RESUMO
Flatworms are known for their remarkable regenerative ability, one which depends on totipotent cells known as germinative cells in cestodes. Depletion of germinative cells with hydroxyurea (HU) affects the regeneration of the parasite. Here, we studied the reduction and recovery of germinative cells in T. crassiceps cysticerci after HU treatment (25 mM and 40 mM of HU for 6 days) through in vitro assays. Viability and morphological changes were evaluated. The recovery of cysticerci's mobility and morphology was evaluated at 3 and 6 days, after 6 days of treatment. The number of proliferative cells was evaluated using EdU. Our results show morphological changes in the size, shape, and number of evaginated cysticerci at the 40 mM dose. The mobility of cysticerci was lower after 6 days of HU treatment at both concentrations. On days 3 and 6 of recovery after 25 mM of HU treatment, a partial recovery of the proliferative cells was observed. Proteomic and Gene Ontology analyses identified modifications in protein groups related to DNA binding, DNA damage, glycolytic enzymes, cytoskeleton, skeletal muscle, and RNA binding.
Assuntos
Proliferação de Células , Hidroxiureia , Taenia , Hidroxiureia/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Taenia/efeitos dos fármacos , Taenia/genética , Taenia/crescimento & desenvolvimento , Taenia/metabolismo , Proteômica/métodos , Proteínas de Helminto/metabolismo , Proteínas de Helminto/genética , Proteoma/metabolismo , Cysticercus/efeitos dos fármacos , Cysticercus/metabolismoRESUMO
Abstract To date, hydroxyurea is the only effective and safe drug that significantly reduces morbidity and mortality of individuals with Sickle cell disease. Twenty years of real-life experience has demonstrated that hydroxyurea reduces pain attacks, vaso-occlusive events, including acute chest syndrome, the number and duration of hospitalizations and the need for transfusion. The therapeutic success of hydroxyurea is directly linked to access to the drug, the dose used and adherence to treatment which, in part, is correlated to the availability of hydroxyurea. This consensus aims to reduce the number of mandatory exams needed to access the drug, prioritizing the requesting physician's report, without affecting patient safety.
Assuntos
Anemia Falciforme , HidroxiureiaRESUMO
INTRODUÇÃO: Atualmente, a hidroxiureia é disponibilizada no SUS como cápsula de 500 mg, entretanto, foram submetidas para a análise do Comitê de Medicamentos da Conitec duas demandas para a incorporação desse medicamento nas formas farmacêuticas de comprimidos de 100 e 100 mg, o que motivou a elaboração desse relatório técnico. A primeira demanda partiu do grupo de especialistas que participam do processo de atualização do Protocolo Clínico e Diretrizes Terapêuticas de Doença Falciforme (PCDTDF). Para essa primeira demanda, o objetivo foi analisar somente o impacto orçamentário de uma possível incorporação da hidroxiureia nas concentrações de 100 e 1000 mg para o tratamento de indivíduos com pelo menos 9 meses de idade. A análise apenas do impacto orçamentário foi realizada porque o referido grupo elaborador do PCDTDF também solicitou a avaliação da ampliação de uso da hidroxiureia para todas as crianças entre 9 meses e 2 anos de idade independentemente de critérios de inclusão, que hoje é a regra para o fornecimento de hidroxiureia nesta
Assuntos
Humanos , Lactente , Hidroxiureia/administração & dosagem , Anemia Falciforme/tratamento farmacológico , Sistema Único de Saúde , Brasil , Eficácia , Análise Custo-Benefício/economiaRESUMO
INTRODUÇÃO: As manifestações clínicas da doença falciforme (DF) estão relacionadas à anemia hemolítica e aos efeitos da falcização intravascular repetida, resultando em vasooclusão e lesão isquêmica, além de morbidade e mortalidade consideráveis em idade precoce. Atualmente, a hidroxiureia é o padrão de tratamento para prevenir crises de dor vasoclusivas na DF, sendo recomendada para crianças entre 9 e 24 meses de idade, quando apresentam determinados sintomas ou complicações. Considerando que o uso precoce desta tecnologia (antes de 2 anos de idade) pode evitar o comprometimento a longo prazo relacionados à evolução da DF, o objetivo do presente relatório é analisar as evidências científicas sobre eficácia, efetividade, segurança, bem como evidências econômicas relacionadas ao uso de hidroxiureia para o tratamento de indivíduos com doença falciforme (SS, Sbeta0 e SD Punjab) entre 9 e 24 meses de idade, independentemente de sintomas e complicações. PERGUNTA: O uso de h
