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1.
Nat Protoc ; 16(1): 405-430, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33311713

RESUMO

Here we describe two protocols for the construction of responsive and activable nanomedicines that regulate the tumor microenvironment (TME). The TME is composed of all non-cellular and cellular components surrounding a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules, and extracellular matrix and has a crucial role in tumor initiation, growth, and metastasis. Owing to the relatively stable properties of the TME compared to tumor cells, which exhibit frequent genetic mutations and epigenetic changes, therapeutic strategies targeting the TME using multifunctional nanomedicines hold great potential for anti-tumor therapy. By regulating tumor-associated platelets and pancreatic stellate cells (PSCs), the two major players in the TME, we can effectively manipulate the physiological barriers for enhanced drug delivery and significantly improve the tumor penetration and therapeutic efficacy of chemotherapeutics. The preparation and characterization of the multifunctional nanoparticles takes ~10 h for tumor-associated platelet regulation and 16 h for PSC regulation. These nanoformulations can be readily applied to regulate other components in the TME to realize synergistic or additive anti-tumor activity.


Assuntos
Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Feminino , Ouro/química , Humanos , Camundongos Endogâmicos BALB C , Nanomedicina/métodos , Neoplasias/patologia , Polímeros/química , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Tretinoína/administração & dosagem , Tretinoína/uso terapêutico
2.
Medicine (Baltimore) ; 99(39): e22256, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991422

RESUMO

BACKGROUND: Striae distensae (SD) are common and aesthetically undesirable dermal lesions. The aim of this study is to comprehensively evaluate the effectiveness of different therapies in treating striae distensae using network meta-analysis. METHODS: A systematic search of electronic databases up to December 1, 2019 was conducted. Randomized controlled trails (RCTs) examining the effectiveness of different methods in treating striae distensae were included. The primary outcomes are clinical effective rate and patient's satisfaction degree. Risk of bias was assessed by the Cochrane risk of bias tool. Network meta-analysis was based on Bayesian framework. RESULTS: Fourteen trails that met the criteria with 651 subjects were included. The results of the network meta-analysis show that topical tretinoin combined bipolar radiofrequency showed the highest probability of being the best method to improve the clinical effectiveness and patient satisfaction rate of treating SD (84.5% and 95.7% respectively), closely followed by bipolar radiofrequency (75.3% and 84.3% respectively). Among laser treatment, CO2 fractional laser is superior to other lasers in the clinical effectiveness and patient satisfaction (72.0% and 58.1% respectively). Statistics showed the topical tretinoin was the worst-performing option in improving the clinical effectiveness and patient satisfaction rate of SD treatment (5.4% and 5.1% respectively). CONCLUSION: Based on the results of network meta-analysis, we recommend treating striae distensae with bipolar radio frequency combined topical tretinoin. The commonly used CO2 fractional laser can be considered as alternative treatment candidate. Additional large-scale RCTs are necessary to obtain more precise estimates of their relative efficacy.


Assuntos
Ceratolíticos/administração & dosagem , Lasers de Gás/uso terapêutico , Ablação por Radiofrequência/métodos , Estrias de Distensão/terapia , Tretinoína/administração & dosagem , Administração Tópica , Adolescente , Adulto , Feminino , Humanos , Masculino , Satisfação do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto Jovem
3.
Life Sci ; 258: 118152, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735881

