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1.
Int J Nanomedicine ; 16: 4481-4494, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239300

RESUMO

Purpose: Apatinib (Apa) is a novel anti-vascular endothelial growth factor with the potential to treat diabetic retinopathy (DR); a serious condition leading to visual impairment and blindness. DR treatment relies on invasive techniques associated with various complications. Investigating topical routes for Apa delivery to the posterior eye segment is thus promising but also challenging due to ocular barriers. Hence, the study objective was to develop Apa-loaded bovine serum albumin nanoparticles (Apa-BSA-NPs) coated with hyaluronic acid (HA); a natural polymer possessing unique mucoadhesive and viscoelastic features with the capacity to actively target CD44 positive retinal cells, for topical administration in DR. Methods: Apa-BSA-NPs were prepared by desolvation using glutaraldehyde for cross-linking. HA-coated BSA-NPs were also prepared and HA: NPs ratio optimized. Nanoparticles were characterized for colloidal properties, entrapment efficiency (EE%), in vitro drug release and mucoadhesive potential. In vitro cytotoxicity on rabbit corneal epithelial cells (RCE) was assessed using MTT assay, while efficacy was evaluated in vivo in a diabetic rat model by histopathological examination of the retina by light and transmission electron microscopy. Retinal accumulation of fluorescently labeled BSA-NP and HA-BSA-NP was assessed using confocal microscope scanning. Results: Apa-HA-BSA-NPs prepared under optimal conditions showed size, PdI and zeta potential: 222.2±3.56 nm, 0.221±0.02 and -37.3±1.8 mV, respectively. High EE% (69±1%), biphasic sustained release profile with an initial burst effect and mucoadhesion was attained. No evidence of cytotoxicity was observed on RCE cells. In vivo histopathological studies on DR rat model revealed alleviated retinal micro- and ultrastructural changes in the topical HA-Apa-BSA-NP treated eyes with normal basement membrane and retinal thickness comparable to normal control and intravitreally injected nanoparticles. Improved retinal accumulation for HA-BSA-NP was also observed by confocal microscopy. Conclusion: Findings present HA-Apa-BSA-NPs as a platform for enhanced topical therapy of DR overcoming the devastating ocular complications of the intravitreal route.


Assuntos
Retinopatia Diabética/metabolismo , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Piridinas/administração & dosagem , Piridinas/química , Soroalbumina Bovina/química , Animais , Retinopatia Diabética/tratamento farmacológico , Liberação Controlada de Fármacos , Tamanho da Partícula , Piridinas/metabolismo , Piridinas/uso terapêutico , Coelhos , Ratos , Retina/metabolismo
2.
J Drugs Dermatol ; 20(5): 552-554, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33938701

RESUMO

Locally-advanced periocular basal cell carcinoma (BCC) pose many therapeutic challenges due to the need to preserve functionality and cosmesis of the orbit and periocular area. Surgical excision and subsequent orbital exenteration are two recognized modalities of treatment. Vismodegib is currently an FDA-approved monotherapy for locally-advanced and metastatic BCC. We present a case of the use of vismodegib as neoadjuvant therapy prior to surgical excision of a locally-advanced periocular recurrent BCC in a 75-year-old male. The patient’s tumor successfully responded to vismodegib allowing surgical excision with clear margins. The orbit was saved in a patient who otherwise would have required complete orbital exenteration. J Drugs Dermatol. 20(5):552-554. doi:10.36849/JDD.5661.


