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1.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805714

RESUMO

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.


Assuntos
Fármacos Cardiovasculares/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/prevenção & controle , Miócitos de Músculo Liso/efeitos dos fármacos , Trifluoperazina/farmacologia , Animais , Antipsicóticos/farmacologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Hipóxia/induzido quimicamente , Hipóxia/genética , Hipóxia/fisiopatologia , Indóis/administração & dosagem , Monocrotalina/administração & dosagem , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Pirróis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Survivina/genética , Survivina/metabolismo
2.
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
4.
BMC Cancer ; 21(1): 291, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33740926

RESUMO

BACKGROUND: Avapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST). METHODS: This retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan-Meier survival curves were compared by Cox regression. RESULTS: Fifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose (n = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan-Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002. CONCLUSIONS: In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST. TRIAL REGISTRATION: The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirróis/administração & dosagem , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Triazinas/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirróis/efeitos adversos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Estudos Retrospectivos , Triazinas/efeitos adversos
5.
Life Sci ; 260: 118261, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795539

RESUMO

AIMS: Rheumatoid arthritis is an autoimmune systemic disorder causing pain, swelling, stiffness, and disability in various joints. This work was designed to evaluate the effect of sitagliptin and tofacitinib on Janus kinase (JAK)/signaling transducer and activator of transcription (STAT) and toll like receptor (TLR-4)/nuclear factor kappa B (NF-κB) signaling pathways in adjuvant induced arthritis in rats. MATERIALS AND METHODS: Severity of arthritis was evaluated and serum was analyzed for inflammatory mediators. The mRNA and protein expression level of the most important members of the two signaling pathways were determined. Lipid profile, transaminases and renal function parameters were assessed. KEY FINDINGS: Sitagliptin and tofacitinib significantly decreased the level of inflammatory parameters, the mRNA and protein expression level of the members of JAK/STAT and TLR-4/NF-κB pathways with more prominent effect of sitagliptin on TLR-4/NF-κB pathway and more expected obvious effect of tofacitinib on JAK/STAT pathway. The combination offered additional anti-inflammatory effect by inhibiting the cross talk between these pathways as inhibition of NF-κB activation decreased the serum level of IL-6 preventing the activation of STAT-3 in tibiotarsal tissues. SIGNIFICANCE: The combination of tofacitinib and sitagliptin normalized serum lipids and blood glucose level which could offer protection against cardiovascular diseases and caused partial reversal of serum transaminases and creatinine levels which can protect against tofacitinb's related hepato and nephrotoxicity. We could conclude that the combination of Sitagliptin with tofacitinib can offer synergistic anti-inflammatory effect and more protective action against side effects of tofacitinib.


Assuntos
Artrite Experimental/tratamento farmacológico , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Fosfato de Sitagliptina/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Inflamatórios , Glicemia/análise , Sinergismo Farmacológico , Quimioterapia Combinada , Hipoglicemiantes , Interleucina-6/sangue , Janus Quinases/metabolismo , Lipídeos/sangue , Masculino , NF-kappa B/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Cross-Talk/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Fator de Transcrição STAT3/metabolismo
6.
Cardiovasc Diabetol ; 19(1): 93, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32560724

