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1.
Pediatr Blood Cancer ; 69(6): e29607, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35373884

RESUMO

BACKGROUND: Hydroxyurea is the primary treatment for sickle cell anemia (SCA), yet real-world implementation in high-income settings is suboptimal. Variation in prescribed hydroxyurea dose and patient adherence in these settings can both affect actual exposure to hydroxyurea. Quantifying the contributions of hydroxyurea dose and medication adherence to the relationship between hydroxyurea exposure and hematologic parameters could inform strategies to optimize exposure and improve outcomes. PROCEDURE: We evaluated the relationship between hydroxyurea exposure, defined by average prescribed dose and adherence, and hematologic parameters using data from children with SCA who were enrolled in two prospective hydroxyurea adherence studies. Hydroxyurea adherence was assessed by video directly observed therapy or electronic pill bottle and medication administration record. Average prescribed dose was abstracted from prescriptions in patients' electronic medical record. Participants with a hydroxyurea exposure >20 mg/kg/day and ≤20 mg/kg/day were included in the higher and lower exposure groups, respectively. RESULTS: Forty-five participants were included in the analysis (56% male; median age 12 years [range 2-19]; 98% Black). Higher exposed participants (n = 23) were prescribed a higher dose (27.2 vs. 24.4 mg/kg/day, p = .002) and had better adherence (0.92 vs. 0.71, p ≤ .001) compared to lower exposed participants (n = 22). Higher exposure was associated with higher fetal hemoglobin (p = .04) and mean corpuscular volume (p = .02). CONCLUSIONS: Higher hydroxyurea exposure is associated with improved hematologic parameters in the high-income setting and is affected by both prescribed dose and adherence. Future studies are needed to optimize both adherence and hydroxyurea prescribing and confirm that increasing exposure improves clinical outcomes in this setting.


Assuntos
Anemia Falciforme , Antidrepanocíticos , Hidroxiureia , Adolescente , Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/uso terapêutico , Criança , Pré-Escolar , Feminino , Hemoglobina Fetal , Humanos , Hidroxiureia/uso terapêutico , Masculino , Adesão à Medicação , Estudos Prospectivos , Adulto Jovem
2.
Int J Hematol ; 115(5): 659-671, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35394259

RESUMO

Polycythemia vera (PV) and essential thrombocythemia (ET) are the two most common subtypes of Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). PV results in erythrocytosis and ET in thrombocytosis. The discovery of JAK2 mutations in the majority of patients with MPN over the last 2 decades has led to the development of JAK inhibitors. Because PV and ET progress relatively slowly, the main treatment strategy for these two diseases is to prevent thrombotic complications. The first-line agent for both PV and ET is hydroxyurea, although some patients are intolerant or refractory to this compound and need other treatment options. Notably, hydroxyurea is contraindicated during pregnancy. In addition to JAK inhibitors, several new agents, such as HDAC inhibitors, LSD1 inhibitors, MDM2 inhibitors and hepcidin mimetics, have been developed as treatment options. Classical agents, such as busulfan and interferon, are still used to treat patients with PV or ET as well. Based on this context, treatment options and pregnancy management for patients with PV or ET are discussed in this review.


Assuntos
Inibidores de Janus Quinases , Transtornos Mieloproliferativos , Policitemia Vera , Trombocitemia Essencial , Aspirina , Feminino , Humanos , Hidroxiureia/uso terapêutico , Janus Quinase 2/genética , Transtornos Mieloproliferativos/complicações , Policitemia Vera/etiologia , Gravidez , Trombocitemia Essencial/genética
3.
J Med Vasc ; 47(1): 39-42, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35393092

RESUMO

Only few cases of vascular dissection and essential thrombocythemia association have been reported. To the best of our knowledge, we reported the second case of aortic dissection and essential thrombocythemia association in a 60-year-old man with positive JAK2V617F mutation who had no history of hypertension or connective tissue disorders. Through this case, we discussed the eventual existence of a causal relationship between the two conditions. We also suggested the use of hydroxyurea as a prevention treatment of thrombosis in myeloproliferative neoplasms.


