RESUMO
Prescribing direct oral anticoagulants (DOACs) with off-label dosage and administration is discouraged due to concerns about their effectiveness and safety. Consequently, our hospital pharmacist established a formulary with physicians for oral anticoagulants. Our study aimed to assess the adherence to this formulary by investigating the rate of appropriate DOAC prescribing. We included patients who were newly prescribed or continued on DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) at our hospital. We calculated the percentage of patients prescribed the correct dosage and administration according to the package insert and compared this across three time periods: pre-intervention (period A; April-September 2019), post-intervention phase 1 (period B; August 2021-January 2022), and post-intervention phase 2 (period C; November 2022-April 2023). We also examined the number of inquiries and consultation requests made by hospital pharmacists regarding DOAC dosage and administration. A total of 782 patients were surveyed (191 in period A, 263 in period B, and 328 in period C). The appropriate prescribing rates for DOACs were 79.1% in period A, 84.4% in period B, and 86.6% in period C. The proportion of cases where hospital pharmacists questioned or consulted doctors about DOAC dosage and administration was 3.7% in period A, 6.1% in period B, and 10.1% in period C. These findings indicate that active intervention by hospital pharmacists using the formulary regarding oral anticoagulant formularies may promote appropriate DOAC use.
Assuntos
Anticoagulantes , Dabigatrana , Formulários de Hospitais como Assunto , Farmacêuticos , Serviço de Farmácia Hospitalar , Pirazóis , Piridonas , Tiazóis , Humanos , Administração Oral , Pirazóis/administração & dosagem , Anticoagulantes/administração & dosagem , Dabigatrana/administração & dosagem , Piridonas/administração & dosagem , Tiazóis/administração & dosagem , Masculino , Idoso , Rivaroxabana/administração & dosagem , Piridinas/administração & dosagem , Feminino , Padrões de Prática Médica/estatística & dados numéricos , Idoso de 80 Anos ou mais , Prescrições de Medicamentos/estatística & dados numéricos , Pessoa de Meia-IdadeAssuntos
Herpes Zoster , Inibidores de Janus Quinases , Humanos , Herpes Zoster/tratamento farmacológico , Herpes Zoster/diagnóstico , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Idoso , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Administração Oral , PiperidinasAssuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/história , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , História do Século XX , História do Século XXI , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/história , /efeitos adversos , Ensaios Clínicos Fase III como Assunto , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Objective: To explore the efficacy and safety of ibrutinib for the treatment of newly treated and relapsed refractory (R/R) lymphoplasmacytic lymphoma (LPL) /Waldenström macroglobulinemia (WM) . Methods: Retrospectively collected clinical data of 98 cases of newly treated and R/R LPL/WM patients who received ibrutinib treatment at the Hematology & Blood Diseases Hospital of the Chinese Academy of Medical Sciences from March 2016 to June 2023, and analyzed their efficacy and safety. Results: A total of 98 LPL/WM patients were included, which consisted of 45 newly treated patients and 53 R/R patients. Of these, 74 were males (75.5%) and the cohort had a median age of 64 (42-87) years. Eighty-eight patients were eligible for efficacy evaluation with a median treatment time of 20.8 (2.1-55.0) months, a major remission rate (MRR) of 78.4%, and an overall response rate (ORR) of 85.2%. The MRR and ORR of the newly treated patients were 78.4% and 86.5%, respectively, whereas the MRR and ORR of the R/R patients were 78.4% and 84.3%, respectively. There were no statistically significant differences in MRR and ORR between the initial treatment and R/R patients (all P values >0.05) . The median follow-up period was 29.1 (2.9-50.3) months and the median overall survival time for newly treated and R/R patients was not reached. The median progression-free survival time was 23.5 (95% CI 10.5-36.5) months and 45.0 (95% CI 34.0-56.0) months, respectively, with no statistically significant differences (all P values >0.05) . There were 25 deceased patients and no deaths were related to ibrutinib treatment. The main adverse reactions of ibrutinib were thrombocytopenia (5.1%) , pneumonia (8.1%) , and hyperuricemia (21.4%) . The incidence of atrial fibrillation was 2.0%. Conclusion: Ibrutinib exhibits good efficacy and safety for newly treated and R/R LPL/WM patients.