RESUMO

BACKGROUND: The potential for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes (T2DM) is of persistent attention. The PRESS XII study primarily aimed to evaluate the efficacy and safety of saroglitazar (2 mg and 4 mg) as compared to pioglitazone 30 mg on glycemic control in patients with type 2 diabetes mellitus. METHODS: In this randomized double-blind study, patients with T2DM [glycosylated hemoglobin (HbA1c) ≥ 7.5%] were enrolled from 39 sites in India. Patients received once-daily doses of either saroglitazar or pioglitazone (1:1:1 allocation ratio) for a total of 24 weeks. Patients were continued in a double blind extension period for an additional 32 weeks. Efficacy evaluations of glycemic parameters [HbA1c (Primary endpoint at week 24), FPG and PPG] and other lipid parameters (TG, LDL-C, VLDL-C, HDL-C, TC, Non HDL-C, Apo A1 and Apo B) were conducted at week 12, 24 and 56 and compared to the baseline levels. The efficacy analyses were performed by using paired t-test and ANCOVA model. RESULTS: A total of 1155 patients were enrolled in this study. The baseline characteristics were similar between the three treatment groups. The within group mean (± SD) change in HbA1c (%) from baseline of the saroglitazar (2 mg and 4 mg) and pioglitazone treatment groups at week 24 were: - 1.38 ± 1.99 for saroglitazar 2 mg; - 1.47 ± 1.92 for saroglitazar 4 mg and - 1.41 ± 1.86 for pioglitazone, respectively. Statistically significant reduction from baseline in HbA1c was observed in each treatment group at week 24 with p-value < 0.016. There was a significant reduction in TG, LDL-C, VLDL-C, TC and Non HDL-C with a significant increase in HDL-C from baseline levels (< 0.016). Most of the AE's were 'mild' to 'moderate' in severity and were resolved by the completion of the study. CONCLUSIONS: Saroglitazar effectively improved glycemic control and lipid parameters over 56 weeks in patients of T2DM receiving background metformin therapy and has a promising potential to reduce the cardiovascular risk in T2DM patients. Trial registration CTRI/2015/09/006203, dated 22/09/2015.


Assuntos
Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Lipídeos/sangue , Fenilpropionatos/administração & dosagem , Pioglitazona/administração & dosagem , Pirróis/administração & dosagem , Biomarcadores/sangue , Glicemia/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Método Duplo-Cego , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Índia/epidemiologia , Fenilpropionatos/efeitos adversos , Pioglitazona/efeitos adversos , Estudos Prospectivos , Pirróis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
8.
Arq. bras. med. vet. zootec. (Online) ; 72(3): 1047-1050, May-June, 2020. ilus
Artigo em Português | LILACS, VETINDEX | ID: biblio-1129749

RESUMO

The aim of the present study was to evaluate the antibacterial behavior of polypyrrole nanoparticles (PPy-NPs) in water against biofilm producer or not S. aureus isolated from cows and goats with mastitis. One hundred and thirty-eight isolates of S. aureus were initially evaluated for biofilm formation by spectrophotometry in microplates. In addition, the minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) of PPy-NPs in water for planktonic S. aureus were determined. From the bovine samples analyzed, 5 (4.46%) S. aureus isolates showed a strong biofilm production, 17 (15.18%) moderate production, 36 (32.14%) with weak production and 54 (48.21%) did not produce biofilms. Strains from goats (26) showed no biofilm production in 18 (69.23%) strains and weak biofilm production in 8 (30.76%) strains. The MIC and MBC of S. aureus to PPy-NPs were found in the same concentration (125搭/mL) in all strains tested, regardless of biofilm production or not. This finding provides a new insight into the interaction between PPy-NPs and S. aureus, and will offer potential benefits for the control of mastitis.(AU)


Assuntos
Animais , Feminino , Bovinos , Pirróis/administração & dosagem , Staphylococcus aureus/efeitos dos fármacos , Cabras/microbiologia , Mastite/veterinária , Biofilmes , Antibacterianos/uso terapêutico
9.
Artigo em Inglês | MEDLINE | ID: mdl-32429245

