary prevention of atherosclerotic cardiovascular diseases in LMICs. Large multicenter trials in LMIC and high-income country (HIC) settings have now clearly demonstrated the beneficial effects of the cardiovascular polypill versus placebo (or usual care) in reducing primary stroke risk by 50%. For survivors of a recent myocardial infarction residing in HICs, the polypill reduced risk of major cardiovascular events by 25% due to improved treatment adherence. Data on the clinical efficacy of the polypill for secondary stroke prevention are scanty both in HICs and LMICs. Cost-effectiveness analyses data from LMICs suggest cost savings with the polypill for primary and secondary prevention of stroke and atherosclerotic cardiovascular diseases. However, major contextual barriers in LMICs need to be surmounted through mixed methods research and hybrid clinical trials to assess its real-world effectiveness, before the adoption of the polypill for primary and secondary atherosclerotic cardiovascular disease prevention in routine clinical practice.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Acidente Vascular Cerebral , Humanos , Países em Desenvolvimento , Inibidores da Agregação Plaquetária/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Combinação de Medicamentos , Anti-Hipertensivos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Resultado do Tratamento , Acidente Vascular Cerebral/tratamento farmacológico , Aterosclerose/complicações
6.
Antimicrob Agents Chemother ; 67(1): e0134622, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36602322

RESUMO

Ceftibuten is an established, oral, third-generation cephalosporin in early clinical development in combination with an oral prodrug of avibactam for the treatment of complicated urinary tract infections, including acute pyelonephritis. We evaluated the in vitro activity of ceftibuten-avibactam against 1,165 Enterobacterales isolates selected from the 2016-2020 ATLAS global surveillance program based upon their ß-lactamase genotype, ß-lactam-susceptible phenotype, species identification, and specimen source (95.8% urine). MICs were determined by CLSI broth microdilution. Avibactam was tested at a fixed concentration of 4 µg/mL. Molecular methods were used to identify ß-lactamase genes. Ceftibuten-avibactam inhibited 90% (MIC90) of ESBL-producing (n = 645), KPC-producing (n = 60), chromosomal AmpC-positive (n = 100), OXA-48-like-producing (n = 50), and acquired AmpC-producing (n = 110) isolates at concentrations of 0.12, 0.5, 1, 2, and 4 µg/mL, respectively. At concentrations of ≤1 and ≤8 µg/mL, ceftibuten-avibactam inhibited 98.4 and 99.2% of ESBL-positive isolates; 96.7 and 100% of KPC-positive isolates; 91.0 and 99.0% of chromosomal AmpC-positive isolates; 86.0 and 96.0% of OXA-48-like-positive isolates; and 85.5 and 91.8% of acquired AmpC-positive isolates. Against ESBL-producing, KPC-producing, chromosomal AmpC-positive, OXA-48-like-producing, and acquired AmpC-producing isolates, ceftibuten-avibactam was 256-, 128-, >64-, >32-, and > 16-fold more potent than ceftibuten alone. The potency of ceftibuten-avibactam was 4-fold greater than ceftazidime-avibactam against ESBL-producing (ceftibuten-avibactam MIC90, 0.12 µg/mL; ceftazidime-avibactam MIC90, 0.5 µg/mL) and KPC-producing (0.5 µg/mL; 2 µg/mL) isolates, equivalent to ceftazidime-avibactam (MIC90, 2 µg/mL) against OXA-48-like-producing isolates, 2-fold less active than ceftazidime-avibactam (1 µg/mL; 0.5 µg/mL) against chromosomal AmpC-positive isolates, and 4-fold less active than ceftazidime-avibactam (4 µg/mL; 1 µg/mL) against acquired AmpC-producing isolates. Continued development of ceftibuten-avibactam appears justified.


