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1.
Nat Commun ; 11(1): 740, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029739

RESUMO

Primary and acquired drug resistance imposes a major threat to achieving optimized clinical outcomes during cancer treatment. Aberrant changes in epigenetic modifications are closely involved in drug resistance of tumor cells. Using BET inhibitor (BETi) resistant leukemia cells as a model system, we demonstrated herein that genome-wide enhancer remodeling played a pivotal role in driving therapeutic resistance via compensational re-expression of pro-survival genes. Capitalizing on the CRISPR interference technology, we identified the second intron of IncRNA, PVT1, as a unique bona fide gained enhancer that restored MYC transcription independent of BRD4 recruitment in leukemia. A combined BETi and CDK7 inhibitor treatment abolished MYC transcription by impeding RNAPII loading without affecting PVT1-mediated chromatin looping at the MYC locus in BETi-resistant leukemia cells. Together, our findings have established the feasibility of targeting enhancer plasticity to overcome drug resistance associated with epigenetic therapies.


Assuntos
Leucemia Experimental/tratamento farmacológico , Leucemia Experimental/genética , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Elementos Facilitadores Genéticos , Feminino , Genes myc/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Células Jurkat , Células K562 , Leucemia Experimental/metabolismo , Camundongos , Modelos Genéticos , Fenilenodiaminas/administração & dosagem , Pirimidinas/administração & dosagem , RNA Polimerase II/metabolismo , RNA Longo não Codificante/genética
2.
ACS Appl Mater Interfaces ; 12(4): 4265-4275, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31903741

RESUMO

Conventional therapeutic approaches to treat malignant tumors such as surgery, chemotherapy, or radiotherapy often lead to poor therapeutic results, great pain, economic burden, and risk of recurrence and may even increase the difficulty in treating the patient. Long-term drug administration and systemic drug delivery for cancer chemotherapy would be accompanied by drug resistance or unpredictable side effects. Thus, the use of photothermal therapy, a relatively rapid tumor elimination technique that regulates autophagy and exerts an antitumor effect, represents a novel solution to these problems. Heat shock protein 90 (HSP90), a protein that reduces photothermal or hypothermic efficacy, is closely related to AKT (protein kinase B) and autophagy. Therefore, it was hypothesized that autophagy could be controlled to eliminate tumors by combining exogenous light with a selective HSP90 inhibitor, for example, SNX-2112. In this study, an efficient tumor-killing strategy using graphene oxide loaded with SNX-2112 and folic acid for ultrafast low-temperature photothermal therapy (LTPTT) is reported. A unique mechanism that achieves remarkable therapeutic performance was discovered, where overactivated autophagy induced by ultrafast LTPTT led to direct apoptosis of tumors and enabled functional recovery of T cells to promote natural immunity for actively participating in the attack against tumors. This LTPTT approach resulted in residual tumor cells being rendered in an "injured" state, opening up the possibility of concurrent antitumor and antirecurrence treatment.


Assuntos
Antineoplásicos/administração & dosagem , Autofagia/efeitos dos fármacos , Autofagia/efeitos da radiação , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Animais , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Camundongos Endogâmicos BALB C , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Fotoquimioterapia/instrumentação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Temperatura
3.
Infez Med ; 27(4): 365-373, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31846985

RESUMO

The fourth HIV strand-transfer integrase inhibitor (INSTI) has been released into the market as part of a single-tablet-regimen (STR) consisting of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). The newest component is thus BIC, a booster-free INSTI with pharmacological characteristics similar to those of dolutegravir (DTG), including high intrinsic antiretroviral potency. The BIC-containing STR underwent clinical development in both treatment-naive and virologically suppressed patients and was found non-inferior to DTG-based comparator arms. In the currently evolving therapeutic scenario, the BIC/FTC/TAF STR regimen represents the smartest response on the side of triple conventional regimens, while new 2-drug regimens have received regulatory approval and nowadays epitomize the search for simpler and lighter antiretroviral regimens. The overall characteristics of BIC/FTC/TAF, however, make this therapeutic option quite comparable in terms of simplicity to the newly approved dual regimens, and the main reasons (e.g., toxicity) accounting in the past for the search of regimens consisting of less than three drugs are no longer in place.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacologia , Emtricitabina/administração & dosagem , Emtricitabina/farmacologia , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Tenofovir/administração & dosagem , Tenofovir/farmacologia , Adenina/administração & dosagem , Adenina/farmacologia , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Humanos , Comprimidos
4.
World J Gastroenterol ; 25(38): 5800-5813, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31636473

