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1.
Arch Esp Urol ; 73(1): 54-59, 2020 Jan.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31950924

RESUMO

 OBJECTIVES: The double-J (DJ) stents are commonly used to relieve the ureteral obstruction. Besides several known benefits, some of the patients encounter stent-related morbidities with considerable effects on the quality of life, general health situation, sexual matters, and daily work performance. In this study, we evaluated the effectiveness of tamsulosin/solifenacin combination and mirabegron in reducing DJ stent-related symptoms. MATERIALS AND METHODS: A total of 120 patients with 28cm 4.7fr DJ catheter inserted due to ureteral obstruction were included in this study. Patients were randomly divided into three groups of 40 each; group one received only oral hydration for six weeks; group two received 0.4 mg tamsulosin/10 mg solifenacin, and group three received 50 mg mirabegron. Preoperative and after 6 weeks, the VAPS, OAB-q index, and IPSSs forms were filled. RESULTS: The mean age of the patients was 41.60 ± 12.34 years. There was no significant difference between the groups in terms of preoperative and postoperative VAPS values (p>0.05). There was a significant difference in postop IPSSs values (p:0.001). It was higher in the hydration group than tamsulosin/solifenacin and mirabegron groups. Postoperative IPSS value of the hydration group was 21.78 ± 2.54 while the tamsulosin/ solifenacin and mirabegron groups were 15.6 ± 4.37 and 13.65 ± 4.97, respectively. The use of mirabegron and tamsulosin/solifenacin combination alleviates the LUTSs related with DJ stent. There was also a significant difference between groups in terms of postoperative OAB-q values (p:0.001). Postoperative OAB-q values in the tamsulosin/solifenacin group were significantly higher than the mirabegron group. Postoperative OAB-q value of the hydration group was 29.95 ± 5.21, while the tamsulosin/solifenacin and mirabegron groups were 23.68 ± 4.07 and 18.15 ± 4.1, respectively. Our results also showed that, as a beta-3 adrenergic receptor agonist, mirabegron can improve the OAB-q scores. CONCLUSION: Tamsulosin and solifenacin combination is a significantly good treatment option for reducing LUTS associated with DJ stents. Mirabegron single therapy showed good results in treating LUTS and better results in treating OAB symptoms related with DJ stents than other therapies.


Assuntos
Acetanilidas , Succinato de Solifenacina , Tansulosina , Tiazóis , Bexiga Urinária Hiperativa , Cateteres Urinários , Agentes Urológicos , Acetanilidas/uso terapêutico , Adulto , Quimioterapia Combinada , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , Succinato de Solifenacina/uso terapêutico , Tansulosina/uso terapêutico , Tiazóis/uso terapêutico , Resultado do Tratamento , Bexiga Urinária Hiperativa/tratamento farmacológico , Agentes Urológicos/uso terapêutico
2.
Expert Opin Pharmacother ; 21(3): 365-376, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31899982

RESUMO

Introduction: Functional Dyspepsia (FD), defined as chronic symptoms originating from the gastroduodenal region in absence of readily identifiable organic disease, is one of the most common gastrointestinal disorders. FD is divided into two subgroups: Post-Prandial Distress Syndrome (PDS) or meal-related FD, characterized by postprandial fullness and early satiation, and Epigastric Pain Syndrome (EPS) or meal-unrelated FD, characterized by epigastric pain and burning.Areas covered: This review summarizes the existing and off-label therapeutic options for FD.Expert opinion: The identification of mechanisms, the Rome IV classification, the reduction of PDS/EPS overlap and pictograms for symptom identification allow a better diagnosis and a more targeted treatment choice. Acotiamide, a first-in-class prokinetic agent available only in Japan and India, is the only agent of proven efficacy for FD, but clinicians use acid-suppressive therapy, prokinetics, neuromodulators and herbal therapies for treating FD symptoms. New emerging targets are duodenal low-grade inflammation with eosinophils and duodenal or other modified luminal microbiota.