Assuntos
Antibacterianos , Gammaproteobacteria , Antibacterianos/farmacologia , Ceftibuteno , Enterobacteriaceae/genética , Ceftazidima/farmacologia , Compostos Azabicíclicos/farmacologia , beta-Lactamases/genética , Combinação de Medicamentos , Testes de Sensibilidade Microbiana
7.
BMJ Open ; 13(1): e063668, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36697043

RESUMO

OBJECTIVES: This pre-post implementation study evaluated the introduction of fixed dose combination (FDC) medications for atherosclerotic cardiovascular disease (ASCVD) secondary prevention into routine care in a humanitarian setting. SETTING: Two Médecins sans Frontières (MSF) primary care clinics serving Syrian refugee and host populations in north Lebanon. PARTICIPANTS: Consenting patients ≥18 years with existing ASCVD requiring secondary prevention medication were eligible for study enrolment. Those with FDC contraindication(s) or planning to move were excluded. Of 521 enrolled patients, 460 (88.3%) were retained at 6 months, and 418 (80.2%) switched to FDC. Of these, 84% remained on FDC (n=351), 8.1% (n=34) discontinued and 7.9% (n=33) were lost to follow-up by month 12. INTERVENTIONS: Eligible patients, enrolled February-May 2019, were switched to Trinomia FDC (atorvastatin 20 mg, aspirin 100 mg, ramipril 2.5/5/10 mg) after 6 months' usual care. During the study, the COVID-19 pandemic, an economic crisis and clinic closures occurred. OUTCOME MEASURES: Descriptive and regression analyses compared key outcomes at 6 and 12 months: medication adherence, non-high density lipoprotein cholesterol (non-HDL-C) and systolic blood pressure (SBP) control. We performed per-protocol, intention-to-treat and secondary analyses of non-switchers. RESULTS: Among 385 switchers remaining at 12 months, total adherence improved 23%, from 63% (95% CI 58 to 68) at month 6, to 86% (95% CI 82 to 90) at month 12; mean non-HDL-C levels dropped 0.28 mmol/L (95% CI -0.38 to -0.18; p<0.0001), from 2.39 (95% CI 2.26 to 2.51) to 2.11 mmol/L (95% CI 2.00 to 2.22); mean SBP dropped 2.89 mm Hg (95% CI -4.49 to -1.28; p=0.0005) from 132.7 (95% CI 130.8 to 134.6) to 129.7 mm Hg (95% CI 127.9 to 131.5). Non-switchers had smaller improvements in adherence and clinical outcomes. CONCLUSION: Implementing an ASCVD secondary prevention FDC improved adherence and CVD risk factors in MSF clinics in Lebanon, with potential for wider implementation by humanitarian actors and host health systems.


Assuntos
COVID-19 , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/epidemiologia , Líbano/epidemiologia , Pandemias , Atorvastatina/uso terapêutico , Combinação de Medicamentos , Colesterol
9.
Artigo em Inglês | MEDLINE | ID: mdl-36700602

RESUMO

BACKGROUND: The spread of carbapenemase- and extended-spectrum ß-lactamase (ESBL)-producing gram-negative bacilli (GNB) represent a global public health threat that limits therapeutic options for hospitalized patients. This study aimed to evaluate the in-vitro susceptibility of ß-lactam-resistant GNB to ceftazidime-avibactam (C/A) and ceftolozane-tazobactam (C/T), and investigate the molecular determinants of resistance. METHODS: Overall, 101 clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected from a general hospital in Brazil were analyzed. Susceptibility to the antimicrobial agents was evaluated using an automated method, and the minimum inhibitory concentrations (MIC50/90) of C/A and C/T were determined using Etest®. The ß-lactamase-encoding genes were investigated using polymerase chain reaction. RESULTS: High susceptibility to C/A and C/T was observed among ESBL-producing Enterobacterales (100% and 97.3% for CLSI and 83.8% for BRCAST, respectively) and carbapenem-resistant P. aeruginosa (92.3% and 87.2%, respectively). Carbapenemase-producing Klebsiella pneumoniae exhibited high resistance to C/T (80%- CLSI or 100%- BRCAST) but high susceptibility to C/A (93.4%). All carbapenem-resistant K. pneumoniae isolates were susceptible to C/A, whereas only one isolate was susceptible to C/T. Both antimicrobials were inactive against metallo-ß-lactamase-producing K. pneumoniae isolates. Resistance genes were concomitantly identified in 44 (44.9%) isolates, with bla CTX-M and bla SHV being the most common. CONCLUSIONS: C/A and C/T were active against microorganisms with ß-lactam-resistant phenotypes, except when resistance was mediated by metallo-ß-lactamases. Most C/A- and C/T-resistant isolates concomitantly carried two or more ß-lactamase-encoding genes (62.5% and 77.4%, respectively).


