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1.
Einstein (Sao Paulo) ; 17(4): eAO4742, 2019 Sep 09.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31508660

RESUMO

OBJECTIVE: To evaluate the induction of DNA damage in peripheral blood mononuclear cells of patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea. METHODS: The study subjects were divided into two groups: one group of 22 patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea, and a Control Group composed of 24 patients with sickle cell disease who were not treated with hydroxyurea. Peripheral blood samples were submitted to peripheral blood mononuclear cell isolation to assess genotoxicity by the cytokinesis-block micronucleus cytome assay, in which DNA damage biomarkers - micronuclei, nucleoplasmic bridges and nuclear buds - were counted. RESULTS: Patients with sickle cell disease treated with hydroxyurea had a mean age of 25.4 years, whereas patients with sickle cell disease not treated with hydroxyurea had a mean age of 17.6 years. The mean dose of hydroxyurea used by the patients was 12.8mg/kg/day, for a mean period of 44 months. The mean micronucleus frequency per 1,000 cells of 8.591±1.568 was observed in the Hydroxyurea Group and 10.040±1.003 in the Control Group. The mean frequency of nucleoplasmic bridges per 1,000 cells and nuclear buds per 1,000 cells for the hydroxyurea and Control Groups were 0.4545±0.1707 versus 0.5833±0.2078, and 0.8182±0.2430 versus 0.9583±0.1853, respectively. There was no statistically significant difference between groups. CONCLUSION: In the study population, patients with sickle cell disease treated with the standard dose of hydroxyurea treatment did not show evidence of DNA damage induction.


Assuntos
Anemia Falciforme/genética , Dano ao DNA/efeitos dos fármacos , Hidroxiureia/farmacologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Adolescente , Adulto , Anemia Falciforme/tratamento farmacológico , Criança , Pré-Escolar , Citocinese , Dano ao DNA/genética , Feminino , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Testes de Mutagenicidade , Mutação/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico/efeitos adversos , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Adulto Jovem
2.
Best Pract Res Clin Haematol ; 32(1): 65-73, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30927977

RESUMO

Myeloproliferative Neoplasms (MPNs) are a group of progressive diseases that share a common pathogenesis, clinical and laboratory features, as well as a spontaneous risk of secondary AML. Certain MPN therapies have been associated with an increased risk of leukemic conversion, with robust data highlighting the highest rates with 32P, chlorambucil, and pipobroman. Herein, we review risk factors for leukemic transformation, including therapy-related MPN-BP, with a focus on the debate surrounding the potential leukemogenicity of hydroxyurea. Lastly, we discuss emerging studies on the association between ruxolitinib and high grade B-cell lymphomas. We conclude that statistical associations have not implicated hydroxyurea monotherapy as leukemogenic. However, it is difficult to definitely disprove an association, as large prospective, controlled studies with decades of follow-up would be needed to draw conclusions. Overall, the concept of therapy-related neoplasms remains important to the field, and mandates judicious selection and sequencing of therapies for MPN patients.


Assuntos
Transformação Celular Neoplásica , Neoplasias Hematológicas , Hidroxiureia/efeitos adversos , Transtornos Mieloproliferativos , Segunda Neoplasia Primária , Pirazóis/efeitos adversos , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias Hematológicas/induzido quimicamente , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Hidroxiureia/uso terapêutico , Transtornos Mieloproliferativos/induzido quimicamente , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/terapia , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/terapia , Pirazóis/uso terapêutico
3.
Cochrane Database Syst Rev ; 3: CD012064, 2019 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-30882896