Assuntos
Adenina , Piperidinas , Pirimidinas , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adenina/análogos & derivados , Estudos Retrospectivos , Adulto , Idoso de 80 Anos ou mais , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Results of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy. METHODS: Patients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle. RESULTS: Twenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell's syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively. CONCLUSION: Targeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing. TRIAL REGISTRATION: NCT04446962.
Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Nervoso Central , Lenalidomida , Piperidinas , Pirazóis , Pirimidinas , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Lenalidomida/efeitos adversos , Adenina/análogos & derivados , Adenina/administração & dosagem , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Masculino , Feminino , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Idoso , Adulto , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Vincristina/efeitos adversos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Prednisona/efeitos adversos , Linfoma/tratamento farmacológicoRESUMO
Cryptosporidium parvum and C. hominis are parasites that cause life-threatening diarrhea in children and immunocompromised people. There is only one approved treatment that is modestly effective for children and ineffective for AIDS patients. Here, screening 278 compounds from the Merck KGaA, Darmstadt, Germany collection and accelerated follow-up enabled by prior investigation of the compounds identifies a series of pyrazolopyrimidine human phosphodiesterase (PDE)-V (hPDE-V) inhibitors with potent anticryptosporidial activity and efficacy following oral administration in C. parvum-infected male mice. The lead compounds affect parasite host cell egress, inhibit both C. parvum and C. hominis, work rapidly, and have minimal off-target effects in a safety screening panel. Interestingly, the hPDE-V inhibitors sildenafil and the 4-aminoquinoline compound 7a do not affect Cryptosporidium. C. parvum expresses one PDE (CpPDE1) continuously during asexual growth, the inhibited life stage. According to homology modeling and docking, the lead compounds interact with CpPDE1. Bulkier amino acids (Val900 and His884) in the CpPDE1 active site replace alanines in hPDE-V and block sildenafil binding. Supporting this, sildenafil kills a CRISPR-engineered Cryptosporidium CpPDE1 V900A mutant. The CpPDE1 mutation also alters parasite susceptibility to pyrazolopyrimidines. CpPDE1 is therefore a validated pyrazolopyrimidine molecular target to exploit for target-based optimization for improved anticryptosporidial development.
Assuntos
Criptosporidiose , Cryptosporidium parvum , Hospedeiro Imunocomprometido , Inibidores de Fosfodiesterase , Animais , Cryptosporidium parvum/efeitos dos fármacos , Masculino , Criptosporidiose/tratamento farmacológico , Criptosporidiose/parasitologia , Camundongos , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/administração & dosagem , Humanos , Administração Oral , Pirimidinas/farmacologia , Pirimidinas/administração & dosagem , Pirazóis/farmacologia , Pirazóis/administração & dosagem , Simulação de Acoplamento MolecularRESUMO
Ruxolitinib cream 1.5% was first approved by the US Food and Drug Administration (FDA) in 2011. Opzelura™ cream was introduced by Incyte Dermatology in 2021 for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis (AD) in non-immunocompromised patients aged ≥12 years, whose clinical manifestations are not controlled with prescribed topical therapies, such as topical corticosteroids, topical calcineurin inhibitors, or topical phosphodiesterase-4 ( PDE4) inhibitors, or when such therapies are not advisable. Ruxolitinib is a Janus kinase (JAK) inhibitor that addresses inflammation in AD. It selectively inhibits JAK1 and JAK2, blocking JAK and activating signal transducer and activator of transcription (STAT), thereby interrupting the cytokine pathways responsible for cutaneous inflammation. The targeted downstream cytokines include Interleukin- 4 (IL-4), IL-13, IL-31, and cytokine thymic stromal lymphopoietin (TSLP), which play pivotal roles in the itching and inflammation experienced by AD patients. Ruxolitinib cream is directly applied as a thin layer over AD lesions twice daily up to 20% body surface area (BSA) using no more than 60 g per week. It can be used for up to 8 weeks on delicate or thin skin surfaces.