RESUMO

BACKGROUND: Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase that is involved in various diseases, including cancers, metabolic diseases, and inflammation-associated diseases. However, the role of SIRT1 in ulcerative colitis (UC) is still confusing. AIM: To investigate the role of SIRT1 in intestinal epithelial cells (IECs) in UC and further explore the underlying mechanisms. METHODS: We developed a coculture model using macrophages and Caco-2 cells. After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide (NAM), the expression of occludin and zona occludens 1 (ZO-1) was assessed by Western blot analysis. Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis. Dextran sodium sulfate (DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d. Transferase-mediated dUTP nick-end labeling (TUNEL) assays were conducted to assess apoptosis in colon tissues. The expression levels of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, caspase-9, and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot. RESULTS: SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis, whereas NAM administration caused the opposite effects. DSS-induced colitis mice treated with SRT1720 had a lower disease activity index (P < 0.01), histological score (P < 0.001), inflammatory cytokine levels (P < 0.01), and apoptotic cell rate (P < 0.01), while exposure to NAM caused the opposite effects. Moreover, SIRT1 activation reduced the expression levels of GRP78, CHOP, cleaved caspase-12, cleaved caspase-9, and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice. CONCLUSION: SIRT1 activation reduces apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12. SIRT1 activation may be a potential therapeutic strategy for UC.


Assuntos
Apoptose , Colite Ulcerativa/patologia , Estresse do Retículo Endoplasmático , Mucosa Intestinal/patologia , Sirtuína 1/metabolismo , Animais , Células CACO-2 , Caspase 12/metabolismo , Técnicas de Cocultura , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Mucosa Intestinal/citologia , Macrófagos , Camundongos , Niacinamida/administração & dosagem , Sirtuína 1/antagonistas & inibidores , Fator de Transcrição CHOP/metabolismo
5.
J Acquir Immune Defic Syndr ; 82(3): 321-328, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609930

RESUMO

BACKGROUND: Bictegravir, coformulated with emtricitabine/tenofovir alafenamide as a fixed-dose combination (B/F/TAF), is recommended for treatment of HIV-1-infection. Multiple studies of B/F/TAF in treatment-naive and virologically suppressed cohorts have shown high efficacy and tolerability with no treatment-emergent resistance through 48 weeks. Participants in these studies have been predominantly men. We report 48-week results from a phase 3 study evaluating switching to B/F/TAF, specifically in a globally distributed trial population of women. METHODS: In this multicenter, randomized, open-label, active-controlled, noninferiority trial (ClinicalTrials.gov NCT02652624), women living with HIV who were virologically suppressed (HIV-1 RNA levels <50 copies/mL) on a regimen containing either TAF or tenofovir disoproxil fumarate were randomly assigned (1:1) to switch to B/F/TAF (50/200/25 mg) or stay on baseline regimen (SBR) once daily for 48 weeks. Primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (U.S. Food and Drug Administration snapshot algorithm); prespecified noninferiority margin was 4%. FINDINGS: We randomized 472 participants and treated 470 (234 B/F/TAF, 236 SBR). Switching to B/F/TAF was noninferior to SBR for the primary outcome, as 1.7% (4/234) vs 1.7% (4/236) had HIV-1 RNA ≥50 copies/mL at week 48 (difference 0.0%, 95.001% confidence interval: -2.9% to 2.9%). No individual receiving B/F/TAF developed treatment-emergent resistance. Both treatments were well-tolerated; no participant discontinued treatment because of an adverse event. INTERPRETATION: Fixed-dose combination B/F/TAF provides a safe and efficacious option for ongoing treatment of HIV in women. This study contributes important data on safety, tolerability, and outcomes of antiretroviral therapy among women living with HIV.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Adenina/administração & dosagem , Adenina/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Contagem de Linfócito CD4 , Emtricitabina/administração & dosagem , Feminino , HIV-1 , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Tenofovir/uso terapêutico , Resultado do Tratamento , Adulto Jovem
6.
Blood ; 134(21): 1811-1820, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31558467