RESUMO

BACKGROUND: Hydroxyurea (hydroxycarbamide) promotes the production of foetal haemoglobin (HbF) by reactivating gamma-genes. Evidence has shown clinical benefits of hydroxyurea in people with sickle cell anemia; however, only a few studies have assessed this treatment in people with beta (ß)-thalassaemia. OBJECTIVES: The primary objective is to review the efficacy of hydroxyurea in reducing or ameliorating the requirement of blood transfusions in people with transfusion-dependent ß-thalassaemia. The second objective is to review the safety of hydroxyurea with regards to severe adverse effects in this population. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and hand searching of journals and conference abstract books. We also searched electronic databases and trial registries, including ClinicalTrials.gov, the WHO ICTRP and PubMed (09 October 2018).Date of last search of the Group's haemoglobinopathies trials register: 04 March 2019. SELECTION CRITERIA: Randomised controlled trials of hydroxyurea in people with transfusion-dependent ß-thalassaemia, compared with placebo or standard treatment or comparing different doses of hydroxyurea. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion in the review, which was verified by a third author. MAIN RESULTS: No trials were eligible for inclusion in this review. AUTHORS' CONCLUSIONS: Currently, there is no high-quality evidence to support or challenge the continued use of hydroxyurea for managing people with transfusion-dependent ß-thalassaemia. Multicentre, randomised controlled trials (compared to placebo or other available treatment, i.e. blood transfusion and iron chelation) are needed in order to assess the efficacy and safety of hydroxyurea for reducing the need for blood transfusion, for maintaining or improving mean haemoglobin levels, as well as for determining its cost-effectiveness.


Assuntos
Transfusão de Sangue/estatística & dados numéricos , Hematínicos/uso terapêutico , Hidroxiureia/uso terapêutico , Talassemia beta/tratamento farmacológico , Hematínicos/efeitos adversos , Humanos , Hidroxiureia/efeitos adversos
4.
Ann Hematol ; 98(5): 1071-1082, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30848334

RESUMO

Thromboembolic events and cardiovascular disease are the most prevalent complications in patients with polycythemia vera (PV) compared with other myeloproliferative disorders and are the major cause of morbidity and mortality in this population. Moreover, a vascular complication such as arterial or venous thrombosis often leads to the diagnosis of PV. The highest rates of thrombosis typically occur shortly before or at diagnosis and decrease over time, probably due to the effects of treatment. Important risk factors include age (≥ 60 years old) and a history of thrombosis; elevated hematocrit and leukocytosis are also associated with an increased risk of thrombosis. The goal of therapy is to reduce the risk of thrombosis by controlling hematocrit to < 45%, a target associated with reduced rates of cardiovascular death and major thrombosis. Low-risk patients (< 60 years old with no history of thrombosis) are managed with phlebotomy and low-dose aspirin, whereas high-risk patients (≥ 60 years old and/or with a history of thrombosis) should be treated with cytoreductive agents. Interferon and ruxolitinib are considered second-line therapies for patients who are intolerant of or have an inadequate response to hydroxyurea, which is typically used as first-line therapy. In this review, we discuss factors associated with thrombosis and recent data on current treatments, including anticoagulation, highlighting the need for more controlled studies to determine the most effective cytoreductive therapies for reducing the risk of thrombosis in patients with PV.


Assuntos
Policitemia Vera , Tromboembolia , Fatores Etários , Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Interferons/uso terapêutico , Flebotomia , Policitemia Vera/complicações , Policitemia Vera/diagnóstico , Policitemia Vera/terapia , Pirazóis/uso terapêutico , Fatores de Risco , Tromboembolia/diagnóstico , Tromboembolia/etiologia , Tromboembolia/terapia , Trombose/diagnóstico , Trombose/etiologia , Trombose/terapia
5.
Ann Hematol ; 98(6): 1421-1426, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30919072

RESUMO

Hydroxyurea (HU) resistance or intolerance occurs in 15 to 24% of patients with polycythemia vera (PV). Resistance to HU is associated with a shortened life expectancy, intolerance has no prognostic value. We assessed the occurrence of HU resistance or intolerance comparing the original (ELNo) versus the modified European Leukemia Net (ELNm) criteria as applied in recent large clinical trials including PV patients. We retrospectively analyzed 106 patients with PV treated with HU at the University Hospitals of Leuven between 1990 and 2016 for occurrence of HU resistance/intolerance when using both ELNo as ELNm. After a mean duration of treatment of 5.1 years, when applying the ELNo 20.7% of patients had shown resistance or intolerance to HU in comparison to 39.6% when using the ELNm. When using the ELNo 4.7% of patients were resistant to HU versus 23.6% when applying the ELNm. In total, 16.0% of patients were HU intolerant. This rate was identical when using both ELNo and ELNm. 20.7% of PV patients were considered as HU-resistant or intolerant when using the original ELN criteria. However, when applying the modified ELN criteria 39.6% of PV patients were resistant or intolerant to HU. In our hands, no patient received a minimum dose of 2 g HU a day, as such the ELNm seem better adapted for daily clinical use. However, the prognostic value of HU-resistance in PV, when defined by the ELNm, still needs to be confirmed.


