Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 52
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Adv Chronic Kidney Dis ; 27(5): 434-441, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33308510

RESUMO

Coronavirus disease 2019, the disease caused by the severe acute respiratory syndrome coronavirus 2 virus, was first identified in the Hubei Province of China in late 2019. Currently, the only role for therapy is treatment of the disease, as opposed to postexposure prophylaxis, however multiple clinical trials are currently ongoing for both treatment and prophylaxis. Treating coronavirus disease 2019 relies on two components; the first is inhibition of the viral entrance and replication within the body and the second is inhibition of an exacerbated immune response which can be seen in patients with severe disease. Many drugs have shown in vitro antiviral activity; however, clinical trials have not been as promising. This review summarizes the current data for the most commonly used drugs for coronavirus disease 2019 and will cover the unique factors that may affect the dosing of these medications in patients with CKD. While clinical trials are ongoing, most are in patients with normal kidney function. During a pandemic, when patients with CKD are at higher risk of both infection and death, it is imperative to include patients these patients in the clinical trials.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Insuficiência Renal Crônica/metabolismo , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , /prevenção & controle , /uso terapêutico , Cloroquina/uso terapêutico , Creatinina/metabolismo , Citidina/análogos & derivados , Citidina/uso terapêutico , Dexametasona/uso terapêutico , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Hidroxicloroquina/uso terapêutico , Hidroxilaminas/uso terapêutico , Imunização Passiva , Interferons/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Lopinavir/uso terapêutico , Pirazinas/uso terapêutico , Eliminação Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Terapia de Substituição Renal , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico
2.
Curr Opin Neurol ; 32(5): 758-763, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31335338

RESUMO

PURPOSE OF REVIEW: To review new developments in the field of amyotrophic lateral sclerosis (ALS) clinical trial design and to review the implications of the latest ALS clinical trials. RECENT FINDINGS: There has been substantial reflection on how clinical trials in ALS are best conducted. The revised Airlie House recommendations are an important milestone and should guide trial design. In addition, innovations using individualized risk-based eligibility criteria, adaptive designs, joint modelling, patient-centred approaches, and remote collection of data show real promise. Edaravone was shown to have benefit on function in a well defined subset of patients with ALS, although there are concerns about the generalizability of the findings. Studies of arimoclomol, inosine, and cellular therapies have demonstrated promising signals in early phase work and are being taken forward into larger studies. Well conducted studies of rasagaline did not show an effect on primary outcome measures. SUMMARY: For many decades there has been regular disappointment with the results of clinical trials. With the innovations in trial design and advances in our basic understanding of the biology of ALS, the prospects for a step change in treatments for people affected by ALS are strong.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Ensaios Clínicos como Assunto , Edaravone/uso terapêutico , Hidroxilaminas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Humanos , Projetos de Pesquisa , Resultado do Tratamento
3.
Eur Rev Med Pharmacol Sci ; 22(4): 950-960, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29509243

RESUMO

OBJECTIVE: Endometrial cancer is increasingly prevalent in western societies and affects mainly postmenopausal women; notably incidence rates have been rising by 1.9% per year on average since 2005. Although the early-stage endometrial cancer can be effectively managed with surgery, more advanced stages of the disease require multimodality treatment with varying results. In recent years, endometrial cancer has been extensively studied at the molecular level in an attempt to develop effective therapies. Recently, a family of compounds that alter epigenetic expression, namely histone deacetylase inhibitors, have shown promise as possible therapeutic agents in endometrial cancer. The present review aims to discuss the therapeutic potential of these agents. MATERIALS AND METHODS: This literature review was performed using the MEDLINE database; the search terms histone, deacetylase, inhibitors, endometrial, targeted therapies for endometrial cancer were employed to identify relevant studies. We only reviewed English language publications and also considered studies that were not entirely focused on endometrial cancer. Ultimately, sixty-four articles published until January 2018 were incorporated into our review. RESULTS: Studies in cell cultures have demonstrated that histone deacetylase inhibitors exert their antineoplastic activity by promoting expression of p21WAF1 and p27KIP1, cyclin-dependent kinase inhibitors, that have important roles in cell cycle regulation; importantly, the transcription of specific genes (e.g., E-cadherin, PTEN) that are commonly silenced in endometrial cancer is also enhanced. In addition to these abstracts effects, novel compounds with histone deacetylase inhibitor activity (e.g., scriptaid, trichostatin, entinostat) have also demonstrated significant antineoplastic activity both in vitro and in vivo, by liming tumor growth, inducing apoptosis, inhibiting angiogenesis and potentiating the effects of chemotherapy. CONCLUSIONS: The applications of histone deacetylase inhibitors in endometrial cancer appear promising; nonetheless, additional trials are necessary to establish the therapeutic role, clinical utility, and safety of these promising compounds.