Assuntos
Dermatite Atópica , Nitrilas , Pirazóis , Pirimidinas , Humanos , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Nitrilas/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Creme para a Pele , Administração Cutânea , Citocinas/metabolismoRESUMO
Liposils, synthesized via the liposome templating method, offer a promising strategy for enhancing liposome stability by employing a silica coating. This study focuses on the development of nanocarriers utilizing silica-coated nanoliposomes for encapsulating the poorly water-soluble drug, ibrutinib. Ibrutinib-loaded nanoliposomes were meticulously formulated using the reverse-phase evaporation technique, serving as templates for silica coating, resulting in spherical liposils with an average size of approximately 240 nanometers. Comprehensive characterization of the liposil's physical and chemical properties was conducted using various analytical methods, including dynamic light scattering, transmission electron microscopy, Fourier-transform infrared spectroscopy, and X-ray diffraction analysis. Liposils demonstrated superior performance compared to ibrutinib-loaded nanoliposomes, showing sustained drug release profiles in simulated intestinal fluids and resistance to simulated gastric fluid, as confirmed by dissolution studies. Moreover, ibrutinib liposils exhibited a significant increase in half-life (4.08-fold) and notable improvement in bioavailability (3.12-fold) compared to ibrutinib suspensions, as determined by pharmacokinetic studies in rats. These findings underscore the potential of liposils as nanocarriers for orally delivering poorly water-soluble drugs, offering enhanced stability and controlled release profiles, thereby improving bioavailability prospects and therapeutic efficacy. This approach holds promise for addressing challenges associated with the oral administration of drugs with limited solubility, thereby advancing drug delivery technologies and clinical outcomes in pharmaceutical research and development.
Assuntos
Adenina , Disponibilidade Biológica , Lipossomos , Piperidinas , Pirazóis , Pirimidinas , Adenina/farmacocinética , Adenina/análogos & derivados , Adenina/administração & dosagem , Adenina/química , Piperidinas/farmacocinética , Piperidinas/administração & dosagem , Piperidinas/química , Animais , Administração Oral , Lipossomos/química , Pirimidinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Pirazóis/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/química , Masculino , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Nanopartículas/química , Ratos Sprague-Dawley , Dióxido de Silício/químicaAssuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Linfocítica Crônica de Células B , Piperidinas , Pirazóis , Pirimidinas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Adenina/análogos & derivados , Adenina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Nitrilas/administração & dosagem , Nitrilas/uso terapêuticoRESUMO
Patients with thrombotic antiphospholipid syndrome (APS) are at high risk for recurrent thrombosis, and indefinite anticoagulation is recommended. Patients with APS merit indefinite anticoagulation, and vitamin K antagonists (VKAs) have historically been the standard treatment. Direct oral anticoagulants (DOACs) present an appealing alternative to VKAs. Due to their pharmacokinetic and pharmacodynamic characteristics, DOACs offer advantages over VKAs, namely the lack of need for laboratory monitoring, the usage of a fixed dosage, and the absence of significant interaction with dietary components and drugs. The efficacy and safety of DOACs in patients with APS have been studied in four phase II/III clinical trials (three with rivaroxaban and one with apixaban). These studies showed DOACs' inferiority compared to VKAs in preventing recurrent thrombosis. Recurrence was significantly greater in patients with arterial thrombotic events and a triple positivity for antiphospholipid antibodies. No differences were observed in the incidence of venous thromboembolism between both groups. Major bleeding was similar in patients treated with DOACs or VKAs. Several observational studies have reported similar results. This review aims to analyse the existing evidence on the efficacy and safety of DOACs for secondary prevention in patients with APS.
