Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 19 de 19
Filter
1.
Medwave ; 20(7): e8010, 2020.
Article in English, Spanish | LILACS | ID: biblio-1122665

ABSTRACT

Las terapias target constituyen hoy en día una alternativa terapéutica cada vez más utilizada para el manejo de pacientes con melanoma metastásico. Sin embargo, se han descrito múltiples efectos farmacológicos adversos asociados a su uso, siendo los cutáneos los de mayor prevalencia. Se presenta el caso de un hombre de 55 años con diagnóstico de melanoma cutáneo metastásico etapa IV, BRAFV600E mutado, en tratamiento con dabrafenib/trametinib que consultó por desarrollo de lesiones nodulares eritematosas sensibles en extremidades superiores e inferiores, asociadas a sensación febril durante el curso del tratamiento. Se descartó alguna infección sobreagregada. Se realizó una biopsia de las lesiones cutáneas, con confirmación diagnóstica histopatológica de una paniculitis mixta de predominio septal, granulomatosa y con vasculitis leucocitoclástica. La paniculitis asociada a esta terapia ha sido descrita en la literatura y se ha considerado un efecto farmacológico inmunomediado adverso, relacionándose a un mejor pronóstico para el melanoma metastásico en tratamiento. Por lo tanto, así como en el caso presentado, se evita la suspensión del fármaco y se asocia terapia sintomática en caso de mayores molestias del paciente. Es de alta relevancia para el dermatólogo conocer e interpretar adecuadamente este efecto adverso farmacológico, y así indicar el manejo más adecuado para el paciente.


Target therapies are currently a therapeutic option increasingly used for the management of patients with metastatic melanoma. However, there are multiple adverse pharmacological effects associated with their use that have been described. Cutaneous adverse reactions are the most frequent. We report the case of a 55-year-old man with a diagnosis of stage IV BRAFV600E-mutated metastatic cutaneous melanoma undergoing treatment with dabrafenib/trametinib, who consulted due to the development of erythematous nodular lesions in the upper and lower limbs associated with febrile sensation during the course of treatment. Infection was ruled out and a biopsy of the skin lesions was done, which provided the histopathological confirmation of a predominantly septal, granulomatous with leukocytoclastic vasculitis, mixed panniculitis. Panniculitis associated with this therapy has been described in the literature and has been considered an immune-mediated pharmacological adverse effect. It is considered to be related to a better prognosis in the treatment of metastatic melanoma. Consequently, as shown in this case report, target therapy should not be discontinued and symptomatic medication should be given to alleviate patient discomfort. The dermatologist should know and properly interpret this adverse effect and prescribe the most appropriate management for the patient.


Subject(s)
Humans , Male , Middle Aged , Panniculitis/chemically induced , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Molecular Targeted Therapy/methods , Oximes/administration & dosage , Pyridones/administration & dosage , Pyrimidinones/administration & dosage , Skin Neoplasms/drug therapy , Panniculitis/diagnosis , Panniculitis/therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Molecular Targeted Therapy/adverse effects , Dermatologists , Imidazoles/administration & dosage , Melanoma/drug therapy
2.
Epidemiol. serv. saúde ; 28(2): e2018325, 2019. tab, graf
Article in English, Portuguese | LILACS | ID: biblio-1012074

ABSTRACT

Objetivo: estimar o impacto orçamentário incremental da terapia-alvo para tratamento de primeira linha do melanoma avançado não cirúrgico e metastático, em comparação à dacarbazina. Métodos: análise de impacto orçamentário na perspectiva do Sistema Único de Saúde (SUS) do Brasil; a partir de dados demográficos e estimativas da incidência, foi delimitada a população no horizonte temporal de três anos (2018-2020) e estimados os custos diretos médicos; foi considerado cenário de referência o tratamento com dacarbazina, e como cenários alternativos a terapia-alvo com vemurafenibe, dabrafenibe, vemurafenibe + cobimetinibe e dabrafenibe + trametinibe; a avaliação das incertezas foi conduzida mediante análise por cenários. Resultados: o impacto orçamentário incremental variou de R$ 451.867.881,00 a R$ 768.860.968,00, representando 0,70 a 1,53% dos gastos anuais totais com medicamentos ambulatoriais no SUS; no melhor e no pior cenário, os resultados variaram de R$ 289.160.835,00 a R$ 1.107.081.926,00. Conclusão: a terapia-alvo, comparada à dacarbazina, implica impacto excessivo no orçamento, desfavorecendo eventual incorporação.