Assuntos
Aneurisma Dissecante , Policitemia Vera , Trombocitemia Essencial , Aneurisma Dissecante/complicações , Aneurisma Dissecante/diagnóstico por imagem , Humanos , Hidroxiureia/uso terapêutico , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Policitemia Vera/complicações , Policitemia Vera/genética , Trombocitemia Essencial/complicações , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/tratamento farmacológico
4.
Chem Phys Lipids ; 244: 105195, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35288127

RESUMO

RBCs membrane loses its integrity during hemoglobinopathies such as ß-thalassemia and sickle cell disease. The severity of ß-thalassemia has been historically linked to the presence of XMN polymorphism which is believed to ameliorate the severity. Here, we investigate the effect of XMN polymorphism on RBC membrane lipidome isolated from patients, using LC-MS/MS based approach. A total of 50 patients were recruited and 28 lipid species were identified in all groups after statistical analyses using volcano plot and ANOVA-SCA, and lipids with higher VIP values extracted from OPLS-DA loading plot. Alteration in lipid levels specifically the membrane lipids such as PC and fatty acids were observed. Samples with XMN polymorphism exhibited up-regulation of lipids involved in membrane stability such as cholenoic acid while PC (O-41:1) was down-regulated when compared to non-XMN samples. Additionally, HU administration to samples also had profound effect on the lipids of patients in both groups. A trend of improvement in the membrane lipids was observed in patients with XMN polymorphism. HU administration has proven to further improve the membrane integrity by upregulating certain membrane lipids in such patients. The study presents a comprehensive analysis of RBC membrane lipidome with respect to the genetic variation and HU administration.


Assuntos
Talassemia beta , Cromatografia Líquida , Humanos , Hidroxiureia , Lipidômica , Lipídeos de Membrana , Espectrometria de Massas em Tandem , Talassemia beta/genética
6.
FEMS Yeast Res ; 22(1)2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35262697

RESUMO

Schizosaccharomyces pombe is an established yeast model for studying the cellular mechanisms conserved in humans, such as the DNA replication checkpoint. The replication checkpoint deals with replication stress caused by numerous endogenous and exogenous factors that perturb fork movement. If undealt with, perturbed forks collapse, causing chromosomal DNA damage or cell death. Hydroxyurea (HU) is an inhibitor of ribonucleotide reductase (RNR) commonly used in checkpoint studies. It produces replication stress by depleting dNTPs, which slows the movement of ongoing forks and thus activates the replication checkpoint. However, HU also causes side effects such as oxidative stress, particularly under chronic exposure conditions, which complicates the studies. To find a drug that generates replication stress more specifically, we tested three other RNR inhibitors gemcitabine, guanazole and triapine in S. pombe under various experimental conditions. Our results show that guanazole and triapine can produce replication stress more specifically than HU under chronic, not acute drug treatment conditions. Therefore, using the two drugs in spot assay, the method commonly used for testing drug sensitivity in yeasts, should benefit the checkpoint studies in S. pombe and likely the research in other model systems.


Assuntos
Ribonucleotídeo Redutases , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Proteínas de Ciclo Celular/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Replicação do DNA , Desoxicitidina/análogos & derivados , Inibidores Enzimáticos/metabolismo , Guanazol , Humanos , Hidroxiureia/farmacologia , Piridinas , Ribonucleotídeo Redutases/genética , Ribonucleotídeo Redutases/metabolismo , Ribonucleotídeo Redutases/farmacologia , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genética , Tiossemicarbazonas
7.
Ann Afr Med ; 21(1): 58-64, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35313407

RESUMO

Background: Sickle cell disease (SCD) remains prevalent in Nigeria and can be complicated by cholelithiasis even in children. There is still a dearth of knowledge about the occurrence of cholelithiasis in these children. The present study is aimed to determine the prevalence of cholelithiasis in pediatric SCD in Lagos and documents relevant socio-demographic and clinical correlates. Subjects and Methods: This was a cross-sectional study of children and adolescents aged 1-19 years with SCD attending the Paediatric Haematology Clinic of the Lagos University Teaching Hospital. One hundred and forty-seven children were consecutively recruited into the study over 3 months and they all had sonographic examination of the gall bladder. The association between cholelithiasis, sociodemographic data, clinical symptoms, laboratory parameters, and the use of hydroxyurea was also documented. Results: The median age (range) of the study participants was 9.0 (1-19) years and majority were males (59.9%). The prevalence of cholelithiasis was 13.6% and the condition was most prevalent in adolescents (21.4%) compared to the younger children (6.5%). All the children with cholelithiasis were asymptomatic. Age and the frequency of crisis were significantly associated with cholelithiasis on multivariate analysis (P = 0.03, 0.045, respectively). The use of hydroxyurea was not significantly related to the occurrence of cholelithiasis. Conclusion: The prevalence of cholelithiasis observed in this study is high. Routine screening of older children and adolescents with SCD, especially with the frequent crisis is suggested. Longitudinal studies to establish the relationship between hydroxyurea and cholelithiasis is also advocated.