Assuntos
Anticoagulantes , Síndrome Antifosfolipídica , Prevenção Secundária , Trombose , Humanos , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/tratamento farmacológico , Administração Oral , Anticoagulantes/uso terapêutico , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Prevenção Secundária/métodos , Trombose/prevenção & controle , Trombose/etiologia , Rivaroxabana/uso terapêutico , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/etiologiaRESUMO
BACKGROUND: Limited real-world evidence is available comparing the safety and effectiveness of apixaban and low-molecular-weight heparins (LMWHs) for preventing recurrent venous thromboembolism (VTE) in patients with active cancer receiving anticoagulation in an extended treatment setting. This study evaluated the risk of bleeding and recurrent VTE in patients with cancer-associated VTE who were prescribed apixaban or LMWH for ≥3 months. METHODS: A US commercial claims database was used to identify adult patients with VTE and active cancer who initiated apixaban or LMWH 30 days following the first VTE diagnosis and had ≥3 months of continuous enrollment and 3 months of primary anticoagulation treatment. Patients were followed from the day after the end of primary anticoagulation treatment until the earliest of: date of disenrollment, discontinuation of index anticoagulant, switch to another anticoagulant, or end of the study period. Inverse-probability treatment weighting (IPTW) was used to balance treatment cohorts. Incidence rates (IRs) for the outcomes were calculated per 100 person-years (PY). Cox proportional hazard models were used to evaluate the adjusted risk of recurrent VTE, major bleeding (MB), and clinically relevant nonmajor bleeding (CRNMB). RESULTS: A total of 13,564 apixaban- and 2,808 LMWH-treated patients were analyzed. Post-IPTW, the treatment cohorts were balanced. Patients receiving apixaban had lower adjusted IRs for recurrent VTE (4.1 vs 9.6 per 100 PY), MB (6.3 vs 12.6), and CRNMB (26.1 vs 36.0) versus LMWH (P<.0001 for all comparisons) during the follow-up period. Patients on apixaban had a lower adjusted risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.34-0.53), MB (HR, 0.50; 95% CI, 0.41-0.61), and CRNMB (HR, 0.76; 95% CI, 0.68-0.85) versus LMWH. CONCLUSIONS: Extended anticoagulation treatment of ≥3 months with apixaban was associated with lower rates of recurrent VTE, MB, and CRNMB compared with LMWH in adults with cancer-associated VTE.
Assuntos
Heparina de Baixo Peso Molecular , Neoplasias , Pirazóis , Piridonas , Tromboembolia Venosa , Humanos , Piridonas/uso terapêutico , Piridonas/efeitos adversos , Piridonas/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/prevenção & controle , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Feminino , Heparina de Baixo Peso Molecular/uso terapêutico , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/administração & dosagem , Masculino , Pessoa de Meia-Idade , Idoso , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Anticoagulantes/administração & dosagem , Hemorragia/induzido quimicamente , Hemorragia/etiologia , Resultado do Tratamento , Adulto , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/administração & dosagemRESUMO
PURPOSE OF REVIEW: To analyze the efficacy and safety of Janus kinase inhibitors (JAKi) in the treatment of pediatric AD. RECENT FINDINGS: Adolescents with moderate and severe atopic dermatitis (AD) need systemic therapies, as stated several recent practice guidelines. (JAKi) have shown their efficacy in the treatment of adult AD, however, there is a lack of information concerning efficacy and safety of their use in pediatric AD. We found that the JAKi's abrocitinib (ABRO), baricitinib (BARI), and upadacitinib (UPA), are all an effective treatment option with a very fast onset of action for adolescents with moderate-to-severe AD. BARI was not effective in children between 2 and 10 years with moderate-to-severe AD. Fortunately, major safety issues with JAKi in adolescents with AD have not been documented in the trials, so far, contrasting with the reports in adults with AD, where these events have very rarely occurred. There are some reports of herpes zoster (HZ) infection in adolescents on JAKi, but it is not a major safety concern. Acne is a relatively common AE with UPA in adolescents; however, it is responsive to standard treatment. This review will help the clinician to choose among the JAKi according to the needs and clinical features of patients with moderate and severe AD. In the following years, with the advent of new biologicals and JAKi, these therapies will fall into place in each phase of the evolution of patients with AD.