Assuntos
Antibacterianos , Lactamas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Brasil , Hospitais Gerais , Ceftazidima/farmacologia , Cefalosporinas/farmacologia , Tazobactam/farmacologia , Combinação de Medicamentos , Bactérias Gram-Negativas/genética , Pseudomonas aeruginosa , Klebsiella pneumoniae , Carbapenêmicos , beta-Lactamases/genética , Testes de Sensibilidade Microbiana
10.
Malar J ; 22(1): 2, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36597076

RESUMO

BACKGROUND: The contribution of artefenomel to the clinical and parasiticidal activity of ferroquine and artefenomel in combination in uncomplicated Plasmodium falciparum malaria was investigated. METHODS: This Phase 2a, randomized, open-label, parallel-group study was conducted from 11th September 2018 to 6th November 2019 across seven centres in Benin, Burkina Faso, Gabon, Kenya, and Uganda. Patients aged ≥ 14-69 years with microscopically confirmed infection (≥ 3000 to ≤ 50,000 parasites/µL blood) were randomized 1:1:1:1 to 400 mg ferroquine, or 400 mg ferroquine plus artefenomel 300, 600, or 1000 mg, administered as a single oral dose. The primary efficacy analysis was a logistic regression evaluating the contribution of artefenomel exposure to Day 28 PCR-adjusted adequate clinical and parasitological response (ACPR). Safety was also evaluated. RESULTS: The randomized population included 140 patients. For the primary analysis in the pharmacokinetic/pharmacodynamic efficacy population (N = 121), the contribution of artefenomel AUC0-∞ to Day 28 PCR-adjusted ACPR was not demonstrated when accounting for ferroquine AUC0-d28, baseline parasitaemia, and other model covariates: odds ratio 1.1 (95% CI 0.98, 1.2; P = 0.245). In the per-protocol population, Day 28 PCR-adjusted ACPR was 80.8% (21/26; 95% CI 60.6, 93.4) with ferroquine alone and 90.3% (28/31; 95% CI 74.2, 98.0), 90.9% (30/33; 95% CI 75.7, 98.1) and 87.1% (27/31; 95% CI 70.2, 96.4) with 300, 600, and 1000 mg artefenomel, respectively. Median time to parasite clearance (Kaplan-Meier) was 56.1 h with ferroquine, more rapid with artefenomel, but similar for all doses (30.0 h). There were no deaths. Adverse events (AEs) of any cause occurred in 51.4% (18/35) of patients with ferroquine 400 mg alone, and 58.3% (21/36), 66.7% (24/36), and 72.7% (24/33) with 300, 600, and 1000 mg artefenomel, respectively. All AEs were of mild-to-moderate severity, and consistent with the known profiles of the compounds. Vomiting was the most reported AE. There were no cases of QTcF prolongation ≥ 500 ms or > 60 ms from baseline. CONCLUSION: The contribution of artefenomel exposure to the clinical and parasitological activity of ferroquine/artefenomel could not be demonstrated in this study. Parasite clearance was faster with ferroquine/artefenomel versus ferroquine alone. All treatments were well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03660839 (7 September, 2018).