Assuntos
Anilidas/administração & dosagem , Carcinoma Basocelular/terapia , Neoplasias Palpebrais/terapia , Recidiva Local de Neoplasia/terapia , Piridinas/administração & dosagem , Neoplasias Cutâneas/terapia , Administração Oral , Idoso , Anilidas/efeitos adversos , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/patologia , Neoplasias Palpebrais/diagnóstico , Neoplasias Palpebrais/patologia , Pálpebras/diagnóstico por imagem , Pálpebras/patologia , Pálpebras/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Margens de Excisão , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Tratamentos com Preservação do Órgão/métodos , Piridinas/efeitos adversos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Resultado do Tratamento
3.
Lancet Oncol ; 22(6): 848-857, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34000246

RESUMO

BACKGROUND: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. METHODS: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. FINDINGS: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths. INTERPRETATION: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. FUNDING: Regeneron Pharmaceuticals and Sanofi.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma Basocelular/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/genética , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Receptor de Morte Celular Programada 1/genética , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
4.
Anticancer Res ; 41(5): 2553-2561, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952483

RESUMO

BACKGROUND/AIM: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have have been shown to improve overall survival in patients with refractory metastatic colorectal cancer. The aim of our study was to evaluate the efficacy and safety profiles of these agents administered in sequence in real world practice. PATIENTS AND METHODS: Clinical data of patients treated beyond the 2°line with REG or FTD/TPI between January 2016 and August 2020, were retrospectively collected from eight institutes in the Lazio Region. RESULTS: We included 49 patients treated with both drug sequences. A total of 28 G3/G4 toxicity events (53.8%) were recorded in the FTD/TPI-to-REG sequence vs. 24 (46.1%) in the reverse sequence. Median overall survival for the patients included in the FTP/TPI-to-REG group was 20 months (95%CI=16.7-23.3) vs. 27 months in the reverse group (95%CI=17.8-36.2). The disease control rate was 45.0% for patients treated with the REG-to-FTD/TPI sequence vs. 24.1% in those treated with the FTD/TPI-to-REG sequence (p=0.18). CONCLUSION: The sequence REG-to-FTD/TPI and vice versa can extend survival, whereas only REG-to-FTD/TPI stabilizes cancer growth.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Timina/administração & dosagem , Trifluridina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Timina/efeitos adversos , Trifluridina/efeitos adversos
6.
J Cancer Res Clin Oncol ; 147(8): 2209-2222, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33891173

RESUMO

PURPOSE: Apatinib, an antiangiogenic drug, has shown beneficial effects only in a fraction of advanced gastric cancer (GC) patients. Given the recent success of immunotherapies, combination of apatinib with immune checkpoint inhibitor may provide sustained and potent antitumor responses. METHODS: Immunocompetent mice with subcutaneous MFC tumors grown were given a combination of apatinib and anti-PD-L1 antibody therapy. GC tissues from patients undergoing curative resection in China were collected, and the density of HEVs, MSI status and tumor-infiltrated lymphocytes were analyzed by immunohistochemical staining. RESULTS: Combined apatinib and PD-L1 blockade therapy synergistically delayed tumor growth and increased survival in MFC-bearing immunocompetent mice. The combination therapy promoted antitumor immunity by increasing the ratio of CD8+ cytotoxic T cells to Foxp3+ Treg cells, the accumulation of CD20+ B cells and the Th1/Th2 cytokine ratio (IFN-γ/IL-10). The combination therapy induced the formation of HEVs through activation of LTßR signaling, thus promoting CD8+ cytotoxic T cell and CD20+ B cell infiltration in tumors. In clinical GC samples, the density of HEVs positively correlated with the intratumoral infiltration of CD8+ cytotoxic T cells and CD20+ B cells. MSI-high GC showed a higher density of HEVs, CD8+ cytotoxic T cells and CD20+ B cells than MSS/MSI-low GC. GC patients with high densities of HEVs, CD8+ cytotoxic T cells and CD20+ B cells had an improved prognosis with superior overall survival. CONCLUSION: Combining apatinib with PD-L1 blockade treatment synergistically enhances antitumor immune responses and promotes HEV formation in GC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Piridinas/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Sinergismo Farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Neovascularização Patológica/tratamento farmacológico , Piridinas/efeitos adversos , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923802