RESUMO

OBJECTIVE: To create a mobile application able to help patients follow medical treatments properly. METHODS: We designed and developed a custom Android/iOS App to remind patients of the pharmaceutical drugs to be taken, of the visits and exams to attend, and to detect their compliance with their personal therapeutic plan. In this paper we describe the App development, UX/UI design, Gamification. TuTOR is an Android and iOS application designed to remind patients of the drugs to be taken, giving them all the information related to their therapeutic plans in a simple and non-invasive way. Thanks to a dedicated back-office, specially designed to meet specific medical information needs, the App can also help physicians detect their patients' compliance with their treatments and modify prescriptions in real time. The App also ensures a state-of-the-art approach to data security and privacy protection. The main feature of TuTOR is the smart therapy assistant, which features dedicated alarms to remind users of taking their prescription drugs. Thanks to the automatic synchronization with a local database, the alert system works even without connection to the Internet. Particular attention was paid during the App's design process: we looked to create an intuitive interface to ensure absolute ease of use, with state-of-the-art visual design aimed at maximizing user experience. Other relevant features include the App's ability to givevisual evidence of the most important drugs to be taken and its note-taking feature, which gives patients the possibility to note down indications on why a specific drug was skipped. The App also keeps track of upcoming medical exams, laboratory tests, and visits on a devoted calendar. It also helps patients by listing therapy contacts, such as physicians' phone numbers, and indicates all medical references by showing, for example, locations of relevant clinics and pharmacies on a map. Thanks to specific visual progress indicators and an innovative gamification approach, the App encourages users to faithfully follow therapy guidelines. With TuTOR, assessing the therapy's state of completion is quick and easy.Thanksto the privacy-by-design approach used, all data managed by the system is compliant with the European Privacy Regulation and it is not available to third parties. EXPECTED RESULTS: A mobile App for medication adherence might increase objectively and subjectively measured adherence.


Assuntos
Artrite Reumatoide , Adesão à Medicação , Aplicativos Móveis , Piperidinas , Inibidores de Proteínas Quinases , Pirimidinas , Pirróis , Adolescente , Adulto , Artrite Reumatoide/tratamento farmacológico , Segurança Computacional , Feminino , Humanos , Piperidinas/administração & dosagem , Gravidez , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Adulto Jovem
11.
Cancer Chemother Pharmacol ; 85(5): 1003-1007, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32306101

RESUMO

PURPOSE: Pexidartinib (PLX3397) is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor under clinical evaluation for potential CNS tumor treatment. This study aims to evaluate plasma pharmacokinetic parameters and estimate CNS penetrance of pexidartinib in a non-human primate (NHP) cerebrospinal fluid (CSF) reservoir model. METHODS: Five male rhesus macaques, each with a previously implanted subcutaneous CSF ventricular reservoir and central venous lines, were used. NHPs received a single dose of 40 mg/kg pexidartinib (human equivalent dose of 800 mg/m2), administered orally as 200 mg tablets. Serial paired samples of blood and CSF were collected at 0-8, 24, 48, and 72 h. Pexidartinib concentrations were assayed by Integrated Analytical Solutions, Inc. (Berkeley, CA, USA) using HPLC/MS/MS. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. RESULTS: Samples from four NHPs were evaluable. Average (± SD) plasma PK parameters were as follows: Cmax = 16.50 (± 6.67) µg/mL; Tmax = 5.00 (± 2.58) h; AUClast = 250.25 (± 103.76) h*µg/mL; CL = 0.18 (± 0.10) L/h/kg. In CSF, pexidartinib was either quantifiable (n = 2), with Cmax values of 16.1 and 10.1 ng/mL achieved 2-4 h after plasma Tmax, or undetected at all time points (n = 2, LLOQCSF = 5 ng/mL). CONCLUSION: Pexidartinib was well-tolerated in NHPs, with no Grade 3 or Grade 4 toxicities. The CSF penetration of pexidartinib after single-dose oral administration to NHPs was limited.


Assuntos
Aminopiridinas , Barreira Hematoencefálica , Pirróis , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Aminopiridinas/administração & dosagem , Aminopiridinas/líquido cefalorraquidiano , Aminopiridinas/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/líquido cefalorraquidiano , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiologia , Neoplasias Encefálicas/tratamento farmacológico , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Glioma/tratamento farmacológico , Macaca mulatta , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/administração & dosagem , Pirróis/líquido cefalorraquidiano , Pirróis/farmacocinética
13.
Lancet Oncol ; 21(5): 671-684, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203698

RESUMO

BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. METHODS: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. FINDINGS: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. INTERPRETATION: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. FUNDING: Incyte Corporation.