Assuntos
Dermatite Atópica , Inibidores de Janus Quinases , Humanos , Dermatite Atópica/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/administração & dosagem , Criança , Adolescente , Purinas/uso terapêutico , Administração Oral , Azetidinas/uso terapêutico , Azetidinas/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Resultado do TratamentoRESUMO
Chronic kidney disease (CKD) remains a significant global health issue and is a leading cause of mortality worldwide. Patients with CKD have an increased risk of developing atrial fibrillation (AF) and venous thromboembolism (VTE). While direct oral anticoagulants (DOACs) have become a standard of care for anticoagulation (AC) in patients with AF and VTE, the appropriate use of these agents in comorbid kidney impairment warrants detailed discussion. This scientific narrative review summarizes the effectiveness and safety of apixaban use in patients with renal dysfunction by assessing the current published pharmacokinetic, interventional, observational, and guideline data. Apixaban is a highly selective, orally active, direct inhibitor of factor Xa, with well-established pharmacokinetics and consistent clinical outcomes across a broad range of patient populations, including those with kidney impairment. Overall, the scientific literature has shown that apixaban has a favorable clinical efficacy and safety profile compared with vitamin K antagonists for patients with AF or VTE and comorbid kidney impairment. These data support the approved label dosing strategy of apixaban in reducing the risk of stroke/systemic embolism in patients with nonvalvular AF and in treating VTE across all ranges of kidney function. Both clinician experience and knowledge of patient-specific factors may be required in the management of comorbid patients with advanced CKD or those requiring dialysis, as data on these patients are limited.
Assuntos
Fibrilação Atrial , Inibidores do Fator Xa , Pirazóis , Piridonas , Insuficiência Renal Crônica , Tromboembolia Venosa , Humanos , Piridonas/farmacocinética , Piridonas/efeitos adversos , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Tromboembolia Venosa/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/epidemiologia , Estudos Observacionais como Assunto , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Anticoagulantes/uso terapêutico , Anticoagulantes/administração & dosagemRESUMO
INTRODUCTION: Zanzalintinib (XL092) is a next-generation anti-VEGFR-related multi-targeted TKI that exhibits immunomodulatory effects. AREAS COVERED: This review explores preclinical and clinical data, along with the future directions associated with zanzalintinib and its combination with immune checkpoint inhibitors (ICIs). EXPERT OPINION: In addition to its anti-VEGFR activity, zanzalintinib demonstrates potential synergistic effects with ICIs through its immunomodulatory impact, attributed to its inhibition of MET and TAM kinases. Recent preclinical studies provide compelling evidence supporting this synergistic potential. Furthermore, a recent phase 1 dose escalation study confirmed the tolerability of the zanzalintinib and anti-PDL1 combination without major safety concerns.Multiple ongoing clinical trials are investigating the combination of zanzalintinib and ICIs across various solid tumor types, including phase 3 studies for renal cell carcinoma, colorectal, and head and neck cancer. These trials aim to elucidate the therapeutic role of this new-generation TKI and ICI combination.However, the identification of reliable predictive biomarkers for the zanzalintinib and ICI combination presents significant challenges. Given the intricate nature of their mechanistic rationale and the difficulties in identifying reliable biomarkers for combined anti-angiogenesis and ICI therapies, addressing this challenge remains a priority for ongoing and future research.