RESUMO

AIMS: Cancer stem cells (CSCs) are the source of tumors and play a key role in the resistance of cancer to therapies. To improve the current therapies against CSCs, in this work we developed a novel system of electrospun polycaprolactone (PCL) nanofibers containing hydroxylated multi-walled carbon nanotubes (MWCNTs-OH) and all-trans retinoic acid (ATRA). MATERIALS AND METHODS: The nanofiber membranes were forged by electrospinning, and the physical and chemical properties of the nanofiber membranes were evaluated by scanning electron microscopy, XRD and Raman etc. The photothermal properties of nanofiber membranes and their effects on CSCs differentiation and cytotoxicity were investigated. Finally, the anti-tumor effect of nanofiber membranes in vivo was evaluated. KEY FINDINGS: The nanofibers formed under optimal conditions were smooth without beads. The nanofibrous membranes with MWCNTs-OH could increase temperature of the medium under near-infrared (NIR) illumination to suppress the viability of glioma stem cells (GSCs). Meanwhile, the added ATRA could further induce the differentiation of GSCs to destroy their stemness and reduce their resistance to heat treatment. Compared with no NIR irradiation, after 2min NIR irradiation, the membranes reduced the in-vitro viability of GSCs by 13.41%, 14.83%, and 26.71% after 1, 2, and 3 days, respectively. After 3 min daily illumination for 3 days, the viability of GSCs was only 22.75%, and similar results were observed in vivo. SIGNIFICANCE: These results showed efficiently cytotoxicity to CSCs by combining heat therapy and differentiation therapy. The nanofiber membranes if inserted at the site after surgical tumor removal, may hinder tumor recurrence.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Glioma/terapia , Nanofibras/uso terapêutico , Células-Tronco Neoplásicas/efeitos dos fármacos , Tretinoína/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Glioma/patologia , Humanos , Hipertermia Induzida/métodos , Masculino , Camundongos Endogâmicos BALB C , Nanofibras/química , Nanotubos de Carbono/química , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Células-Tronco Neoplásicas/patologia , Poliésteres/química , Poliésteres/uso terapêutico , Tretinoína/administração & dosagem
5.
Int J Hematol ; 112(4): 487-495, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32683599

RESUMO

Management of acute myeloid leukemia during pregnancy (P-AML) is a challenging endeavor with limited evidence-based information available. To truly achieve the goal of improving P-AML patients, additional evidence-based research is necessary. We retrospectively reviewed cases of 17 patients diagnosed with P-AML, including seven for acute promyelocytic leukemia (APL) from January 2012 to June 2019. Among the non-APL, 90% patients (9/10) ended pregnancy prior to induction chemotherapy. The median intervals between diagnosis and start of chemotherapy were 5 days (range 1-14 days). Four patients elected to delay chemotherapy by more than one week. Of the seven APL patients, six received all-trans retinoic acid (ATRA) before the diagnostic molecular results. Five patients underwent cesarean sections (CS) and all newborns were alive (four preterm and one full-term deliveries). Overall, approximately 94% of the patients (16/17) are currently alive in remission. To treat P-AML patients in a safer manner, balancing the risk of progressing to advanced disease and proceeding with pregnancy is required. We consider a slight delay (less than 14 days) in the termination of pregnancy may not differ the prognosis to patients with non-APL. For APL, patients will benefit from prompt administration of ATRA for highly suspected cases.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Complicações Hematológicas na Gravidez/tratamento farmacológico , Tretinoína/administração & dosagem , Adulto , Cesárea , Prática Clínica Baseada em Evidências , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Gravidez , Complicações Hematológicas na Gravidez/diagnóstico , Resultado da Gravidez , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Medição de Risco , Fatores de Tempo , Adulto Jovem
6.
Int J Hematol ; 112(3): 349-360, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32524309

RESUMO

We stratified patients with newly diagnosed acute promyelocytic leukemia (APL) according to a white blood cell (WBC) count of ≥ 3 × 109/L (high risk) or < 3 × 109/L (low risk) before administering risk-adapted chemotherapy in combination with all-trans retinoic acid (ATRA). In total, 27 low-risk and 23 high-risk patients were assigned to receive induction and three courses of consolidation with ATRA and anthracycline, followed by 2-year maintenance regimen. High-risk group additionally received cytarabine during 1st consolidation and another one-shot idarubicin treatment during 3rd consolidation. We prospectively monitored measurable residual disease (MRD) after induction and each consolidation. In the low-risk and high-risk groups, 5-year disease-free survival (DFS) rates were 86.5% and 81.2% (p = 0.862), and 5-year overall survival rates were 100% and 84.8% (p = 0.062), respectively. In the MRD-negative and MRD-positive groups, 5-year DFS rates were 91.7% and 78.4% (p = 0.402) and 84.7% and 60.0% (p = 0.102) after induction and 1st consolidation, respectively. Relapse rates were 8.3% and 13.3% (p = 0.570) and 9.0% and 40.0% (p = 0.076) after induction and 1st consolidation, respectively. Achieving MRD-negativity after 1st consolidation, rather than after induction, was a potential predictor of relapse and DFS in patients with APL treated with ATRA + chemotherapy.