Objetivo: estimar el impacto presupuestario incremental de la terapia dirigida para tratamiento de primera línea del melanoma avanzado no quirúrgico y metastásico comparado con la dacarbazina. Métodos: análisis de impacto presupuestario, en la perspectiva del Sistema Único de Salud (SUS) de Brasil; a partir de datos demográficos y estimaciones de incidencia se delimitó la población en un horizonte temporal de tres años (2018-2020) y se estimaron los costos directos médicos. El escenario de referencia fue el tratamiento con dacarbazina y los escenarios alternativos la terapia dirigida con vemurafenib, dabrafenib, vemurafenib + cobimetinib y dabrafenib + trametinib; la evaluación de incertidumbre se llevó a cabo mediante análisis por escenarios. Resultados: el impacto presupuestario incremental varió de R$ 451.867.881,00 a R$ 768.860.968,00, representando 0,70 a 1,53% de gastos anuales totales con medicamentos de ambulatorios en el SUS; en el mejor y el peor escenario los resultados variaron de R$ 289.160.835,00 a R$ 1.107.081.926,00. Conclusión: el uso de terapia dirigida comparado a la dacarbazina implica en impacto excesivo en el presupuesto, desfavoreciendo una eventual incorporación.


Objective: to estimate the incremental budget impact of target therapy for first-line treatment of advanced non-surgical and metastatic melanoma compared to dacarbazine treatment. Methods: budget impact analysis, from the Brazilian National Health System (SUS) perspective; based on demographic data and incidence estimates, the population over a three-year time horizon (2018-2020) was delimited and the direct medical costs were estimated; the reference scenario was treatment with dacarbazine, and the alternative scenarios were target therapy with vemurafenib, dabrafenib, vemurafenib + cobimetinib and dabrafenib + trametinib; uncertainty assessment was conducted through scenario analysis. Results: the incremental budget impact ranged from R$ 451,867,881.00 to R$ 768,860,968.00, representing 0.70 to 1.53% of total SUS annual outpatient drugs expenditure; in best and worst scenario, results ranged from R$ 289,160,835.00 to R$ 1,107,081,926.00. Conclusion: the use of target therapy compared to dacarbazine implies an excessive impact on the budget, this bring unfovorable to its possible incorporation.


Subject(s)
Humans , Costs and Cost Analysis/trends , Dacarbazine/administration & dosage , Dacarbazine/therapeutic use , Molecular Targeted Therapy/methods , Molecular Targeted Therapy/trends , Melanoma/drug therapy , Melanoma/epidemiology , Skin Neoplasms/drug therapy , Unified Health System , Public Health/trends , Health Care Costs/trends , Neoplasm Metastasis/drug therapy , Antineoplastic Agents/economics
3.
Int. braz. j. urol ; 44(2): 219-237, Mar.-Apr. 2018. tab, graf
Article in English | LILACS | ID: biblio-892967

ABSTRACT

ABSTRACT We conducted a systematic review and meta-analysis of the literature on the efficacy of the targeted therapies in the treatment of advanced RCC and, via an indirect comparison, to provide an optimal treatment among these agents. A systematic search of Medline, Scopus, Cochrane Library and Clinical Trials unpublished was performed up to Jan 1, 2015 to identify eligible randomized trials. Outcomes of interest assessing a targeted agent included progression free survival (PFS), overall survival (OS) and objective response rate (ORR). Thirty eligible randomized controlled studies, total twentyfourth trails (5110 cases and 4626 controls) were identified. Compared with placebo and IFN-α, single vascular epithelial growth factor (receptor) tyrosine kinase inhibitor and mammalian target of rapamycin agent (VEGF(r)-TKI & mTOR inhibitor) were associated with improved PFS, improved OS and higher ORR, respectively. Comparing sorafenib combination vs sorafenib, there was no significant difference with regard to PFS and OS, but with a higher ORR. Comparing single or combination VEGF(r)-TKI & mTOR inhibitor vs BEV + IFN-α, there was no significant difference with regard to PFS, OS, or ORR. Our network ITC meta-analysis also indicated a superior PFS of axitinib and everolimus compared to sorafenib. Our data suggest that targeted therapy with VEGF(r)-TKI & mTOR inhibitor is associated with superior efficacy for treating advanced RCC with improved PFS, OS and higher ORR compared to placebo and IFN-α. In summary, here we give a comprehensive overview of current targeted therapies of advanced RCC that may provide evidence for the adequate targeted therapy selecting.