Résumé Contexte: La drépanocytose (SCD) reste répandue au Nigéria et peut être compliquée par une cholélithiase même chez les enfants. Il y a encore un manque de connaissances sur la survenue de la cholélithiase chez ces enfants. La présente étude vise à déterminer la prevalence de la cholélithiase dans la drépanocytose pédiatrique à Lagos et documente les corrélats sociodémographiques et cliniques pertinents. Sujets et méthodes: ce était une étude transversale menée auprès d'enfants et d'adolescents âgés de 1 à 19 ans atteints de drépanocytose et fréquentant la clinique d'hématologie pédiatrique de Lagos Hôpital universitaire. Cent quarante-sept enfants ont été recrutés consécutivement dans l'étude pendant 3 mois et ils ont tous eu un examen échographique de la vésicule biliaire. L'association entre cholélithiase, données sociodémographiques, symptômes cliniques, laboratoire paramètres, et l'utilisation de l'hydroxyurée a également été documentée. Résultats: l'âge médian (intervalle) des participants à l'étude était de 9,0 (1­19) ans et la majorité étaient des hommes (59,9%). La prévalence de la cholélithiase était de 13,6% et la maladie était la plus répandue chez les adolescents (21,4%) par rapport aux enfants plus jeunes (6,5%). Tous les enfants atteints de cholélithiase étaient asymptomatiques. L'âge et la fréquence des crises étaient significativement associée à la cholélithiase sur l'analyse multivariée (P = 0,03, 0,045, respectivement). L'utilisation de l'hydroxyurée n'était pas significativement liées à la survenue de cholélithiase. Conclusion: La prévalence de la cholélithiase observée dans cette étude est élevée. Dépistage de routine les enfants plus âgés et les adolescents atteints de SCD, en particulier avec la crise fréquente, sont suggérés. Études longitudinales pour établir la relation entre l'hydroxyurée et la cholélithiase est également préconisée. Mots-clés: Adolescents, enfants, cholélithiase, Nigéria, drépanocytose.


Assuntos
Anemia Falciforme , Colelitíase , Adolescente , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Criança , Colelitíase/epidemiologia , Estudos Transversais , Feminino , Humanos , Hidroxiureia/uso terapêutico , Masculino , Nigéria/epidemiologia
8.
Ann Med ; 54(1): 683-693, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35234095

RESUMO

BACKGROUND: Sickle cell disease (SCD) results in severe complications, such as anaemia and pain episodes. Hydroxyurea (HU) is efficacious in SCD, yet adherence remains low. OBJECTIVE: To assess the relationship of HU adherence to health care utilization and patients' characteristics. METHODS: This is a 5-year retrospective chart review. Patients' demographics and medical history were collected from the electronic medical record (EMR). HU adherence was evaluated using foetal haemoglobin "HbF%", mean corpuscular volume "MCV", and absolute neutrophil count "ANC". Age groups included children (<12 years), adolescents (12-17 years), and young adults (≥18 years). RESULTS: A total of 113 SCD patients on HU were included (median age 14 years, IQR 10-20; 50% female; 88% HbSS). Young adults had significantly higher HU adherence compared to adolescents and children, including higher median HbF% (24.2 vs. 12.4 vs. 8.6, p = .003), MCV (fl) (106.4 vs. 96.2 vs. 95.4, p = .01) and lower ANC (103/ml) (3.25 vs. 4.9 vs. 4.2, p = .01), respectively. Patients with chronic pain had lower HU adherence (HbF% 15.3 vs. 10.7, p = .04; ANC 3.6 vs. 6.3, p = .002; MCV 102.3 vs. 93.1, p = .1). Patients with higher HbF or MCV and lower ANC had significantly less frequent emergency room visits (rs=-0.26, p = .01; rs=-0.23, p = .01; rs=0.24, p = .01) and hospitalizations (rs=-0.27, p = .01; rs=-0.31, p = .01; rs=0.21, p = .02) as well as shorter length of stays (rs=-0.27, p = .0045; rs=-.34, p = 0.004; rs=0.23, p = .02), respectively. Similar trends in HU adherence and health care utilization were seen in subgroup analysis of only HbSS patients. There was no significant association of HU adherence to patients' sex, socio-economic status, distance from hospital, and HU duration. CONCLUSIONS: Young adults with SCD had significantly higher HU adherence compared to children and adolescents. Patients with lower HU adherence and/or chronic pain had increased health care utilization. Future studies examining barriers to adherence and evaluating interventions to optimize HU adherence in SCD are warranted.KEY MESSAGESYoung adults with SCD had significantly higher HU adherence, as reflected in their laboratory markers, compared to children and adolescents.Patients with higher HU adherence and/or those without chronic pain had lower or less frequent health care utilization.No significant association of HU adherence to patients' sex, socio-economic status and distance from hospital.