Assuntos
Resistência a Medicamentos , Hidroxiureia/uso terapêutico , Policitemia Vera/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Febre/induzido quimicamente , Seguimentos , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/farmacologia , Úlcera da Perna/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Policitemia Vera/complicações , Policitemia Vera/mortalidade , Prognóstico , Estudos Retrospectivos , Trombose/epidemiologia , Trombose/etiologia
7.
Probl Radiac Med Radiobiol ; 23: 517-523, 2018 Dec.
Artigo em Inglês, Ucraniano | MEDLINE | ID: mdl-30582869

RESUMO

In this paper, a clinical case of combination of chronic myeloid leukemia and T-lymphoblastic lymphoma is present-ed, which is currently a rather rare finding for a clinician. The diagnosis of T-lymphoblastic lymphoma is establishedafter 2 years from the verification of chronic myeloid leukemia. The course of diseases and approaches to treatmentare described.The pathogenetic relationship between myeloid and lymphoid diseases remains unclear and is likely to be the resultof several factors - radiation, chemical and, consequently, genetic disorders.


Assuntos
Antineoplásicos/uso terapêutico , Acidente Nuclear de Chernobyl , Exposição Ambiental/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Linfoma de Células T/patologia , Exposição à Radiação/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Linfoma de Células T/complicações , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/etiologia , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Radiação Ionizante , Resultado do Tratamento , Ucrânia , Vincristina/uso terapêutico
8.
Int J Mol Sci ; 19(12)2018 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-30544930

RESUMO

The cytostatic agent hydroxyurea (HU) has proven to be beneficial for a variety of conditions in the disciplines of oncology, hematology, infectious disease and dermatology. It disrupts the S phase of the cell cycle by inhibiting the ribonucleotide reductase enzyme, thus blocking the transformation of ribonucleotides into deoxyribonucleotides, a rate limiting step in DNA synthesis. HU is listed as an essential medicine by the World Health Organization. Several studies have indicated that HU is well tolerated and safe in pregnant women and very young pediatric patients. To our knowledge, only a few controlled studies on the adverse effects of HU therapy have been done in humans. Despite this, the prevalence of central nervous system abnormalities, including ischemic lesions and stenosis have been reported. This review will summarize and present the effects of HU exposure on the prenatal and perinatal development of the rat cerebellar cortex and deep cerebellar nuclei neurons. Our results call for the necessity to better understand HU effects and define the administration of this drug to gestating women and young pediatric patients.


Assuntos
Hidroxiureia/efeitos adversos , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica , Recém-Nascido , Microscopia Eletrônica , Gravidez
9.
Environ Toxicol Pharmacol ; 60: 91-99, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29679812

RESUMO

Nimbolide is known to be an antioxidant found in neem plant. Hydroxyurea is a medication frequently used in sickle-cell disease, different cancers and HIV infection. The present study aimed to evaluate the adverse effect of HU and possible amelioration by nimbolide in Wistar rats. To test our hypothesis, we performed genotoxicity tests, biochemical assays, and histopathological studies. We observed that HU caused higher levels of genotoxicity in the treated animals. The observed genetic and oxidative damage might be due to the presence of reactive species as HU increased the level of the malondialdehyde-a biomarker of oxidative damage. Interestingly, co-treatment of animals with HU and nimbolide showed a lower level of damage. We conclude that nimbolide significantly protects the cells from the adverse effect of HU and could be considered as a potential adjuvant for the patients under HU therapy.


Assuntos
Antineoplásicos/efeitos adversos , Antioxidantes/administração & dosagem , Aberrações Cromossômicas/efeitos dos fármacos , Hidroxiureia/efeitos adversos , Limoninas/administração & dosagem , Animais , Antioxidantes/farmacologia , Aberrações Cromossômicas/induzido quimicamente , Modelos Animais de Doenças , Limoninas/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Testes de Mutagenicidade , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
10.
Ann Hematol ; 97(4): 617-627, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29396713

RESUMO

Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov .


Assuntos
Antineoplásicos/uso terapêutico , Interferons/uso terapêutico , Janus Quinases/antagonistas & inibidores , Policitemia Vera/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Sangria/efeitos adversos , Terapia Combinada/efeitos adversos , Estudos Cross-Over , Monitoramento de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Interferons/efeitos adversos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Policitemia Vera/metabolismo , Policitemia Vera/fisiopatologia , Policitemia Vera/terapia , Padrões de Prática Médica , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Reprodutibilidade dos Testes , Esplenomegalia/etiologia , Esplenomegalia/prevenção & controle
11.
Intern Med ; 57(9): 1297-1300, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29279479

RESUMO

A 73-year-old man with primary myelofibrosis (PMF) was being treated with hydroxyurea, which was changed to ruxolitinib treatment because of worsening constitutional symptoms. Although ruxolitinib rapidly induced relief, he developed a high-grade fever. A comprehensive fever work-up found no apparent cause of the fever, except for PMF. Therefore, we increased the dose of ruxolitinib and added prednisolone, which was gradually withdrawn with resolution of the fever. However, the patient subsequently developed disseminated tuberculosis and died eight months after initiation of ruxolitinib. Our case highlights the importance of assessing and monitoring the immune status of patients receiving ruxolitinib.


Assuntos
Hidroxiureia/efeitos adversos , Prednisolona/efeitos adversos , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/mortalidade , Pirazóis/efeitos adversos , Tuberculose Miliar/induzido quimicamente , Tuberculose Miliar/mortalidade , Idoso , Evolução Fatal , Humanos , Hidroxiureia/uso terapêutico , Masculino , Prednisolona/uso terapêutico , Mielofibrose Primária/diagnóstico , Pirazóis/uso terapêutico
12.
Future Oncol ; 14(2): 137-150, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29056075

RESUMO

Ruxolitinib (Rux), a JAK1/2 inhibitor, has been approved for patients with myelofibrosis and in polycythemia vera with inadequate response/intolerance to hydroxycarbamide. Studies have demonstrated that Rux improves disease-related symptoms and splenomegaly. A late emerging observation from two Phase III trials was that Rux was associated with survival advantage in comparison with placebo or other available therapies in myelofibrosis. Important data suggest that for polycythemia vera Rux improved control of blood counts. Main hematological side effects are anemia and thrombocytopenia predominantly at the beginning of the treatment. Some studies and case reports highlighted potential risks of nonmelanoma skin cancers and increased risk of infection including reactivation of hepatitis B, tuberculosis or herpes zoster infections after Rux treatment.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Doenças Mieloproliferativas-Mielodisplásicas/tratamento farmacológico , Policitemia Vera/tratamento farmacológico , Pirazóis/uso terapêutico , Idoso , Animais , Contagem de Células Sanguíneas , Ensaios Clínicos Fase III como Assunto , Modelos Animais de Doenças , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Hidroxiureia/efeitos adversos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/genética , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Cromossomo Filadélfia , Policitemia Vera/genética , Policitemia Vera/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacocinética , Resultado do Tratamento
13.
Int J Hematol ; 107(2): 173-184, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28956263

RESUMO

Ruxolitinib, a potent JAK1/JAK2 inhibitor, was found to be superior to the best available therapy (BAT) in controlling hematocrit, reducing splenomegaly, and improving symptoms in the phase 3 RESPONSE study of patients with polycythemia vera with splenomegaly who experienced an inadequate response to or adverse effects from hydroxyurea. We report findings from a subgroup analysis of Japanese patients in RESPONSE (n = 18). The composite response rate (hematocrit control and spleen response) was higher in patients receiving ruxolitinib (50.0%) than in those receiving BAT (8.3%). A total of 50.0% of patients randomized to ruxolitinib achieved a spleen response vs 8.3% of those receiving BAT; 100 and 33.3% of patients in the respective groups achieved hematocrit control, with mean hematocrit in ruxolitinib-treated patients remaining stable at < 45% throughout the study. Similarly, a higher proportion of ruxolitinib-treated patients achieved complete hematologic remission (33.3 vs 16.7%). Ruxolitinib also led to rapid improvements in pruritus. All responses with ruxolitinib were durable to week 80, and its safety profile was consistent with that in the overall study. These findings suggest that ruxolitinib is an effective and well-tolerated treatment option for Japanese patients with polycythemia vera with an inadequate response to or adverse effects from hydroxyurea.