RESUMO

Thromboembolic complications are a leading cause of morbidity and mortality in cancer patients. Cancer patients often present with an increased risk for thrombosis including hypercoagulation, so the application of antiplatelet strategies to oncology warrants further investigation. This study investigated the effects of anastrozole and antiplatelet therapy (aspirin/clopidogrel cocktail or atopaxar) treatment on the tumour responses of luminal phenotype breast cancer cells and induced hypercoagulation. Ethical clearance was obtained (M150263). Blood was co-cultured with breast cancer cell lines (MCF7 and T47D) pre-treated with anastrozole and/or antiplatelet drugs for 24 h. Hypercoagulation was indicated by thrombin production and platelet activation (morphological and molecular). Gene expression associated with the epithelial-to-mesenchymal transition (EMT) was assessed in breast cancer cells, and secreted cytokines associated with tumour progression were evaluated. Data were analysed with the PAST3 software. Our findings showed that antiplatelet therapies (aspirin/clopidogrel cocktail and atopaxar) combined with anastrozole failed to prevent hypercoagulation and induced evidence of a partial EMT. Differences in tumour responses that modulate tumour aggression were noted between breast cancer cell lines, and this may be an important consideration in the clinical management of subphenotypes of luminal phenotype breast cancer. Further investigation is needed before this treatment modality (combined hormone and antiplatelet therapy) can be considered for managing tumour associated-thromboembolic disorder.


Assuntos
Anastrozol/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Coagulação Sanguínea , Neoplasias da Mama/tratamento farmacológico , Transição Epitelial-Mesenquimal , Inibidores da Agregação Plaquetária/efeitos adversos , Trombofilia/prevenção & controle , Adulto , Anastrozol/administração & dosagem , Anastrozol/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Neoplasias da Mama/complicações , Células Cultivadas , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Iminas/administração & dosagem , Iminas/efeitos adversos , Iminas/uso terapêutico , Células MCF-7 , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Trombina/metabolismo , Trombofilia/tratamento farmacológico , Trombofilia/etiologia
8.
Medicine (Baltimore) ; 100(17): e25630, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907117

RESUMO

ABSTRACT: Advanced gastric cancer (AGC) patients are not tolerant to the toxicities of traditional chemotherapy and its second-line therapeutic regimens are limited. The aim of the present study is to evaluate the efficacy and safety of apatinib combined with S-1 as the second-line therapy for AGC patients.Patients with AGC were enrolled in this study. Patients received oral apatinib (250 mg to 500 mg once daily) and S-1(40 mg/m2 twice daily) on days 1-14. Each cycle was 28 days and one course of treatment consisted of 2 cycles. Clinical efficacy and adverse events (AEs) were observed. Kaplan-Meier method was used for survival analysis.From November 2015 to December 2017, 58 AGC patients who failed first-line chemotherapy were enrolled and assessed retrospectively. According to the Response Evaluation Criteria in Solid Tumors (RECIST) standard, all patients were evaluable for response. None achieved CR, and 10 (17.2%) achieved PR (95% CI 7.2%-27.3%). SD was observed in 58.6% (34/58) of patients (95% CI 45.6%-71.7%) and NR in 24.1% (14/58) of patients (95% CI 12.8%-35.5%). The objective response rate (ORR) and the disease control rate (DCR) were 17.2% and 75.8% respectively. The median progression-free survival (PFS) and median overall survival (OS) were 143.1 days (95% CI 121.7-164.5) and 211.6 days (95% CI 162.9-219.7) respectively. The multivariate analysis showed that the ECOG PS was the independent factor of PFS and OS for AGC patients (PFS: HR = 3.565, 95% CI: 2.25-5.65, P < .001; OS: HR = 3.676, 95% CI: 2.29-5.89, P < .001). The main AEs were fatigue (72.4%), hypertension (46.6%), and leukopenia (48.3%).Apatinib combined with S-1 showed promising efficiency and was well tolerated as the second-line therapy for AGC patients. ECOG PS was the independent factor of PFS and OS for AGC patients. AEs were moderate and controllable, and leukopenia or hypertension was predictable factors for the PFS and OS of AGC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ácido Oxônico/administração & dosagem , Piridinas/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Tegafur/administração & dosagem , Adulto , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Adulto Jovem
9.
Expert Rev Clin Pharmacol ; 14(6): 661-670, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33847204