Assuntos
Quimioterapia de Consolidação , Leucemia Promielocítica Aguda/tratamento farmacológico , Neoplasia Residual/mortalidade , Tretinoína/uso terapêutico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Feminino , Previsões , Humanos , Idarubicina/administração & dosagem , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Prognóstico , Estudos Prospectivos , Recidiva , Taxa de Sobrevida , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto Jovem
7.
Ann Hematol ; 99(5): 973-982, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32270215

RESUMO

In this study, we investigated the safety and efficacy of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). The patients had been classified as unfit to receive anthracycline-based chemotherapy due to high-risk factors for early death. Twenty-five patients with APL receiving ATO/ATRA between 2007 and 2018 were divided into 3 groups as follows: elderly patients (age ≥ 70 years) with poor performance status (32%); patients with severe active infections at diagnosis (56%); and patients with multiple significant comorbidities (24%) who were unfit for conventional chemotherapy, regardless of age. Induction therapy comprised 0.15 mg/kg/day ATO combined with 45 mg/m2/day ATRA until patients attained complete remission (CR). Notably, only one patient (4.0%) died of septic shock 2 days after the ATO treatment had been initiated. The remaining 24 patients attained CR despite their serious and desperate conditions at diagnosis. In total, 44%, 28%, and 32% of the patients experienced neutropenia (grade 3 or 4), thrombocytopenia, and hepatopathy, respectively. Twenty-three of the 24 patients in CR proceeded to consolidation therapy and attained complete molecular remission with favorable overall survival (90.7%). This study demonstrates the safety and efficacy profile of ATO/ATRA first-line therapy for patients with APL and high-risk features for early death.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Promielocítica Aguda , Adulto , Idoso , Trióxido de Arsênio/administração & dosagem , Trióxido de Arsênio/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Tretinoína/administração & dosagem , Tretinoína/efeitos adversos
8.
Curr Med Sci ; 40(1): 55-62, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32166665

RESUMO

The present study aimed to explore the molecular mechanisms underlying the increase of nicotinamide adenine dinucleotide phosphate:quinine oxidoreductase 1 (NQO1) and γ-glutamylcysteine synthetase (γ-GCS) in brain tissues after intracerebral hemorrhage (ICH). The microglial cells obtained from newborn rats were cultured and then randomly divided into the normal control group (NC group), model control group (MC group), rosiglitazone (RSG) intervention group (RSG group), retinoic-acid intervention group (RSG+RA group), and sulforaphane group (RSG+SF group). The expression levels of NQO1, γ-GCS, and nuclear factor E2-related factor 2 (Nrf2) were measured by real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. The results showed that the levels of NQO1, γ-GCS and Nrf2 were significantly increased in the MC group and the RSG group as compared with those in the NC group (P<0.01). They were found to be markedly decreased in the RSG+RA group and increased in the RSG+SF group when compared with those in the MC group or the RSG group (P<0.01). The RSG+SF group displayed the highest levels of NQO1, γ-GCS, and Nrf2 among the five groups. In conclusion, a medium dose of RSG increased the anti-oxidative ability of thrombin-activated microglia by increasing the expression of NQO1 and γ-GCS. The molecular mechanisms underlying the increase of NQO1 and γ-GCS in thrombin-activated microglia may be associated with the activation of Nrf2.


Assuntos
Hemorragia Cerebral/genética , Glutamato-Cisteína Ligase/genética , Microglia/citologia , NAD(P)H Desidrogenase (Quinona)/genética , Fator 2 Relacionado a NF-E2/genética , PPAR gama/genética , Trombina/farmacologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Modelos Animais de Doenças , Feminino , Glutamato-Cisteína Ligase/metabolismo , Isotiocianatos/administração & dosagem , Isotiocianatos/farmacologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , PPAR gama/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Rosiglitazona/administração & dosagem , Rosiglitazona/farmacologia , Tretinoína/administração & dosagem , Tretinoína/farmacologia
9.
Drug Deliv Transl Res ; 10(1): 146-158, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31529371