Assuntos
Hidroxiureia/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Policitemia Vera/tratamento farmacológico , Pirazóis/uso terapêutico , Esplenomegalia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Feminino , Hematócrito , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia Vera/sangue , Policitemia Vera/complicações , Esplenomegalia/etiologia , Resultado do Tratamento
14.
Ter Arkh ; 90(7): 23-29, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30701919

RESUMO

AIM: A comparative evaluation of the effectiveness of different therapeutic strategies in patients with polycythemia vera (PV) and essential thrombocythemia (ET). MATERIALS AND METHODS: Patients with PV or ET, diagnosed according to the criteria WHO 2016 were included in the study. The primary endpoint - 6 months of therapy (clinical-hematological and molecular responses). The secondary endpoint - 12 months of therapy (clinico-hematologic, molecular, histological responses). Sixty three patients were included in the analysis: the first group consisted of 33 patients who received the therapy with ce-pegiterferone alpha-2b (ce-pegalpha-INF-α-2b), 10 of them received previous treatment; the second group - 23 patients btained hydroxycarbamide; the third group - 7 patients were treated with recombinant interferon alpha therapy (rINFα). In comparison groups, differences in age were revealed: patients receiving hydroxycarbamide therapy were older. Phlebotomy occurred in 36% of patients in the first group, 9% in the second group, and 14% in the third group. RESULTS: By the 6th month of therapy, 43% of the patients receiving the ce-pegalpha-INF-α-2b had complete clinical-hematologic response, 36% had partial clinical-hematologic remission and stabilization of the disease was established in 21% cases. No disease progression occured. By the 12th month of therapy, statistically significant differences in terms of efficacy between the different therapeutic groups (p = 0.2462, Fisher's exact test). In all three groups, the allelic load of JAK2V617F decreased: from 50 to 19%, from 22.3 to 15.8%, from 50 to 7.19%, respectively. The lower the allele load positively correlated with better response to therapy, which was observed in all analyzed groups. Hematologic adverse events (AEs) were more frequently observed in patients receiving ce-pegalpha-INF-α-2b therapy. Local reactions developed on 3-7 days of therapy as a hyperemic macula at the injection site. Both these reactions and hair loss did not influence on patient's condition. In the second group (patients with hydroxycarbamide therapy) there were changes in the skin and mucous membranes: dry skin, stomatitis, and in older patients new keratomas appeared. The flu-like syndrome was the most common adverse event associated with the therapy of ce-pegalpha-INF-α-2b, which fully relived during the first month of therapy. There was only one case with the flu-like syndrome we observed at the 11th month of therapy. As a rule, the biochemical blood test changes did not influence on patient's condition, were mostly associated with dietary violations, had a tendency to self-resolution and did not require medical interventions. Serious AEs were reported in one case - pulmonary embolism in a patient treated with rINFα. The reasons for the therapy discontinue in group 1: toxic hepatitis, intolerance, by the request of the patient, inadequate efficacy of therapy; in group 2: skin toxicity, in group 3: thromboses. CONCLUSION: Treatment of ce-pegalpha-INF-α-2b in patients with PV and ET is highly effective - the most patients pbtained clinical and hematological responses. There were no statistically significant differences in these parameters in comparison with hydroxycarbamide and rINFα. The use of the ce-pegalpha-INF-α-2b had an acceptable safety profile. The estimated therapeutic dose should be calculated according to body weight. To reduce the frequency of hematologic AE, titration of the drug dose is required.


Assuntos
Hidroxiureia/uso terapêutico , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Adulto , Frequência do Gene , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Interferon alfa-2/administração & dosagem , Interferon alfa-2/efeitos adversos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Janus Quinase 2/genética , Pessoa de Meia-Idade , Mutação , Policitemia Vera/sangue , Policitemia Vera/genética , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Trombocitemia Essencial/sangue , Trombocitemia Essencial/genética , Resultado do Tratamento
15.
Adv Exp Med Biol ; 1034: 211-226, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29256133

RESUMO

In addition to main categories of medications believed to have negative impacts on male reproduction, there are a number of miscellaneous drugs with some evidence for such adverse reactions. Because of its widespread use and over-the-counter availability, the H2 receptor antagonist cimetidine is most concerning. As a competitive antagonist at androgen receptors, it can impact the HPG axis and semen quality. In this chapter, we review the studies of this drug and other histamine H2 receptor antagonists in men and experimental species. Several other medications are concerning and the evidence for negative effects on reproduction are covered: colchicine, domperidone, hydroxyurea, metformin, metoclopramide, mifepristone, retinoids, and statins.