RESUMO

Targeting both CD20 and phosphatidylinositol 3-kinase (PI3K), a protein that is critically involved in B-cell maturation, could be an efficacious strategy for treating B-cell malignancies. The safety of the next-generation compounds umbralisib, a PI3K-δ inhibitor, plus ublituximab, an anti-CD20 monoclonal antibody (combination referred to as U2), was evaluated in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL) in this phase 1/1b study. Phase 1 dose escalation was performed with a 3 + 3 design to establish the maximum tolerated dose. In this portion, ublituximab was given intravenously (NHL, 900 mg; CLL, 600 or 900 mg) for 12 cycles. Umbralisib was given orally once daily at 800 or 1200 mg (initial formulation) or 400 to 1200 mg (micronized formulation) in the phase 1 dose escalation portion, and at 800 to 1200 mg in the phase 1b portion until progression, toxicity, or study removal. The maximum tolerated dose was not reached in either the CLL or NHL cohort, and only 1 dose-limiting toxicity was observed. U2 had low instances of grade 3 or higher diarrhea (8%), pneumonia (8%), or hepatic toxicity (4%). Treatment discontinuation due to adverse events occurred in 13% of patients, and umbralisib dose reductions occurred in 15% of patients. The overall response rate for all patients was 46% with 17% complete responses. The median duration of response was 20 months (95% confidence interval, 11.3-not reached). U2 was well tolerated, and no new safety signals were observed over single-agent umbralisib. Preliminary efficacy with this combination is promising and warrants further investigation. This study was registered at www.clinicaltrials.gov as #NCT02006485.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico
7.
Expert Opin Investig Drugs ; 28(8): 667-673, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31353973

RESUMO

Introduction: A PEGylated form of irinotecan, a topoisomerase I inhibitor, is now available in commerce; its safety and efficacy have been tested in platinum resistant/refractory ovarian cancer (PROC) patients. This novel agent is known as Etirinotecan Pegol (EP). EP, like irinotecan, exerts its action through its principal metabolite SN-38. Areas covered: This drug evaluation article focuses on the most recent investigations and clinical progress regarding EP, a long-acting polymer conjugate of irinotecan for the treatment of PROC. Expert opinion: EP provides prolonged and continuous exposure of SN-38 in tumors, when compared to its parent drug irinotecan. Results from phase II studies are comparable in terms of efficacy to other agents of proven use in PROC. A limitation of the use of EP is the schedule-dependent toxicities (mainly diarrhea and dehydration). In the future, EP could be investigated in association with other agents, even in attempts to restore sensitivity to other treatments. PROC remains a very difficult setting and EP might be a valid agent for patients with good performance status that have exhausted therapeutic options. In such a setting, participation in clinical trials is strongly encouraged.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Inibidores da Topoisomerase I/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/patologia , Polietilenoglicóis/efeitos adversos , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/farmacologia
8.
Psychiatr Danub ; 31(2): 157-161, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291219

RESUMO

Schizophrenia and bipolar disorders are serious psychiatric disorders with substantial health risks. Asenapine is a new second-generation antipsychotic, available as a sublingual tablet, approved in Europe for the treatment of moderate-to-severe manic episodes in adults, and in US for manic or mixed episodes of bipolar I disorder in adults and adolescents. In this review, we searched the available literature to appreciate the role of asenapine in the management of psychiatric conditions such as bipolar disorders and schizophrenia and describe its mechanism of action, efficacy and tolerability. Asenapine has demonstrated efficacy in the management of bipolar disorders and schizophrenia, while a possible role in the management of borderline personality disorder and agitation needs further research. Asenapine has favourable side effects profile and combining with other pharmacological treatment in post-traumatic stress disorder has shown promising results. Asenapine fulfils important requirements of efficacy and tolerability as an anti-psychotic. These findings should support psychiatrists and pharmacists in the care of their patients while on asenapine.