Assuntos
Anemia Falciforme , Hidroxiureia , Adolescente , Anemia Falciforme/tratamento farmacológico , Criança , Feminino , Hospitalização , Humanos , Hidroxiureia/uso terapêutico , Masculino , Adesão à Medicação , Estudos Retrospectivos , Adulto Jovem
9.
J Hematol Oncol ; 15(1): 20, 2022 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-35241123

RESUMO

Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the ßb globin gene that result in sickle hemoglobin production. Sickle hemoglobin polymerization leads to red blood cell sickling, chronic hemolysis and vaso-occlusion. Acute and chronic pain as well as end-organ damage occur throughout the lifespan of individuals living with SCD resulting in significant disease morbidity and a median life expectancy of 43 years in the USA. In this review, we discuss advances in the diagnosis and management of four major complications: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. We also discuss advances in disease-modifying and curative therapeutic options for SCD. The recent availability of L-glutamine, crizanlizumab and voxelotor provides an alternative or supplement to hydroxyurea, which remains the mainstay for disease-modifying therapy. Five-year event-free and overall survival rates remain high for individuals with SCD undergoing allogeneic hematopoietic stem cell transplant using matched sibling donors. However, newer approaches to graft-versus-host (GVHD) prophylaxis and the incorporation of post-transplant cyclophosphamide have improved engraftment rates, reduced GVHD and have allowed for alternative donors for individuals without an HLA-matched sibling. Despite progress in the field, additional longitudinal studies, clinical trials as well as dissemination and implementation studies are needed to optimize outcomes in SCD.


Assuntos
Anemia Falciforme , Dor Crônica , Doença Enxerto-Hospedeiro , Anemia Falciforme/complicações , Anemia Falciforme/diagnóstico , Anemia Falciforme/terapia , Dor Crônica/tratamento farmacológico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Hemoglobina Falciforme , Humanos , Hidroxiureia/uso terapêutico
10.
PLoS One ; 17(3): e0265261, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35303036

RESUMO

Hydroxyurea (HDU) is a widely used medication for various malignancies, thalassemia, and sickle cell anemia with reported side effects. The current study investigated HDU- induced hepatic injury and the protective potential of the royal jelly (RJ) against this hepatotoxic effect in the light of hepatic oxidative/ antioxidative status, pro-inflammatory cytokine, apoptosis signaling pathway, and histopathology. Sixty albino rats were used (n = 10/group) for 60 days: control, RJ (100 mg/kg body weight, orally), HDU (225 mg/kg body weight, orally), 2HDU (450 mg/kg body weight, orally), and HDU + RJ groups. HDU-treated rats showed significant elevation of liver function tests as aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, as well as malondialdehyde and nitric oxide (oxidative biomarkers) and significant decreased hepatic antioxidant molecules (reduced glutathione, superoxide dismutase, and glutathione peroxidase), compared to a control group, that more pronounced in the high dose of HDU. In addition, HDU induced significant upregulation of TNF-α and the Caspase-3 apoptotic pathway. Moreover, the liver of HDU treated groups showed various hepatic lesions from mild to severe necrotic changes related to the HDU dose. However, administration of RJ with HDU improved liver function tests, liver histology, and hepatic oxidative/antioxidative status concerning HDU groups. Furthermore, oral RJ administration with HDU significantly lessens the immune-expression area % of TNF-α and Caspase-3. Thus, the royal jelly has antioxidant, anti-inflammatory, and anti-apoptotic properties against HDU- induced hepatic injury and could be, therefore, used as adjuvant therapy in patients with long-term HDU medication.