Assuntos
Benzamidas/uso terapêutico , Dispepsia/tratamento farmacológico , Tiazóis/uso terapêutico , Dor Abdominal/fisiopatologia , Humanos , Período Pós-Prandial , Síndrome
3.
Rev Med Suisse ; 15(674): 2232-2235, 2019 Dec 04.
Artigo em Francês | MEDLINE | ID: mdl-31804034

RESUMO

The use of direct oral anticoagulants (DOACs) has been largely -implemented in the management of venous thromboembolic disease in non-cancer patients. In cancer-associated thrombosis, low molecular weight heparins (LMWHs) and especially dalteparin have long been the reference standard therapy. Following the publication of two randomised trials comparing edoxaban and rivaroxaban to -dalteparin, DOACs now represent an alternative with an interesting efficacy and safety profile. Moreover, they offer the comfort of an oral administration and a lower cost. In patients with gastrointestinal or genitourinary cancers however, a higher bleeding risk has been shown with DOACs. LMWHs thus remain the treatment of choice in this group of patients.


Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Neoplasias/complicações , Tromboembolia Venosa/complicações , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Dalteparina/administração & dosagem , Dalteparina/uso terapêutico , Heparina de Baixo Peso Molecular/administração & dosagem , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Rivaroxabana/administração & dosagem , Rivaroxabana/uso terapêutico , Tiazóis/administração & dosagem , Tiazóis/uso terapêutico
5.
PLoS Negl Trop Dis ; 13(9): e0007779, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31553716

RESUMO

BACKGROUND: Fascioliasis is a neglected zoonosis with major public health implications in humans. Although triclabendazole (TCBZ) is the drug of choice, there are records of TCBZ failure worldwide. TCBZ-resistant fascioliasis is treated with alternative approved drugs including nitazoxanide (NTZ), with varying levels of efficacy. Data on NTZ efficacy after TCBZ failure in Egypt is scarce. This study evaluated the efficacy of NTZ in cases of TCBZ failure during an outbreak of fascioliasis in Assiut governorate of Upper Egypt. METHODOLOGY/PRINCIPAL FINDINGS: This prospective study included 67 patients from the outpatient clinic in Manfalout locality of Assiut governorate with clinical manifestations of acute fascioliasis. These included high eosinophilia (> 6% eosinophils in peripheral blood), positive anti-Fasciola antibodies, and hepatic focal lesions (HFL) or ascites on abdominal ultrasound or computed tomography. All patients initially received TCBZ at recommended doses. Patients were followed up after 1 month to assess response. According to the responses, patients were categorized as non-responders and responders. The non-responders received a trial of NTZ and were re-assessed for response based on clinical manifestations, eosinophil count, and abdominal ultrasound. Patients not responding to NTZ received additional doses of TCBZ. One month after initial TCBZ treatment, 37 patients responded well to TCBZ, while 30 patients failed to respond with persistence of fever, abdominal pain, high eosinophilia, and HFL. Most non-responders were male (56.7%); females predominated among TCBZ responders (62.2%). The mean age of the non-responders was relatively lower, at 20.57 ± 14.47 years (p = 0.004). Following NTZ therapy, HFL disappeared in 9/30 (30%) patients and eosinophil counts normalized in only 2 (6.7%) patients, indicating an overall efficacy of 36.6%. The remaining cases received additional doses of TCBZ with complete clinical, pathological, and radiological resolution. CONCLUSIONS/SIGNIFICANCE: Nitazoxanide was partially effective in TCBZ failure in acute human fascioliasis in Upper Egypt. Further studies with larger samples are highly encouraged and further research is urgently needed to find new therapeutic alternatives to TCBZ.


Assuntos
Fasciolíase/tratamento farmacológico , Tiazóis/uso terapêutico , Triclabendazol/uso terapêutico , Adolescente , Adulto , Animais , Anticorpos Anti-Helmínticos/sangue , Antiparasitários/uso terapêutico , Criança , Pré-Escolar , Egito , Eosinofilia , Fasciola/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Falha de Tratamento
6.
Infez Med ; 27(3): 336-339, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31545780

RESUMO

Caused by the protozoan Giardia lamblia, giardiasis is one of the most common parasitic diarrheal infections affecting humans. Although a variety of antigiardial drugs are available to treat infections in humans, failure of conventional treatment with nitroimidazoles for giardiasis has been increasingly reported. We describe the follow-up of a patient with recurrent giardiasis refractory to nitroimidazoles. Despite the different therapies received, the symptomatology and parasitic forms of G. lamblia persisted in the patient. There is no standard treatment regimen for giardiasis refractory to nitroimidazoles. When treatment failure is confirmed, it is necessary to switch to second-line regimens.