Assuntos
Antineoplásicos/metabolismo , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Feminino , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/genética , Humanos , Ácidos Hidroxâmicos/metabolismo , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Hidroxilaminas/metabolismo , Hidroxilaminas/farmacologia , Hidroxilaminas/uso terapêutico , Quinolinas/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico
4.
Neurology ; 90(7): e565-e574, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29367439

RESUMO

OBJECTIVE: To examine the safety and tolerability as well as the preliminary efficacy of arimoclomol, a heat shock protein co-inducer that promotes nascent protein folding, in patients with rapidly progressive SOD1 amyotrophic lateral sclerosis (ALS). METHODS: This was a double-blind, placebo-controlled trial in which patients with rapidly progressive SOD1-mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS). RESULTS: Thirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32-1.80). ALSFRS-R and FEV6 declined more slowly in the arimoclomol group, with treatment differences of 0.5 point/month (95% CI -0.63 to 1.63) and 1.24 percent predicted/month (95% CI -2.77 to 5.25), respectively, and the CAFS similarly favored arimoclomol. CONCLUSIONS: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. Although not powered for therapeutic effect, the consistency of results across the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of arimoclomol. CLINICALTRIALSGOV IDENTIFIER: NCT00706147. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. The study lacked the precision to conclude, or to exclude, an important therapeutic benefit of arimoclomol.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Hidroxilaminas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Adulto , Idoso , Esclerose Amiotrófica Lateral/genética , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Hidroxilaminas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Índice de Gravidade de Doença , Superóxido Dismutase-1/genética , Análise de Sobrevida , Resultado do Tratamento
5.
Nat Commun ; 8: 14612, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28266544

RESUMO

Defective lysosomal acidification contributes to virtually all lysosomal storage disorders (LSDs) and to common neurodegenerative diseases like Alzheimer's and Parkinson's. Despite its fundamental importance, the mechanism(s) underlying this defect remains unclear. The v-ATPase, a multisubunit protein complex composed of cytosolic V1-sector and lysosomal membrane-anchored V0-sector, regulates lysosomal acidification. Mutations in the CLN1 gene, encoding PPT1, cause a devastating neurodegenerative LSD, INCL. Here we report that in Cln1-/- mice, which mimic INCL, reduced v-ATPase activity correlates with elevated lysosomal pH. Moreover, v-ATPase subunit a1 of the V0 sector (V0a1) requires palmitoylation for interacting with adaptor protein-2 (AP-2) and AP-3, respectively, for trafficking to the lysosomal membrane. Notably, treatment of Cln1-/- mice with a thioesterase (Ppt1)-mimetic, NtBuHA, ameliorated this defect. Our findings reveal an unanticipated role of Cln1 in regulating lysosomal targeting of V0a1 and suggest that varying factors adversely affecting v-ATPase function dysregulate lysosomal acidification in other LSDs and common neurodegenerative diseases.