Assuntos
Antioxidantes , Hidroxiureia , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Peso Corporal , Caspase 3/metabolismo , Ácidos Graxos , Humanos , Hidroxiureia/farmacologia , Fígado/metabolismo , Estresse Oxidativo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
11.
Oxid Med Cell Longev ; 2022: 1792894, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35251467

RESUMO

Excessive reactive oxygen species (ROS) contribute to damage of retinal cells and the development of retinal diseases including age-related macular degeneration (AMD). ROS result in increased metabolites of lipoxygenases (LOXs), which react with ROS to induce lipid peroxidation and may lead to ferroptosis. In this study, the effect of 5-LOX inhibition on alleviating ROS-induced cell death was evaluated using sodium iodate (NaIO3) in the retinal pigment epithelium (RPE) cell line ARPE-19 and a mouse model investigating oxidative stress in AMD. We demonstrated that NaIO3 induced cell death in the RPE cells through mechanisms including ferroptosis. Inhibition of 5-LOX with specific inhibitor, Zileuton, or siRNA knockdown of ALXO5 mitigated NaIO3-induced lipid peroxidation, mitochondrial damage, DNA impairment, and cell death in ARPE-19 cells. Additionally, in the mouse model, pretreatment with Zileuton reduced the NaIO3-induced lipid peroxidation of RPE cells, cell death in the photoreceptor layer of the retina, inflammatory responses, and degeneration of both the neuroretina and RPE monolayer cells. Our results suggest that 5-LOX plays a crucial role in ROS-induced cell death in the RPE and that regulating 5-LOX activity could be a useful approach to control ROS and ferroptosis-induced damage, which promote degeneration in retinal diseases.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Iodatos/efeitos adversos , Degeneração Macular/induzido quimicamente , Degeneração Macular/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Animais , Araquidonato 5-Lipoxigenase/genética , Linhagem Celular , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes/métodos , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/análogos & derivados , Inibidores de Lipoxigenase/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Substâncias Protetoras/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Transfecção/métodos
12.
Int J Mol Sci ; 23(5)2022 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-35269563

RESUMO

Young sex chromosomes possess unique and ongoing dynamics that allow us to understand processes that have an impact on their evolution and divergence. The genus Silene includes species with evolutionarily young sex chromosomes, and two species of section Melandrium, namely Silene latifolia (24, XY) and Silene dioica (24, XY), are well-established models of sex chromosome evolution, Y chromosome degeneration, and sex determination. In both species, the X and Y chromosomes are strongly heteromorphic and differ in the genomic composition compared to the autosomes. It is generally accepted that for proper cell division, the longest chromosomal arm must not exceed half of the average length of the spindle axis at telophase. Yet, it is not clear what are the dynamics between males and females during mitosis and how the cell compensates for the presence of the large Y chromosome in one sex. Using hydroxyurea cell synchronization and 2D/3D microscopy, we determined the position of the sex chromosomes during the mitotic cell cycle and determined the upper limit for the expansion of sex chromosome non-recombining region. Using 3D specimen preparations, we found that the velocity of the large chromosomes is compensated by the distant positioning from the central interpolar axis, confirming previous mathematical modulations.


Assuntos
Cromátides/fisiologia , Cromossomos Sexuais/fisiologia , Silene/fisiologia , Cromossomos de Plantas/fisiologia , Evolução Molecular , Hidroxiureia/farmacologia , Hibridização in Situ Fluorescente , Microscopia Confocal , Mitose , Silene/genética
13.
J Pediatr Hematol Oncol ; 44(3): e799-e803, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35319512

RESUMO

Although hydroxyurea (HU) is an effective treatment for sickle cell anemia, uptake remains low. Shared decision-making (SDM) is a recommended strategy for HU initiation to elicit family preferences; however, clinicians lack SDM training. We implemented an immersive virtual reality (VR) curriculum at 8 pediatric institutions to train clinicians on SDM that included counseling virtual patients. Clinicians' self-reported confidence significantly improved following the VR simulations on all communication skills assessed, including asking open-ended questions, eliciting specific concerns, and confirming understanding (Ps≤0.01 for all). VR may be an effective method for educating clinicians to engage in SDM for HU.