Assuntos
Antiprotozoários/uso terapêutico , Giardia lamblia , Giardíase/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Adulto , Albendazol/uso terapêutico , Antiprotozoários/administração & dosagem , Furazolidona/uso terapêutico , Giardia lamblia/efeitos dos fármacos , Humanos , Masculino , Metronidazol/administração & dosagem , Metronidazol/análogos & derivados , Metronidazol/uso terapêutico , Tiazóis/uso terapêutico , Tinidazol/uso terapêutico , Falha de Tratamento
7.
Artigo em Inglês | MEDLINE | ID: mdl-31527426

RESUMO

Noise is one of the most common causes of hearing loss in industrial countries. There are many studies about chemical agents to prevent noise-induced hearing loss (NIHL). However, there is no commercially available drug yet. Retinoic acid is an active metabolite of Vitamin A; it has an anti-apoptic role in NIHL. This study aims to verify the differences among selective agonists of retinoic acid receptors (RARs) in NIHL. All-trans retinoic acid (ATRA), AM80 (selective retinoic acid receptor α agonist), AC261066 (Selective retinoic acid receptor ß1 agonist), and CD1530 (Selective retinoic acid λ agonist) were injected to 6-7 weeks old CJ5BL/6 mice before noise (110 dB for 3 h) exposure. In the auditory brainstem response test pre-, post 1, 3, and 7 days after noise exposure, not only ATRA but all kinds of selective RAR agonists showed protective effects in hearing threshold and wave I amplitude. Though there was no significant difference in the level of protective effects between agonists, α agonist showed the most prominent effect in preserving hearing function as well as outer hair cells after noise exposure. In conclusion, selective agonists of RAR demonstrate comparable protective effects against NIHL to retinoic acid. Given that these selective RAR agonists have less side effects than retinoic acid, they may be promising potential drugs against NIHL.


Assuntos
Benzoatos/uso terapêutico , Perda Auditiva Provocada por Ruído/prevenção & controle , Naftóis/uso terapêutico , Receptores do Ácido Retinoico/agonistas , Tetra-Hidronaftalenos/uso terapêutico , Tiazóis/uso terapêutico , Tretinoína/uso terapêutico , Animais , Camundongos Endogâmicos C57BL , Ruído/efeitos adversos
8.
Lancet ; 394(10206): 1335-1343, 2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31492505

RESUMO

BACKGROUND: We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI). METHODS: ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed. FINDINGS: From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority). INTERPRETATION: In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events. FUNDING: Daiichi Sankyo.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Fibrinolíticos/uso terapêutico , Intervenção Coronária Percutânea , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Vitamina K/antagonistas & inibidores , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/cirurgia , Idoso , Fibrilação Atrial/complicações , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Stents , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle
9.
Expert Opin Pharmacother ; 20(13): 1539-1550, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31381378

RESUMO

Introduction: Systemic Mastocytosis (SM) is a complex family of rare diseases, against which pharmacological therapies are still very few. It is a c-kit driven disease, whose disregulation leads to uncontrolled activation and proliferation of mast cells (MCs) with consequent release of effector molecules which are responsible for its clinical manifestations. Areas covered: Masitinib is a relatively new potential drug against SM and its chemical structure strictly derives from imatinib, the first tyrosine kinase inhibitor which entered the pharmaceutical market about 15 years ago. In this review, the authors present masitinib in all its properties, from chemistry to pharmacology and toxicity to its potential clinical application in SM, focusing the discussion on the few clinical trials in which it has been involved, with a particular attention on the still open challenge to determine how to measure the response to therapy. Expert opinion: In spite of their similarity in chemistry and biological activity against submolecular targets, masitinib is much more selective towards c-kit receptors than other tyrosine kinases, such as Bcl-Abl. Furthermore, its ability to inhibit degranulation, cytokine production and MCs migration from bone marrow gives it a great chance to become an important therapeutic option for selected SM patients.