Assuntos
Colangiocarcinoma/tratamento farmacológico , Morfolinas/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Proteínas de Fusão Oncogênica/genética , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Receptores de Fatores de Crescimento de Fibroblastos/genética
15.
Medicine (Baltimore) ; 99(11): e19520, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176102

RESUMO

Proton pump inhibitors (PPIs) have been the first line treatment for gastroesophageal reflux disease (GERD). The aim of this study was to evaluate the efficacy of vonoprazan (VPZ), a potassium-competitive acid blocker for reflux esophagitis (RE), nonerosive reflux disease (NERD), and PPI-resistant GERD patients.An open-label, single-center, observational study in our hospital was performed from August 2016 to August 2017. All patients diagnosed with GERD were asked to self-report a questionnaire of frequency scale for the symptoms of GERD (FSSG) and rate their degree of satisfaction with the treatment of GERD during outpatient visit. A total of 200 (RE 47, NERD 49, PPI-resistant GERD 104) patients were included in the present study. The primary endpoint was the change of FSSG and the proportion of degree of satisfaction with the treatment at the end of the initial therapy. A percentage of improvement (improvement rate) and resolution (resolution rate) at the end of the initial therapy were evaluated. Secondary endpoint included the proportion of patients with symptomatic relapse in the 24-week maintenance phase.FSSG and the degree of satisfaction were significantly improved after the initial therapy in every group. Improvement and resolution rate after the initial therapy were 83.0% and 67.0% in RE, 66.7% and 60.4% in NERD, and 76.0% and 60.4% in PPI-resistant group. There was no significance between after the initial therapy and 24 weeks in improvement and resolution rate. Thirty-two of the total 48 patients did not take VPZ at 24 weeks. Total FSSG score in each group was 1.67 ±â€Š1.97, 2.71 ±â€Š4.91, and 4.0 ±â€Š4.93. The nonrelapse rate at 24 weeks in each group was 66.7%, 60.0%, and 50.0%. The resolution rate at 24 weeks in each group was 38.9%, 45.0%, and 30.0%.The VPZ therapy is effective for initial and maintenance therapy and improves heartburn and patient's satisfaction significantly in all 3 groups. Among patients who stopped taking VPZ during the maintenance period, 42.0% of RE and NERD group and 30% of PPI-resistant group experience complete remission from GERD at 24 weeks by introduction of VPZ.


Assuntos
Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Feminino , Refluxo Gastroesofágico/fisiopatologia , Humanos , Masculino , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Inquéritos e Questionários , Resultado do Tratamento
16.
Cancer Chemother Pharmacol ; 85(4): 805-816, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32185484