Assuntos
Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Transtorno da Personalidade Borderline/tratamento farmacológico , Europa (Continente) , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Estados Unidos
9.
Cell Mol Neurobiol ; 39(8): 1165-1175, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31270711

RESUMO

Bone cancer pain (BCP), which is induced by primary or metastatic bone cancer, remains a clinically challenging problem due to the poor understanding of its mechanisms. Sirtuin 1 (SIRT1) plays an important role in various pain models. Intrathecal administration of SRT1720, a SIRT1 activator, attenuates BCP in a rat model. However, the expression and activity of SIRT1 during the development and maintenance of BCP remain unknown. Furthermore, the underlying mechanism of SIRT1 in BCP remains ambiguous. In this study, we detected the time course of SIRT1 expression and activity in the spinal cord of mice with BCP and examined whether SRT1720 alleviated BCP by inhibiting metabotropic glutamatergic receptor (mGluR) 1/5 expression. In addition, we downregulated spinal SIRT1 expression in normal mice through an intrathecal injection of AAV-SIRT1-shRNA and then assessed pain behavior and mGluR1/5 expression. Mice with BCP developed significant mechanical allodynia and spontaneous flinching, accompanied by decreased levels of the SIRT1 protein, mRNA, and activity in the spinal cord. The SRT1720 treatment produced an analgesic effect on tumor-bearing mice and decreased the spinal levels of the mGluR1/5 protein and mRNA. In contrast, the AAV-SIRT1-shRNA treatment induced pain behavior in normal mice and increased the spinal levels of the mGluR1/5 protein and mRNA. The results suggested a critical role for SIRT1 in the development and maintenance of BCP and further indicated that activation of SIRT1 in the spinal cord by SRT1720 functionally reverses BCP in mice by inhibiting mGluR1/5.


Assuntos
Neoplasias Ósseas/complicações , Dor do Câncer/etiologia , Dor do Câncer/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Sirtuína 1/metabolismo , Animais , Comportamento Animal , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Injeções Espinhais , Masculino , Camundongos , Medula Espinal/metabolismo , Medula Espinal/patologia , Regulação para Cima/efeitos dos fármacos
10.
AAPS PharmSciTech ; 20(5): 182, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31054050

RESUMO

A feasibility evaluation of the addition of fumed silica (SiO2) into an agitated dryer to aid spray-dried solid dispersion intermediate (SDSDi) flow during secondary drying and discharge is described. The quantity of SiO2 to enhance the flow character of SDSDi was assessed by measuring particle size distribution, bulk density, and flow-through-an-orifice. Results indicate that the addition of the SiO2 did not alter the drying kinetics and did not impact the bulk particle size distribution of the SDSDi. While bulk density of SDSDi increased with the addition of SiO2, the flow, and thus the recovery of the SDSDi-SiO2 batch from the secondary dryer, was significantly higher than that for the intermediate alone. Imaging indicated uniform distribution of SiO2 in the bulk powder and coating on intermediate particles. Premixing and co-sieving of the SiO2 with a portion of pre-dry SDSDi promotes the uniform distribution of SiO2 within the bulk powder bed.


Assuntos
Coloides , Dióxido de Silício/química , Dessecação , Estudos de Viabilidade , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Tamanho da Partícula , Pós , Pirrolidinas/administração & dosagem , Tecnologia Farmacêutica , Tiazóis/administração & dosagem
11.
Cancer Cell ; 35(5): 721-737.e9, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31056398

RESUMO

The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.