Assuntos
Neoplasias , Inibidores de Proteínas Quinases , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Animais , Neoplasias/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Pirazóis/farmacologia , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Sinergismo Farmacológico , Benzofuranos , QuinazolinasRESUMO
Momelotinib, an oral Janus kinase (JAK) 1/2 and activin A receptor type 1 inhibitor, improved symptoms, splenomegaly, and anemia in patients with myelofibrosis (MF). This sub-analysis of SIMPLIFY-1 evaluated the efficacy and safety of momelotinib versus ruxolitinib in Japanese patients with JAK inhibitor (JAKi)-naïve MF. Patients were randomized 1:1 to receive momelotinib 200 mg once daily or ruxolitinib 20 mg twice daily (or modified based on label) for 24 weeks, after which patients could receive open-label momelotinib. The primary endpoint was splenic response rate (SRR; ≥ 35% reduction in spleen volume) at 24 weeks; main secondary endpoints were total symptom score (TSS) response (≥ 50% reduction) and transfusion independence (TI) rates. Fifteen Japanese patients (momelotinib, n = 6; ruxolitinib, n = 9) were enrolled; all completed treatment. At Week 24, SRR was 50.0% with momelotinib and 44.4% with ruxolitinib. TSS response rates were 33.3% and 0%, and TI rates were 83.3% and 44.4%. Any-grade treatment-related adverse event (TRAE) rates were 83.3% with momelotinib and 88.9% with ruxolitinib. Grade 3/4 TRAE rates were 0% and 55.6%, with specific events being anemia (55.6%) and vertigo (11.1%) with ruxolitinib. Momelotinib was well tolerated, improved spleen and symptom responses, and reduced transfusion requirements in Japanese patients with JAKi-naïve MF.
Assuntos
Benzamidas , Nitrilas , Mielofibrose Primária , Pirazóis , Pirimidinas , Humanos , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Mielofibrose Primária/tratamento farmacológico , Pessoa de Meia-Idade , Masculino , Idoso , Feminino , Resultado do Tratamento , Benzamidas/uso terapêutico , Japão , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Adulto , Idoso de 80 Anos ou mais , População do Leste AsiáticoRESUMO
Lichen planus is a chronic auto-inflammatory disease that primarily affects mucocutaneous regions. There are many variants of lichen planus including cutaneous, oral, nail, follicular, and erosive forms. Without any disease-specific treatment options, multi-variant lichen planus can be a challenging disease to manage. We present a 61-year-old woman with multivariant lichen planus that was refractory to numerous systemic and topical therapies. Subsequently, her cutaneous and vulvovaginal lesions improved with the use of oral baricitinib and the erosive oral lesions improved with topical ruxolitinib.
Assuntos
Azetidinas , Líquen Plano , Nitrilas , Purinas , Pirazóis , Pirimidinas , Sulfonamidas , Humanos , Feminino , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Nitrilas/uso terapêutico , Pessoa de Meia-Idade , Purinas/uso terapêutico , Purinas/administração & dosagem , Azetidinas/uso terapêutico , Azetidinas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Líquen Plano/tratamento farmacológico , Líquen Plano/patologia , Administração OralRESUMO
Therapeutic plasma exchange (TPE) is used as an effective treatment modality for a variety of autoimmune disorders. Apart from its desired effect of removing pathological blood components, it also can remove coagulation factors and drugs. Currently, there is an insufficient amount of information regarding the use of direct oral anticoagulants in this setting. In this article, we present a case report of a patient with myasthenia gravis and chronic anticoagulation with apixaban who underwent a series of TPE while continuing apixaban treatment. We observed that only 10% of daily dose was removed by the procedure and plasma levels of apixaban corresponded with expected range. TPE was not associated with shortened drug plasma half-life. We did not observe any significant alteration of apixaban pharmacokinetics during the period of TPE therapy, as well as no thrombotic or bleeding events. This case report supports the use of apixaban in patients treated by TPE, nevertheless, to firmly establish apixaban efficacy and safety profile in this clinical setting further research is needed.