Subject(s)
Humans , Carcinoma, Renal Cell/drug therapy , Molecular Targeted Therapy/methods , Kidney Neoplasms/drug therapy , Carcinoma, Renal Cell/pathology , Randomized Controlled Trials as Topic , Disease-Free Survival , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Vascular Endothelial Growth Factor A/antagonists & inhibitors , ErbB Receptors/antagonists & inhibitors , Kidney Neoplasms/pathology
4.
Medicina (B.Aires) ; 77(6): 497-504, dic. 2017. ilus
Article in Spanish | LILACS | ID: biblio-894528

ABSTRACT

Las Rho GTPasas son una familia de proteínas que actúan como interruptores moleculares en diversas vías de señalización coordinando la regulación de distintos procesos celulares. La desregulación de dichas proteínas se vincula con transformación maligna y progresión tumoral en distintos tipos de cáncer. Por estos motivos, en los últimos años las Rho GTPasas fueron postuladas como blancos moleculares interesantes. En este trabajo describimos las distintas estrategias estudiadas utilizando a las Rho GTPasas como blanco y su grado de avance, mostrando una estrategia novedosa para el tratamiento del cáncer.


Rho GTPases are molecular switches that control the different cellular processes. Deregulation of these proteins is associated to transformation and malignant progression in several cancer types. Given the evidence available of the role of Rho GTPases in cancer it is suggested that these proteins can serve as potential therapeutic targets. This review focuses on the strategies used to develop Rho GTPases modulators and their potential use in therapeutic settings.


Subject(s)
Humans , rho GTP-Binding Proteins/antagonists & inhibitors , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Antineoplastic Agents/therapeutic use , rho GTP-Binding Proteins/physiology , Neoplasms/enzymology
5.
Clinics ; 72(10): 588-594, Oct. 2017. tab, graf
Article in English | LILACS | ID: biblio-890681

ABSTRACT

OBJECTIVES: With the development of next-generation sequencing (NGS) technologies, DNA sequencing has been increasingly utilized in clinical practice. Our goal was to investigate the impact of genomic evaluation on treatment decisions for heavily pretreated patients with metastatic cancer. METHODS: We analyzed metastatic cancer patients from a single institution whose cancers had progressed after all available standard-of-care therapies and whose tumors underwent next-generation sequencing analysis. We determined the percentage of patients who received any therapy directed by the test, and its efficacy. RESULTS: From July 2013 to December 2015, 185 consecutive patients were tested using a commercially available next-generation sequencing-based test, and 157 patients were eligible. Sixty-six patients (42.0%) were female, and 91 (58.0%) were male. The mean age at diagnosis was 52.2 years, and the mean number of pre-test lines of systemic treatment was 2.7. One hundred and seventy-seven patients (95.6%) had at least one identified gene alteration. Twenty-four patients (15.2%) underwent systemic treatment directed by the test result. Of these, one patient had a complete response, four (16.7%) had partial responses, two (8.3%) had stable disease, and 17 (70.8%) had disease progression as the best result. The median progression-free survival time with matched therapy was 1.6 months, and the median overall survival was 10 months. CONCLUSION: We identified a high prevalence of gene alterations using an next-generation sequencing test. Although some benefit was associated with the matched therapy, most of the patients had disease progression as the best response, indicating the limited biological potential and unclear clinical relevance of this practice.


Subject(s)
Humans , Male , Female , Adolescent , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Genomics/methods , Neoplasms/drug therapy , Neoplasms/genetics , Sequence Analysis, DNA/methods , Disease Progression , Disease-Free Survival , Genomics/trends , Kaplan-Meier Estimate , Molecular Targeted Therapy/methods , Neoplasm Metastasis , Neoplasms/mortality , Neoplasms/pathology , Precision Medicine/methods , Receptor, ErbB-2/antagonists & inhibitors , Reproducibility of Results , Sequence Analysis, DNA/trends , Time Factors , Treatment Outcome
6.
Mem. Inst. Oswaldo Cruz ; 111(12): 721-730, Dec. 2016. tab, graf
Article in English | LILACS | ID: biblio-829257

ABSTRACT

The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays.