RESUMO

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disease, whose natural course has been deeply modified thanks to the development of new therapeutic approaches. The Janus kinase inhibitors (Jakinibs) represent the newest class of drugs introduced for treating RA. Among these, Filgotinib (FIL) has been developed as Janus kinase1 (JAK1) selective inhibitor, specifically targeting key pro-inflammatory mediators in RA pathogenesis. AREAS COVERED: This narrative review provides an overview on FIL as new therapeutic approach for RA, with focus on its pharmacological properties, clinical efficacy, and safety profile. The following electronic databases were adopted for the study search: PubMed, Google Scholar, ClinicalTrials.gov and Abstract archive from the American College of Rheumatology and the European Alliance of Associations for Rheumatology. EXPERT OPINION: The phase II and phase III randomized controlled trials (RCTs) performed so far and their long-term extensions showed a comparable clinical efficacy of FIL to biologic treatments, with an acceptable safety profile. Thanks to these data, FIL was approved in Europe and Japan for the treatment of active RA, increasing the spectrum of therapeutic approaches and improving the possibility of a more tailored therapeutic strategy. Real-life data and head-to-head clinical trials will be needed to confirm its efficacy and safety.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Piridinas/administração & dosagem , Triazóis/administração & dosagem , Animais , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Artrite Reumatoide/enzimologia , Artrite Reumatoide/patologia , Humanos , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Piridinas/efeitos adversos , Piridinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Triazóis/efeitos adversos , Triazóis/farmacologia
10.
Medicine (Baltimore) ; 100(14): e25175, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832078

RESUMO

RATIONALE: Neo-adjuvant systemic therapy includes endocrine therapy and chemotherapy, which is widely used. Luminal breast cancer is resistant to chemotherapy and is more likely to not respond to chemotherapy before surgery. Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor. Palbociclib with letrozole combination therapy was an effective chemotherapy in metastatic luminal type breast cancer and had fewer side effects; however, the benefit of palbociclib in neoadjuvant systemic therapy is unclear. PATIENT CONCERNS: A 50-year-old female patient visited our hospital with palpable lump in the right breast. The lymph nodes fixed in the ipsilateral axilla. DIAGNOSIS: The patient was diagnosed with invasive ductal carcinoma of the right breast; the nuclear grade was moderate. The ipsilateral fixed lymph node was diagnosed as metastasis. The breast cancer subtype was luminal A type and was positive for estrogen receptor and progesterone receptor, and negative for HER2/neu and Ki-67 marker index <10% on immunohistochemistry. INTERVENTIONS: Neo-systemic therapy was performed with 3 cycles of adriamycin with docetaxel. After follow-up study, the breast and axillary lesions progressed. Palbociclib with letrozole was administered as second neo-systemic therapy for 10 months. Subsequently, breast-conserving surgery with sentinel lymph node biopsy was performed. OUTCOMES: In the postoperative pathologic result, 4 mm invasive lesion remained, and the sentinel lymph node biopsy was negative. The results achieved a residual cancer burden classification class 1. CONCLUSION: Second-line neo-systemic therapy can further reduce the size of the tumor and increase the likelihood of avoiding the side effects of surgery. Palbociclib with letrozole may be a good treatment in the preoperative stage for luminal breast cancer that is resistant to chemotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Letrozol/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Metástase Linfática/patologia , Mastectomia Segmentar , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos
11.
Postgrad Med ; 133(4): 449-459, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33730977