Assuntos
Antimaláricos , Malária Falciparum , Humanos , Antimaláricos/farmacologia , Plasmodium falciparum , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Aminoquinolinas/uso terapêutico , Resultado do Tratamento , Combinação de Medicamentos
11.
Trials ; 24(1): 2, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36597163

RESUMO

BACKGROUND: Oral chloral hydrate is widely used in pediatric sedation. Intranasal dexmedetomidine has been increasingly used for pediatric sedation; however, its improvement is warranted. The combination of dexmedetomidine with ketamine can improve onset and hemodynamic stability while maintaining sedative efficacy. This study aims to determine the efficacy and safety of intranasal combination of dexmedetomidine and ketamine compared to oral chloral hydrate. METHODS: This is a prospective, parallel-arm, single-blinded, two-center, superiority randomized controlled trial with 1:1 allocation, designed to compare the effects of intranasal combination of dexmedetomidine and ketamine with those of oral chloral hydrate. We shall enroll 136 patients aged < 7 years old in this study. Prior to the procedure, we shall randomize each patient into the control group (oral chloral hydrate 50 mg/kg) or study group (intranasal dexmedetomidine 2 µg/kg and ketamine 3 mg/kg). The primary outcome will be the rate of achieving an adequate sedation level (6-point Pediatric Sedation State Scale 1, 2, or 3) within 15 min. In addition, we shall measure the sedation time, sedation failure rate, completion of procedure, adverse events, patient acceptance, and physician satisfaction. DISCUSSION: This study will provide evidence of the efficacy and safety of the intranasal combination of dexmedetomidine and ketamine in comparison with oral chloral hydrate. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04820205. Registered on 19th March 2021.


Assuntos
Dexmedetomidina , Ketamina , Criança , Humanos , Administração Intranasal , Administração Oral , Hidrato de Cloral/administração & dosagem , Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Ketamina/administração & dosagem , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Combinação de Medicamentos
12.
J Cardiovasc Pharmacol Ther ; 28: 10742484221146375, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36594416

RESUMO

AIMS: In recent large trials, sacubitril/valsartan demonstrated favorable effects in patients with HF. However, many patients do not achieve the target dose of treatment. This study investigated the factors linked to up-titration of sacubitril/valsartan in patients with heart failure and preserved ejection fraction (HFpEF). METHODS: Using a multicenter retrospective database, 204 consecutive patients with HFpEF (left ventricular ejection fraction ≥ 40%) who were treated with sacubitril/valsartan between October 2020 and March 2022 were analyzed. Up-titration was defined as an increase in dosage above 24/26 mg BID beyond 12 weeks after the initiation of sacubitril/valsartan. RESULTS: Among the patients, 55% underwent up-titration, and 8% discontinued the drug. The baseline systolic blood pressure (SBP) was higher in patients with up-titration than in those with no up-titration; SBP values similar to that at baseline were observed between the 2 groups at 2 to 4 weeks and at 12 weeks after the commencement of sacubitril/valsartan treatment. The majority of those who discontinued sacubitril/valsartan did so because of hypotension. The multivariable logistic regression model showed that a history of hypertension, history of atrial fibrillation, baseline SBP, and baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 were associated with sacubitril/valsartan up-titration. CONCLUSION: Approximately half of all patients did not undergo up-titration, and 8% of those with HFpEF discontinued the sacubitril/valsartan therapy. For aggressive up-titration and continuation of sacubitril/valsartan, patients with lower baseline SBP, renal dysfunction, absence of a history of hypertension, and presence of atrial fibrillation may require more careful monitoring.


Assuntos
Fibrilação Atrial , Insuficiência Cardíaca , Hipertensão , Humanos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico , Fibrilação Atrial/tratamento farmacológico , Estudos Retrospectivos , Tetrazóis/efeitos adversos , Função Ventricular Esquerda , Resultado do Tratamento , Antagonistas de Receptores de Angiotensina/efeitos adversos , Valsartana/efeitos adversos , Combinação de Medicamentos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico
13.
Zhonghua Yi Xue Za Zhi ; 103(2): 117-124, 2023 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-36597739