Subject(s)
Humans , Antimalarials/chemistry , Aspartic Acid Endopeptidases/chemistry , Cysteine Endopeptidases/chemistry , Molecular Dynamics Simulation , Protozoan Proteins/chemistry , Thapsigargin/chemistry , Computational Biology/methods , Molecular Targeted Therapy/methods
7.
Braz. j. infect. dis ; 20(6): 610-618, Nov.-Dec. 2016. tab, graf
Article in English | LILACS | ID: biblio-828160

ABSTRACT

ABSTRACT Aptamers are short single-stranded RNA or DNA oligonucleotides that are capable of binding various biological targets with high affinity and specificity. Their identification initially relies on a molecular process named SELEX (Systematic Evolution of Ligands by EXponential enrichment) that has been later modified in order to improve aptamer sensitivity, minimize duration and cost of the assay, as well as increase target types. Several biochemical modifications can help to enhance aptamer stability without affecting significantly target interaction. As a result, aptamers have generated a large interest as promising tools to compete with monoclonal antibodies for detection and inhibition of specific markers of human diseases. One aptamer-based drug is currently authorized and several others are being clinically evaluated. Despite advances in the knowledge of parasite biology and host-parasite interactions from "omics" data, protozoan parasites still affect millions of people around the world and there is an urgent need for drug target discovery and novel therapeutic concepts. In this context, aptamers represent promising tools for pathogen identification and control. Recent studies have reported the identification of "aptasensors" for parasite diagnosis, and "intramers" targeting intracellular proteins. Here we discuss various strategies that have been employed for intracellular expression of aptamers and expansion of their possible application, and propose that they may be suitable for the clinical use of aptamers in parasitic infections.


Subject(s)
Humans , Parasitic Diseases/diagnosis , Parasitic Diseases/therapy , Aptamers, Nucleotide/genetics , SELEX Aptamer Technique/methods , Molecular Targeted Therapy/methods , Parasitic Diseases/prevention & control , Biomarkers/analysis
8.
Einstein (Säo Paulo) ; 14(2): 294-299, tab
Article in English | LILACS | ID: lil-788038

ABSTRACT

ABSTRACT Recent advances in the understanding of tumor driver mutations, signaling pathways that lead to tumor progression, and the better understanding of the interaction between tumor cells and the immune system are revolutionizing cancer treatment. The pace at which new treatments are approved and the prices at which they are set have made it even more difficult to offer these treatments in countries like Brazil. In this review we present for the non-oncologist these new treatments and compare their availability in Brazilian public health system and private health system with that of developed countries.


RESUMO Avanços recentes na compreensão de mutações promotoras de desenvolvimento do câncer, sinalização que leva à progressão de tumores, e o avanço no entendimento da interação entre as células tumorais e o sistema imunológico estão revolucionando o tratamento do câncer. A velocidade com que novos tratamentos são aprovados e o alto custo das medicações dificultam a disponibilização de terapêuticas em países como o Brasil. Nesta revisão, apresentamos ao não oncologista esses novos tratamentos e comparamos sua disponibilidade nos sistemas público e privado de saúde no Brasil com os países desenvolvidos.


Subject(s)
Humans , Medical Oncology/trends , Neoplasms/therapy , Brazil , Molecular Targeted Therapy/methods , Molecular Targeted Therapy/trends , Immunotherapy/trends
9.
Article in English | WPRIM | ID: wpr-21470

ABSTRACT

Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH.


Subject(s)
Antineoplastic Agents, Hormonal/adverse effects , Disease Management , Disease Progression , Endometrial Hyperplasia/classification , Female , Gonadotropin-Releasing Hormone/therapeutic use , Humans , Hysterectomy , Molecular Targeted Therapy/methods , Progesterone Congeners/therapeutic use , Risk Factors , Tamoxifen/adverse effects
10.
Rev. bras. enferm ; 68(4): 594-602, jul.-ago. 2015. tab, ilus
Article in Portuguese | LILACS, BDENF | ID: lil-761089

ABSTRACT

RESUMOObjetivo:compreender o significado atribuído pela família à sua vivência no processo de recuperação da criança acometida por doença aguda, após a alta hospitalar e elaborar um modelo teórico a respeito dessa experiência. O Interacionismo Simbólico foi adotado como referencial teórico e a Grounded Theory como metodológico.Método:os dados foram coletados por meio de entrevista e observação participante com 11 famílias, totalizando 15 entrevistas. A análise levou à formulação de um Modelo Teórico composto por dois fenômenos interativos: Mobilizando-se para resgatar o equilíbrio de seu funcionamento e Sofrendo com a possibilidade de reintegrar a criança.Resultados:estes revelaram que a família mantém-se em alerta para identificar precocemente alterações de saúde da criança na tentativa de evitar uma reinternação.Conclusão:os efeitos da doença e hospitalização continuam a manifestar-se no funcionamento familiar, gerando sofrimento mesmo após a alta e a recuperação da criança.