RESUMO

Background: Lasmiditan is a selective serotonin (1F) receptor agonist approved for acute treatment of migraine with 3 doses: 50, 100, and 200 mg.Objective: To help provide dosing insights, we assessed the efficacy and safety of lasmiditan in patients who treated two migraine attacks with the same or different lasmiditan doses.Methods: Integrated analyses used data from the migraine attack treated in either of two controlled, Phase 3, single attack studies (SAMURAI/SPARTAN), and after the first attack treated in the open-label GLADIATOR extension study. Eight patient groups were created based on the initial dose received in SAMURAI or SPARTAN and the subsequent dose in GLADIATOR: placebo-100, placebo-200, 50-100, 50-200, 100-100, 100-200, 200-100, 200-200. Migraine pain freedom, migraine-related functional disability freedom, most bothersome symptom (MBS) freedom, and pain relief were evaluated at 2-h post-dose. The occurrence of most common treatment-emergent adverse events (MC-TEAE) was evaluated. Shift analyses were performed for pain freedom and ≥1 MC-TEAE. The incidence of patients with a specific outcome from the first and subsequent doses were compared within each dose change group using McNemar's test.Results: Small, but consistent, increases in incidences of pain freedom, migraine-related functional disability freedom, MBS freedom, and pain relief occurred when the second lasmiditan dose was higher than the initial dose. For patients starting on 50 mg, increasing to 100 or 200 mg provided a positive efficacy-TEAE balance, despite an increase in incidence of ≥1 MC-TEAE. For patients starting on 100 mg, increasing to 200 mg provided a positive efficacy-TEAE balance. If the initial dose was 100 or 200 mg, the incidence of patients experiencing ≥1 MC-TEAE decreased or stayed the same with their subsequent dose, regardless of dose. Decreasing from 200 to 100 mg led to a decrease in patients with pain freedom and ≥1 MC-TEAE, resulting in a neutral efficacy-TEAE balance. Shift analyses supported these findings.Conclusion: A positive efficacy-TEAE balance exists for patients increasing their lasmiditan dose for treatment of a subsequent migraine attack. These results could be important for optimizing dosing for individual patients.Clinicaltrials.gov: SAMURAI (NCT02439320); SPARTAN (NCT02605174); GLADIATOR (NCT02565186).


Assuntos
Benzamidas/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Agonistas do Receptor de Serotonina/uso terapêutico , Adulto , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/efeitos adversos , Índice de Gravidade de Doença
12.
Aging (Albany NY) ; 13(6): 8408-8420, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33713398

RESUMO

BACKGROUND: A substantial number of patients with esophageal squamous cell carcinoma (ESCC) do not achieve complete remission after definitive concurrent chemoradiotherapy (dCRT). We performed this retrospective study to evaluate the efficacy and safety of apatinib combined with S-1/capecitabine as the oral maintenance therapy for these patients. METHODS: Thirty-nine ESCC patients with residual disease after dCRT were included. Patients were treated with apatinib combined with S-1 /capecitabine after dCRT. Efficacy, toxicity, and survival were analyzed. RESULTS: Of the 39 patients, 5 (12.8%) achieved a partial response and 29 (74.4%) achieved stable disease, yielding a disease control rate of 87.2%. The median progression-free survival (PFS) and overall survival (OS) were 27.5 (95%CI: 14.9 - 40.1) and 38.1 (95%CI: 31.3 - 44.8) months. Most frequent adverse events were of grade 1 to 2. Multivariate analysis revealed the occurrence of any adverse events (HR = 0.274, 95%[CI] = 0.119 - 0.630) correlated to better PFS and occurrence of proteinuria (HR = 0.108, 95%[CI] = 0.025 - 0.456) predicted better OS. CONCLUSION: The oral combination therapy consisting of apatinib and S-1/capecitabine showed a tolerable toxicity profile and achieved satisfactory disease control in ESCC patients with residual disease after dCRT.