RESUMO

Objective: To investigate the efficacy of sacubitril/valsartan in peritoneal dialysis (PD) patients with heart failure with preserved ejection fraction (HFpEF) and its effect on residual renal function. Methods: PD patients with HFpEF in Ningbo First Hospital from March 2018 to August 2021 were retrospectively enrolled and divided into study group with sacubitril/valsartan and control group with valsartan. The clinical baseline data before treatment and clinical indicators during follow-up (6 and 12 months after treatment) were collected and compared between the two groups, and the adverse reactions were also recorded. Results: A total of 99 patients were included in the study. There were 61 patients in the study group, including 44 males and 17 females, with a mean age of (52±13) years. Meanwhile, there were 38 patients in the control group, including 23 males and 15 females, with a mean age of (57±14) years. There was no statistically significant difference in clinical baseline data between the two groups (e.g., age, sex, body mass index, duration of dialysis) (all P>0.05). The N-terminal pro-B-type natriuretic peptide (NT-proBNP) and left ventricular end-systolic dimension (LVDs) were lower, but the left ventricular ejection fraction (LVEF) was higher in the study group than those in the control group at 6 and 12 months after treatment (all P<0.05). The systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the two groups were lower than baseline values at 6 and 12 months after treatment respectively, with statistically significant differences (all P<0.05). However, there were no statistically significant differences in the decreases of SBP and DBP between the two groups at 6 and 12 months after treatment (all P>0.05). The decrease extents in residual estimated glomerular filtration rate (eGFR) [0.52 (-0.05, 1.19) vs 1.72 (0.97, 2.39) ml·min-1·(1.73 m2)-1, P<0.001]and 24-h residual urine volume [200 (-100, 300) vs 300 (137, 400) ml, P=0.018] at 12 months after treatment were lower in the study group than those in the control group. During the follow-up period, hyperkalemia occurred in 16 cases (26.2%) and 13 cases (34.2%) in the study group and the control group, and hypotension occurred in 3 cases (4.9%) and 1 case (2.6%) in the study group and the control group, respectively. There were no adverse reactions such as cough and angioneurotic edema in the two groups. Conclusions: Sacubitril/valsartan can safely and effectively improve cardiac function and lower blood pressure in PD patients with HFpEF. Compared with valsartan, sacubitril/valsartan may be more beneficial to delay the loss of residual renal function in PD patients with HFpEF.


Assuntos
Insuficiência Cardíaca , Diálise Peritoneal , Masculino , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Volume Sistólico/fisiologia , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Estudos Retrospectivos , Tetrazóis/uso terapêutico , Função Ventricular Esquerda/fisiologia , Valsartana/uso terapêutico , Combinação de Medicamentos , Rim/fisiologia , Antagonistas de Receptores de Angiotensina/uso terapêutico
14.
J Drugs Dermatol ; 22(1): 54-59, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36607767

RESUMO

BACKGROUND: Benzoyl peroxide (BPO) has been used extensively in industry and health care for more than a century and has been approved for the treatment of acne for over 60 years. Recently, BPO received a second approved indication by the US Food and Drug Administration (FDA) for the treatment of rosacea. Topical BPO use has historically been limited by tolerability, photosensitivity, oxidation, and, uncommonly, contact allergy. Research has led to enhanced efficacy and tolerability, as well as the combination of BPO with other topical medications. These advances have allowed extended use of BPO in additional dermatologic conditions that may not have been feasible in the past. Additionally, the role of BPO in preventing antibiotic resistance cannot be underestimated. Here, we discuss the historical limitations of BPO and recent advances developed to overcome these limitations. We also describe newly approved BPO medications and their role in aiding antibiotic stewardship. J Drugs Dermatol. 2023;22(1):54-59. doi:10.36849/JDD.7150.


Assuntos
Acne Vulgar , Fármacos Dermatológicos , Dermatologia , Humanos , Peróxido de Benzoíla/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Acne Vulgar/tratamento farmacológico , Administração Tópica , Géis/uso terapêutico , Combinação de Medicamentos , Resultado do Tratamento
15.
Malar J ; 22(1): 7, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609279