Assuntos
Endopeptidase Clp/genética , Endopeptidase Clp/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Mitocôndrias/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Endopeptidase Clp/química , Feminino , Células HCT116 , Células HEK293 , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Modelos Moleculares , Mutação Puntual , Conformação Proteica/efeitos dos fármacos , Proteólise , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Acta Biomed ; 90(2): 187-196, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31124995

RESUMO

BACKGROUND AND AIMS: In literature systematic data on treatment with the fixed-dose combination of sofosbuvir and velpatasvir for 12 weeks in anti-HCV/HCV RNA positive subjects with mild fibrosis and naïve to previous Interferon free regimen are scanty. A meta-analysis has been performed to evaluate the efficacy of velpatasvir plus sofosbuvir combination in these patients. METHODS: All randomized or non-randomized studies,  investigating the sustained virological response rate to sofosbuvir plus velpatasvir without ribavirin for 12 weeks in subjects naïve to previous DAA therapy and with fibrosis F0-F2 or F0-F3, were included in the meta-analysis. RESULTS: A total of 16 studies enrolling 4,907 subjects met the inclusion criteria and were included in this meta-analysis. The prevalence of SVR by sofosbuvir and velpatasvir was 98% (95% CI 96-99%) in the 4,907 subjects without cirrhosis. The prevalence of SVR was similar considering the 9 clinical studies and the 7 real-world studies (98%, CI 95%: 96-99% and 98%; CI 95%: 96-99%, respectively). Considering the 4 studies enrolling 1,371 subjects without advanced liver fibrosis the prevalence of SVR was also high [96% (95% CI: 94-98%)]. Data indicate a prevalence of SVR ranging to 95-100% according to the different HCV genotypes. CONCLUSION: Sofosbuvir plus velpatasvir therapeutic regimen was highly effective in HCV patients without advanced liver disease naïve to previous DAA regimen independently the different HCV genotypes.


Assuntos
Carbamatos/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Sofosbuvir/administração & dosagem , Resposta Viral Sustentada , Antivirais/administração & dosagem , Ensaios Clínicos Controlados como Assunto , Esquema de Medicação , Combinação de Medicamentos , Feminino , Hepacivirus , Humanos , Masculino , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Resultado do Tratamento
13.
Future Oncol ; 15(19): 2211-2225, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31074641

RESUMO

The increasing incidence of breast cancer brain metastases is a major clinical problem with its associated poor prognosis and limited treatment options. The long-acting topoisomerase-1 inhibitor, etirinotecan pegol, was designed to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Motivated by improved survival findings from subgroup analyses from the Phase III BEACON trial, this ongoing randomized, Phase III trial compares etirinotecan pegol to drugs commonly used for advanced breast cancer in patients with stable, treated breast cancer brain metastases who have been previously treated with an anthracycline, taxane and capecitabine. The primary end point is overall survival. Secondary end points include objective response rate, progression-free survival and time to CNS disease progression or recurrence in patients with/without CNS lesions present at study entry. Trial registration number: NCT02915744.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Adulto , Idoso , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Polietilenoglicóis/efeitos adversos , Intervalo Livre de Progressão , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos
14.
PLoS One ; 14(4): e0214795, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30946776