RESUMO

Liposomal drug delivery has become an established technology platform to deliver dual drugs to produce synergistic effects and reduce the adverse effects of traditional chemotherapy. Gambogic acid (GA) and retinoic acid (RA) are both effective anticancer components, but their low water-solubility (gambogic acid < 0.0050 mg/mL, retinoic acid 0.0048 < mg/mL) makes it difficult to load both drugs into the liposomes actively using the conventional method. We have successfully used solvent-assisted active loading technology (SALT) to load the insoluble drugs into the internal water phase via water-miscible organic solvent. Gambogic acid and retinoic acid co-encapsulated liposomes (weight ratio of GA to RA = 1:2, GRL) exhibited the strongest synergistic effect; combination index (CI) was 0.614 in 4T1 cells. Our studies demonstrated that GRL had uniform droplet size of about 130 nm, high stability, and controlled release behavior. GRL outperformed gambogic acid and retinoic acid solution (GRS) in pharmacokinetic profiles for a longer half-life and increased AUC. Comparing to GRS, GL, and RL, GRL showed increased cytotoxicity and apoptosis in 4T1 cells and showed the strongest anti-tumor ability in the in vivo anti-tumor efficacy. Overall, the SALT was a promising method to active loading poorly soluble drugs into liposomes, and the results showed GRL possessed a great potential for use in synergistic anticancer therapy.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Tretinoína/administração & dosagem , Xantonas/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Cápsulas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Lipossomos , Camundongos , Tamanho da Partícula , Solventes , Tretinoína/química , Tretinoína/farmacologia , Xantonas/química , Xantonas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Leukemia ; 34(3): 914-918, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31611624
11.
J Pediatr Hematol Oncol ; 42(4): 322-325, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-30807394

RESUMO

Acute promyelocytic leukemia (APL) is rare in patients with Down syndrome (DS). Cytotoxic chemotherapy combined with all-trans retinoic acid (ATRA) has been a standard treatment for APL, but is potentially intolerable for DS patients because of their vulnerability to cytotoxic agents. We report here a case of a 10-year-old girl with DS and APL successfully treated with a combination of ATRA and arsenic trioxide, a therapy emerging as a new standard for APL. She achieved molecular remission and completed the therapy without significant toxicities. ATRA/arsenic trioxide combination therapy would be a preferable option for DS patients with APL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Síndrome de Down/tratamento farmacológico , Leucemia Promielocítica Aguda/tratamento farmacológico , Trióxido de Arsênio/administração & dosagem , Criança , Feminino , Humanos , Tretinoína/administração & dosagem
12.
J Clin Oncol ; 38(6): 623-632, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31851556

RESUMO

PURPOSE: High CD33 expression in acute myeloid leukemia (AML) with mutated NPM1 provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate GO in combination with intensive induction and consolidation therapy in NPM1-mutated AML. PATIENTS AND METHODS: Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all-trans-retinoic acid with or without GO. The early (P = .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment. RESULTS: Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04; P = .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm (P = .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm (P = .005), with no difference in the cumulative incidence of death (P = .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and FLT3 internal tandem duplication-negative patients with respect to EFS and CIR. CONCLUSION: The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Gemtuzumab/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia de Consolidação/métodos , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Idarubicina/administração & dosagem , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Estudos Prospectivos , Tretinoína/administração & dosagem , Adulto Jovem
14.
Cutan Ocul Toxicol ; 39(1): 43-53, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31741401

RESUMO

Purpose: Androgenic alopecia (AGA) is a condition of progressive hair loss and involves follicular miniaturization triggered mainly due to varying levels of androgen besides environmental and genetic factors, which may also play some role. Minoxidil (MXD) has been considered as most effective therapeutic moiety to treat this disorder. Another drug Tretinoin (TRET) is known for its comedolytic activity and is reported to enhance percutaneous absorption of MXD. Presently both these drugs are being utilized for treatment of androgenic alopecia (AGA) in solution form which poses several problems in terms of poor solubility of drug, frequency of application and side effects.Materials and methods: Current work investigates liposomal hydrogel system for simultaneous delivery of MXD and TRET to overcome the limitations of existing formulation. Successful development of liposomes was commenced by thin film hydration method and various parameters affecting desired characteristics like size, morphology, entrapment efficiency; stability and ex vivo permeation were optimized. The formulated liposomes were further characterized for various physicochemical properties and evaluated for in vivo irritancy study in animals.Results and discussion: Results suggested prepared liposomes to be stable, homogenous and capable to hold both the drugs within. Association with hydrogel enhanced the permeation of MXD through skin ex vivo but TRET retained on the skin. Liposome loaded hydrogel was found to be non-irritant to skin.Conclusion: Overall developed system showed potential for effective and simultaneous delivery of both the drugs.