Assuntos
Humanos , Lactente , Hidroxiureia/uso terapêutico , Anemia Falciforme/tratamento farmacológico , Sistema Único de Saúde , Brasil , Eficácia , Análise Custo-Benefício/economiaRESUMO
Sickle cell disease (SCD) is associated with a high occurrence of complications due to vaso-occlusive phenomenon such as stroke. This retrospective cohort study aimed to examine the clinical and laboratory characteristics of 120 children and adolescents with SCD and analyze the factors associated with overt stroke incidence. All relevant data were obtained from patient medical records. Survival analysis was used to compare the demographic, clinical, and laboratory characteristics between patients with and those without overt stroke. The patients were 52.5% female with a mean (SD) age of 11.2 (4.3) years. The incidence of overt stroke in this cohort was nine out of 956.7 patient-years, resulting in an incidence density of 0.94 cases/100 patient-years. Reports of greater than or equal to two previous attacks of dactylitis and greater than or equal to three episodes of acute chest syndrome (ACS)/pneumonia were associated with overt stroke and an increase in reticulocyte count and red blood cell distribution width (RDW). In conclusion, a history of a high number of dactylitis, ACS/pneumonia, increased RDW, and reticulocytosis was associated with overt stroke occurrence in children and adolescents with SCD. Future studies with a higher stroke incidence in the evaluated sample are necessary to confirm this hypothesis.
Assuntos
Síndrome Torácica Aguda , Anemia Falciforme , Pneumonia , Acidente Vascular Cerebral , Criança , Humanos , Adolescente , Feminino , Masculino , Estudos Retrospectivos , Hidroxiureia , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Síndrome Torácica Aguda/etiologia , Síndrome Torácica Aguda/complicações , Pneumonia/complicaçõesRESUMO
Sickle cell disease (SCD) is a genetic disorder that has been associated with priapism. The role of hydroxyurea, a common SCD therapy, in influencing the nitric oxide (NO)-cGMP pathway and its effect on priapism is unclear. To investigate the effect of hydroxyurea treatment on smooth muscle relaxation of corpus cavernosum induced by stimulation of the NO-cGMP pathway in SCD transgenic mice and endothelial NO synthase gene-deficient (eNOS-/-) mice, which are used as model of priapism associated with the low bioavailability of endothelial NO. Four-month-old wild-type (WT, C57BL/6), SCD transgenic, and eNOS-/- male mice were treated with hydroxyurea (100 mg/Kg/day) or its vehicle (saline) daily for three weeks via intraperitoneal injections. Concentration-response curves for acetylcholine (ACh), sodium nitroprusside (SNP), and electrical field stimulation (EFS) were generated using strips of mice corpus cavernosum. The SCD mice demonstrated an amplified CC relaxation response triggered by ACh, EFS, and SNP. The corpus cavernosum relaxation responses to SNP and EFS were found to be heightened in the eNOS-/- group. However, the hydroxyurea treatment did not alter these escalated relaxation responses to ACh, EFS, and SNP in the corpus cavernosum of the SCD group, nor the relaxation responses to EFS and SNP in the eNOS-/- group. In conclusion, hydroxyurea is not effective in treating priapism associated with SCD. It is likely that excess plasma hemoglobin and reactive oxygen species, which are reported in SCD, are reacting with NO before it binds to GCs in the smooth muscle of the corpus cavernosum, thus preventing the restoration of baseline NO/cGMP levels. Furthermore, the downregulation of eNOS in the penis may impair the pharmacological action of hydroxyurea at the endothelial level in SCD mice. This study emphasize the urgency for exploring alternative therapeutic avenues for priapism in SCD that are not hindered by high plasma hemoglobin and ROS levels.