RESUMO

BACKGROUND: Newer direct-acting antiviral therapies are increasingly becoming the therapy of choice in patients with hepatitis C virus (HCV) infection. Here, we report the safety and effectiveness of sofosbuvir/velpatasvir (SOF/VEL) and ledipasvir/sofosbuvir (LDV/SOF) in real-world cohorts in Germany. METHODS: Patients initiated on SOF/VEL 12 weeks or LDV/SOF 8, 12 or 24 weeks regimens in a single German centre were included in this study. Data on treatment outcomes and adverse events (AE) were analysed in patients with available sustained virologic response 12 weeks after cessation of treatment (SVR12) information overall and by subgroups. RESULTS: This study included 115 patients who received SOF/VEL from July-2016 to July-2017, and 249 patients who received LDV/SOF from November-2014 to September-2015. Overall, SVR12 was achieved in 99% of patients on SOF/VEL ± ribavirin 12 weeks independent of HCV genotype, treatment history, or cirrhosis status, and in 96% of patients treated with LDV/SOF 8 weeks or LDV/SOF ± ribavirin 12 or 24 weeks. In genotype 1 treatment-naïve, non-cirrhotic patients, ≥99% achieved SVR12 across SOF/VEL and LDV/SOF regimens. Likewise, 100% of genotype 3-cirrhotic patients on SOF/VEL ± ribavirin regimens achieved SVR12. Grade 3/4 AE were reported in 13 (5.2%) patients on LDV/SOF and in 1 (<1%) patient on SOF/VEL. CONCLUSION: Overall, SOF/VEL and LDV/SOF achieved high SVR rates in a broad patient population. We showed the effectiveness of SOF/VEL as a pan-genotypic regimen, and regardless of treatment history or cirrhosis status. Use of such therapies improves outcomes and contributes towards the global efforts to eradicate HCV.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Sofosbuvir/uso terapêutico , Uridina Monofosfato/análogos & derivados , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Estudos de Coortes , Esquema de Medicação , Combinação de Medicamentos , Feminino , Fluorenos/administração & dosagem , Fluorenos/efeitos adversos , Genótipo , Alemanha , Hepacivirus/genética , Hepatite C Crônica/virologia , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Ribavirina/uso terapêutico , Segurança , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/uso terapêutico , Adulto Jovem
15.
Nanomedicine (Lond) ; 14(7): 889-910, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30874464

RESUMO

AIM: To prepare nanostructured lipid carriers (NLCs) loaded with asenapine maleate (ASPM) to increase its oral bioavailability by intestinal lymphatic uptake. MATERIALS & METHODS: ASPM-NLCs were prepared by ultrasound dispersion technique, by adopting Design of Experiment approach, and characterized. RESULTS: The optimized formulation exhibited good physicochemical parameters. Differential scanning calorimetry and x-ray diffraction studies indicated the amorphized nature of ASPM in lipid matrix. In vitro drug release study indicated the sustained release of drug from NLCs. ASPM-NLCs showed greater permeability across Caco2 cells and everted rat ileum. ASPM-NLCs showed greater cellular uptake, superior preclinical oral bioavailability and higher efficacy in reducing the L-DOPA-carbidopa-induced locomotor count compared with plain drug. CONCLUSION: ASPM-NLCs were successfully developed that showed enhanced performance both in vitro and in vivo.


Assuntos
Portadores de Fármacos/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Lipídeos/química , Maleatos/química , Nanoestruturas/química , Administração Oral , Animais , Materiais Biocompatíveis/química , Disponibilidade Biológica , Transporte Biológico , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Excipientes/química , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Masculino , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos , Resultado do Tratamento
16.
BMC Nephrol ; 20(1): 36, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30717681