Assuntos
Reprodução/efeitos dos fármacos , Animais , Cimetidina/efeitos adversos , Cimetidina/uso terapêutico , Colchicina/efeitos adversos , Colchicina/uso terapêutico , Domperidona/efeitos adversos , Domperidona/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Masculino , Metoclopramida/efeitos adversos , Metoclopramida/uso terapêutico , Mifepristona/efeitos adversos , Mifepristona/uso terapêutico , Retinoides/efeitos adversos , Retinoides/uso terapêutico
16.
In Vivo ; 31(6): 1221-1223, 2017 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29102950

RESUMO

A patient treated for 4 months with hydroxycarbamide (hydroxyurea) for chronic myelomonocytic leukemia was admitted to hospital for recently developed severe dyspnea and acute respiratory failure. The computed tomographic scan of the chest showed diffuse ground glass opacities, some centrilobular low-density nodules (resembling hypersensitivity pneumonitis-like pattern), and minimal interstitial reticulation of the subpleural region. The analysis of bronchoalveolar lavage fluid excluded infection, as did serological examinations. The patient was started on oxygen therapy and with relief of thrombocytopenia and suspected hemolytic anemia, hydroxyurea treatment was discontinued. The patient underwent steroid therapy, with a rapid progressive improvement of clinical and radiological features. As hydroxyurea is increasingly used for a number of systemic disorders, physicians must be aware of its potential lung toxicity, requiring immediate cessation of the treatment and empiric corticosteroid therapy.


Assuntos
Alveolite Alérgica Extrínseca/diagnóstico , Dispneia/diagnóstico por imagem , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Pulmão/diagnóstico por imagem , Insuficiência Respiratória/diagnóstico por imagem , Idoso de 80 Anos ou mais , Alveolite Alérgica Extrínseca/induzido quimicamente , Alveolite Alérgica Extrínseca/patologia , Dispneia/induzido quimicamente , Dispneia/tratamento farmacológico , Dispneia/patologia , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Leucemia Mielomonocítica Crônica/complicações , Leucemia Mielomonocítica Crônica/diagnóstico por imagem , Pulmão/patologia , Masculino , Oxigênio/administração & dosagem , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/patologia , Esteroides/administração & dosagem , Tomografia Computadorizada por Raios X
18.
Afr Health Sci ; 17(1): 255-261, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29026400

RESUMO

BACKGROUND: The clinical prospects of hydroxyurea therapy in the management of sickle cell disease (SCD) require evaluation in the Nigerian setting to develop indigenous guidelines. This survey examines the pattern of hydroxyurea therapy, its clinico-haematologic benefits and safety profile in Nigerian SCD subjects. METHODS: A cross sectional pilot survey was carried out among 60 adult SCD subjects over 3 months. Data on clinical phenotypes, relevant haematological parameters and details of hydroxyurea therapy were obtained using a structured questionnaire through an interview process and case file review. RESULTS: The median age was 30 years. Thirty-four (56.7%) of the subjects are aware of hydroxyurea therapy in SCD. Twenty-four (40%) SCD patients had previously used hydroxyurea. Only 4 subjects were fully compliant. Reasons for non-compliance included poor knowledge and lack of funds. In particular, hydroxyurea reduced leucocyte count and increased mean red cell volume (MCV) in compliant subjects. CONCLUSION: Hydroxyurea use is low among Nigerian SCD subjects despite its proven efficacy/clinical prospects in the developed nations. Large scale multicenter studies and clinical trials are needed to form a basis for developing standard local treatment protocol for its use.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/administração & dosagem , Hidroxiureia/administração & dosagem , Hidroxiureia/uso terapêutico , Cooperação do Paciente , Adolescente , Adulto , Anemia Falciforme/psicologia , Antidrepanocíticos/efeitos adversos , Estudos Transversais , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Hidroxiureia/efeitos adversos , Contagem de Leucócitos , Masculino , Projetos Piloto , Fatores Socioeconômicos , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
19.
Expert Rev Hematol ; 10(10): 891-901, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28891355