Assuntos
Anemia Falciforme , Priapismo , Humanos , Camundongos , Masculino , Animais , Priapismo/etiologia , Priapismo/complicações , Óxido Nítrico/metabolismo , Hidroxiureia/farmacologia , Hidroxiureia/uso terapêutico , Camundongos Endogâmicos C57BL , Pênis , Nitroprussiato/farmacologia , Nitroprussiato/metabolismo , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/metabolismo , Camundongos Transgênicos , Relaxamento Muscular , Acetilcolina/metabolismo , Fenótipo , Hemoglobinas/metabolismoRESUMO
Metabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with SCD enrolled in the WALK-PHaSST study (clinicaltrials gov. Identifier: NCT00492531). Clinical covariates informed the biological interpretation of metabolomics data, including genotypes (hemoglobin [Hb] SS, hemoglobin SC), history of recent transfusion (HbA%), response to hydroxyurea treatment (fetal Hb%). We investigated metabolic correlates to the degree of intravascular hemolysis, cardiorenal function, as determined by tricuspid regurgitation velocity (TRV), estimated glomerular filtration rate (eGFR), and overall hazard ratio (unadjusted or adjusted by age). Recent transfusion events or hydroxyurea treatment were associated with elevation in plasma-free fatty acids and decreases in acyl-carnitines, urate, kynurenine, indoles, carboxylic acids, and glycine- or taurine-conjugated bile acids. High levels of these metabolites, along with low levels of plasma S1P and L-arginine were identified as top markers of hemolysis, cardiorenal function (TRV, eGFR), and overall hazard ratio. We thus uploaded all omics and clinical data on a novel online portal that we used to identify a potential mechanism of dysregulated red cell S1P synthesis and export as a contributor to the more severe clinical manifestations in patients with the SS genotype compared to SC. In conclusion, plasma metabolic signatures - including low S1P, arginine and elevated kynurenine, acyl-carnitines and bile acids - are associated with clinical manifestation and therapeutic efficacy in SCD patients, suggesting new avenues for metabolic interventions in this patient population.
Assuntos
Anemia Falciforme , Doença da Hemoglobina SC , Humanos , Hidroxiureia/uso terapêutico , Cinurenina/uso terapêutico , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Doença da Hemoglobina SC/complicações , Hemólise , Hemoglobina Falciforme , Ácidos e Sais Biliares/uso terapêuticoRESUMO
Introduction: To examine the use of telehealth for delivery of health care in persons with sickle cell disease in a resource-constrained country during the COVID-19 pandemic. Methods: This study was a retrospective review of patient encounters at the Sickle Cell Unit (SCU), Jamaica during a 3-year period, March 10, 2019 to March 9, 2022 and a comparison of endpoints between 1 year before and 2 years during the pandemic. Primary endpoints of registration numbers, day-care admissions, and study visits were obtained from logbooks and the electronic medical records. Additional endpoints included well visits, hydroxyurea (HU) visits, and bone pain crisis. Results: Patients registered at the clinic on 17,295 occasions, with 7,820 in the pre-pandemic year decreasing by 43.8% and 35% in the 2 subsequent pandemic years. Overall, study visits increased by 4.9% and 1.3% in the pandemic years. They increased in adults by 13.1% and 8.9% but fell by 3.2% and 6.2% in children. Fewer people were seen in the pandemic years, with children showing a 20.7% decline in numbers. Tele-visits accounted for 31.4% of all study visits during the pandemic years and increased by 23.6% between the pandemic years. There were more well-visits and HU visits, but fewer pain visits and day-care admissions in the pandemic years. Conclusions: The SCU maintained health care delivery for a high-risk population during the pandemic, with tele-visits mitigating the short-fall from in-person visits. Tele-visits may be more acceptable to adults with a chronic illness and may be a suitable alternative for delivering health care.