Assuntos
Anemia Falciforme , Hematologia , Realidade Virtual , Anemia Falciforme/tratamento farmacológico , Criança , Currículo , Humanos , Hidroxiureia/uso terapêutico
14.
Am J Hematol ; 97(5): 603-612, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35142007

RESUMO

Hydroxyurea reduces pain crises, acute chest syndrome, and blood transfusions in sickle cell disease (SCD), but potential detrimental effects on fertility and birth outcomes impede its use. Data on the effects of hydroxyurea taken for SCD during conception and pregnancy are scarce. The Sickle Cell Disease Implementation Consortium collected self-reported pregnancy history, corresponding hydroxyurea use, and pregnancy outcomes in women with SCD in the clinical setting. Among 1285 women 18-45 years of age, 737 (57.4%) reported 1788 pregnancies (1079 live births, 394 miscarriages, 40 stillbirths, 207 abortions, 48 current pregnancies, and 20 missing outcomes) of which 241 (15.9%) live births, miscarriages or stillbirths were conceived while on hydroxyurea. In univariate analyses, pregnancy number more than three, severe sickle genotype, history of stillbirth or miscarriage, and chronic kidney disease at enrollment were covariates significantly associated with a pregnancy ending in miscarriage or stillbirth. After adjustment for covariates and additional SCD severity markers in multivariate analyses, hydroxyurea use during conception and pregnancy, but not during conception only, was associated with an increase in the odds ratio (OR) of miscarriage or stillbirth (OR 2.21, 95% confidence interval [CI] 1.40-3.47). In analyses of live birth outcomes, hydroxyurea use during conception and pregnancy was associated with birth weight < 5.5 pounds in full-term infants (OR 2.98, 95% CI 1.09-7.38) but not with prematurity or serious medical problems at birth. These findings suggest that hydroxyurea use may be safe up to the time of conception, but that clinicians should continue to advise caution regarding use during pregnancy.


Assuntos
Aborto Espontâneo , Anemia Falciforme , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Feminino , Humanos , Hidroxiureia/efeitos adversos , Lactente , Recém-Nascido , Nascido Vivo , Gravidez , Resultado da Gravidez
15.
Eur Rev Med Pharmacol Sci ; 26(2): 526-533, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35113429

RESUMO

OBJECTIVE: The diagnosis and treatment of sepsis are costly to healthcare services, and it is an important disease with high mortality rates. In the pathogenesis of sepsis, for which we still cannot provide a complete cure, there is increased cytokine release and organ damage. Hydroxyurea has been shown to reduce leukocyte counts, decrease inflammatory cytokines, and limit organ inflammation in ischemia-reperfusion models. This study aimed to evaluate leukocyte counts, interleukin-1 beta (IL-1ß), IL-6, and tumor necrosis factor-alpha (TNF-α) cytokine values and organ inflammatory processes in hydroxyurea-treated rats with an experimental sepsis model. MATERIALS AND METHODS: After ethical approval, rats were randomly divided into three groups, control (n= 7), sepsis (n= 7), and hydroxyurea (n= 7). Sepsis was created using the cecal ligation and puncture (CLP) method in rats other than in the control group. Rats in the hydroxyurea group received hydroxyurea (200 mg/kg) intragastrically, and the control and sepsis groups received sterile distilled water. IL-1ß, IL-6, and TNF-α levels were measured at 0, 8, and 24 hours after CLP in all rats. Blood samples were collected at the time of sacrification 24 hours after CLP and analyzed for the complete blood count. Tissue specimens were taken for histopathologic examination. RESULTS: Cytokine levels (IL-1ß, IL-6, TNF-α), white blood cell counts, and tissue damage were increased after the sepsis model in rats. It was found that the cytokine levels at the 8th hour, white blood cell count, and brain tissue damage in the hydroxyurea group were decreased significantly compared with the sepsis group. CONCLUSIONS: Early hydroxyurea treatment in rats with sepsis decreases proinflammatory cytokine (IL-1ß, IL-6, and TNF-α) levels and thus reduces brain damage.