RESUMO

PURPOSE: Metarrestin is a first-in-class pyrrolo-pyrimidine-derived small molecule targeting a marker of genome organization associated with metastasis and is currently in preclinical development as an anti-cancer agent. Here, we report the in vitro ADME characteristics and in vivo pharmacokinetic behavior of metarrestin. METHODS: Solubility, permeability, and efflux ratio as well as in vitro metabolism of metarrestin in hepatocytes, liver microsomes and S9 fractions, recombinant cytochrome P450 (CYP) enzymes, and potential for CYP inhibition were evaluated. Single dose pharmacokinetic profiles after intravenous and oral administration in mice, rat, dog, monkey, and mini-pig were obtained. Simple allometric scaling was applied to predict human pharmacokinetics. RESULTS: Metarrestin had an aqueous solubility of 150 µM at pH 7.4, high permeability in PAMPA and moderate efflux ratio in Caco-2 assays. The compound was metabolically stable in liver microsomes, S9 fractions, and hepatocytes from six species, including human. Metarrestin is a CYP3A4 substrate and, in mini-pigs, is also directly glucuronidated. Metarrestin did not show cytochrome P450 inhibitory activity. Plasma concentration-time profiles showed low to moderate clearance, ranging from 0.6 mL/min/kg in monkeys to 48 mL/min/kg in mice and moderate to high volume of distribution, ranging from 1.5 L/kg in monkeys to 17 L/kg in mice. Metarrestin has greater than 80% oral bioavailability in all species tested. The excretion of unchanged parent drug in urine was < 5% in dogs and < 1% in monkeys over collection periods of ≥ 144 h; in bile-duct cannulated rats, the excretion of unchanged drug was < 1% in urine and < 2% in bile over a collection period of 48 h. CONCLUSIONS: Metarrestin is a low clearance compound which has good bioavailability and large biodistribution after oral administration. Biotransformation appears to be the major elimination process for the parent drug. In vitro data suggest a low drug-drug interaction potential on CYP-mediated metabolism. Overall favorable ADME and PK properties support metarrestin's progression to clinical investigation.


Assuntos
Sistema Enzimático do Citocromo P-450/química , Microssomos Hepáticos/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirróis/administração & dosagem , Pirróis/farmacocinética , Administração Oral , Animais , Biotransformação , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Feminino , Haplorrinos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Suínos , Porco Miniatura , Distribuição Tecidual
17.
Pharm Biol ; 58(1): 225-230, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32202190

RESUMO

Context: Naringenin and tofacitinib are often used together for treatment of rheumatoid arthritis in Chinese clinics.Objective: This experiment investigates the effect of naringenin on the pharmacokinetics of tofacitinib in rats.Materials and methods: Twelve Sprague-Dawley rats were randomly divided into two groups (experimental group and control group). The experimental group was pre-treated with naringenin (150 mg/kg/day) for two weeks before dosing tofacitinib, and equal amounts of CMC-Na solution in the control group. After a single oral administration of 5 mg/kg of tofacitinib, 50 µL blood samples were directly collected into 1.5 mL heparinized tubes via the caudal vein at 0.083, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. The plasma concentration of tofacitinib was quantified by UPLC/MS-MS.Results: Results indicated that naringenin could significantly affect the pharmacokinetics of tofacitinib. The AUC0-24 of tofacitinib was increased from 1222.81 ± 222.07 to 2016.27 ± 481.62 ng/mL/h, and the difference was significant (p < 0.05). Compared with the control group, the Tmax was increased from 0.75 ± 0.29 to 3.00 ± 0.00 h (p < 0.05), and the MRT(0-24) was increased from 4.90 ± 0.51 to 6.57 ± 0.66 h (p < 0.05), but the clearance was obviously decreased from 4.10 ± 0.72 to 2.42 ± 0.70 L/h/kg (p < 0.05) in experimental group. Although the Cmax and t1/2 of tofacitinib were increased, there were no significant differences (p > 0.05).Conclusions: This research demonstrated a drug-drug interaction between naringenin and tofacitinib possibly when preadministered with naringenin; thus, we should pay attention to this possibility in the clinic.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/farmacocinética , Flavanonas/farmacologia , Piperidinas/farmacologia , Piperidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinas/farmacocinética , Pirróis/farmacologia , Pirróis/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Área Sob a Curva , Artrite Reumatoide/tratamento farmacológico , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Flavanonas/administração & dosagem , Piperidinas/administração & dosagem , Piperidinas/sangue , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Pirróis/administração & dosagem , Pirróis/sangue , Ratos Sprague-Dawley , Razão Sinal-Ruído
18.
Leukemia ; 34(8): 2150-2162, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32060401