Assuntos
Inibidores do Fator Xa , Troca Plasmática , Pirazóis , Piridonas , Humanos , Piridonas/administração & dosagem , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Troca Plasmática/métodos , Inibidores do Fator Xa/administração & dosagem , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/terapia , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Feminino , Pessoa de Meia-Idade , Meia-Vida , Masculino , IdosoRESUMO
Vitiligo, an autoimmune condition characterized by depigmented skin patches due to the loss of functional melanocytes, has been linked to dysregulation in the JAK-STAT signaling pathway, particularly in IFN-g signaling. The use of JAK inhibitors, such as ruxolitinib cream, a JAK1 and JAK2 inhibitor, presents a promising approach for vitiligo treatment. This study aims to systematically assess the effectiveness and safety of ruxolitinib cream in patients with vitiligo. We conducted a systematic review and meta-analysis following PRISMA guidelines to evaluate the efficacy and safety of ruxolitinib cream for the treatment of vitiligo. A comprehensive search of PubMed, Google Scholar, and Cochrane Library databases for randomized controlled trials (RCTs). Data selection, screening, extraction, and risk of bias assessment were meticulously performed. Statistical analysis was conducted using Review Manager Software, version 5.4, with significant heterogeneity addressed through appropriate methods. Our meta-analysis included 3 studies with 830 vitiligo patients. Significant improvements were observed in F-VASI, T-VASI, F-BSA, and T-BSA scores, with greater efficacy at 24 weeks compared to 12 weeks [MD -24.17, 95% CI (-31.78 to -16.56), P < 0.00001], [MD -14.12, 95% CI (-20.54 to -7.70); P < 0.0000], [MD -16.25, 95% CI (-22.20 to -10.31), P < 0.00001], [MD -9.19, 95% CI (-13.47 to -4.92); P < 0.00001]. Ruxolitinib showed increased risk ratios for F-VASI75, F-VASI90, and F-VASI50, indicating better outcomes with longer treatment durations [MD 2.9, 95% CI 1.88-4.49; P < 0.00001], [MD 4.66, 95% CI 2.09-10.39; P = 0.0002], [MD 2.53, 95% CI 1.84-3.46; P < 0.00001]. No significant differences were found in mild and moderate adverse events, while severe cases favored ruxolitinib. Placebo had a significant advantage in any adverse events, with no significant difference in drug-related adverse events. Serious adverse events did not significantly differ between groups. The findings strongly support the efficacy of ruxolitinib therapy in improving various parameters over time for treating vitiligo. However, thorough consideration of its safety profile, particularly concerning adverse events and potential side effects, is warranted. Further studies with larger sample sizes are needed to confirm these conclusions.
Assuntos
Nitrilas , Pirazóis , Pirimidinas , Vitiligo , Vitiligo/tratamento farmacológico , Humanos , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Resultado do Tratamento , Creme para a Pele/administração & dosagem , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Stroke prevention guidance for patients with atrial fibrillation (AF) uses evidence generated from randomised controlled trials (RCTs). However, applicability to patient groups excluded from trials remains unknown. Real-world patient data provide an opportunity to evaluate outcomes in a trial analogous population of direct oral anticoagulants (DOACs) users and in patients otherwise excluded from RCTs; however, there remains uncertainty on the validity of methods and suitability of the data. Successful reference trial emulation can support the generation of evidence around treatment effects in groups excluded or underrepresented in trials. We used linked United Kingdom primary care data to investigate whether we could emulate the pivotal ARISTOTLE trial (apixaban versus warfarin) and extend the analysis to investigate the impact of warfarin time in therapeutic range (TTR) on results. METHODS AND FINDINGS: Patients with AF in the UK Clinical Practice Research Datalink (CPRD Aurum) prescribed apixaban or warfarin from 1 January 2013 to 31 July 2019 were selected. ARISTOTLE eligibility criteria were applied to this population and matched to the RCT apixaban arm on baseline characteristics creating a trial-analogous apixaban cohort; this was propensity-score matched to