RESUMO

BACKGROUND: It has been more than 20 years since the malaria epidemiologic shift to school-aged children was noted. In the meantime, school-aged children (5-15 years) have become increasingly more vulnerable with asymptomatic malaria prevalence reaching up to 70%, making them reservoirs for subsequent transmission of malaria in the endemic communities. Intermittent Preventive Treatment of malaria in schoolchildren (IPTsc) has proven to be an effective tool to shrink this reservoir. As of 3rd June 2022, the World Health Organization recommends IPTsc in moderate and high endemic areas. Even so, for decision-makers, the adoption of scientific research recommendations has been stifled by real-world implementation challenges. This study presents methodology, challenges faced, and mitigations used in the evaluation of the implementation of IPTsc using dihydroartemisinin-piperaquine (DP) in three councils (Handeni District Council (DC), Handeni Town Council (TC) and Kilindi DC) of Tanga Region, Tanzania so as to understand the operational feasibility and effectiveness of IPTsc on malaria parasitaemia and clinical malaria incidence. METHODS: The study deployed an effectiveness-implementation hybrid design to assess feasibility and effectiveness of IPTsc using DP, the interventional drug, against standard of care (control). Wards in the three study councils were the randomization unit (clusters). Each ward was randomized to implement IPTsc or not (control). In all wards in the IPTsc arm, DP was given to schoolchildren three times a year in four-month intervals. In each council, 24 randomly selected wards (12 per study arm, one school per ward) were chosen as representatives for intervention impact evaluation. Mixed design methods were used to assess the feasibility and acceptability of implementing IPTsc as part of a more comprehensive health package for schoolchildren. The study reimagined an existing school health programme for Neglected Tropical Diseases (NTD) control include IPTsc implementation. RESULTS: The study shows IPTsc can feasibly be implemented by integrating it into existing school health and education systems, paving the way for sustainable programme adoption in a cost-effective manner. CONCLUSIONS: Through this article other interested countries may realise a feasible plan for IPTsc implementation. Mitigation to any challenge can be customized based on local circumstances without jeopardising the gains expected from an IPTsc programme. Trial registration clinicaltrials.gov, NCT04245033. Registered 28 January 2020, https://clinicaltrials.gov/ct2/show/NCT04245033.


Assuntos
Antimaláricos , Malária , Quinolinas , Humanos , Criança , Antimaláricos/uso terapêutico , Tanzânia/epidemiologia , Malária/epidemiologia , Malária/prevenção & controle , Malária/tratamento farmacológico , Quinolinas/uso terapêutico , Combinação de Medicamentos
16.
Malar J ; 22(1): 9, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36611179

RESUMO

BACKGROUND: In 2004, Ethiopia adopted artemether-lumefantrine (AL, Coartem®) as first-line treatment for the management of uncomplicated Plasmodium falciparum malaria. Continuous monitoring of AL therapeutic efficacy is crucial in Ethiopia, as per the World Health Organization (WHO) recommendation. This study aimed to assess the therapeutic efficacy of AL in the treatment of uncomplicated P. falciparum infection. METHODS: A 28 day onearm, prospective evaluation of the clinical and parasitological response to AL was conducted at Shecha Health Centre, Arba Minch town, Southern Ethiopia. Patients were treated with six-dose regimen of AL over three days and monitored for 28 days with clinical and laboratory assessments. Participant recruitment and outcome classification was done in accordance with the 2009 WHO methods for surveillance of anti-malarial drug efficacy guidelines. RESULTS: A total of 88 study participants were enrolled and 69 of them completed the study with adequate clinical and parasitological response. Two late parasitological failures were observed, of which one was classified as a recrudescence by polymerase chain reaction (PCR). The PCRcorrected cure rate was 98.6% (95% CI 92.3-100). AL demonstrated a rapid parasite and fever clearance with no parasitaemia on day 2 and febrile cases on day 3. Gametocyte clearance was complete by day three. No serious adverse events were reported during the 28 days follow-up. CONCLUSION: The study demonstrated high therapeutic efficacy and good safety profile of AL. This suggests the continuation of AL as the first-line drug for the treatment of uncomplicated P. falciparum malaria in Ethiopia. Periodic therapeutic efficacy studies and monitoring of markers of resistance are recommended for early detection of resistant parasites.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Humanos , Lactente , Combinação Arteméter e Lumefantrina/uso terapêutico , Antimaláricos/efeitos adversos , Etiópia/epidemiologia , Artemisininas/efeitos adversos , Artemeter/uso terapêutico , Plasmodium falciparum , Combinação de Medicamentos , Fluorenos/efeitos adversos , Resultado do Tratamento , Etanolaminas/efeitos adversos , Malária Falciparum/epidemiologia , Febre/tratamento farmacológico
17.
Ann Med ; 55(1): 276-284, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36594446