RESUMO

BACKGROUND: Only a few prospective trials exist regarding the use of novel direct-acting antiviral agents (DAAs) in kidney transplant recipients (KTR) with chronic hepatitis C virus (HCV) infection. METHODS: This prospective single-center trial evaluated treatment with daclatasvir (DCV) and sofosbuvir (SOF) over 12 weeks in 16 adult chronic HCV infected KTR and eGFR > 30 ml/min/1.73m2. Primary endpoint was sustained virological response 12 weeks after end of therapy (SVR12). Beside baseline liver biopsy, hepatic function and glucose metabolism were regularly assessed. RESULTS: Four of 16 study patients had previously failed interferon-based HCV treatment. Liver biopsy showed mostly moderate fibrosis score before therapy with DCV/SOF was initiated at a median of 10.3 years after transplantation. In total, 15 of 16 KTR achieved SVR12. One patient showed early viral relapse because of resistance-associated variants (RAVs) in the HCV NS5A region. Rescue treatment with SOF/velpatasvir/voxilaprevir resulted in SVR12. DAAs treatment led to significant improvement of liver metabolism and glucose tolerance accompanied with no therapy-associated major adverse events and excellent tolerability. CONCLUSIONS: Our study demonstrates safety, efficacy and functional benefit of DCV/SOF treatment in KTR with chronic HCV infection. We provide data on rescue strategies for treatment failures due to present RAVs and amelioration of hepatic function and glucose tolerance. TRIAL REGISTRATION: Registry name: European Clinical Trials Register; Trial registry number (Eudra-CT): 2014-004551-32 , Registration date: Aug 28th 2015.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Transplante de Rim , Sofosbuvir/uso terapêutico , Viremia/tratamento farmacológico , Adulto , Idoso , Antivirais/administração & dosagem , Biópsia por Agulha , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/uso terapêutico , Carbamatos/administração & dosagem , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Quimioterapia Combinada , Feminino , Intolerância à Glucose/induzido quimicamente , Hepacivirus/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Fígado/patologia , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/sangue , Terapia de Salvação , Sofosbuvir/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento , Carga Viral , Proteínas não Estruturais Virais/antagonistas & inibidores , Viremia/complicações , Viremia/patologia
17.
AAPS PharmSciTech ; 20(2): 44, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30617712

RESUMO

Asenapine maleate (AM)-loaded self-microemulsifying drug delivery system (AM-SMEDDS) was prepared to increase its oral bioavailability. AM-SMEDDS was developed using Capryol 90, Cremophor EL, and Transcutol HP as oil, surfactant, and cosurfactant, respectively, by spontaneous emulsification method. Pseudoternary diagram showed maximum region at 3:1 ratio of Cremophor EL/Transcutol HP. The AM-SMEDDS showed globule size and zeta potential of 21.1 ± 1.2 nm and - 19.3 ± 1.8 mV, respectively. Globules were found to be of spherical shape and uniformly distributed by transmission electron microscopy. In vitro drug release study showed 99.2 ± 3.3% of drug release at the end of 8 h in phosphate buffer pH 6.8. Ex vivo drug release study showed only 15% of drug diffusion through stomach and ~ 85% drug was diffused through intestinal membrane. Confocal and flow cytometry study showed that cellular uptake of coumarin-6 loaded SMEDDS was significantly enhanced by Caco-2 cells as that of coumarin-6 solution. The relative bioavailability of AM-SMEDDS was found to be 23.53 times greater than AM suspension. Intestinal lymphatic transport study using Cycloheximide (CHX) showed that the AUCtotal of AM-SMEDDS reduced about 35.67% compared with that without the treatment of CHX indicating involvement of lymphatic system in intestinal absorption of AM-loaded SMEDDS. These findings demonstrated the potential of SMEDDS for oral bioavailability improvement of AM via lymphatic uptake. Graphical Abstract.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Emulsificantes/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Administração Oral , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/química , Antipsicóticos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Emulsificantes/administração & dosagem , Emulsificantes/química , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Absorção Intestinal/fisiologia , Ratos , Ratos Sprague-Dawley , Solubilidade
18.
J Pharm Biomed Anal ; 166: 183-188, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30654206

RESUMO

Inflachromene (ICM), a novel microglia inhibitor, is under development to treat neuroinflammatory disorders. For the pharmacokinetic evaluation of ICM, we developed quantitative ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method in rat plasma. Protein precipitation method with acetonitrile (ACN) was used for plasma sample preparation. The analyte and carbamazepine (the internal standard) were separated by the chromatography on an ACQUITY UPLC™ BEH C18 column running gradient mobile phase system made up of 0.1% [v/v] formic acid in water and 0.1% [v/v] formic acid in acetonitrile. For the quantification of ICM, the ion transitions, m/z 378.2→187.1 (ICM) and m/z 237.1→194.1 (IS) were monitored in multiple reaction monitoring (MRM) mode. Standard calibration curve showed excellent linearity with the correlation coefficient (R2) of 0.99 within the concentration range of 0.05-10 µg/mL. The precision and accuracy were within acceptable limits (all < 20%). ICM was degraded time and temperature dependently in rat plasma. The analytical method was successfully utilized in a pharmacokinetic study following intravenous and oral administration of ICM in rats.