Assuntos
Citocinas , Sepse , Animais , Hidroxiureia/farmacologia , Inflamação , Ratos , Sepse/tratamento farmacológico , Fator de Necrose Tumoral alfa
16.
PLoS One ; 17(2): e0263424, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35113975

RESUMO

BACKGROUND: Sickle cell disease (SCD) incurs vaso-occlusive episodes and organ damage, including nephropathy. Despite displaying characteristics of vascular dysfunction, SCD patients tend to present relatively lower systemic blood pressure (BP), via an unknown mechanism. We investigated associations between BP and renin-angiotensin-system (RAS) components in SCD and determined whether an inhibitor of angiotensin converting enzyme (ACE; often used to slow SCD glomerulopathy) further modulates BP and RAS components in a murine model of SCD. METHODS: BP was compared in human subjects and mice with/without SCD. Plasma angiotensin II, ACE and renin were measured by immunoassay. BP was reevaluated after treating mice with enalapril (25 mg/kg, 5x/week) for 5 weeks; plasma and organs were stored for angiotensin II and ACE activity measurement, and quantitative real-time PCR. RESULTS: Diastolic BP and systolic BP were significantly lower in patients and mice with SCD, respectively, compared to controls. Reduced BP was associated with increased plasma renin and markers of kidney damage (mice) in SCD, as well as significantly decreased plasma ACE concentrations and ACE enzyme activity. As expected, enalapril administration lowered BP, plasma angiotensin II and organ ACE activity in control mice. In contrast, enalapril did not further reduce BP or organ ACE activity in SCD mice; however, plasma angiotensin II and renin levels were found to be significantly higher in enalapril-treated SCD mice than those of treated control mice. CONCLUSION: Relative hypotension was confirmed in a murine model of SCD, in association with decreased ACE concentrations in both human and murine disease. Given that ACE inhibition has an accepted role in decreasing BP, further studies should investigate mechanisms by which ACE depletion, via both Ang II-dependent and alternative pathways, could contribute to reduce BP in SCD and understand how ACE inhibition confers Ang II-independent benefits on kidney function in SCD.


Assuntos
Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/fisiopatologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peptidil Dipeptidase A/biossíntese , Adolescente , Adulto , Angiotensina II/metabolismo , Animais , Diástole , Modelos Animais de Doenças , Feminino , Humanos , Hidroxiureia/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Renina/sangue , Sistema Renina-Angiotensina , Sístole , Adulto Jovem
17.
Int J Med Sci ; 19(2): 321-330, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35165517

RESUMO

Aim: Endoplasmic reticulum-associated degradation (ERAD), which involves degradation of improperly folded proteins retained in the ER, is implicated in various diseases including chronic kidney disease. This study is aimed to determine the role of ERAD in Klotho deficiency of mice and human kidney tubular epithelial cells (HK-2) with renal interstitial fibrosis (RIF). Methods: Following establishment of a mouse RIF model by unilateral ureteral obstruction (UUO), a specific ERAD inhibitor, Eeyarestatin I (EerI), was administered to experimental animals by intraperitoneal injection. Serum and kidney samples were collected for analysis 10 days after operation. Soluble Klotho levels were measured by enzyme-linked immunosorbent assay, while the degree of kidney injury was assessed by renal histopathology. Renal Klotho expression was determined by quantitative real-time PCR, immunohistochemical and western blotting analyses. ERAD and unfolded protein response (UPR) were evaluated by detecting associated components such as Derlin-1, glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4) and protein disulfide isomerase (PDI). HK-2 cells were exposed to transforming growth factor (TGF)-ß1 with or without EerI, and expressions of related proteins including Klotho, Derlin-1, GRP78, ATF4 and PDI were determined by western blotting analyses. Results: UUO induced severe kidney injuries and RIF. Klotho expression in both serum and kidney tissue was obviously downregulated, while Derlin-1 was notably upregulated, indicating that ERAD was activated to potentially degrade improperly folded Klotho protein in this model. Intriguingly, treatment with EerI led to significantly increased Klotho expression, especially soluble (functional) Klotho. Furthermore, specific inhibition of ERAD increased expression of GRP78, ATF4 and PDI compared with the UUO group. The consistent results in vitro were also obtained in TGF-ß1-treated HK-2 cells exposed to EerI. These observations suggest that UPR was remarkably enhanced in the presence of ERAD inhibition and compensated for excess improperly folded proteins, subsequently contributing to the additional production of mature Klotho protein. Conclusion: ERAD is involved in Klotho deficiency in RIF and its specific inhibition significantly promoted Klotho expression, possibly through enhanced UPR. This may represent a novel regulatory mechanism and new therapeutic target for reversing Klotho deficiency.