RESUMO

INTRODUCTION: Sickle cell disease (SCD) represents one of the most common monogenic blood disorders worldwide, with an incidence of over 300,000 newborns affected per year. Reproductive challenges for men and women with SCD have been previously reviewed; however, evidence-based strategies to prevent and manage infertility and increase fecundity are lacking in women with SCD, which is one of the most important factors for quality of life. Areas covered: This review article summarizes the known risk factors for infertility, low fecundity, and premature menopause related to SCD. Expert commentary: Women with SCD have unique risk factors that may impact their ability to conceive, including chronic inflammation, oxidative stress, transfusion-related hemochromatosis, and ovarian sickling, causing ischemia and reperfusion injury to the ovary. Contraception is strongly recommended while on hydroxyurea therapy during reproductive years and discontinuing hydroxyurea for family planning and during pregnancy based on teratogenicity in animal studies. Hematopoietic stem cell transplantation (HSCT), the only curative therapy, sometimes involves conditioning regimens containing alkylating agents and total body irradiation that contribute to infertility and premature ovarian failure. Prior to HSCT or gene therapy, we strongly recommend referral to a reproductive endocrinologist to discuss fertility preservation and surrogacy options for all women with SCD.


Assuntos
Anemia Falciforme/complicações , Fertilidade , Infertilidade/etiologia , Insuficiência Ovariana Primária/etiologia , Anemia Falciforme/terapia , Transfusão de Sangue , Dor Crônica/etiologia , Dor Crônica/terapia , Feminino , Preservação da Fertilidade/métodos , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Gravidez , Saúde Reprodutiva , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos
20.
J Assoc Physicians India ; 65(6): 22-25, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28782309

RESUMO

INTRODUCTION: Male Sickle cell disease (SCD) patients often have moderate to severe hypogonadism resulting in abnormal seminal fluid parameters due to testicular dysfunction. Hydroxyurea (HU), the only drug found to be effective in preventing morbidity and mortality in sickle cell disease patients has been found to further aggravate the testicular dysfunction. MATERIAL AND METHODS: This was a prospective study done at a tertiary care hospital over 26 months between September 2011 to October 2013. 100 male sickle cell disease patients of age group 15 to 45 years were recruited in the study. We evaluated seminal fluid indices in all patients and the effect of hydroxyurea on seminal fluid parameters. Hydroxyurea was given at low dose of 10mg/kg/day orally to patients with frequent vaso-occlusive crisis and frequent need of blood transfusion. Seminal fluid analysis was done according to WHO criteria before starting hydroxyurea and every 3 months after initiation of hydroxyurea. Patients with abnormal seminal parameters before hydroxyurea therapy were not given hydroxyurea therapy. Patients with abnormal sperm parameters were subjected for FNAC of testis. In sickle cell disease patients with hydroxyurea therapy, who developed abnormal seminal fluid parameters, hydroxyurea was stopped for 3 months and seminal fluid parameters were re-evaluated. Patients who had recovery of seminal indices after hydroxyurea cessation were restarted with hydroxyurea therapy at low dose. RESULTS: Among Sickle cell disease patients without hydroxyurea therapy, 18% of patients developed oligospermia and 4% developed azoospermia. Among sickle cell disease patients with hydroxyurea therapy, 20% of patients developed oligospermia and 10% developed azoospermia. Seminal fluid parameters reverted back to normal after stoppage of hydroxyurea for 3 months in 73% of patients. CONCLUSIONS: Alteration of sperm parameters is seen in a significant number of sickle cell disease patients. Also, alterations of seminal fluid parameters are exacerbated by hydroxyurea treatment even with low dose. Therefore, treatment with hydroxyurea in adolescent and adult male sickle cell disease patients should be preceded by routine assessment of seminal fluid parameters and followed up regularly every 3 months for any change in seminal fluid parameters for evidence of hydroxyurea toxicity.


Assuntos
Anemia Falciforme/tratamento farmacológico , Antidrepanocíticos/efeitos adversos , Azoospermia/etiologia , Hidroxiureia/efeitos adversos , Oligospermia/etiologia , Adolescente , Adulto , Anemia Falciforme/complicações , Antidrepanocíticos/administração & dosagem , Fertilidade , Humanos , Hidroxiureia/administração & dosagem , Hipogonadismo/tratamento farmacológico , Hipogonadismo/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
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