RESUMENObjetivo:comprender el significado atribuido por la familia de su experiencia en la recuperación de los niños afectados por el proceso de la enfermedad aguda, después de la descarga y desarrollar un modelo teórico sobre la experiencia. El Interaccionismo Simbólico fue adoptado como un teórico y la Teoría Fundamentada como metodológico.Método:los datos fueron recolectados a través de entrevistas y observación participante con 11 familias, con un total de 15 entrevistas. El análisis dio lugar a la formulación de un modelo teórico consta de dos fenómenos interactivos: Movilización para restaurar el balance de su funcionamiento y Sufriendo con la posibilidad de reinternar el niño.Resultados:éstos revelaron que la familias e mantiene en alerta para la identificación temprana de la salud el niño en un intento de evitar un reingreso.Conclusión:Los efectos de la enfermedad y la hospitalización aún se manifiesta en el funcionamiento familiar, que produce sufrimiento, incluso después de la descarga y la recuperación del niño.


ABSTRACTObjective:to understand the meaning attributed by the family to its experience in the recovery process of a child affected by an acute disease after discharge, and to develop a theoretical model of this experience. Symbolic interactionism was adopted as a theoretical reference, and grounded theory was adopted as a methodological reference.Method:data were collected through interviews and participant observation with 11 families, totaling 15 interviews. A theoretical model consisting of two interactive phenomena was formulated from the analysis: Mobilizing to restore functional balance and Suffering from the possibility of a child's readmission.Results:the family remains alert to identify early changes in the child's health, in an attempt to avoid rehospitalization.Conclusion:the effects of the disease and hospitalization continue to manifest in family functioning, causing suffering even after the child's discharge and recovery.


Subject(s)
Humans , Animals , Mice , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Neoplastic Stem Cells/metabolism , Signal Transduction , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/antagonists & inhibitors , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Disease Progression , Molecular Targeted Therapy/methods , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology
11.
Arq. bras. cardiol ; 104(3): 185-194, 03/2015. tab, graf
Article in English | LILACS | ID: lil-742788

ABSTRACT

Background: Ruthenium (Ru) tetraamines are being increasingly used as nitric oxide (NO) carriers. In this context, pharmacological studies have become highly relevant to better understand the mechanism of action involved. Objective: To evaluate the vascular response of the tetraamines trans-[RuII(NH3)4(Py)(NO)]3+, trans-[RuII(Cl)(NO) (cyclan)](PF6)2, and trans-[RuII(NH3)4(4-acPy)(NO)]3+. Methods: Aortic rings were contracted with noradrenaline (10−6 M). After voltage stabilization, a single concentration (10−6 M) of the compounds was added to the assay medium. The responses were recorded during 120 min. Vascular integrity was assessed functionally using acetylcholine at 10−6 M and sodium nitroprusside at 10−6 M as well as by histological examination. Results: Histological analysis confirmed the presence or absence of endothelial cells in those tissues. All tetraamine complexes altered the contractile response induced by norepinephrine, resulting in increased tone followed by relaxation. In rings with endothelium, the inhibition of endothelial NO caused a reduction of the contractile effect caused by pyridine NO. No significant responses were observed in rings with endothelium after treatment with cyclan NO. In contrast, in rings without endothelium, the inhibition of guanylate cyclase significantly reduced the contractile response caused by the pyridine NO and cyclan NO complexes, and both complexes caused a relaxing effect. Conclusion: The results indicate that the vascular effect of the evaluated complexes involved a decrease in the vascular tone induced by norepinephrine (10−6 M) at the end of the incubation period in aortic rings with and without endothelium, indicating the slow release of NO from these complexes and suggesting that the ligands promoted chemical stability to the molecule. Moreover, we demonstrated that the association of Ru with NO is more stable when the ligands pyridine and cyclan ...