Assuntos
Capecitabina/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Ácido Oxônico/administração & dosagem , Piridinas/administração & dosagem , Tegafur/administração & dosagem , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimiorradioterapia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Cancer Sci ; 112(6): 2361-2370, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33686772

RESUMO

Milademetan (DS-3032, RAIN-32) is an orally available mouse double minute 2 (MDM2) antagonist with potential antineoplastic activity owing to increase in p53 activity through interruption of the MDM2-p53 interaction. This phase I, dose-escalating study assessed the safety, tolerability, efficacy, and pharmacokinetics of milademetan in 18 Japanese patients with solid tumors who relapsed after or were refractory to standard therapy. Patients aged ≥ 20 years received oral milademetan once daily (60 mg, n = 3; 90 mg, n = 11; or 120 mg, n = 4) on days 1 to 21 in a 28-day cycle. Dose-limiting toxicities, safety, tolerability, maximum tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. The most frequent treatment-emergent adverse events included nausea (72.2%), decreased appetite (61.1%), platelet count decreased (61.1%), white blood cell count decreased (50.0%), fatigue (50.0%), and anemia (50.0%). Dose-limiting toxicities (three events of platelet count decreased and one nausea) were observed in the 120-mg cohort. The plasma concentrations of milademetan increased in a dose-dependent manner. Stable disease was observed in seven out of 16 patients (43.8%). Milademetan was well tolerated and showed modest antitumor activity in Japanese patients with solid tumors. The recommended dose for phase II was considered to be 90 mg in the once-daily 21/28-day schedule. Future studies would be needed to further evaluate the potential safety, tolerability, and clinical activity of milademetan in patients with solid tumors and lymphomas. The trial was registered with Clinicaltrials.jp: JapicCTI-142693.


Assuntos
Antineoplásicos/administração & dosagem , Indóis/administração & dosagem , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Bibliotecas de Moléculas Pequenas/administração & dosagem , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Estudos de Coortes , Esquema de Medicação , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Japão , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/metabolismo , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Bibliotecas de Moléculas Pequenas/efeitos adversos , Bibliotecas de Moléculas Pequenas/farmacocinética
14.
Clin Drug Investig ; 41(5): 449-457, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33723806

RESUMO

BACKGROUND AND OBJECTIVE: Lemborexant is a dual orexin receptor antagonist recently approved in the USA, Japan, and Canada for the treatment of adults with insomnia. Because some pharmacotherapy for insomnia causes respiratory depression, this study assessed the effects of lemborexant treatment on respiratory safety parameters. METHODS: This single-dose, randomized, double-blind, placebo-controlled, three-period crossover study enrolled healthy adult and elderly subjects (n = 17). Subjects were randomized to one of three treatment sequences, each consisting of three treatment periods in which they received a single dose of placebo, lemborexant 10 mg, or lemborexant 25 mg. Each treatment period was separated by a washout period of at least 14 days. Assessments included pharmacodynamic respiratory parameters (peripheral capillary oxygen saturation (SpO2) and apnea-hypopnea index (AHI)) and safety. RESULTS: There were no significant differences for either dose of lemborexant versus placebo in mean peripheral capillary oxygen saturation (SpO2; least squares mean (LSM) difference (95% confidence interval (CI)): lemborexant 10 mg, -0.36 (-0.78 to 0.07); lemborexant 25 mg, - 0.29 (- 0.72 to 0.14)) or AHI (LSM difference (95% CI): lemborexant 10 mg, 0.52 (- 1.72 to 2.76); lemborexant 25 mg, - 1.16 (- 3.40 to 1.08)) during sleep. Additionally, significant differences were not observed for the percentage of total sleep during which SpO2 was < 85% (LSM difference (95% CI): lemborexant 10 mg, 0.004 (- 0.058 to 0.067); lemborexant 25 mg, 0.044 (- 0.018 to 0.107)) or < 80% (LSM difference (95% CI): lemborexant 10 mg, 0.001 (- 0.002 to 0.005); lemborexant 25 mg, 0.002 (-0.001 to 0.006)) for either lemborexant dose versus placebo. There was also no significant difference for lemborexant 10 mg versus placebo, for which SpO2 was < 90% during total sleep time (LSM difference (95% CI): 0.185 (- 0.034 to 0.405)). CONCLUSION: Overall, lemborexant at recommended doses did not have a negative effect on mean SpO2 or AHI and was well tolerated in this cohort of healthy subjects.