Assuntos
Anti-Inflamatórios/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/sangue , Microglia/efeitos dos fármacos , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Área Sob a Curva , Disponibilidade Biológica , Calibragem , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Meia-Vida , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Injeções Intravenosas , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
19.
Drug Dev Ind Pharm ; 45(4): 548-559, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30623677

RESUMO

Self-emulsifying drug delivery systems (SES) were developed to improve oral bioavailability of asenapine maleate (ASM), an antipsychotic drug with challenging amphiphobic nature and extensive pre-systemic metabolism. ASM-SES was prepared by choosing the proportion of oil, surfactant, co-surfactant from constructed phase diagram. The in vitro and ex vivo evaluation was done. In vivo evaluation was done through pharmacokinetic and pharmacodynamic studies. Role of lymphatic absorption was studied by lymphatic absorption inhibition study. A formulation consisting of 9.9%, 59.4%, 29.7% and 1% of oil, surfactant, co-surfactant, and drug respectively was considered as optimized formulation. After various evaluation test, the globule size and zeta potential for optimized formulation (SES4) were found to be 137.9 nm and -28.8 mV respectively. A maximum of 99.64 ± 0.16% of ASM was released from SES4 in 60 minutes of time. The flux (ex vivo study) increased by 2.33 folds, which prove the enhanced release and permeation of ASM when loaded into SES. The animals administered with SES4 showed higher activity and good pharmacodynamic response than the control and ASM-Suspension, which may be due to the greater availability of the drug. The maximum pharmacodynamic response was observed at the tmax determined by Pharmacokinetic studies. The bioavailability increased by 1.64 folds with 16.55 ± 3.11% as extend of lymphatic absorption (r = 0.9732). Good in vitro in vivo correlation was observed. ASM-SES is a novel approach to effectively deliver ASM and improve the oral bioavailability.


Assuntos
Antipsicóticos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Administração Oral , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Disponibilidade Biológica , Química Farmacêutica , Galinhas , Avaliação Pré-Clínica de Medicamentos , Emulsões , Excipientes/química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Camundongos , Tamanho da Partícula , Ratos Wistar , Solubilidade , Tensoativos
20.
Expert Opin Pharmacother ; 20(4): 385-397, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30698467

RESUMO

INTRODUCTION: Current antiretroviral therapy is more effective and simpler than in previous times due to the development of new drugs with improved pharmacokinetic and pharmacodynamic profiles and the advent of single pill regimens with low toxicity that facilitate long-term adherence. The recent approval of the novel potent integrase strand-transfer inhibitor bictegravir (BIC) co-formulated with emtricitabine (FTC) and tenofovir alafenamide (TAF) in a fixed daily dose pill, B/F/TAF, adds to the list of single-tablet regimens available to treat HIV infection. Areas covered: This review provides an overview of the pharmacological and clinical information obtained from MEDLINE/PubMed publications and the latest international conferences. Expert opinion: BIC is a potent antiretroviral with an improved resistance profile over previous integrase inhibitors. Its combination with the new tenofovir prodrug TAF and FTC creates an effective regimen B/F/TAF for treatment-naïve patients and for those switching from another successful combination. B/F/TAF's favorable pharmacokinetic profile, simple dose, low pill burden, and few drug-drug interactions or treatment-related adverse events, will make it one of the preferred regimens in the future.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Adenina/administração & dosagem , Adenina/análogos & derivados , Animais , Fármacos Anti-HIV/uso terapêutico , Combinação de Medicamentos , Interações Medicamentosas , Emtricitabina/administração & dosagem , Emtricitabina/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Comprimidos
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