Fundamento: As tetra-aminas de rutênio cada vez mais se destacam como carreadoras da molécula de óxido nítrico. Desse modo, estudos farmacológicos tornam-se altamente relevantes, afim de melhor compreender o mecanismo de ação envolvido. Objetivo: Avaliar a resposta vascular das tetra-aminas trans-[RuII(NH3)4(Py)(NO)]3+, trans-[RuII(Cl)(NO)(Cyclan)](PF6)2 e trans-[RuII(NH3)4(4-acPy)(NO)]3+. Métodos: Anéis de aorta foram pré-contraídos com noradrenalina (10-6M). Após estabilização da tensão, concentração única (10-6M) dos compostos foi adicionada ao banho de incubação. As respostas foram registradas ao longo de 120 minutos. A integridade vascular foi avaliada funcionalmente (acetilcolina 10-6M; nitroprussiato de sódio 10-6M) e histologicamente Resultados: A análise histológica confirmou a presença ou não de células endoteliais nos tecidos analisados. Todos os complexos alteraram a resposta contrátil induzida pela noradrenalina, resultando em aumento de tônus seguido de efeito relaxante. Em anéis com endotélio, a inibição do óxido nítrico endotelial causou redução do efeito contrátil da piridina óxido nítrico. Não foram observadas respostas significativas em anéis com endotélio referente ao composto cyclan óxido nítrico. Por outro lado, em anéis sem endotélio, a inibição da guanilato ciclase reduziu significativamente a resposta contrátil dos complexos piridina óxido nítrico e cyclan óxido nítrico, levando ambos os compostos a um efeito relaxante. Conclusão: Os resultados obtidos demonstram que o efeito vascular dos complexos avaliados apresentaram diminuição no tônus vascular induzido pela noradrenalina (10-6M) ao final do tempo de incubação, em anéis com e sem endotélio, indicando liberação lenta da molécula de óxido nítrico do composto estudado e sugerindo que os ligantes causaram estabilidade química à molécula. Demonstramos que a ligação rutênio óxido nítrico é mais estável quando utilizamos os ligantes piridina e cyclan para a formulação ...


Subject(s)
Animals , Humans , Mice , Apoptosis/physiology , MicroRNAs/physiology , Endothelial Cells/physiology , MicroRNAs/antagonists & inhibitors , MicroRNAs/metabolism , Molecular Targeted Therapy/methods , Neoplasms/physiopathology , Ribonuclease III/deficiency , Ribonuclease III/physiology , Up-Regulation , Vascular Endothelial Growth Factor A/physiology
12.
Korean Journal of Urology ; : 673-679, 2015.
Article in English | WPRIM | ID: wpr-128358

ABSTRACT

After the approval and introduction of mirabegron, tadalafil, and botulinum toxin A for treatment of lower urinary tract symptoms/overactive bladder, focus of interest has been on their place in therapy versus the previous gold standard, antimuscarinics. However, since these agents also have limitations there has been increasing interest in what is coming next - what is in the pipeline? Despite progress in our knowledge of different factors involved in both peripheral and central modulation of lower urinary tract dysfunction, there are few innovations in the pipe-line. Most developments concern modifications of existing principles (antimuscarinics, beta3-receptor agonists, botulinum toxin A). However, there are several new and old targets/drugs of potential interest for further development, such as the purinergic and cannabinoid systems and the different members of the transient receptor potential channel family. However, even if there seems to be good rationale for further development of these principles, further exploration of their involvement in lower urinary tract function/dysfunction is necessary.


Subject(s)
Adrenergic beta-3 Receptor Agonists/therapeutic use , Botulinum Toxins, Type A/therapeutic use , Drug Therapy, Combination , Humans , Molecular Targeted Therapy/methods , Muscarinic Antagonists/therapeutic use , Neuromuscular Agents/therapeutic use , Urinary Bladder, Overactive/drug therapy
13.
Article in English | WPRIM | ID: wpr-55728

ABSTRACT

The global burden of advanced stage cervical cancer remains significant, particular in resource poor countries where effective screening programs are absent. Unfortunately, a proportion of patients will be diagnosed with advanced stage disease, and may suffer from persistent or recurrent disease despite treatment with combination chemotherapy and radiation. Patients with recurrent disease have a poor salvage rate, with an expected 5-year survival of less than 10%. Recently, significant gains have been made in the antiangiogenic arena; nonetheless the need to develop effective alternate targeted strategies is implicit. As such, a review of molecular targeted therapy in the treatment of this disease is warranted. In an era of biologics, combined therapy with cytotoxic drugs and molecular targeted agents, represents an exciting arena yet to be fully explored.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Female , Histone Deacetylase Inhibitors/therapeutic use , Humans , Molecular Targeted Therapy/methods , ErbB Receptors/antagonists & inhibitors , Salvage Therapy/methods , Uterine Cervical Neoplasms/drug therapy
14.
Yonsei Medical Journal ; : 1526-1532, 2014.
Article in English | WPRIM | ID: wpr-221610

ABSTRACT

PURPOSE: Pulmonary arterial hypertension (PAH) is an orphan disease showing poor prognosis. The purpose of study was to evaluate clinical factors influencing outcomes in PAH. MATERIALS AND METHODS: Patients who were diagnosed with PAH at a single center were reviewed retrospectively. Forty patients (34.9+/-14.5 years, 80% of female) were enrolled. RESULTS: Causes were congenital heart disease in 24 (60%), connective tissue disease in 8 (20%) and idiopathic PAH in 6 (15%). Sixteen patients (40%) were WHO functional class III or IV at the time of diagnosis. Twenty seven patients (67.5%) received molecular targeted therapy. During follow-up (53.6+/-45.5 months), 10 patients (25%) died and 1-, 2-, and 8 year survival rates were 91.3%, 78.7%, and 66.8%, respectively. As expected, median survival of patients with functional class I or II were significantly longer than patients with III or IV (p=0.041). Interestingly, patients with molecular targeted therapy showed longer survival than conventional therapy (p=0.021). CONCLUSION: WHO functional class at the time of diagnosis was the strong predictor of survival, and molecular targeted therapy could significantly improve the survival. Therefore, early screening and intensive management would be crucial to improve the prognosis in the patient with PAH.