RESUMO

BACKGROUND: Globally, the prevalence of hypertension and the accompanying burden of cardiovascular disease are increasing. Through drug utilization research, we can understand the prescription status of hypertension patients and promote rational drug use. The purpose of this retrospective study was to describe the current prescription pattern of antihypertensive drugs in Chinese patients and determine the compliance level of treatment guidelines. MATERIALS AND METHODS: Around 11.1 million patients who received a prescription for antihypertensive therapy between January 2021 to December 2021 were obtained from a database of Hangzhou Kang Sheng Health Consulting CO., Ltd. RESULTS: The mean age of hypertensive patients was 54.75 ± 12.98 years. About 6.7 million (60.30%) were males. About 46.07% of patients had comorbidities. The most common classes of antihypertensive medications used were calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs). Around 78.33% of participants were on monotherapy. Diuretics + ARBs and Diuretics + CCBs + ARBs were the most commonly prescribed pattern in two-drug combination therapy and three-drug combination therapy, respectively. CONCLUSIONS: CCBs and ARBs were the two most frequently prescribed for patients with hypertension. The prescription pattern of antihypertensive medications in the study largely complied with recommended Chinese hypertension guidelines.Key messagesCardiovascular disease is the most common complication of hypertension.Calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs) are the two most commonly used drugs for hypertension patients in China.The proportion of combination prescription pattern in Chinese hypertensive patients is low.


Assuntos
Anti-Hipertensivos , Hipertensão , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Feminino , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Estudos Retrospectivos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Diuréticos/uso terapêutico , Prescrições , Combinação de Medicamentos
18.
Int J Mol Sci ; 24(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36674961

RESUMO

Opioid drugs have analgesic properties used to treat chronic and post-surgical pain due to descending pain modulation. The use of opioids is often associated with adverse effects or clinical issues. This study aimed to evaluate the toxicity of opioids by exposing the neuroblastoma cell line (SH-SY5Y) to 0, 1, 10, and 100 µM oxycodone and naloxone for 24 h. Analyses were carried out to evaluate cell cytotoxicity, identification of cell death, DNA damage, superoxide dismutase (SOD), glutathione S-transferase (GST), and acetylcholinesterase (AChE) activities, in addition to molecular docking. Oxycodone and naloxone exposure did not alter the SH-SY5Y cell viability. The exposure to 100 µM oxycodone and naloxone significantly increased the cells' DNA damage score compared to the control group. Naloxone exposure significantly inhibited AChE, GST, and SOD activities, while oxycodone did not alter these enzymes' activities. Molecular docking showed that naloxone and oxycodone interact with different amino acids in the studied enzymes, which may explain the differences in enzymatic inhibition. Naloxone altered the antioxidant defenses of SH-SY5Y cells, which may have caused DNA damage 24 h after the exposure. On the other hand, more studies are necessary to explain how oxycodone causes DNA damage.


Assuntos
Neuroblastoma , Oxicodona , Humanos , Oxicodona/efeitos adversos , Naloxona/farmacologia , Acetilcolinesterase , Simulação de Acoplamento Molecular , Constipação Intestinal/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Linhagem Celular , Superóxido Dismutase , Preparações de Ação Retardada/uso terapêutico , Combinação de Medicamentos
19.
Phytomedicine ; 110: 154630, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36608499