RESUMO

To target mechanisms critical for multiple myeloma (MM) plasma cell adaptations to genomic instabilities and further sustain MM cell killing, we here specifically trigger DNA damage response (DDR) in MM cells by a novel BCMA antibody-drug conjugate (ADC) delivering the DNA cross-linking PBD dimer tesirine, MEDI2228. MEDI2228, more effectively than its anti-tubulin MMAF-ADC homolog, induces cytotoxicity against MM cells regardless of drug resistance, BCMA levels, p53 status, and the protection conferred by bone marrow stromal cells and IL-6. Distinctly, prior to apoptosis, MEDI2228 activates DDRs in MM cells via phosphorylation of ATM/ATR kinases, CHK1/2, CDK1/2, and H2AX, associated with expression of DDR-related genes. Significantly, MEDI2228 synergizes with DDR inhibitors (DDRi s) targeting ATM/ATR/WEE1 checkpoints to induce MM cell lethality. Moreover, suboptimal doses of MEDI2228 and bortezomib (btz) synergistically trigger apoptosis of even drug-resistant MM cells partly via modulation of RAD51 and accumulation of impaired DNA. Such combination further induces superior in vivo efficacy than monotherapy via increased nuclear γH2AX-expressing foci, irreversible DNA damages,  and tumor cell death, leading to significantly prolonged host survival. These results indicate leveraging MEDI2228 with DDRi s or btz as novel combination strategies, further supporting ongoing clinical development of MEDI2228 in patients with relapsed and refractory MM.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Antígeno de Maturação de Linfócitos B/imunologia , Bortezomib/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Imunoconjugados/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Benzodiazepinas/administração & dosagem , Linhagem Celular Tumoral , Dano ao DNA , Sinergismo Farmacológico , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Pirróis/administração & dosagem
19.
Drugs ; 80(3): 323-328, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32020557

RESUMO

Ubrogepant (Ubrelvy™) is an orally administered, small molecule, highly-selective, calcitonin gene-related peptide (CGRP) antagonist that was developed by Allergan under license to Merck & Co. as an acute treatment for migraine. In December 2019, ubrogepant received its first global approval in the USA for the acute treatment of migraine (± aura) in adults. This article summarizes the milestones in the development of ubrogepant leading to its first global approval for the acute treatment of migraine (± aura) in adults.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Aprovação de Drogas , Transtornos de Enxaqueca/tratamento farmacológico , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Administração Oral , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Humanos , Piridinas/administração & dosagem , Pirróis/administração & dosagem
20.
J Am Acad Dermatol ; 82(4): 823-831, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32029304

RESUMO

BACKGROUND: Previous studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD). OBJECTIVE: This study aimed to evaluate the efficacy and safety of delgocitinib 0.5% ointment. METHODS: In part 1, a 4-week double-blind period, Japanese patients aged 16 years or older with moderate or severe AD were randomly assigned in a 2:1 ratio to delgocitinib 0.5% ointment or vehicle ointment. Eligible patients entered part 2, a 24-week extension period, to receive delgocitinib 0.5% ointment. RESULTS: At the end of treatment in part 1, the least-squares mean percent changes from baseline in the modified Eczema Area and Severity Index score, the primary efficacy endpoint, were significantly greater in the delgocitinib group than in the vehicle group (-44.3% vs 1.7%, P < .001). The improvement in modified Eczema Area and Severity Index score was maintained in part 2. Most adverse events were mild and unrelated to delgocitinib across the study periods. LIMITATIONS: Only Japanese patients were included. The vehicle-controlled period lasted only 4 weeks. In part 2, topical corticosteroids were allowed for the treatment of worsening of AD. CONCLUSION: Delgocitinib ointment was effective and well tolerated in Japanese adult patients with moderate to severe AD for up to 28 weeks.


Assuntos
Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Pirróis/uso terapêutico , Adulto , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacocinética , Masculino , Pomadas , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Pirróis/farmacocinética , Resultado do Tratamento , Adulto Jovem
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