Assuntos
Mastocitose Sistêmica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tiazóis/uso terapêutico , Humanos , Mesilato de Imatinib/farmacologia , Mastócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/metabolismo
10.
Indian J Med Res ; 149(5): 600-609, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31417027

RESUMO

Paediatric chronic myeloid leukaemia (CML) has biological and clinical differences from adult CML. Management of paediatric CML presents unique challenges in growing children, and there are no specific guidelines for paediatric CML. This review focusses on the clinical characteristics, diagnostic issues and management of paediatric CML. Major studies that provide the basis of managing paediatric CML are summerized here. Studies conducted on adult CML patients were used to guide the management of places where studies were lacking in paediatric CML. Recently, dasatinib and nilotinib have been approved for treatment of paediatric CML, and their role has been discussed in the current management perspective. Allogeneic transplant, fertility and vaccination in paediatric CML, have also been discussed.


Assuntos
Dasatinibe/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Tiazóis/uso terapêutico , Antineoplásicos/uso terapêutico , Criança , Análise Custo-Benefício , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Pediatria/tendências , Pirimidinas/uso terapêutico
11.
World Neurosurg ; 131: 209-212, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442658

RESUMO

BACKGROUND: Antiplatelet agents are typically administered before and after treatment using flow-diverter stents (FDS) to prevent thrombotic complications, but the effects of anticoagulants are unclear. We present a patient with a giant aneurysm treated with an FDS. The thrombus within the aneurysm was dissolved when a direct factor Xa inhibitor was administered to treat lower limb venous thrombosis that occurred secondary to steroid use. CASE DESCRIPTION: A 60-year-old woman with a 30-mm giant thrombosed aneurysm in the cavernous segment of the right internal carotid artery presenting with headache and right abducens nerve palsy was treated by placing an FDS. Diplopia and increased pain in her right eye appeared on postoperative day 7, and both were alleviated by continuous oral administration of prednisolone. Angiography 3 months postoperatively revealed that the aneurysm thrombosis had progressed, and there were signs of healing. However, at the same time, lower limb venous thrombosis occurred, which was treated by continuous edoxaban. Six months after surgery, her headaches worsened and angiography showed that the aneurysm was again contrast enhanced and that the thrombus within the aneurysm had dissolved. After discontinuing edoxaban 9 months after surgery, the aneurysmal thrombosis had again rapidly progressed. CONCLUSIONS: Administration of a direct factor Xa inhibitor during healing after placing an FDS may cause dissolution of an existing thrombus; therefore factor Xa inhibitors must be used with caution.


Assuntos
Doenças das Artérias Carótidas/etiologia , Inibidores do Fator Xa/uso terapêutico , Aneurisma Intracraniano/etiologia , Trombose Intracraniana/tratamento farmacológico , Piridinas/uso terapêutico , Stents/efeitos adversos , Tiazóis/uso terapêutico , Doenças do Nervo Abducente/cirurgia , Artéria Carótida Interna/cirurgia , Feminino , Humanos , Perna (Membro)/irrigação sanguínea , Pessoa de Meia-Idade , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Trombose Venosa/tratamento farmacológico
13.
Immunohorizons ; 3(8): 402-411, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439624

RESUMO

Chronically activated CD4+ T cells drive uncontrolled inflammation, leading to tissue damage in various autoimmune disorders, such as rheumatoid arthritis (RA). Investigation of the molecular mechanisms involved in RA and recent analysis of transcriptomic profiles has implicated members of the nuclear receptor (NR) superfamily in RA. NRs are required for the development, differentiation, and effector function of CD4+ T cells; therefore, it is thought that NRs are important in shaping the CD4+ T cell repertoire and associated inflammation in RA. Despite their relevance, the full potential of the NR superfamily in RA, either as biomarkers or disease targets, has not been harnessed. To gain insight on the NR members that are closely associated with RA disease activity, we generated an expression atlas for the NR superfamily in CD4+ T cells isolated either in a steady state or over the course of collagen-induced arthritis mouse model of RA. We observed discrete expression patterns among the NR superfamily during the disease stages. NRs that instigate anti-inflammatory programs underwent major downregulation during disease onset; however, during the fully developed disease stage we noticed that NRs that induce proinflammatory programs had reduced transcript levels. These animal findings corroborated well with the expression patterns of NRs in clinical samples obtained from RA patients. Furthermore, we observed that targeting NRs using synthetic ligands alleviates the progression of collagen-induced arthritis. Overall, our data demonstrates the potential of the NR superfamily as novel therapeutic targets for the treatment of autoimmune disorders.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Anticorpos/imunologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/patologia , Colágeno Tipo II/imunologia , Colágeno Tipo II/farmacologia , Citocinas/metabolismo , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Fenilacetatos/uso terapêutico , Retinoides/uso terapêutico , Líquido Sinovial/metabolismo , Tiazóis/uso terapêutico , Tiossemicarbazonas/uso terapêutico , Transcrição Genética
14.
Endocrinology ; 160(11): 2600-2617, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31322702