Assuntos
Hidrogéis , Lipossomos , Minoxidil/química , Minoxidil/farmacologia , Tretinoína/química , Tretinoína/farmacocinética , Administração Tópica , Alopecia/tratamento farmacológico , Animais , Transporte Biológico , Quimioterapia Combinada , Ceratolíticos/administração & dosagem , Ceratolíticos/química , Ceratolíticos/farmacologia , Masculino , Minoxidil/administração & dosagem , Minoxidil/efeitos adversos , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Dermatopatias/induzido quimicamente , Tretinoína/administração & dosagem , Tretinoína/efeitos adversos , Vasodilatadores/administração & dosagem , Vasodilatadores/química , Vasodilatadores/farmacologia
15.
J Clin Oncol ; 38(3): 257-270, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31794324

RESUMO

PURPOSE: DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all-trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety. RESULTS: The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms. CONCLUSION: The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Decitabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tretinoína/administração & dosagem , Ácido Valproico/administração & dosagem
16.
J Cosmet Sci ; 71(6): 439-454, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33413787

RESUMO

Centella asiatica has many applications in cosmetics, including wrinkle treatments, but its effectiveness remains to be clarified. This systematic review study aimed to demonstrate the efficacy and safety of C. asiatica for reducing facial wrinkles. PubMed, Excerpta Medica dataBASE (EMBASE), Cochrane Central Register of clinical trials, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Thai Library Integrated System, and Thai university database/journals were searched until May 2019. Five double-blinded randomised controlled trials, including 172 Asian females, were included. Endpoints were wrinkling measured by visual score, image analysis, and participant satisfaction. Two placebo-controlled studies applied gel/creams containing C. asiatica or asiaticoside for 12 w to periorbital skin. Two studies applied tretinoin or Pueraria mirifica contralaterally and by network meta-analysis C. asiatica appeared more effective than P. mirifica but possibly less than tretinoin. Asiaticoside applied as a lipstick for 8 w reduced lip wrinkling. Skin hydration was markedly raised by C. asiatica but not tretinoin. One study reported 10 adverse events for C. asiatica and 35 for tretinoin. Cochrane risk of bias was generally low, reporting was weak, and lack of C. asiatica standardization prevents general application. From the reported data, it is possible to conclude that C. asiatica improved lip and periocular wrinkles, and may replace retinoids if its long-term safety is established and C. asiatica is standardized.


Assuntos
Centella , Cosméticos , Envelhecimento da Pele , Feminino , Humanos , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Tretinoína/administração & dosagem
17.
Anticancer Res ; 39(12): 6537-6546, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810919

RESUMO

BACKGROUND/AIM: PLX4032 is commonly used in the treatment of advanced melanoma patients with BRAF-V600E mutation. The aim of this study was to elucidate the mechanisms by which up-regulation of PIN1 confers PLX4032 resistance in melanoma. MATERIALS AND METHODS: The expression of PIN1 as well as the cytotoxic effects of combinatorial treatment of PLX4032 and all-trans retinoic acid (ATRA) were investigated by immunoblotting, MTT assay, TUNEL assay, and soft agar assay. RESULTS: PIN1 expression is up-regulated in A375R cells, a PLX4032-resistant subline of melanoma cells generated from an A375 cell line, compared to parental A375 cells. Indeed, PIN1 positively regulated the expression of EGFR in A375R cells and led to activation of the RAF/MEK/ERK pathway. Importantly, PLX4032, when used in combination with ATRA, an inhibitor of PIN1, reduced EGFR expression, and consequently reduced cell viability and anchorage-independent growth of A375R cells compared to PLX4032 alone. Furthermore, co-treatment with ATRA and PLX4032 increased cleaved PARP and DNA fragmentation in A375R cells. CONCLUSION: PIN1 plays an important role in the development of PLX4032 resistance through up-regulation of EGFR expression.