Assuntos
Antagonistas dos Receptores de Orexina/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/efeitos adversos , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos , Adulto Jovem
15.
Oncology ; 99(5): 327-335, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33677453

RESUMO

INTRODUCTION: The clinical outcome of ramucirumab in multi-molecular targeted agent (MTA) sequential therapy for unresectable hepatocellular carcinoma (u-HCC) was assessed in comparison with that of prior tyrosine kinase inhibitor (TKI) therapy. METHODS: Sixteen patients who received ramucirumab as part of multi-MTA sequential therapy for u-HCC were enrolled in a retrospective, cohort study. Ramucirumab was started as 2nd line in 7 patients, 3rd line in 5 patients, and 4th line in 4 patients. RESULTS: The overall response rate was 6.3%, the disease control rate (DCR) was 50.0%, median progression-free survival was 2.0 months (evaluated by mRECIST), median overall survival (OS) with ramucirumab was 7.9 months, and the median OS from 1st-line therapy was 28.1 months. One month after the start of ramucirumab, α-fetoprotein (AFP) decreased in 6 of 12 cases (50.0%), and the DCR in AFP-decreased cases was 83.3%. The DCR of ramucirumab was 66.7% in cases in which disease control was obtained by prior TKI therapy, whereas it was 0.0% in the cases in which disease control was not obtained by prior TKI therapy. Examining the adverse events, no new safety concerns were confirmed. CONCLUSION: The AFP response to ramucirumab and the treatment response to prior TKI therapy are associated with treatment response to ramucirumab.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Prognóstico , Piridinas/administração & dosagem , Quinolinas/administração & dosagem , Estudos Retrospectivos , Sorafenibe/administração & dosagem , Taxa de Sobrevida
16.
Medicine (Baltimore) ; 100(8): e24741, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663087

RESUMO

BACKGROUND: The objective of this study is to systematically evaluate the efficacy and safety of the calcitonin gene-related peptide (CGRP) receptor antagonist ubrogepant for the treatment of acute migraine. METHODS: Randomized controlled trials (RCTs) of ubrogepant for treatment of acute migraine were identified in PubMed, MEDLINE, EMBASE, and the Cochrane Library from database establishment to June 2020; we also searched ClinicalTrials.gov manually during the same period. Then, RevMan 5.3 software was used to perform a meta-analysis on each outcome measure. RESULTS: A total of 5 RCTs involving 4903 patients were included; there were 3358 cases in the ubrogepant group and 1545 cases in the placebo group. The meta-analysis showed the following results: at 2 hours postdose, the percentages of participants reporting pain relief and the absence of photophobia, nausea, and phonophobia were significantly higher in the ubrogepant group than in the placebo group (odds ratio [OR] = 1.71, 95%CI: 1.48-1.97, P < .00001; OR = 1.33, 95%CI: 1.22-1.45, P < .00001; OR = 1.07, 95%CI: 1.03-1.11, P = .0006; OR = 1.21, 95%CI: 1.14-1.28, P < .00001). The incidence of common adverse events was similar between the 2 groups (P > .05). CONCLUSION: Ubrogepant is effective and safe for the treatment of acute migraine. REGISTRATION NUMBER: PROSPERO CRD42019145286.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Humanos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
18.
Expert Opin Investig Drugs ; 30(4): 301-307, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33683991