Assuntos
Hidroxilaminas/uso terapêutico , Doenças por Armazenamento dos Lisossomos/enzimologia , Lisossomos/metabolismo , Tioléster Hidrolases/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Complexo 2 de Proteínas Adaptadoras/metabolismo , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Endossomos/enzimologia , Células HEK293 , Humanos , Lipoilação , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Camundongos , Distribuição Aleatória
6.
Diabetes Obes Metab ; 19(7): 936-943, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28155245

RESUMO

AIM: To determine the effect of Scriptaid, a compound that can replicate aspects of the exercise adaptive response through disruption of the class IIa histone deacetylase (HDAC) corepressor complex, on muscle insulin action in obesity. MATERIALS AND METHODS: Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily intraperitoneal injection for 4 weeks. Whole-body and skeletal muscle metabolic phenotyping of mice was performed, in addition to echocardiography, to assess cardiac morphology and function. RESULTS: Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function. CONCLUSION: These data show that pharmacological targeting of the class IIa HDAC corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity.


Assuntos
Cardiotônicos/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Coração/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Hidroxilaminas/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Obesidade/tratamento farmacológico , Quinolinas/uso terapêutico , Animais , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/uso terapêutico , Cardiotônicos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Ecocardiografia , Ecocardiografia Doppler , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Coração/diagnóstico por imagem , Coração/fisiopatologia , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/efeitos adversos , Hidroxilaminas/efeitos adversos , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Miocárdio/patologia , Obesidade/etiologia , Obesidade/patologia , Obesidade/fisiopatologia , Tamanho do Órgão , Quinolinas/efeitos adversos
7.
J Vet Med Sci ; 78(12): 1903-1905, 2017 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-27594275

RESUMO

Our previous study suggested that the highly toxic α,ß-unsaturated aldehyde acrolein, a byproduct of oxidative stress, plays a major role in acetaminophen-induced liver injury. In this study, to determine the involvement of acrolein in the liver injury and to identify novel therapeutic options for the liver damage, we examined two putative acrolein scavengers, a thiol compound cysteamine and a hydroxylamine N-benzylhydroxylamine, in cell culture and in mice. Our results showed that cysteamine and N-benzylhydroxylamine effectively prevented the cell toxicity of acrolein in vitro and acetaminophen-induced liver injury in vivo, which suggested that acrolein is involved in the liver damage, and these two drugs can be potential therapeutic options for this condition.


Assuntos
Acetaminofen/toxicidade , Acroleína/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Cisteamina/farmacologia , Overdose de Drogas/tratamento farmacológico , Hidroxilaminas/farmacologia , Fígado/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cisteamina/uso terapêutico , Overdose de Drogas/patologia , Humanos , Hidroxilaminas/uso terapêutico , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
8.
Sci Transl Med ; 8(355): 355ra118, 2016 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-27605553

RESUMO

Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla(-/-)), Sandhoff disease (Hexb(-/-)), and Niemann-Pick disease type C (Npc1(-/-)) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb(-/-) and Npc1(-/-) mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.


Assuntos
Proteínas de Choque Térmico/uso terapêutico , Esfingolipidoses/tratamento farmacológico , Administração Intravenosa , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Proteínas Morfogenéticas Ósseas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Doença de Fabry/tratamento farmacológico , Doença de Fabry/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Glicoesfingolipídeos/metabolismo , Proteínas de Choque Térmico/farmacologia , Humanos , Hidroxilaminas/farmacologia , Hidroxilaminas/uso terapêutico , Injeções Intraperitoneais , Peptídeos e Proteínas de Sinalização Intracelular , Lisossomos/efeitos dos fármacos , Lisossomos/patologia , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Proteínas/metabolismo , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Esfingolipidoses/patologia , Distribuição Tecidual
9.
Expert Opin Pharmacother ; 17(12): 1669-82, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27356036