Subject(s)
Adult , Antihypertensive Agents/therapeutic use , Disease Management , Familial Primary Pulmonary Hypertension , Female , Heart Defects, Congenital/complications , Humans , Hypertension/complications , Hypertension, Pulmonary/classification , Kaplan-Meier Estimate , Male , Middle Aged , Molecular Targeted Therapy/methods , Prognosis , Retrospective Studies , Survival Rate
15.
Article in English | WPRIM | ID: wpr-175271

ABSTRACT

Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1alpha, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress-dependent responses. Thus, APE1/Ref-1 acts as a 'hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed.


Subject(s)
Animals , DNA Damage , DNA Repair , DNA-(Apurinic or Apyrimidinic Site) Lyase/analysis , Humans , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Neurodegenerative Diseases/drug therapy , Oxidative Stress , Phytochemicals/pharmacology , Polymorphism, Genetic , Protein Interaction Maps
16.
Article in English | WPRIM | ID: wpr-109972

ABSTRACT

OBJECTIVE: To synthesize mesoporous silica-core-shell magnetic nanoparticles (MNPs) encapsulated by liposomes (Lipo [MNP@m-SiO2]) in order to enhance their stability, allow them to be used in any buffer solution, and to produce trastuzumab-conjugated (Lipo[MNP@m-SiO2]-Her2Ab) nanoparticles to be utilized in vitro for the targeting of breast cancer. MATERIALS AND METHODS: The physiochemical characteristics of Lipo[MNP@m-SiO2] were assessed in terms of size, morphological features, and in vitro safety. The multimodal imaging properties of the organic dye incorporated into Lipo[MNP@m-SiO2] were assessed with both in vitro fluorescence and MR imaging. The specific targeting ability of trastuzumab (Her2/neu antibody, Herceptin(R))-conjugated Lipo[MNP@m-SiO2] for Her2/neu-positive breast cancer cells was also evaluated with fluorescence and MR imaging. RESULTS: We obtained uniformly-sized and evenly distributed Lipo[MNP@m-SiO2] that demonstrated biological stability, while not disrupting cell viability. Her2/neu-positive breast cancer cell targeting by trastuzumab-conjugated Lipo[MNP@m-SiO2] was observed by in vitro fluorescence and MR imaging. CONCLUSION: Trastuzumab-conjugated Lipo[MNP@m-SiO2] is a potential treatment tool for targeted drug delivery in Her2/neu-positive breast cancer.


Subject(s)
3T3 Cells , Animals , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents/administration & dosage , Breast Neoplasms/chemistry , Cell Line, Tumor , Drug Delivery Systems/methods , Female , Ferric Compounds/chemistry , Humans , Liposomes , Magnetite Nanoparticles/administration & dosage , Mice , Molecular Targeted Therapy/methods , Nanoconjugates/administration & dosage , Nanoparticles/chemistry , Receptor, ErbB-2/immunology , Silicon Dioxide/administration & dosage
17.
Int. braz. j. urol ; 39(6): 768-778, Nov-Dec/2013. tab, graf
Article in English | LILACS | ID: lil-699127

ABSTRACT

Objectives At present there are several drugs for the treatment of advanced renal cell carcinoma (ARCC). The main objective of this work was to perform a systematic review (SR) and meta-analysis (MA) of clinical randomized studies that compared target cell therapies (TCT). Materials and Methods SR identified clinical randomized trials that compared TCT versus interferon-alpha in the treatment of patients with ARCC. In order to analyze efficiency, it was evaluated free-survival progression (FSP), total survival (TS) and response rate (RR). Results In relation to first line treatment, seven studies of TCT were identified using sunitinib, sorafenib, bevacizumab and temsirolimus; and two studies with sorafenib and everolimus for second line treatment. Relative risk (RRi) of MA for FSP of first line therapies was: 0.83, CI = 0.78-0.87, I2 = 94% and p < 0.00001. Best results of RR of specific FSP among studies were: 0.38, sunitinib, CI = 0.25-0.58, bevacizumab, 0.62, CI = 0.47-0.83; and temsirolimus, 0.78, CI = 0.70-0.87. MA didn't show any benefit regarding TS of first line treatment of all analyzed drugs. As for RR significant results were: sunitinib, 3.83 CI = 2.86-5.12; bevacizumab, 2.52 CI = 1.78-3.57 and bevacizumab, 1.97 CI = 1.43-2.71. Conclusions: For first line treatment, sunitinib was the most effective TCT in relation to FPS; there was no alteration of TS and RR was small but significant for sunitinib and bevacizumab. Available studies could not conclude any results for second line treatments. .