RESUMO

There are no officially approved therapies for metastatic pheochromocytomas apart from ultratrace 131I-metaiodbenzylguanidine therapy, which is approved only in the United States. We have, therefore, investigated the antitumor potential of molecular-targeted approaches in murine pheochromocytoma cell lines [monocyte chemoattractant protein (MPC)/monocyte chemoattractant protein/3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)], immortalized mouse chromaffin Sdhb-/- cells, three-dimensional pheochromocytoma tumor models (MPC/MTT spheroids), and human pheochromocytoma primary cultures. We identified the specific phosphatidylinositol-3-kinase α inhibitor BYL719 and the mammalian target of rapamycin inhibitor everolimus as the most effective combination in all models. Single treatment with clinically relevant doses of BYL719 and everolimus significantly decreased MPC/MTT and Sdhb-/- cell viability. A targeted combination of both inhibitors synergistically reduced MPC and Sdhb-/- cell viability and showed an additive effect on MTT cells. In MPC/MTT spheroids, treatment with clinically relevant doses of BYL719 alone or in combination with everolimus was highly effective, leading to a significant shrinkage or even a complete collapse of the spheroids. We confirmed the synergism of clinically relevant doses of BYL719 plus everolimus in human pheochromocytoma primary cultures of individual patient tumors with BYL719 attenuating everolimus-induced AKT activation. We have thus established a method to assess molecular-targeted therapies in human pheochromocytoma cultures and identified a highly effective combination therapy. Our data pave the way to customized combination therapy to target individual patient tumors.


Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Feocromocitoma/tratamento farmacológico , Tiazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Everolimo/farmacologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Tiazóis/farmacologia
15.
Hypertension ; 74(3): 597-605, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31352829

RESUMO

Hypertension is a risk factor for both stroke and bleeding in patients with atrial fibrillation. Data are sparse regarding the interaction between blood pressure and the efficacy and safety of direct oral anticoagulants. In the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48), 19,679 patients with atrial fibrillation and hypertension were categorized according to average systolic blood pressure (SBP) and diastolic blood pressure (DBP). The primary efficacy and safety end points were the time to the first stroke or systemic embolic event and the time to the first International Society of Thrombosis and Hemostasis major bleeding event, respectively. Risk was calculated using Cox proportional hazards models based on average SBP and DBP and adjusting for 18 clinical characteristics. The efficacy and safety of a higher dose edoxaban regimen (60/30 mg) versus warfarin were evaluated with stratification by average SBP and DBP. Stroke/systemic embolic event occurred significantly more frequently in patients with elevated average SBP (hazard ratio, 2.01; 95% CI, 1.50-2.70 for SBP ≥150 mm Hg relative to 130-139 mm Hg) or DBP (hazard ratio, 2.36; 95% CI, 1.76-3.16 for DBP ≥90 mm Hg relative to 75-<85 mm Hg). The higher dose edoxaban regimen reduced stroke/systemic embolic event across the full range of SBP (Pinteraction=0.55) and DBP (Pinteraction=0.44) compared with warfarin. The higher dose edoxaban regimen reduced the risk of major bleeding events, including intracranial hemorrhage, without modification by average SBP (Pinteraction=0.29). The relative safety of edoxaban was most pronounced in patients with elevated DBP (Pinteraction=0.007). The efficacy and safety of edoxaban were consistent across the full range of SBP, while the superior safety of edoxaban was most pronounced among patients with elevated DBP.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Varfarina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/diagnóstico , Comorbidade , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Hipertensão/diagnóstico , Modelos Logísticos , Masculino , Segurança do Paciente , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/fisiopatologia , Análise de Sobrevida , Resultado do Tratamento
16.
Expert Rev Clin Pharmacol ; 12(9): 859-865, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31352834

RESUMO

Introduction: Thrombocytopenia is a common hematological abnormality in patients with chronic liver disease (CLD), occurring in 64%~84% of patients with cirrhosis or fibrosis. Due to the increased risk of bleeding, thrombocytopenia potentially affects management of CLD, such as surgery or liver biopsy. Avatrombopag is a new oral thrombopoietin (TPO) receptor agonist, activating TPO receptor and increasing megakaryocytic proliferation/differentiation and platelet production. Areas covered: This review summarizes the collected data concerning pharmacokinetics, clinical efficacy, safety and tolerability profiles of avatrombopag for the management of thrombocytopenia in patients with CLD. Expert opinion: Avatrombopag is recently approved by Food and Drug Administration (FDA) for the treatment of thrombocytopenia in patients with CLD who are scheduled to undergo a procedure. Based on the available clinical trials, avatrombopag is superior to placebo in reducing the need for platelet transfusions or rescue procedures for bleeding. Avatrombopag is also recommended as alternative to platelet transfusions.


Assuntos
Hepatopatias/complicações , Tiazóis/uso terapêutico , Tiofenos/uso terapêutico , Trombocitopenia/tratamento farmacológico , Doença Crônica , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Cirrose Hepática/complicações , Hepatopatias/fisiopatologia , Transfusão de Plaquetas/métodos , Receptores de Trombopoetina/agonistas , Tiazóis/efeitos adversos , Tiazóis/farmacologia , Tiofenos/efeitos adversos , Tiofenos/farmacologia , Trombocitopenia/etiologia
17.
J Thromb Thrombolysis ; 48(3): 382-386, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31228036

RESUMO

Malignancy is a well-established risk factor for venous thromboembolism and while low-molecular-weight heparin therapy has been standard of care for cancer-associated thrombosis for many years, many patients find injection therapy burdensome. The direct oral anticoagulant edoxaban has been shown to be noninferior to dalteparin for the treatment of cancer-associated thrombosis. In a Markov simulation model, edoxaban with 6-month time horizon and a United States societal perspective with 2017 US dollars, edoxaban was the preferred strategy in the general cancer population (6-month cost $6061 with 0.34 quality adjusted life years) and in a subgroup of patients with gastrointestinal malignancy (6-month cost $7227 with 0.34 quality adjusted life years). The incremental cost effectiveness ratio of dalteparin compared to edoxaban was $1,873,535 in the general oncology population and $694,058 in the gastrointestinal malignancy population.


Assuntos
Análise Custo-Benefício , Dalteparina/uso terapêutico , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Trombose/tratamento farmacológico , Trombose/economia , Anticoagulantes/economia , Anticoagulantes/uso terapêutico , Dalteparina/economia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/economia , Humanos , Cadeias de Markov , Modelos Teóricos , Neoplasias/complicações , Piridinas/economia , Anos de Vida Ajustados por Qualidade de Vida , Tiazóis/economia , Trombose/etiologia , Estados Unidos
18.
Int J Mol Sci ; 20(12)2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226783

RESUMO

This review provides details about three small molecules that were recently approved by the FDA for the treatment of thrombocytopenia. The new treatments include lusutrombopag, avatrombopag, and fostamatinib. The first two drugs are orally active thrombopoietin receptor (TPO-R) agonists which are FDA-approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Fostamatinib is orally active prodrug that, after activation, becomes spleen tyrosine kinase (SYK) inhibitor. Fostamatinib is currently used to treat chronic and refractory immune thrombocytopenia in patients who have had insufficient response to previous treatment. Chemical structures, available dosage forms, recommended dosing, pharmacokinetics, results of toxicity studies in animals, most frequent adverse effects, significant outcomes of the corresponding clinical trials, and their use in specific patient populations are thoroughly described. Described also is a comparative summary of the different aspects of five currently available therapies targeting TPO-R or SYK for the treatment of thrombocytopenia.


Assuntos
Cinamatos/uso terapêutico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Tiazóis/uso terapêutico , Tiofenos/uso terapêutico , Trombocitopenia/tratamento farmacológico , Animais , Cinamatos/química , Cinamatos/farmacologia , Desenvolvimento de Medicamentos , Humanos , Oxazinas/química , Oxazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de Trombopoetina/agonistas , Receptores de Trombopoetina/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Tiazóis/química , Tiazóis/farmacologia , Tiofenos/química , Tiofenos/farmacologia , Trombocitopenia/metabolismo
19.
Cell Mol Life Sci ; 76(20): 4103-4115, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250032

RESUMO

Cardiovascular diseases (CVDs) are among the leading threats to human health. The advanced glycation end product (AGE) and receptor for AGE (RAGE) signaling pathway regulates the pathogenesis of CVDs, through its effects on arterial stiffness, atherosclerosis, mitochondrial dysfunction, oxidative stress, calcium homeostasis, and cytoskeletal function. Targeting the AGE/RAGE pathway is a potential therapeutic strategy for ameliorating CVDs. Vitamin D has several beneficial effects on the cardiovascular system. Experimental findings have shown that vitamin D regulates AGE/RAGE signaling and its downstream effects. This article provides a comprehensive review of the mechanistic insights into AGE/RAGE involvement in CVDs and the modulation of the AGE/RAGE signaling pathways by vitamin D.


Assuntos
Cardiomiopatias Diabéticas/prevenção & controle , Produtos Finais de Glicação Avançada/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocardite/prevenção & controle , Receptor para Produtos Finais de Glicação Avançada/genética , Vitamina D/uso terapêutico , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestrutura , Animais , Cálcio/metabolismo , Cardiotônicos/uso terapêutico , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Regulação da Expressão Gênica , Produtos Finais de Glicação Avançada/sangue , Guanidinas/uso terapêutico , Humanos , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miocardite/sangue , Miocardite/genética , Miocardite/patologia , Estresse Oxidativo/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/sangue , Transdução de Sinais , Tiazóis/uso terapêutico , Rigidez Vascular/efeitos dos fármacos , Vitamina D/sangue
20.
Thromb Res ; 180: 37-42, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31200341

RESUMO

INTRODUCTION: While trials have demonstrated non-inferiority of direct oral anticoagulant drugs (DOAC) to low-molecular-weight heparins (LMWH) for the treatment of cancer associated thrombosis (CAT), it is unclear if the newer intervention is cost-effective. METHODS: We performed a cost-utility analysis using a Markov state-transition model over a time horizon of 60 months in a hypothetical cohort of 65-year-old patients with active malignancy and first acute symptomatic CAT who were eligible to receive either rivaroxaban/edoxaban or dalteparin. We obtained transition probability, relative risk, cost, and utility inputs from the literature. We estimated the differential impact on costs and quality-adjusted life years (QALYs) per patient and performed one-way and probabilistic sensitivity analyses to test the robustness of results. RESULTS: Using the base-case analysis over 60 months, DOAC versus dalteparin was associated with an incremental cost reduction of $24,129 with an incremental QALY reduction of 0.04. In the one-way sensitivity analysis, the cost of dalteparin contributed the most to the incremental cost difference; relative risk of death related to underlying cancer contributed the most of the incremental QALY difference. The probabilistic sensitivity analysis confirmed the base-case analysis, with a large reduction in cost but small reduction in QALYs. CONCLUSION: Rivaroxaban or edoxaban as compared to dalteparin is cost saving from a payer's perspective for the treatment of CAT. Professional organizations and healthcare systems may want to consider this analysis in future practice recommendations.


Assuntos
Anticoagulantes/uso terapêutico , Dalteparina/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Piridinas/uso terapêutico , Rivaroxabana/uso terapêutico , Tiazóis/uso terapêutico , Trombose/tratamento farmacológico , Anticoagulantes/economia , Análise Custo-Benefício , Dalteparina/economia , Inibidores do Fator Xa/economia , Humanos , Neoplasias/complicações , Piridinas/economia , Anos de Vida Ajustados por Qualidade de Vida , Rivaroxabana/economia , Tiazóis/economia , Trombose/complicações , Trombose/economia
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