warfarin users in the CPRD Aurum. ARISTOTLE outcomes were assessed using Cox proportional hazards regression stratified by prior warfarin exposure status during 2.5 years of patient follow-up and results benchmarked against the trial results before treatment effectiveness was further evaluated based on (warfarin) TTR. The dataset comprised 8,734 apixaban users and propensity-score matched 8,734 warfarin users. Results [hazard ratio (95% confidence interval)] confirmed apixaban noninferiority for stroke or systemic embolism (SE) [CPRD 0.98 (0.82,1.19) versus trial 0.79 (0.66,0.95)] and death from any cause [CPRD 1.03 (0.93,1.14) versus trial 0.89 (0.80,0.998)] but did not indicate apixaban superiority. Absolute event rates for stroke/SE were similar for apixaban in CPRD Aurum and ARISTOTLE (1.27%/year), whereas a lower event rate was observed for warfarin (CPRD Aurum 1.29%/year, ARISTOTLE 1.60%/year). Analysis by TTR suggested similar effectiveness of apixaban compared with poorly controlled warfarin (TTR < 0.75) for stroke/SE [0.91 (0.73, 1.14)], all-cause death [0.94 (0.84, 1.06)], and superiority for major bleeding [0.74 (0.63, 0.86)]. However, when compared with well-controlled warfarin (TTR ≥ 0.75), apixaban was associated with an increased hazard for all-cause death [1.20 (1.04, 1.37)], and there was no significant benefit for major bleeding [1.08 (0.90, 1.30)]. The main limitation of the study's methodology are the risk of residual confounding, channelling bias and attrition bias in the warfarin arm, and selection bias and misclassification in the analysis by TTR. CONCLUSIONS: Analysis of noninterventional data generated results demonstrating noninferiority of apixaban versus warfarin consistent with prespecified benchmarking criteria. Unlike in ARISTOTLE, superiority of apixaban versus warfarin was not seen, possible due to the lower proportion of Asian patients and higher proportion of patients with well-controlled warfarin compared to ARISTOTLE. This methodological template can be used to investigate treatment effects of oral anticoagulants in patient groups excluded from or underrepresented in trials and provides a framework that can be adapted to investigate treatment effects for other conditions.
Assuntos
Anticoagulantes , Fibrilação Atrial , Pirazóis , Piridonas , Acidente Vascular Cerebral , Varfarina , Humanos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Varfarina/uso terapêutico , Varfarina/efeitos adversos , Varfarina/administração & dosagem , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Anticoagulantes/administração & dosagem , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/etiologia , Reino Unido/epidemiologia , Feminino , Idoso , Masculino , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Administração Oral , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Resultado do Tratamento , Hemorragia/induzido quimicamente , Inibidores do Fator Xa/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/administração & dosagemRESUMO
BACKGROUND: Following the COVID-19 pandemic, microvascular and macrovascular thrombotic problems emerged that required anticoagulants. Apixaban (RN) is a factor Xa inhibitor that treats deep vein thrombosis and the two forms of artery diseases (coronary artery disease and peripheral artery disease). MATERIALS AND METHODS: The study objective was to create fast-disintegrating Apixaban Oral Thin Films (OTF) with the help of various super disintegrants to shorten disintegration time and enhance drug release in order to assist patients who have difficulty in swallowing conventional dosage forms and increase bioavailability. OTF was created using the solvent casting method. A 22 factorial design was employed in Design-Expert® software to develop an ideal formula. RESULTS: The optimized film formula pH, drug content, disintegration time, folding endurance, and dissolution rate were estimated, and the film was subjected to a short-term stability study. The optimized formula exhibited a cumulative drug release of 93.47% in 60 sec. CONCLUSION: The drug's in vitro release pattern shows first-order kinetics and fickian diffusion was the mechanism of drug release. These findings supported that Apixaban OTFs offer a quick release of the medication from the administration site into the systemic circulation.