Assuntos
Degradação Associada com o Retículo Endoplasmático/genética , Rim/patologia , Nefrite Intersticial/enzimologia , Obstrução Ureteral/enzimologia , Animais , Modelos Animais de Doenças , Fibrose , Humanos , Hidrazonas/administração & dosagem , Hidroxiureia/administração & dosagem , Hidroxiureia/análogos & derivados , Injeções Intraperitoneais , Túbulos Renais/citologia , Camundongos
18.
Sci Rep ; 12(1): 2752, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177777

RESUMO

Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in ß-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent ß-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10-20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE ß-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent ß-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE ß-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene.


Assuntos
Hidroxiureia/administração & dosagem , Talassemia beta/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Transfusão de Sangue , Método Duplo-Cego , Feminino , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Humanos , Masculino , Polimorfismo Genético , Talassemia beta/sangue , Talassemia beta/genética
19.
BMC Health Serv Res ; 22(1): 42, 2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-34998394

RESUMO

BACKGROUND: The costs associated with the treatment of sickle cell disease (SCD) are understudied in low and middle-income countries (LMIC). We evaluated the cost of treating SCD-related acute complications and the potential cost-savings of hydroxyurea in a specialized hematology center in Brazil. METHODS: The costs (US dollars) of emergency department (ED) and hospitalizations from SCD-related complications between 01.01.2018 and 06.30.2018 were ascertained using absorption and micro-costing approaches. The reasons for acute hospital visits were grouped as: 1) vaso-occlusive (VOC) pain, 2) infection, 3) anemia exacerbation, and 4) chronic organ damage complications. Hydroxyurea adherence was estimated by medication possession ratio (MPR) during the study period. RESULTS: In total, 1144 patients, median age 17 years (range 0-70), 903 (78.9%) with HbSS/HbSß0-thalassemia, 441 (38.5%) prescribed hydroxyurea, visited the ED, of whom 381 (33%) were admitted. VOC accounted for 64% of all ED visits and 60% of all admissions. Anemia exacerbation was the most expensive reason for ED visit ($321.87/visit), while chronic organ damage carried the highest admission cost ($2176.40/visit). Compared with other genotypes, individuals with HbSS/HbSß0-thalassemia were admitted more often (79% versus 21%, p < 0.0001), and their admission costs were higher ($1677.18 versus $1224.47/visit, p = 0.0001). Antibiotics and analgesics accounted for 43% and 42% of the total ED costs, respectively, while housing accounted for 46% of the total admission costs. Costs of ED visits not resulting in admissions were lower among HbSS/HbSß0-thalassemia individuals with hydroxyurea MPR ≥65% compared with visits by patients with MPR <65% ($98.16/visit versus $182.46/visit, p = 0.0007). No difference in admission costs were observed relative to hydroxyurea use. DISCUSSION: In a LMIC hematology-specialized center, VOCs accounted for most acute visits from patients with SCD, but costs were highest due to anemia exacerbation. Analgesics, antibiotics, and housing drove most expenses. Hydroxyurea may reduce ED costs among individuals with HbSS/HbSß0-thalassemia but is dependent on adherence level.


Assuntos
Anemia Falciforme , Adolescente , Adulto , Idoso , Anemia Falciforme/tratamento farmacológico , Anemia Falciforme/epidemiologia , Criança , Pré-Escolar , Custos e Análise de Custo , Serviço Hospitalar de Emergência , Hospitalização , Humanos , Hidroxiureia/uso terapêutico , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Adulto Jovem
20.
J Oncol Pharm Pract ; 28(3): 646-663, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35060419

RESUMO

Patients with sickle cell disease (SCD) experience significant disease-related morbidity including multiorgan damage, chronic anemia, and debilitating pain crises. While hydroxyurea has been the primary disease modifying modality in SCD, novel therapies with unique mechanism of action have recently been approved. This review article examines the evidence surrounding the available SCD therapies to guide pharmacists on potential treatment selection and management strategies for patients with SCD. A systematic search of online databases was performed to identify literature on the management of SCD. While the newly approved novel agents have demonstrated clinical benefit it remains unclear how these agents fit into the treatment paradigm. Pharmacists should be aware of the data supporting the use of these novel agents to optimize use on a patient-specific basis.


Assuntos
Anemia Falciforme , Farmacêuticos , Anemia Falciforme/tratamento farmacológico , Humanos , Hidroxiureia/uso terapêutico , Dor/tratamento farmacológico
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