Assuntos
Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Tretinoína/administração & dosagem , Vemurafenib/administração & dosagem , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Melanoma/metabolismo , Camundongos , Tretinoína/farmacologia , Vemurafenib/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Drugs Dermatol ; 18(12): 1218-1225, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31860209

RESUMO

BACKGROUND: While it is generally considered to be a disease of adolescence, acne affects an increasing number of adults, especially women. Although data exist on the use of retinoids in adult females, there is no universal agreement as to the age of onset of adult female acne, or data on the efficacy and tolerability dependent on age. A novel tretinoin 0.05% lotion formulation has been shown to be effective and well-tolerated in acne patients with moderate or severe disease. OBJECTIVE: To evaluate the safety and efficacy of once-daily tretinoin 0.05% lotion in women with moderate or severe acne categorized into different age groups (13-19, 20-29, and 30+ years). METHODS: Post hoc analysis of two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies. Women (aged 13-19 years, N=357; 20-29 years, N=352; 30+ years, N=156) with moderate or severe acne were randomized (1:1) to receive tretinoin 0.05% lotion or vehicle, once-daily for 12 weeks. Efficacy assessments included changes in baseline inflammatory/noninflammatory lesions and treatment success (at least 2-grade reduction in Evaluator's Global Severity Score [EGSS] and 'clear'/'almost clear') and Quality of Life (QoL) using the validated Acne-QoL questionnaire. Safety and adverse events (AEs) where evaluated throughout; cutaneous tolerability assessed at each study visit using a 4-point scale (where 0=none and 3=severe). RESULTS: At baseline, 91.9% (N=794) of women in the post hoc analysis had moderate (EGSS=3) and 8.1% (N=70) severe (EGSS=4) acne, with the highest proportion of women (11.1%, N=39) having severe acne being aged 20-29 years. Baseline inflammatory lesion counts were similar across the three age ranges, with more comedonal lesions (44.5) in adolescent females (aged 13-19 years). Quality of life at baseline was much better in adolescent females and may be age-related for some domains (self-perception and role-social). At week 12, there appeared to be an age-related improvement in both inflammatory and noninflammatory lesion counts, and treatment success although the differences between groups were not significant. Mean percent reduction in inflammatory and noninflammatory lesion counts for each age group (13-19, 20-29, and 30+ years old respectively) were 55.3% (P=0.019 versus vehicle), 55.8% (P=0.080) and 63.5%; and 47.1% (P<0.001), 55.2% (P=0.002) and 59.0% (P=0.030). Treatment success for the 3 groups was achieved by 23.2% (P=0.023), 21.3%, and 30.7% of patients, respectively, at week 12; differences between age groups were not significant. Quality of Life improved in all age groups, although changes with tretinoin 0.05% lotion were only significant compared with vehicle in adult females aged 20-29 years (self-perception, role-emotional and acne symptoms); improvements in each domain score by week 12 were also greatest in this age group. The majority of AEs were mild and transient; the most common treatment emergent AEs were application site pain and dryness especially in the older adult females (aged 30+ years). Local cutaneous safety and tolerability assessments were generally mild and improved by week 12. There were transient increases in scaling, burning and stinging in the adolescent females, peaking at week 4; all mean scores were ≤0.6 where 1=mild. CONCLUSIONS: Tretinoin 0.05% lotion was significantly more effective than vehicle in achieving treatment success and reducing inflammatory and comedonal lesions in adult and adolescent females with moderate or severe acne. There appear to be age-related efficacy and tolerability benefits favoring adult females. J Drugs Dermatol. 2019;18(12):1218-1225.


Assuntos
Acne Vulgar/tratamento farmacológico , Ceratolíticos/administração & dosagem , Tretinoína/administração & dosagem , Acne Vulgar/patologia , Administração Cutânea , Adolescente , Adulto , Fatores Etários , Método Duplo-Cego , Feminino , Humanos , Ceratolíticos/efeitos adversos , Qualidade de Vida , Índice de Gravidade de Doença , Creme para a Pele , Inquéritos e Questionários , Resultado do Tratamento , Tretinoína/efeitos adversos , Adulto Jovem
19.
Leuk Lymphoma ; 60(13): 3107-3115, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842650

RESUMO

The application of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the treatment of acute promyelocytic leukemia (APL). More than 80-90% of patients are expected to be cured with a combination of ATRA, ATO and/or chemotherapy. In this review, we focus on the remaining obstacles to a cure for all patients with APL. We review the issue of early death and coagulopathy and discuss the particular challenges in the care of patients with high-risk APL and patients with relapsed APL. We also give recommendations and highlight ongoing efforts to improve the persistently high early death rate and the outcomes of high risk and relapsed APL patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Hemorragia/mortalidade , Leucemia Promielocítica Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Indução de Remissão/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Trióxido de Arsênio/administração & dosagem , Trióxido de Arsênio/efeitos adversos , Intervalo Livre de Doença , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Incidência , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/patologia , Mortalidade , Recidiva Local de Neoplasia/epidemiologia , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Padrão de Cuidado , Fatores de Tempo , Tretinoína/administração & dosagem , Tretinoína/efeitos adversos
20.
J Drugs Dermatol ; 18(11): 1128-1138, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31741356

RESUMO

Background: There has been an increasing interest in gender and racial differences both in the pathogenesis and treatment of acne vulgaris (acne), and postinflammatory hyperpigmentation (PIH) is a major concern in patients of color. Female acne patients report more anxiety and depression with acne improvement positively influencing Quality of Life (QoL) than their male counterparts, and there are differences in acne presentation. The first lotion formulation of tretinoin was developed using novel polymeric emulsion technology to provide an important alternative option to treat these acne patients, especially those who may be sensitive to the irritant effects of other tretinoin formulations. Objective: To determine the impact of gender and race on the efficacy and safety of tretinoin 0.05% lotion in treating moderate or severe acne. Methods: Post hoc analysis of 2 multicenter, randomized, double-blind, vehicle-controlled Phase 3 studies in moderate-to-severe acne. Subjects (aged 9 to 58 years, N=1640) were randomized (1:1) to receive tretinoin 0.05% lotion or vehicle, once-daily for 12 weeks. Efficacy assessments included changes in baseline inflammatory and noninflammatory lesions and treatment success (at least 2-grade reduction in Evaluator's Global Severity Score [EGSS] and clear/almost clear). Quality of Life was assessed using the validated Acne QoL scale. Safety, adverse events (AEs), cutaneous tolerability, and hypo-/hyper-pigmentation (using a 4-point scale where 0=none and 3=severe) were evaluated at each study visit. Results: At week 12, mean percent reduction in inflammatory lesion counts were 56.9% and 53.4% respectively in female and male patients compared with 47.1% and 39.4% with vehicle (P≤0.001), with females statistically significant to males at week 8 [P=0.026]). Mean percent reduction in noninflammatory lesion counts in females and males were 51.7% and 46.1% respectively, compared with 34.9% and 29.7% with vehicle (P<0.001), with females statistically significant to males at week 12 (P=0.035). Treatment success was achieved by 23.6% and 16.1% of female and male patients treated with tretinoin 0.05% lotion by week 12 (P≤0.001 vs vehicle) with females statistically significant compared with males (P=0.013). Significant differences in inflammatory lesion count reductions were reported in Caucasian patients from week 8, and Black African/American male patients at week 12. Only male patients reported significant differences in both races in terms of noninflammatory lesions, and only Caucasian patients reported significant differences in treatment success. Female patients treated with tretinoin 0.05% lotion had statistically significant improvements in each Acne QoL domain (except role-social) compared with vehicle. Improvements in QoL in male subjects were only statistically different for acne symptoms. Tretinoin 0.05% lotion was well-tolerated in both genders. There were more treatment-related AEs in the female subpopulation, with a significantly greater incidence of skin dryness (P=0.006), that was more common in the younger Caucasian females. Conclusions: Tretinoin 0.05% lotion has been shown to be effective and well tolerated in moderate-to-severe acne. Treatment was significantly more effective in females than males. Tretinoin 0.05% lotion was well tolerated by both genders, although there was a higher incidence of treatment-related AEs, especially skin dryness, in females. There were racial and gender differences in QoL and beneficial effects on PIH in those patients most at risk. J Drugs Dermatol. 2019;18(11):1128-1138.


Assuntos
Acne Vulgar/tratamento farmacológico , Ceratolíticos/administração & dosagem , Tretinoína/administração & dosagem , Acne Vulgar/etnologia , Acne Vulgar/patologia , Administração Cutânea , Adolescente , Adulto , Criança , Método Duplo-Cego , Esquema de Medicação , Grupos Étnicos , Feminino , Identidade de Gênero , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do Tratamento , Estados Unidos , Adulto Jovem
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