RESUMO

BACKGROUND: Shenmai Injection (SMI), a Chinese herbal injection, is widely used in China for the adjuvant treatment of patients with dilated cardiomyopathy (DCM), yet its clinical efficacy and safety remain controversial. PURPOSE: The aim of this study was to systematically evaluate the efficacy and safety of SMI in the treatment of DCM. METHODS: Randomised controlled trials (RCTs) of SMI in the treatment of DCM were searched for and collected from the PubMed, EMBASE, Cochrane Library, SinoMed, Wan Fang, CNKI, and VIP databases between the dates of establishment of each database and July 1, 2022. The methodological quality of the included studies was assessed, while the risk of bias was based on the Cochrane Collaboration tool. All data were analysed using the R software. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was applied to rate the quality of the evidence. RESULTS: In total, 16 RCTs, including 1,455 participants, were examined in this study. Evidence showed that the combination of SMI treatment and conventional treatment appears to significantly increase the clinical efficacy rate (OR=3.65, 95%CI (2.52, 5.28), p < 0.01), improve cardiac function (e.g. increase left ventricular ejection fraction (LVEF) (MD=5.31, 95%CI (4.21, 6.40), p < 0.01), decrease left ventricular end-diastolic dimension (LVEDD) (MD=-4.57, 95% CI (-7.10, -2.04); p < 0.01) and left ventricular end-systolic diameter (LVESD) (MD=-2.46, 95% CI (-3.60, -1.33); p < 0.01), decrease brain natriuretic peptide (BNP) (MD=-215.85, 95% CI (-241.61, -190.10); p < 0.01) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (MD=-504.42, 95% CI (-687.73, -321.10); p < 0.01), and increase 6-min walk distance (6MWD) (MD=114.08, 95% CI (42.32, 185.85); p < 0.01).In addition, no serious adverse effects associated with SMI were observed during the study period, thus suggesting that SMI is safe. However, the quality of evidence for these results was rated as "very low" to "low", mainly due to the poor methodological quality of the included RCTs, the small sample size, the high heterogeneity, and potential publication bias. CONCLUSION: In the present work, we provide evidence that combined SMI therapy is beneficial and safe for improving cardiac function in patients with DCM. However, due to limitations posed by the low methodological quality of the included trials, more rigorous and high-quality RCTs are needed to provide solid evidence.


Assuntos
Cardiomiopatia Dilatada , Medicamentos de Ervas Chinesas , Humanos , Cardiomiopatia Dilatada/tratamento farmacológico , Peptídeo Natriurético Encefálico , Medicamentos de Ervas Chinesas/uso terapêutico , Combinação de Medicamentos , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Sci Rep ; 13(1): 409, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624299

RESUMO

Solanum nigrum L. (Black nightshade), is one of the most troublesome weeds of summer crops such as corn, soybean, sunflower, etc. To study the effect of combined Castor oil as an adjuvant with different doses of Lumax (Mesotrion + S-metolacholor + Terbuthylazine) on the physiological behavior of Solanum nigrum L., a greenhouse experiment was conducted in randomized complete block design with four replications in agricultural faculty of the University of Tabriz in 2021. A foliar application of Lumax increased proline, malondialdehyde, and hydrogen peroxide concentrations and superoxide dismutase, catalase, and peroxidase activity. The content of protein and photosynthetic pigments (Chlorophyll a, b, and carotenoids) also decreased significantly by using Lumax herbicide. Applying castor oil in combination with Lumax intensifies oxidative stress and lipid peroxidation. Results showed that by increasing the herbicide doses in comparison with control (non-herbicide), Area, Fm, Fv, Fv/Fm, Fv/F0, Sm, Sm/Tfm, and Fv/F0 decreased 48.32%, 19.52%, 27.95%, 10.47%, 50.90%, 28.34%, 79.38%, and 50.90%, respectively and F0, F0/Fm increased 46.76% and 82.38%, respectively. Castor oil showed a synergistic effect on Lumax herbicide and enhanced its efficacy on Solanum nigrum. The presented results supported the view that by evaluating chlorophyll a fluorescence parameters, we would realize herbicide (alone or mixed with any adjacent) efficacy before the visual symptoms appear in the plant.


Assuntos
Óleo de Rícino , Herbicidas , Solanum nigrum , Antioxidantes/metabolismo , Óleo de Rícino/farmacologia , Clorofila A/metabolismo , Fluorescência , Fotossíntese , Solanum nigrum/efeitos dos fármacos , Solanum nigrum/metabolismo , Concentração Osmolar , Herbicidas/farmacologia , Combinação de Medicamentos
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