RESUMO

Introduction: Biliary tract cancers (BTCs) [including cholangiocarcinoma and gallbladder cancer] are rare cancers associated with poor survival; most patients have advanced disease at diagnosis. Current chemotherapy reference regimens include cisplatin and gemcitabine as first-line; and oxaliplatin and 5-fluorouracil (FOLFOX) in second-line. Molecular profiling has identified several actionable therapeutic targets including isocitrate dehydrogenase (IDH)1 mutations. Ivosidenib is a reversible inhibitor of mutant IDH1; it is currently approved for the treatment of acute myeloid leukemia and has been studied in patients with advanced cholangiocarcinoma.Areas covered: This article introduces current treatments for BTC and sheds light on the mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of ivosidenib in advanced cholangiocarcinoma. The authors conclude with insights on the changing treatment paradigm created by emerging drugs and precision approaches.Expert opinion: Ivosidenib is well tolerated, with good oral exposure and long half-life as shown by phase I data. In a phase III study, ivosidenib has demonstrated improved progression-free survival compared to placebo (median 2.7 vs 1.4 months; hazard ratio 0.37; 95% confidence interval 0.25-0.54; one-sided p < 0.0001); it has also demonstrated a trend toward increased overall survival in patients with cholangiocarcinoma and disease progression on prior chemotherapy. Final survival data from this study are pending presentation. Increased use of molecular profiling will continue to identify potential therapeutic targets and improve the prognosis of patients with these cancers.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Sistema Biliar/tratamento farmacológico , Glicina/análogos & derivados , Piridinas/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Neoplasias do Sistema Biliar/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacologia , Humanos , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Piridinas/farmacologia , Taxa de Sobrevida
19.
N Engl J Med ; 384(9): 829-841, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33657295

RESUMO

BACKGROUND: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known. METHODS: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point. RESULTS: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib. CONCLUSIONS: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).


Assuntos
Anilidas/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/administração & dosagem , Piridinas/administração & dosagem , Sunitinibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Análise de Intenção de Tratamento , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Piridinas/efeitos adversos , Qualidade de Vida , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sunitinibe/efeitos adversos , Análise de Sobrevida
20.
J Drugs Dermatol ; 20(2): 156-165, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33538567

RESUMO

Basal cell carcinoma (BCC) is the most common malignancy in fair-skinned populations. Most cases are successfully treated with surgery, but in advanced BCC—including locally advanced BCC and metastatic BCC—surgery is likely to result in substantial morbidity or unlikely to be effective. In those patients, the systemic Hedgehog inhibitors (HHIs) sonidegib and vismodegib are the only approved pharmacologic treatment option. Although a number of clinical studies highlight the similarities and differences between the two HHIs, no head-to-head clinical comparison is available. Results from the pivotal BOLT and ERIVANCE clinical studies for sonidegib and vismodegib, respectively, demonstrate similar efficacy measured by objective response rate, complete response rate, and histologic tumor subtype. Safety results for both studies are comparable with similar common adverse events reported for muscle spasms, alopecia, and dysgeusia. A notable difference between sonidegib and vismodegib is their respective pharmacokinetic profiles with sonidegib reaching peak concentration in plasma within 2–4 hours of dosing and steady state in plasma achieved by week 17 of treatment, while vismodegib reaches peak plasma concentration approximately 2 days after a single dose and steady state within 21 days of repeated dosing. This review compares efficacy, safety, and pharmacokinetics of sonidegib and vismodegib based on published literature to date. J Drugs Dermatol. 2021;20(2):156-165. doi:10.36849/JDD.5657 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.


Assuntos
Anilidas/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Carcinoma Basocelular/tratamento farmacológico , Proteínas Hedgehog/antagonistas & inibidores , Piridinas/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Alopecia/induzido quimicamente , Alopecia/epidemiologia , Anilidas/efeitos adversos , Anilidas/farmacocinética , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacocinética , Carcinoma Basocelular/sangue , Carcinoma Basocelular/mortalidade , Carcinoma Basocelular/patologia , Ensaios Clínicos Fase II como Assunto , Disgeusia/induzido quimicamente , Disgeusia/epidemiologia , Proteínas Hedgehog/metabolismo , Humanos , Estudos Multicêntricos como Assunto , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Piridinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Espasmo/induzido quimicamente , Espasmo/epidemiologia
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