RESUMO

INTRODUCTION: Amyotrophic lateral sclerosis (ALS), one in a family of age-related neurodegenerative disorders, is marked by predominantly cryptogenic causes, partially elucidated pathophysiology, and elusive treatments. The challenges of ALS are illustrated by two decades of negative drug trials. AREAS COVERED: In this article, we lay out the current understanding of disease genesis and physiology in relation to drug development in ALS, stressing important accomplishments and gaps in knowledge. We briefly consider clinical ALS, the ongoing search for biomarkers, and the latest in trial design, highlighting major recent and ongoing clinical trials; and we discuss, in a concluding section on future directions, the prion-protein hypothesis of neurodegeneration and what steps can be taken to end the drought that has characterized drug discovery in ALS. EXPERT OPINION: Age-related neurodegenerative disorders are fast becoming major public health problems for the world's aging populations. Several agents offer promise in the near-term, but drug development is hampered by an interrelated cycle of obstacles surrounding etiological, physiological, and biomarkers discovery. It is time for the type of government-funded, public-supported offensive on neurodegenerative disease that has been effective in other fields.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/genética , Biomarcadores/metabolismo , Ensaios Clínicos como Assunto , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/genética , Humanos , Hidroxilaminas/uso terapêutico , Memantina/uso terapêutico , Riluzol/uso terapêutico , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Vitamina B 12/análogos & derivados , Vitamina B 12/uso terapêutico
10.
Sci Transl Med ; 8(331): 331ra41, 2016 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-27009270

RESUMO

Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients more than 50 years of age. Previous therapeutic trials have targeted the inflammatory features of sIBM but all have failed. Because protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated arimoclomol in an investigator-led, randomized, double-blind, placebo-controlled, proof-of-concept trial in sIBM patients and showed that arimoclomol was safe and well tolerated. Although arimoclomol improved some IBM-like pathology in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in the proof-of-concept patient trial.


Assuntos
Homeostase , Miosite de Corpos de Inclusão/metabolismo , Proteínas/metabolismo , Adenosina Trifosfatases/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ensaios Clínicos como Assunto , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Hidroxilaminas/farmacologia , Hidroxilaminas/uso terapêutico , Mediadores da Inflamação/metabolismo , Camundongos , Contração Muscular/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Mutação/genética , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Mioblastos/patologia , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/fisiopatologia , Ratos , Resultado do Tratamento , Proteína com Valosina
11.
Sci Rep ; 5: 17066, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26602448

RESUMO

UNLABELLED: Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H: Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, ß-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. ß-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD(+)/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of ß-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from ß-lap-induced lethality and blunted PARP1 hyperactivation. Combining ß-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + ß-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. SIGNIFICANCE: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer.


Assuntos
Reparo do DNA/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Animais , Autofagia/efeitos dos fármacos , Catalase/genética , Catalase/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , DNA Glicosilases/antagonistas & inibidores , DNA Glicosilases/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Dicumarol/farmacologia , Feminino , Humanos , Hidroxilaminas/farmacologia , Hidroxilaminas/uso terapêutico , Camundongos , Camundongos Nus , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transplante Heterólogo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
12.
Hum Mol Genet ; 24(19): 5416-32, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26160911

RESUMO

Neurodegeneration is a devastating manifestation in the majority of >50 lysosomal storage disorders (LSDs). Neuronal ceroid lipofuscinoses (NCLs) are the most common childhood neurodegenerative LSDs. Mutations in 13 different genes (called CLNs) underlie various types of NCLs, of which the infantile NCL (INCL) and congenital NCL (CNCL) are the most lethal. Although inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1) cause INCL, those in the CLN10 gene encoding cathepsin D (CD) underlie CNCL. PPT1 is a lysosomal thioesterase that cleaves the thioester linkage in S-acylated proteins required for their degradation by lysosomal hydrolases like CD. Thus, PPT1 deficiency causes lysosomal accumulation of these lipidated proteins (major constituents of ceroid) leading to INCL. We sought to determine whether there is a common pathogenic link between INCL and CNCL. Using biochemical, histological and confocal microscopic analyses of brain tissues and cells from Cln1(-/-) mice that mimic INCL, we uncovered that Cln10/CD is overexpressed. Although synthesized in the endoplasmic reticulum, the CD-precursor protein (pro-CD) is transported through endosome to the lysosome where it is proteolytically processed to enzymatically active-CD. We found that despite Cln10 overexpression, the maturation of pro-CD to enzymatically active-CD in lysosome was disrupted. This defect impaired lysosomal degradative function causing accumulation of undegraded cargo in lysosome leading to INCL. Notably, treatment of intact Cln1(-/-) mice as well as cultured brain cells derived from these animals with a thioesterase-mimetic small molecule, N-tert-butyl-hydroxylamine, ameliorated the CD-processing defect. Our findings are significant in that they define a pathway in which Cln1 mutations disrupt the maturation of a major degradative enzyme in lysosome contributing to neuropathology in INCL and suggest that lysosomal CD deficiency is a common pathogenic link between INCL and CNCL.


Assuntos
Encéfalo/metabolismo , Catepsina D/metabolismo , Lipofuscinoses Ceroides Neuronais/patologia , Tioléster Hidrolases/genética , Animais , Encéfalo/patologia , Catepsina D/deficiência , Criança , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Hidroxilaminas/administração & dosagem , Hidroxilaminas/uso terapêutico , Lisossomos/metabolismo , Camundongos , Mutação , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/genética
13.
Arh Hig Rada Toksikol ; 66(4): 285-90, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26751860

RESUMO

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The cause is unknown and no effective treatment currently exists. For ALS, there is only a drug Riluzole and a promising substance arimoclomol. The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels. The majority of ALS cases are sporadic (SALS) and a subset of patients has an inherited form of the disease, familial ALS (FALS), with a common SOD1 mutation, also present in SALS. A few of the mutant genes identified in FALS have also been found in SALS. Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS- and FTD-causing mutations known to date. TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the pathological protein of FALS, SALS and, less frequently, FTD. The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes. TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins. Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins. This review addresses new advances that are being made in our understanding of the molecular mechanisms of both diseases, which may eventually translate into new treatment options.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/genética , Proteínas de Ligação a DNA/genética , Demência Frontotemporal/genética , Hidroxilaminas/uso terapêutico , Mutação/genética , Riluzol/uso terapêutico , Humanos
14.
Pharmacol Ther ; 141(1): 40-54, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23978556

RESUMO

Arimoclomol is a hydroxylamine derivative, a group of compounds which have unique properties as co-inducers of heat shock protein expression, but only under conditions of cellular stress. Arimoclomol has been found to be neuroprotective in a number of neurodegenerative disease models, including Amyotrophic Lateral Sclerosis (ALS), and in mutant Superoxide Dismutase 1 (SOD1) mice that model ALS, Arimoclomol rescues motor neurons, improves neuromuscular function and extends lifespan. The therapeutic potential of Arimoclomol is currently under investigation in a Phase II clinical trial for ALS patients with SOD1 mutations. In this review we summarize the evidence for the neuroprotective effects of enhanced heat shock protein expression by Arimoclomol and other inducers of the Heat Shock Response. ALS is a complex, multifactorial disease affecting a number of cell types and intracellular pathways. Cells and pathways affected by ALS pathology and which may be targeted by a heat shock protein-based therapy are also discussed in this review. For example, protein aggregation is a characteristic pathological feature of neurodegenerative diseases including ALS. Enhanced heat shock protein expression not only affects protein aggregation directly, but can also lead to more effective clearance of protein aggregates via the unfolded protein response, the proteasome-ubiquitin system or by autophagy. However, compounds such as Arimoclomol have effects beyond targeting protein mis-handling and can also affect additional pathological mechanisms such as oxidative stress. Therefore, by targeting multiple pathological mechanisms, compounds such as Arimoclomol may be particularly effective in the development of a disease-modifying therapy for ALS and other neurodegenerative disorders.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/metabolismo , Proteínas de Choque Térmico/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Hidroxilaminas/farmacologia , Hidroxilaminas/uso terapêutico , Animais , Indução Enzimática/efeitos dos fármacos , Proteínas de Choque Térmico/biossíntese , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Modelos Biológicos , Terapia de Alvo Molecular/métodos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico
16.
Nat Neurosci ; 16(11): 1608-17, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24056696

RESUMO

Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disease (LSD) that has no effective treatment. It is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 deficiency impairs the cleavage of thioester linkage in palmitoylated proteins (constituents of ceroid), preventing degradation by lysosomal hydrolases. Consequently, accumulation of lysosomal ceroid leads to INCL. Thioester linkage is cleaved by nucleophilic attack. Hydroxylamine, a potent nucleophilic cellular metabolite, may have therapeutic potential for INCL, but its toxicity precludes clinical application. We found that a hydroxylamine derivative, N-(tert-Butyl) hydroxylamine (NtBuHA), was non-toxic, cleaved thioester linkage in palmitoylated proteins and mediated lysosomal ceroid depletion in cultured cells from INCL patients. In Ppt1(-/-) mice, which mimic INCL, NtBuHA crossed the blood-brain barrier, depleted lysosomal ceroid, suppressed neuronal apoptosis, slowed neurological deterioration and extended lifespan. Our findings provide a proof of concept that thioesterase-mimetic and antioxidant small molecules such as NtBuHA are potential drug targets for thioesterase deficiency diseases such as INCL.


Assuntos
Hidroxilaminas/uso terapêutico , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/genética , Fármacos Neuroprotetores/uso terapêutico , Tioléster Hidrolases/deficiência , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Isótopos de Carbono/metabolismo , Células Cultivadas , Córtex Cerebral/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hidroxilaminas/metabolismo , Hidroxilaminas/farmacologia , Longevidade/efeitos dos fármacos , Longevidade/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Lipofuscinoses Ceroides Neuronais/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/ultraestrutura , Fármacos Neuroprotetores/metabolismo , Palmitoil Coenzima A/efeitos dos fármacos , Palmitoil Coenzima A/metabolismo , Fatores de Tempo
17.
Acta Pharmacol Sin ; 34(8): 1093-100, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23708552

RESUMO

AIM: Fluopsin C, an antibiotic isolated from Pseudomonas jinanesis, has shown antitumor effects on several cancer cell lines. In the current study, the oncotic cell death induced by fluopsin C was investigated in human breast adenocarcinoma cells in vitro. METHODS: Human breast adenocarcinoma cell lines MCF-7 and MD-MBA-231 were used. The cytotoxicity was evaluated using MTT assay. Time-lapse microscopy and transmission electron microscopy were used to observe the morphological changes. Cell membrane integrity was assessed with propidium iodide (PI) uptake and lactate dehydrogenase (LDH) assay. Flow cytometry was used to measure reactive oxygen species (ROS) level and mitochondrial membrane potential (Δψm). A multimode microplate reader was used to analyze the intracellular ATP level. The changes in cytoskeletal system were investigated with Western blotting and immunostaining. RESULTS: Fluopsin C (0.5-8 µmol/L) reduced the cell viability in dose- and time-dependent manners. Its IC50 values in MCF-7 and MD-MBA-231 cells at 24 h were 0.9 and 1.03 µmol/L, respectively. Fluopsin C (2 µmol/L) induced oncosis in both the breast adenocarcinoma cells characterized by membrane blebbing and swelling, which was blocked by pretreatment with the pan-caspase inhibitor Z-VAD-fmk. In MCF-7 cells, fluopsin C caused PI uptake into the cells, significantly increased LDH release, induced cytoskeletal system degradation and ROS accumulation, decreased the intracellular ATP level and Δψm. Noticeably, fluopsin C exerted comparable cytotoxicity against the normal human hepatocytes (HL7702) and human mammary epithelial cells with the IC50 values at 24 h of 2.7 and 2.4 µmol/L, respectively. CONCLUSION: Oncotic cell death was involved in the anticancer effects of fluopsin C on human breast adenocarcinoma cells in vitro. The hepatoxicity of fluopsin C should not be ignored.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Adenocarcinoma/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/química , Linhagem Celular Tumoral , Células Epiteliais/química , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Humanos , Hidroxilaminas/farmacologia , Hidroxilaminas/uso terapêutico , Células MCF-7
18.
IDrugs ; 13(7): 482-96, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20582873

RESUMO

Recent years have seen an explosion of research into increasingly prevalent neurodegenerative diseases. Arimoclomol (BRX-220), being developed by CytRx Corp, is an oral therapeutic candidate for the treatment of amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease. ALS is a fatal, incurable disorder, which can present as sporadic (90 to 95% of cases) or familial (5 to 10% of cases) forms. The etiology of sporadic ALS remains unknown and much of the understanding of ALS pathogenesis has been derived through study of its familial forms; in particular, through study of autosomal dominant mutations in the SOD1 (copper/zinc superoxide dismutase) gene, which cause approximately 20% of familial ALS cases. Under conditions of excessive stress, arimoclomol induces amplification of the cytoprotective heat shock response in order to protect motor neurons from death. Comprehensive in vivo and in vitro studies demonstrated its effect in the prevention of neuronal loss and promotion of motor neuron survival, even after symptom onset. Clinical trials have reported good tolerability and safety. This paper discusses the rationale for arimoclomol use in ALS, the preclinical and clinical evidence collected to date, the likelihood of its promising preclinical results translating to humans, and the relevance of this research for neurodegeneration as a whole.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Proteínas de Choque Térmico/metabolismo , Hidroxilaminas/farmacologia , Hidroxilaminas/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Esclerose Amiotrófica Lateral/fisiopatologia , Animais , Chaperoninas/agonistas , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Hidroxilaminas/efeitos adversos , Hidroxilaminas/farmacocinética , Degeneração Neural/tratamento farmacológico , Degeneração Neural/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Fisiológico
19.
ChemMedChem ; 5(1): 79-85, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19943277

RESUMO

Herein we report the synthesis and neuroprotective effects of new N-alkyl-1,2,4-oxadiazolidine-3,5-diones and their corresponding synthetic intermediates, N-alkylhydroxylamines and N-1-alkyl-3-carbonyl-1-hydroxyureas, in an in vitro model of ischemia. We found five analogues that protect HT22 cells from death in the concentration range of 1-5 muM. Because members of the MAP kinase family are known to be key players in nerve cell survival and death, we characterized the role of these kinases in the neuroprotective mechanisms of the newly synthesized analogues. The results indicate that these compounds provide neuroprotection through distinct mechanisms of action.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Hidroxilaminas/química , Hidroxiureia/química , Fármacos Neuroprotetores/síntese química , Oxidiazóis/química , Animais , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hidroxilaminas/síntese química , Hidroxilaminas/uso terapêutico , Hidroxiureia/síntese química , Hidroxiureia/uso terapêutico , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Oxidiazóis/síntese química , Oxidiazóis/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Int J Mol Med ; 25(1): 25-9, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19956898

RESUMO

A group of histone deacetylase (HDAC) inhibitors has been shown to suppress the growth of a variety of human tumor lines in vitro and in vivo and they are among the most promising candidates for anti-cancer therapeutic agents. We investigated the ability of scriptaid, a novel HDAC inhibitor and trichostatin A (TSA) to enhance cell killing by radiation in radioresistant SQ-20B cells derived from human head and neck squamous carcinoma. SQ-20B cells were treated with scriptaid or TSA in combination with radiation. Cell survival was determined by a colony formation assay and protein levels were examined by Western blotting. DNA double strand breaks were measured by a gamma-H2AX focus assay. Radiosensitization was observed for SQ-20B cells incubated with scriptaid at 5 microM or TSA at 0.1 microM for 24 h. Radiosensitization by scriptaid was accompanied by a prolonged retention of gamma-H2AX foci, suggesting that the enhancement of radiation cell killing by scriptaid involved inhibition of DNA double strand break repair. In addition, treatment with scriptaid suppressed expression of Ku80, but not Ku70. Scriptaid may be a useful radiosensitizer in the treatment of radioresistant human carcinomas.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Hidroxilaminas/uso terapêutico , Quinolinas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Carcinoma de Células Escamosas/radioterapia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Autoantígeno Ku , Radiação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA