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1.
Hematol Oncol ; 37(5): 569-577, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31674027

RESUMO

Romidepsin is a class I selective histone deacetylase (HDAC) inhibitor approved by the Food and Drug Administration (FDA) for relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), treated with at least one prior systemic therapy. Currently, there is paucity of real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. This national, multicenter study presents real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. Patients diagnosed and treated with romidepsin for R/R CTCL or PTCL between 2013 and 2018 were retrospectively reviewed. Outcomes included overall survival (OS), event-free survival (EFS), overall response rate (ORR), complete response (CR), and adverse events. Fifty-three patients with R/R PTCL (n = 42) or CTCL (n = 11) were included. Among CTCL patients, median OS was not reached, ORR was 25%, and none achieved CR. Among PTCL patients, median OS was 7.1 months, EFS was 1.9 months, ORR rate was 33%, and 12.5% achieved CR. In a univariate analysis, predictors for longer EFS include any response to therapy, number of previous lines, and PTCL subclass (with better results for angioimmunobalstic T-cell lymphoma). In a univariate and multivariate analysis for OS, treatment response was the only factor predicting OS (OR 4.48; CI 95%, 1.57-12.79; P = .005). Most grade 3 and 4 adverse events were hematological (35%). Infections were reported in 34% of patients. This real-life experience with romidepsin confirms the results of the pivotal phase II trials. PTCL subtype and the number of previous lines of therapy have an impact on EFS. In addition, patients who had good response to romidepsin benefited most in terms of both EFS and OS. Efforts should be done to identify those patients.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Cutâneo de Células T/mortalidade , Linfoma Cutâneo de Células T/patologia , Linfoma de Células T Periférico/mortalidade , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Retratamento , Resultado do Tratamento
2.
Blood ; 134(17): 1395-1405, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31471376

RESUMO

The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non-T-cell lymphoma. The overall response rate in all, non-T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
3.
Parasit Vectors ; 12(1): 226, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088525

RESUMO

BACKGROUND: Helminthiases are very prevalent worldwide, yet their treatment and control rely on a handful of drugs. Emodepside, a marketed broad-spectrum veterinary anthelminthic with a unique mechanism of action, undergoing development for onchocerciasis is an interesting anthelmintic drug candidate. We tested the in vitro and in vivo activity of emodepside on nematode species that serve as models for human soil-transmitted helminth infection as well as on schistosomes. METHODS: In vitro viability assays were performed over a time course of 72 hours for Trichuris muris, Necator americanus, Ancylostoma ceylanicum, Heligmosomoides polygyrus, Strongyloides ratti, Schistosoma mansoni and Schistosoma haematobium. The drug effect was determined by the survival rate for the larvae and by phenotypical scores for the adult worms. Additionally, mice infected with T. muris and hamsters harboring hookworm infection (N. americanus or A. ceylanicum) were administered orally with emodepside at doses ranging from 1.25 to 75 mg/kg. Expelled worms in the feces were counted until 3 days post-drug intake and worms residing in the intestines were collected and counted after dissection. RESULTS: After 24 hours, emodepside was very active in vitro against both larval and adult stages of the nematodes T. muris, A. ceylanicum, N. americanus, H. polygyrus and S. ratti (IC50 < 4 µM). The good in vitro activity was confirmed in vivo. Hamsters infected with the hookworms were cured when administered orally with 2.5 mg/kg of the drug. Emodepside was also highly active in vivo against T. muris (ED50 = 1.2 mg/kg). Emodepside was moderately active on schistosomula in vitro (IC50 < 8 µM) 24 h post-drug incubation and its activity on adult S. mansoni and S. haematobium was low (IC50: 30-50 µM). CONCLUSIONS: Emodepside is highly active against a broad range of nematode species both in vitro and in vivo. The development of emodepside for treating soil-transmitted helminth infections should be pursued.


Assuntos
Anti-Helmínticos/farmacologia , Depsipeptídeos/farmacologia , Nematoides/efeitos dos fármacos , Schistosomatidae/efeitos dos fármacos , Administração Oral , Animais , Anti-Helmínticos/uso terapêutico , Cricetinae , Depsipeptídeos/uso terapêutico , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Fezes/parasitologia , Feminino , Infecções por Uncinaria/tratamento farmacológico , Humanos , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Necator americanus/efeitos dos fármacos , Schistosoma mansoni/efeitos dos fármacos , Trichuris/efeitos dos fármacos
4.
Eur J Clin Pharmacol ; 75(7): 979-984, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30838424

RESUMO

PURPOSE: Knowledge on unintended consequences of product withdrawals is limited. Fusafungine, indicated for treatment of upper respiratory airways disease (URAD), was withdrawn in the EU on May 28, 2016. Given concerns about possible substitution with antibiotics, this study aimed to assess the impact of the withdrawal of fusafungine on prescribing of antibiotics and other treatments. METHODS: The study was conducted using data from general practitioner (GP) and ear, nose and throat (ENT) practices in IMS® Disease Analyzer Germany. The quarterly prevalence of fusafungine prescribing was analysed for consultations involving the most common URAD between May 29, 2013 and May 28, 2017 in regular fusafungine-prescribing practices. Trends in the quarterly prevalence of antibiotics (AB), other nasal or throat preparations (N&T) and tyrothricin were analyzed. Practices with no fusafungine prescribing during the study served as controls. Changes in prescribing trend were evaluated using interrupted time series regression analysis. RESULTS: In fusafungine-prescribing practices, withdrawal of fusafungine was associated with an immediate increase in prescribing of other N&Ts among patients consulting for URAD (+ 6.4%, 95% CI 2.3-10.5% in GP practices and + 9.0%, 95% CI 5.5-12.5% in ENT practices). There was no increase in antibiotic prescribing. In ENT practices; a small transient increase in tyrothricin prescribing occurred. No changes were seen in non-fusafungine-prescribing practices. CONCLUSIONS: Withdrawal of fusafungine was not associated with increased prescribing of antibiotics but was associated with increased prescribing of other N&Ts. The unintended impact of substitution to other treatments should be considered routinely when products are withdrawn or restricted in other ways.


Assuntos
Antibacterianos/uso terapêutico , Depsipeptídeos/uso terapêutico , Padrões de Prática Médica , Infecções Respiratórias/tratamento farmacológico , Retirada de Medicamento Baseada em Segurança , Alemanha , Humanos , Farmacovigilância
5.
J Acquir Immune Defic Syndr ; 80(5): 605-613, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30768485

RESUMO

OBJECTIVES: Few single latency-reversing agents (LRAs) have been tested in vivo, and only some of them have demonstrated an effect, albeit weak, on the decrease of latent reservoir. Therefore, other LRAs and combinations of LRAs need to be assessed. Here, we evaluated the potential of combined treatments of therapeutically promising LRAs, disulfiram and romidepsin. SETTING AND METHODS: We assessed the reactivation potential of individual disulfiram or simultaneous or sequential combined treatments with romidepsin in vitro in latently infected cell lines of T-lymphoid and myeloid origins and in ex vivo cultures of CD8-depleted peripheral blood mononuclear cells isolated from 18 HIV-1 combination antiretroviral therapy-treated individuals. RESULTS: We demonstrated heterogeneous reactivation effects of disulfiram in vitro in various cell lines of myeloid origin and no latency reversal neither in vitro in T-lymphoid cells nor ex vivo, even if doses corresponding to maximal plasmatic concentration or higher were tested. Disulfiram+romidepsin combined treatments produced distinct reactivation patterns in vitro. Ex vivo, the combined treatments showed a modest reactivation effect when used simultaneously as opposed to no viral reactivation for the corresponding sequential treatment. CONCLUSIONS: Exclusive reactivation effects of disulfiram in myeloid latency cell lines suggest that disulfiram could be a potential LRA for this neglected reservoir. Moreover, distinct reactivation profiles pinpoint heterogeneity of the latent reservoir and confirm that the mechanisms that contribute to HIV latency are diverse. Importantly, disulfiram+romidepsin treatments are not potent ex vivo and most likely do not represent an effective drug combination to achieve high levels of latency reversal in vivo.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Depsipeptídeos/uso terapêutico , Dissulfiram/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Fármacos Anti-HIV/administração & dosagem , Linhagem Celular , Depsipeptídeos/administração & dosagem , Dissulfiram/administração & dosagem , Quimioterapia Combinada , HIV-1/fisiologia , Humanos
6.
Proc Natl Acad Sci U S A ; 116(11): 4810-4815, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30792355

RESUMO

Ca2+ leak via ryanodine receptor type 2 (RyR2) can cause potentially fatal arrhythmias in a variety of heart diseases and has also been implicated in neurodegenerative and seizure disorders, making RyR2 an attractive therapeutic target for drug development. Here we synthesized and investigated the fungal natural product and known insect RyR antagonist (-)-verticilide and several congeners to determine their activity against mammalian RyR2. Although the cyclooligomeric depsipeptide natural product (-)-verticilide had no effect, its nonnatural enantiomer [ent-(+)-verticilide] significantly reduced RyR2-mediated spontaneous Ca2+ leak both in cardiomyocytes from wild-type mouse and from a gene-targeted mouse model of Ca2+ leak-induced arrhythmias (Casq2-/-). ent-(+)-verticilide selectively inhibited RyR2-mediated Ca2+ leak and exhibited higher potency and a distinct mechanism of action compared with the pan-RyR inhibitors dantrolene and tetracaine and the antiarrhythmic drug flecainide. ent-(+)-verticilide prevented arrhythmogenic membrane depolarizations in cardiomyocytes without significant effects on the cardiac action potential and attenuated ventricular arrhythmia in catecholamine-challenged Casq2-/- mice. These findings indicate that ent-(+)-verticilide is a potent and selective inhibitor of RyR2-mediated diastolic Ca2+ leak, making it a molecular tool to investigate the therapeutic potential of targeting RyR2 hyperactivity in heart and brain pathologies. The enantiomer-specific activity and straightforward chemical synthesis of (unnatural) ent-(+)-verticilide provides a compelling argument to prioritize ent-natural product synthesis. Despite their general absence in nature, the enantiomers of natural products may harbor unprecedented activity, thereby leading to new scaffolds for probe and therapeutic development.


Assuntos
Antiarrítmicos/química , Antiarrítmicos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/fisiopatologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Depsipeptídeos/uso terapêutico , Dimerização , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Rianodina/metabolismo , Estereoisomerismo
7.
Pharmacol Res ; 142: 192-204, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30807866

RESUMO

Renal interstitial fibrosis is the most common of all the forms of chronic kidney disease (CKD). Research has shown that histone deacetylases (HDACs) participate in the process leading to renal fibrosis. However, the effects of class I HDAC inhibitors on the mechanisms of onset and progression of renal interstitial fibrosis are still unclear. Here, we present the effects and mechanisms of action of FK228 (a selective inhibitor of class I HDACs) in the murine model of unilateral ureteral obstruction (UUO) and in vitro models. We investigated the antifibrotic role of FK228 in a murine model of UUO. We used two key effector cell populations, rat renal interstitial fibroblasts and renal tubular epithelial cells exposed to recombinant transforming growth factor-beta 1 (TGF-ß1), to explore the mechanistic pathways among in vitro models. The results indicated that FK228 significantly suppressed the production of extracellular matrix (ECM) in both in vivo and in vitro models. FK228 inhibited renal fibroblast activation and proliferation and increased the acetylation of histone H3. We found that FK228 also inhibited the small mothers against decapentaplegic (Smad) and non-Smad signaling pathways. So FK228 could significantly suppress renal interstitial fibrosis via Smad and non-Smad pathways. FK228 may be the basis for a new and effective medicine for alleviating renal fibrosis in the future.


Assuntos
Depsipeptídeos/uso terapêutico , Histona Desacetilases/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Ratos , Fator de Crescimento Transformador beta1 , Obstrução Ureteral
8.
Pharmacol Res ; 141: 264-275, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30634050

RESUMO

Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyper-stimulation of G protein couple receptors (GPCRs) and downstream signaling components. Although GPCR blockade is a key component of current anti-hypertensive strategies, whether hypertension is better managed by directly targeting G proteins has not been thoroughly investigated. Here, we tested whether inhibiting Gq/11 proteins in vivo and ex vivo using natural cyclic depsipeptide, FR900359 (FR) from the ornamental plant, Ardisia crenata, and YM-254890 (YM) from Chromobacterium sp. QS3666, or it's synthetic analog, WU-07047 (WU), was sufficient to reverse hypertension in mice. All three inhibitors blocked G protein-dependent vasoconstriction, but to our surprise YM and WU and not FR inhibited K+-induced Ca2+ transients and vasoconstriction of intact vessels. However, each inhibitor blocked whole-cell L-type Ca2+ channel current in vascular smooth muscle cells. Subcutaneous injection of FR or YM (0.3 mg/kg, s.c.) in normotensive and hypertensive mice elicited bradycardia and marked blood pressure decrease, which was more severe and long lasting after the injection of FR relative to YM (FRt1/2 ≅ 12 h vs. YMt1/2 ≅ 4 h). In deoxycorticosterone acetate (DOCA)-salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg), without any effect on heart rate. Our results together support the hypothesis that increased LTCC and Gq/11 activity is involved in the pathogenesis of hypertension, and that dual targeting of both proteins can reverse hypertension and associated cardiovascular disorders.


Assuntos
Anti-Hipertensivos/uso terapêutico , Depsipeptídeos/uso terapêutico , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Hipertensão/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Animais , Anti-Hipertensivos/química , Ardisia/química , Chromobacterium/química , Depsipeptídeos/química , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/antagonistas & inibidores , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos Cíclicos/química , Vasoconstrição/efeitos dos fármacos
9.
Expert Opin Biol Ther ; 19(3): 197-209, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30658046

RESUMO

INTRODUCTION: Peripheral T-cell lymphoma (PTCL) is a relatively rare, heterogeneous group of mature T-cell neoplasms generally associated with poor prognosis, partly because of refractoriness against conventional cytotoxic chemotherapies. To improve the outcome of patients with PTCL, the clinical development of several novel agents is currently under investigation. AREAS COVERED: Since the first approval of pralatrexate (dihydrofolate reductase inhibitor) by the US Food and Drug Administration, belinostat, romidepsin (histone deacetylase inhibitors), and brentuximab vedotin (anti-CD30 antibody-drug conjugate) have been approved in the US, and many other countries. In addition, mogamulizumab (anti-CC chemokine receptor 4 antibody), chidamide (histone deacetylase inhibitor), and forodesine (purine nucleoside phosphorylase inhibitor) have been approved in Asian countries, including China, and Japan. In this review, we have summarized the available data regarding these approved agents and new agents currently under development for PTCL. EXPERT OPINION: Novel agents will be a promising therapeutic option in selected patients with relapsed/refractory PTCL and will change the daily clinical practice in the treatment of PTCL. However, these are not a curative option when used as a single agent. Further clinical developments are expected, comprising 1) combination therapies of new agents with cytotoxic chemotherapies; 2) 'novel-novel' combinations; 3) immune therapies, including chimeric antigen receptor T-cell therapy; and 4) predictive marker analysis.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Aminopiridinas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Benzamidas/uso terapêutico , China , Depsipeptídeos/uso terapêutico , Aprovação de Drogas , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Imunoconjugados/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas/uso terapêutico
10.
Future Oncol ; 15(2): 109-120, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30111169

RESUMO

Plitidepsin is a marine-derived anticancer compound isolated from the Mediterranean tunicate Applidium albicans. It exerts pleiotropic effects on cancer cells, most likely by binding to the eukaryotic translation eEF1A2. This ultimately leads to cell-cycle arrest, growth inhibition and induction of apoptosis via multiple pathway alterations. Recently, a Phase III randomized trial in patients with relapsed/refractory multiple myeloma reported outcomes for plitidepsin plus dexamethasone compared with dexamethasone. Median progression-free survival was 3.8 months in the plitidepsin arm and 1.9 months in the dexamethasone arm (HR: 0.611; p = 0.0048). Here, we review preclinical data regarding plitidepsins mechanism of action, give an overview of clinical trial results across different tumor types as well as the latest results in multiple myeloma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Depsipeptídeos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Urocordados/química , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Organismos Aquáticos/química , Ensaios Clínicos Fase III como Assunto , Depsipeptídeos/farmacologia , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Mieloma Múltiplo/mortalidade , Recidiva Local de Neoplasia/mortalidade , Fator 1 de Elongação de Peptídeos/metabolismo , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Chem Rec ; 18(12): 1854-1876, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30537358

RESUMO

DNA methylation and histone acetylation are widely studied epigenetic modifications. They are involved in numerous pathologies such as cancer, neurological disease, inflammation, obesity, etc. Since the discovery of the epigenome, numerous compounds have been developed to reverse DNA methylation and histone acetylation aberrant profile in diseases. Among them several were inspired by Nature and have a great interest as therapeutic molecules. In the quest of finding new ways to target epigenetic mechanisms, the use of chemical tools is a powerful strategy to better understand epigenetic mechanisms in biological systems. In this review we will present natural products reported as DNMT or HDAC inhibitors for anticancer treatments. We will then discuss the use of chemical tools that have been used in order to explore the epigenome.


Assuntos
Produtos Biológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Produtos Biológicos/farmacologia , Catequina/química , Catequina/farmacologia , Catequina/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Depsipeptídeos/uso terapêutico , Epigenômica , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , S-Adenosilmetionina/química , S-Adenosilmetionina/farmacologia , S-Adenosilmetionina/uso terapêutico
12.
Parasit Vectors ; 11(1): 589, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30449275

RESUMO

BACKGROUND: A spot-on formulation containing fluralaner (280 mg/ml) plus moxidectin (14 mg/ml) (Bravecto® Plus) was developed for the treatment of nematode infections as well as providing 12 weeks of protection against insect and acarine parasites in cats. The effectiveness and safety of this product against feline gastrointestinal nematodes was assessed in naturally-infested, client-owned cats under field conditions in Albania, Bulgaria, Germany and Hungary. METHODS: To be eligible for enrollment in this investigator-blinded study cats had to be at least 10 weeks-old, weigh at least 1.2 kg, be clinically healthy, and have a faecal sample testing positive for nematodes no more than eight days prior to treatment. Cats were stratified into blocks of three in order of presentation at each center and randomly allocated in a 2:1 ratio to be treated topically on Day 0 with fluralaner plus moxidectin (minimum dose rates 40 mg/kg and 2 mg/kg, respectively) or emodepside plus praziquantel (minimum dose rates 3 mg/kg and 12 mg/kg, respectively) (Profender®). Faecal samples were collected from cats prior to treatment and 14 ± 4 days later. RESULTS: There were 182 cats randomized to the fluralaner plus moxidectin group, and 91 to the emodepside plus praziquantel group. Prior to treatment the most commonly identified nematode egg was Toxocara cati, found in 79.1 and 82.4% of cats in the fluralaner plus moxidectin and emodepside plus praziquantel groups, respectively. Eggs of Toxascaris leonina were found in 8.2 and 6.6% of cats; of hookworms in 30.8 and 24.2%; and of Capillaria spp. in 7.1 and 4.3%, respectively. After treatment, faecal samples from 98.3% of fluralaner plus moxidectin treated and 96.6% of emodepside plus praziquantel-treated cats were free of nematode ova. Geometric mean faecal egg count reductions for T. cati, the only eggs found in post-treatment faecal samples, were 99.97% and 99.93%, respectively. Treatment with fluralaner plus moxidectin was non-inferior to emodepside plus praziquantel. Both products were safe and well tolerated by cats treated under field conditions. CONCLUSIONS: This field study confirms that, in addition to 12-week extended duration flea and tick control, fluralaner plus moxidectin provides broad spectrum treatment of nematodes in cats.


Assuntos
Doenças do Gato/tratamento farmacológico , Inseticidas/uso terapêutico , Isoxazóis/uso terapêutico , Macrolídeos/uso terapêutico , Nematoides/efeitos dos fármacos , Infecções por Nematoides/veterinária , Administração Tópica , Animais , Doenças do Gato/epidemiologia , Doenças do Gato/parasitologia , Gatos , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Depsipeptídeos/uso terapêutico , Europa Oriental/epidemiologia , Fezes/parasitologia , Feminino , Alemanha/epidemiologia , Inseticidas/administração & dosagem , Inseticidas/efeitos adversos , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Macrolídeos/administração & dosagem , Macrolídeos/efeitos adversos , Infecções por Nematoides/tratamento farmacológico , Infecções por Nematoides/epidemiologia , Infecções por Nematoides/parasitologia , Contagem de Ovos de Parasitas/veterinária , Praziquantel/administração & dosagem , Praziquantel/efeitos adversos , Praziquantel/uso terapêutico , Distribuição Aleatória , Método Simples-Cego , Sifonápteros/efeitos dos fármacos , Sifonápteros/parasitologia , Resultado do Tratamento
13.
Cell Chem Biol ; 25(11): 1337-1349.e12, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30122371

RESUMO

The natural product family of macrocyclic lipodepsipeptides containing the 4-amido-2,4-pentadienoate functionality possesses intriguing cytotoxic selectivity toward hypoxic cancer cells. These subpopulations of cancer cells display increased metastatic potential and resistance to chemo- and radiotherapy. In this paper, we present studies on the mechanism of action of these natural products in hypoxic cancer cells and show that this involves rapid and hypoxia-selective collapse of mitochondrial integrity and function. These events drive a regulated cell death process that potentially could function as a powerful tool in the fight against chemo- and radiotherapy-resistant cancer cells. Toward that end, we demonstrate activity in two different mouse tumor models.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Mitocôndrias/efeitos dos fármacos , Hipóxia Tumoral/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Depsipeptídeos/uso terapêutico , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo
14.
Mol Pain ; 14: 1744806918788648, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29956587

RESUMO

Painful burn injuries are among the most debilitating form of trauma, globally ranking in the top 15 leading causes of chronic disease burden. Despite its prevalence, however, chronic pain after burn injury is under-studied. We previously demonstrated the contribution of the Rac1-signaling pathway in several models of neuropathic pain, including burn injury. However, Rac1 belongs to a class of GTPases with low therapeutic utility due to their complex intracellular dynamics. To further understand the mechanistic underpinnings of burn-induced neuropathic pain, we performed a longitudinal study to address the hypothesis that inhibition of the downstream effector of Rac1, Pak1, will improve pain outcome following a second-degree burn injury. Substantial evidence has identified Pak1 as promising a clinical target in cognitive dysfunction and is required for dendritic spine dysgenesis associated with many neurological diseases. In our burn injury model, mice exhibited significant tactile allodynia and heat hyperalgesia and dendritic spine dysgenesis in the dorsal horn. Activity-dependent expression of c-fos also increased in dorsal horn neurons, an indicator of elevated central nociceptive activity. To inhibit Pak1, we repurposed an FDA-approved inhibitor, romidepsin. Treatment with romidepsin decreased dendritic spine dysgenesis, reduced c-fos expression, and rescued pain thresholds. Drug discontinuation resulted in a relapse of cellular correlates of pain and in lower pain thresholds in behavioral tests. Taken together, our findings identify Pak1 signaling as a potential molecular target for therapeutic intervention in traumatic burn-induced neuropathic pain.


Assuntos
Queimaduras/complicações , Espinhas Dendríticas/patologia , Neuralgia/etiologia , Neuralgia/metabolismo , Pele/inervação , Quinases Ativadas por p21/metabolismo , Animais , Antibióticos Antineoplásicos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Depsipeptídeos/uso terapêutico , Modelos Animais de Doenças , Feminino , Estudos Longitudinais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/tratamento farmacológico , Limiar da Dor/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Medula Espinal/patologia , Proteínas rac1 de Ligação ao GTP/metabolismo
15.
Nat Neurosci ; 21(4): 564-575, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29531362

RESUMO

Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of ß-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA-receptor function and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism underlying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing SHANK3 mutations.


Assuntos
Transtorno Autístico/complicações , Regulação da Expressão Gênica/genética , Histona Desacetilases/metabolismo , Proteínas do Tecido Nervoso/deficiência , Transtornos do Comportamento Social , Animais , Transtorno Autístico/genética , Depsipeptídeos/uso terapêutico , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Asseio Animal/efeitos dos fármacos , Asseio Animal/fisiologia , Inibidores de Histona Desacetilases/uso terapêutico , Locomoção/efeitos dos fármacos , Locomoção/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Córtex Pré-Frontal/patologia , Desempenho Psicomotor/efeitos dos fármacos , Transtornos do Comportamento Social/enzimologia , Transtornos do Comportamento Social/etiologia , Transtornos do Comportamento Social/terapia , Potenciais Sinápticos/efeitos dos fármacos , Potenciais Sinápticos/genética
16.
Int J Mol Sci ; 19(3)2018 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-29558431

RESUMO

Various organisms exist in the oceanic environment. These marine organisms provide an abundant source of potential medicines. Many marine peptides possess anticancer properties, some of which have been evaluated for treatment of human cancer in clinical trials. Marine anticancer peptides kill cancer cells through different mechanisms, such as apoptosis, disruption of the tubulin-microtubule balance, and inhibition of angiogenesis. Traditional chemotherapeutic agents have side effects and depress immune responses. Thus, the research and development of novel anticancer peptides with low toxicity to normal human cells and mechanisms of action capable of avoiding multi-drug resistance may provide a new method for anticancer treatment. This review provides useful information on the potential of marine anticancer peptides for human therapy.


Assuntos
Antineoplásicos/farmacologia , Organismos Aquáticos/química , Produtos Biológicos/farmacologia , Depsipeptídeos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Produtos Biológicos/uso terapêutico , Produtos Biológicos/toxicidade , Depsipeptídeos/uso terapêutico , Depsipeptídeos/toxicidade
17.
Parasitol Res ; 117(5): 1581-1590, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29574514

RESUMO

The efficacy of anthelmintic treatment at 1, 3, and 6 month intervals was evaluated in a prospective controlled field study with naturally exposed Lithuanian village dogs by monthly coproscopy during 1 year. A placebo-treated control group (C) (n = 202) and groups treated with two broad-spectrum anthelmintics, febantel/pyrantel-embonate/praziquantel (Drontal® Plus, Bayer) (D1, D3, D6; n = 113-117) and emodepside/praziquantel (Profender®, Bayer) (P1, P3, P6; n = 114-119), were included. At the beginning of the study, eggs of Toxocara canis (4.02%) and T. cati (0.44%) identified morphometrically and/or molecularly and eggs of taeniid- (0.78%) and Capillaria-like eggs (5.03%) were present in the feces without significant differences in prevalence between groups. Significant decreases in excretion of T. canis eggs was found 1 month after the treatment with Drontal® Plus in February (D1) and with Profender® in October (P1), November (P1), December (P3), February (P1), and March (P1, P3), as compared to controls in the same months. The incidence of egg excretion per dog at least once a year was significantly lower in group P1 for T. canis (4.24%; p < 0.01) and in groups D1, P1 for taeniid eggs (0%; p < 0.01 and p < 0.001), when compared to controls (16.96 and 6.70%, respectively). A critical analyses of factors possibly responsible for intestinal passage of canine helminth eggs revealed that chained dogs excreted T. canis eggs more frequently 1 month after treatment compared to dogs in pens, particularly from November to March (p = 0.01). The incidence of single detection of T. cati eggs was significantly increased in chained dogs (12.46%) as compared to fenced dogs (1.08%; p = 0.0001).


Assuntos
Anti-Helmínticos/uso terapêutico , Depsipeptídeos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Doenças do Cão/parasitologia , Guanidinas/uso terapêutico , Contagem de Ovos de Parasitas/veterinária , Praziquantel/uso terapêutico , Pamoato de Pirantel/uso terapêutico , Teníase/tratamento farmacológico , Toxocaríase/tratamento farmacológico , Animais , Cães , Fezes/parasitologia , Feminino , Intestinos/parasitologia , Lituânia , Estudos Longitudinais , Estudos Prospectivos , Taenia/efeitos dos fármacos , Teníase/veterinária , Toxocara canis/efeitos dos fármacos , Resultado do Tratamento
18.
Nihon Yakurigaku Zasshi ; 151(3): 122-129, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29526921

RESUMO

Romidepsin (Brand name: ISTODAX® for Injection 10 mg) is a novel antitumor drug that inhibits histone deacetylase (HDAC). Romidepsin strongly inhibited class I HDAC activity in vitro and demonstrated a strong antitumor activity against human tumor cell line xenograft in vivo. Based on its demonstrated efficacy against T-cell lymphoma in early clinical studies, multicenter phase II clinical studies in overseas with romidepsin were conducted in patients with cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), followed by approval for the treatment of CTCL and PTCL in the U.S. and other countries. Thereafter, domestic phase I/II studies were planned. The phase I study was designed to evaluate the tolerability of romidepsin in Japanese patients with relapsed or refractory PTCL/CTCL and thereby determine the recommended dose, as patients were administered romidepsin by intravenous infusion at a dose of 9 or 14 mg/m2 over 4 hours on days 1, 8 and 15 of each 28-day cycle, and 14 mg/m2 was determined as the recommended dose for phase II. While the phase II study was designed to include 40 Japanese patients with relapsed or refractory PTCL to evaluate the efficacy and safety of romidepsin. Treatment response was 42.5% and the most common AEs of Grade ≥ 3 were lymphopenia (74.0%), neutropenia (54.0%), leukocytopenia (46.0%) and thrombocytopenia (38.0%). The overall safety profile was considered to be within the acceptable range. On the basis of these result, romidepsin was approved in July 2017 for the treatment of relapsed or refractory PTCL in Japan.


Assuntos
Depsipeptídeos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Linfoma de Células T Periférico/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Depsipeptídeos/administração & dosagem , Depsipeptídeos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Infusões Intravenosas , Resultado do Tratamento
19.
Int J Antimicrob Agents ; 51(6): 897-904, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29432868

RESUMO

Enterococci are commensal micro-organisms present in the gastrointestinal tract of humans. Although normally innocuous to the host, strains of enterococcus exhibiting resistance to vancomycin (VRE) have been associated with high rates of infection and mortality in immunocompromised patients. Decolonization of VRE represents a key strategy to curb infection in highly-susceptible patients. However, there is a dearth of decolonizing agents available clinically that are effective against VRE. The present study found that niclosamide, an anthelmintic drug, has potent antibacterial activity against clinical isolates of vancomycin-resistant Enterococcus faecium (minimum inhibitory concentration 1-8 µg/mL). E. faecium mutants exhibiting resistance to niclosamide could not be isolated even after multiple (10) serial passages. Based upon these promising in-vitro results and the limited permeability of niclosamide across the gastrointestinal tract (when administered orally), niclosamide was evaluated in a VRE colonization-reduction murine model. Remarkably, niclosamide outperformed linezolid, an antibiotic used clinically to treat VRE infections. Niclosamide was as effective as ramoplanin in reducing the burden of vancomycin-resistant E. faecium in the faeces, caecal content and ileal content of infected mice after only 8 days of treatment. Linezolid, in contrast, was unable to decrease the burden of VRE in the gastrointestinal tract of mice. The results obtained indicate that niclosamide warrants further evaluation as a novel decolonizing agent to suppress VRE infections.


Assuntos
Antibacterianos/uso terapêutico , Reposicionamento de Medicamentos , Intestinos/microbiologia , Niclosamida/uso terapêutico , Enterococos Resistentes à Vancomicina/crescimento & desenvolvimento , Animais , Depsipeptídeos/uso terapêutico , Fezes/microbiologia , Humanos , Linezolida/uso terapêutico , Camundongos , Testes de Sensibilidade Microbiana , Oxiclozanida/farmacologia , Rafoxanida/farmacologia , Salicilanilidas/farmacologia , Vancomicina/farmacologia , Resistência a Vancomicina , Enterococos Resistentes à Vancomicina/efeitos dos fármacos
20.
Cell Host Microbe ; 23(1): 14-26, 2018 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-29324227

RESUMO

Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is life long. HIV persists during ART due to long-lived and proliferating latently infected CD4+ T cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Briostatinas/uso terapêutico , Linfócitos T CD4-Positivos/virologia , Depsipeptídeos/uso terapêutico , Infecções por HIV/virologia , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Indóis/uso terapêutico , Panobinostat , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Vorinostat
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