Subject(s)
Female , Humans , Male , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Molecular Targeted Therapy/methods , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/secondary , Disease Progression , Kidney Neoplasms/mortality , Neoplasm Metastasis , Randomized Controlled Trials as Topic , Survival Analysis , Treatment Outcome
18.
Braz. j. med. biol. res ; 46(6): 465-485, 02/jul. 2013. tab, graf
Article in English | LILACS | ID: lil-679202

ABSTRACT

Most drugs function by binding reversibly to specific biological targets, and therapeutic effects generally require saturation of these targets. One means of decreasing required drug concentrations is incorporation of reactive metal centers that elicit irreversible modification of targets. A common approach has been the design of artificial proteases/nucleases containing metal centers capable of hydrolyzing targeted proteins or nucleic acids. However, these hydrolytic catalysts typically provide relatively low rate constants for target inactivation. Recently, various catalysts were synthesized that use oxidative mechanisms to selectively cleave/inactivate therapeutic targets, including HIV RRE RNA or angiotensin converting enzyme (ACE). These oxidative mechanisms, which typically involve reactive oxygen species (ROS), provide access to comparatively high rate constants for target inactivation. Target-binding affinity, co-reactant selectivity, reduction potential, coordination unsaturation, ROS products (metal-associated vs metal-dissociated; hydroxyl vs superoxide), and multiple-turnover redox chemistry were studied for each catalyst, and these parameters were related to the efficiency, selectivity, and mechanism(s) of inactivation/cleavage of the corresponding target for each catalyst. Important factors for future oxidative catalyst development are 1) positioning of catalyst reduction potential and redox reactivity to match the physiological environment of use, 2) maintenance of catalyst stability by use of chelates with either high denticity or other means of stabilization, such as the square planar geometric stabilization of Ni- and Cu-ATCUN complexes, 3) optimal rate of inactivation of targets relative to the rate of generation of diffusible ROS, 4) targeting and linker domains that afford better control of catalyst orientation, and 5) general bio-availability and drug delivery requirements.


Subject(s)
Humans , Peptide Hydrolases/pharmacokinetics , Reactive Oxygen Species/pharmacology , Coordination Complexes/pharmacokinetics , Molecular Targeted Therapy/methods , Oxidation-Reduction , Peptide Hydrolases/chemical synthesis , Biological Availability , Catalysis , Genes, env , Peptidyl-Dipeptidase A/metabolism
19.
J. appl. oral sci ; 20(2): 128-138, Mar.-Apr. 2012. ilus, tab
Article in English | LILACS | ID: lil-626410

ABSTRACT

Recently, new treatment approaches have been developed to target the host component of periodontal disease. This review aims at providing updated information on host-modulating therapies, focusing on treatment strategies for inhibiting signal transduction pathways involved in inflammation. Pharmacological inhibitors of MAPK, NFκB and JAK/STAT pathways are being developed to manage rheumatoid arthritis, periodontal disease and other inflammatory diseases. Through these agents, inflammatory mediators can be inhibited at cell signaling level, interfering on transcription factors activation and inflammatory gene expression. Although these drugs offer great potential to modulate host response, their main limitations are lack of specificity and developments of side effects. After overcoming these limitations, adjunctive host modulating drugs will provide new therapeutic strategies for periodontal treatment.


Subject(s)
Humans , Inflammation Mediators/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/therapeutic use , Molecular Targeted Therapy/methods , Periodontal Diseases/therapy , Signal Transduction/drug effects , Biofilms , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Intracellular Signaling Peptides and Proteins/immunology , Janus Kinases/immunology , Janus Kinases/metabolism , Mitogen-Activated Protein Kinases/immunology , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/immunology , NF-kappa B/metabolism , Periodontal Diseases/etiology , Periodontal Diseases/immunology , STAT Transcription Factors/immunology , STAT Transcription Factors/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL