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1.
Chem Biol Interact ; 315: 108906, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31760042

RESUMO

The microtubule inhibitor (MTI) class of chemotherapeutics provide an effective treatment for several different types of cancers, however, severe chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting toxicity in patients that limits their use. While CIPN was predicted with MTIs based on histopathology and functional effects in non-clinical toxicology studies, these investigations often require large numbers of animals and long term studies. As in vitro MT assays have been used for decades to study mechanisms of efficacy, we hypothesized that those same assays could be used to study mechanisms of peripheral neuropathy and predict severe CIPN. We analyzed published data on in vitro microtubule (MT) properties for different MTIs that cause varying levels of peripheral neuropathy in patients. Eribulin, vinorelbine and vinfluinine, which all have less severe CIPN than the vinca alkaloids or taxanes, have unique MT properties consisting of reduced affinity and limited binding to MTs (i.e. bind only to the ends and not along the length). Binding more potently to tubulin in the absence of neuronal BIII tubulin was also observed with eribulin and may suggest specificity for tumor tubulin over neuronal tubulin. These are possible mechanisms for causing less severe deleterious effects on MTs in peripheral nerves leading to reduced severity of CIPN. Our analyses demonstrated that in vitro tools used to study the mechanisms of action in inducing severe CIPN (i.e MTI interactions with MTs) warrant further investigation and may be useful for developing next generation MTIs with reduced CIPN.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Microtúbulos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Moduladores de Tubulina/efeitos adversos , Moduladores de Tubulina/uso terapêutico , Animais , Humanos , Microtúbulos/metabolismo , Neoplasias/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Tubulina (Proteína)/metabolismo
2.
BMJ Case Rep ; 12(7)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266757

RESUMO

A 51-year-old South African female of Ashkenazi Jewish descent was admitted with acute pleuritic chest pain, shortness of breath, fatigue and fever. She experienced vague abdominal and calf pains for 30 years. Her monozygotic twin was investigated independently for recurrent abdominal pain. Despite initially responding to antibiotics, treating suspected pneumonia, she developed recurrent fevers and pleuritic chest pain. After thorough investigation without significant findings, she re-attended days after discharge with similar symptoms. Familial Mediterranean fever (FMF) was suggested as she met diagnostic criteria and responded to colchicine, though FMF normally presents before 20 years old. Genetic testing showed no pathogenic mutations but heterozygous P369S and R408Q mutations. The significance of these mutations remains unclear, as they are found in asymptomatic patients, suggesting incomplete penetrance. She remains well, with full symptom resolution, but mixed auto-inflammatory syndrome may be a more appropriate diagnosis in symptomatic patients with both P369S and R408Q mutations.


Assuntos
Doenças Hereditárias Autoinflamatórias/genética , Mutação/genética , Colchicina/uso terapêutico , Diagnóstico Diferencial , Febre Familiar do Mediterrâneo/genética , Feminino , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Síndrome , Moduladores de Tubulina/uso terapêutico
3.
Medicine (Baltimore) ; 98(26): e16065, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261514

RESUMO

BACKGROUND: Apatinib is an oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Some clinical trials have demonstrated that apatinib is efficacious against advanced nonsquamous NSCLC. OBJECTIVE: This study aimed to probe efficacy and safety of apatinib plus docetaxel, as the second or above line treatment, in advanced nonsquamous NSCLC. DESIGN: Multicenter, prospective, single arm study. SETTING: Three teaching hospitals centers in the Sichuan. PARTICIPANTS: Fourteen patients with stage IVA/B nonsquamous NSCLC had previously received at least 1 platinum-based chemotherapy regimen. INTERVENTION: Patients who were enrolled between November 2016 and January 2018 were given docetaxel (75 mg/m, i.v., d1) plus oral apatinib (250 mg/d), 4 weeks as one cycle, until disease progression or intolerance to adverse events (AE). MAIN OUTCOME MEASURES: The primary endpoint was progression-free survival (PFS). The secondary endpoints comprised objective response rate (ORR), disease control rate (DCR), overall survival (OS), and AE incidence rate. RESULTS: All patients carried adenocarcinoma by pathological type. The median follow-up duration was 9.76 months. Out of 14 cases, 12 were evaluable, showing ORR of 33.33%, DCR of 66.67%, DCR of 50% in cases with brain metastasis, median PFS of 2.92 months (95% CI: 1.38-4.48), and 6-month OS of 80%. Primary AEs encompassed: leukopenia in 7 cases (58.33%), hand-foot skin reaction in 5 cases (41.67%), and diarrhea in 4 cases (33.33%). Among them, grade 3 AEs were: leukopenia in 4 cases (33.33%), and hand-foot skin reaction in 1 case (8.33%). No grade 4/5 AEs were reported. Univariate and multivariate analysis were conducted respectively for PFS and OS. These factors encompassed: gender, age, gene mutations, clinical stage, ECOG scores, quantity of metastatic foci, brain metastasis, and hand-foot skin reaction. Results demonstrated zero risk factors for PFS or OS. CONCLUSION: Apatinib plus docetaxel, as the second or above line treatment, is effective and safe against advanced nonsquamous NSCLC, with good tolerance profile. TRIAL REGISTRATION: NCT03416231.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Progressão da Doença , Docetaxel/efeitos adversos , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Dados Preliminares , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/efeitos adversos , Retratamento , Análise de Sobrevida , Resultado do Tratamento , Moduladores de Tubulina/efeitos adversos , Moduladores de Tubulina/uso terapêutico
4.
Neurochem Res ; 44(8): 1796-1806, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292803

RESUMO

Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks significant hypnotic and euphoric effects rendering it safe in terms of addictive potential. In 1954, Hans Lettré first described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960's, yet no effect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not affect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apoptosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-κB, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood-brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy.


Assuntos
Antimitóticos/uso terapêutico , Glioblastoma/tratamento farmacológico , Noscapina/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antimitóticos/farmacologia , Linhagem Celular Tumoral , Humanos , Mitose/efeitos dos fármacos , Noscapina/farmacologia , Moduladores de Tubulina/farmacologia
5.
Eur J Med Chem ; 178: 177-194, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185410

RESUMO

Microtubule is one of the important targets for cancer treatment. A novel class of diaryl substituted imidazo[4,5-c]pyridin-2-ones and imidazo[4,5-c]pyridines were designed based on combination principles by merging the structures of ß-lactams and purine-type compounds known as tubulin polymerization inhibitor and katanin activity up-regulator, respectively. Their antitumor activities were evaluated in vitro and the mechanism was elucidated, leading to the identification of 1,6-diaryl-1H-imidazo[4,5-c]pyridin-2(3H)-one 20b as the first bifunctional agent that can target both tubulin and katanin simultaneously. The in vivo assays verified that compound 20b significantly inhibited xenograft tumor growth with good pharmacokinetic characteristics, demonstrating a promising potential for further development into anti-tumor drug candidates with a unique mechanism of dual-targeting microtubule.


Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Katanina/antagonistas & inibidores , Piridinas/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Carcinoma Endometrioide/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Katanina/metabolismo , Ligantes , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Clin Rheumatol ; 38(9): 2577-2584, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31127463

RESUMO

INTRODUCTION/OBJECTIVES: Familial Mediterranean Fever is the most common autoinflammatory disease. As chronic inflammation may result in increased arterial stiffness, we aimed to investigate indices of arterial stiffness in patients with Familial Mediterranean Fever and their associations with disease-related factors and colchicine treatment. METHOD: The study was conducted with 43 patients with Familial Mediterranean Fever, including 30 children, in attack free period and 42 healthy controls. Arterial stiffness was assessed by carotid-femoral pulse wave velocity and augmentation index. RESULTS: Patients with Familial Mediterranean Fever presented similar carotid-femoral pulse wave velocity values to controls, but significantly higher augmentation index values (patients versus controls, 19.76% and 9.96%, P < 0.05). Augmentation index, adjusted for age and sex, was associated with complete response compared with partial response to treatment (B = - 17.78, 95% CI - 31.17 to - 4.40, P < 0.05) and the presence of M694V.M680I genotype (B = - 16.75, 95% CI - 33.81 to 0.30, P = 0.05). Carotid-femoral pulse wave velocity presented an inverse relationship with colchicine treatment duration (B = - 0.003, 95% CI - 0.006 to - 0.00, P < 0.05). Pulse wave velocity values adjusted for age and systolic blood pressure were associated with attack frequency (B = 0.48, 95% CI 0.01 to 0.96, P < 0.05). Addition of colchicine treatment duration to the model attenuated the association between carotid-femoral pulse wave velocity and attack frequency supporting the protective role of colchicine. CONCLUSIONS: The normal values of carotid-femoral pulse wave velocity in Familial Mediterranean Fever patients may reflect the compliance to colchicine treatment, which seems to have a protective role against arterial stiffness. However, the increased values of augmentation index need further investigation. KEY POINTS: • FMF patients are prone to present increased cardiovascular risk possibly due to inflammation. • Colchicine treatment may have protective role against arterial stiffness in FMF. • The normal values of cf-PWV in FMF patients may reflect the compliance to colchicine.


Assuntos
Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/fisiopatologia , Moduladores de Tubulina/uso terapêutico , Rigidez Vascular/fisiologia , Adolescente , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Criança , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Humanos , Masculino , Análise de Onda de Pulso , Adulto Jovem
7.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141929

RESUMO

Deoxypodophyllotoxin (DPT) is a cyclolignan compound that exerts anti-cancer effects against various types of cancers. DPT induces apoptosis and inhibits the growth of breast, brain, prostate, gastric, lung, and cervical tumors. In this study, we sought to determine the effect of DPT on cell proliferation, apoptosis, motility, and tumorigenesis of three colorectal cancer (CRC) cell lines: HT29, DLD1, and Caco2. DPT inhibited the proliferation of these cells. Specifically, the compound-induced mitotic arrest in CRC cells by destabilizing microtubules and activating the mitochondrial apoptotic pathway via regulation of B-cell lymphoma 2 (Bcl-2) family proteins (increasing Bcl-2 associated X (BAX) and decreasing B-cell lymphoma-extra-large (Bcl-xL)) ultimately led to caspase-mediated apoptosis. In addition, DPT inhibited tumorigenesis in vitro, and in vivo skin xenograft experiments revealed that DPT significantly decreased tumor size and tumor weight. Taken together, our results suggest DPT to be a potent compound that is suitable for further exploration as a novel chemotherapeutic for human CRC.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Podofilotoxina/análogos & derivados , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/uso terapêutico , Células CACO-2 , Neoplasias Colorretais/metabolismo , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Podofilotoxina/farmacologia , Podofilotoxina/uso terapêutico , Moduladores de Tubulina/uso terapêutico
8.
Rheumatol Int ; 39(6): 1099-1105, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31020337

RESUMO

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a recurrent fever syndrome for which tonsillectomy is a therapeutic option curing the disease in most patients. Recurrence after remission with tonsillectomy is extremely rare. Increasing number of reports on diverse disease manifestations in PFAPA could give us clues about the disease etiopathogenesis. We aimed to describe a patient with recurrence of PFAPA syndrome after tonsillectomy and to review the previous studies including similar cases. We report a 17-year-old boy with PFAPA syndrome who experienced remission for 3 years after tonsillectomy and was later found to harbor an MEFV mutation when the disease relapsed. He responded well to colchicine treatment at relapse. The literature review revealed 14 articles describing 24 similar PFAPA patients. The therapeutic options include single-dose corticosteroids and nonsteroidal anti-inflammatory drugs during attacks, cimetidine, and resurgery. The presented case was the only one heterozygous for an MEFV mutation and treated with colchicine at disease relapse. Albeit rare, the reoccurrence of PFAPA after tonsillectomy could occur. The presence of such patients opposes with the hypothesis that the trigger or immune dysregulation in PFAPA pathogenesis resides in tonsils.


Assuntos
Colchicina/uso terapêutico , Febre/terapia , Linfadenopatia/terapia , Faringite/terapia , Estomatite Aftosa/terapia , Tonsilectomia , Moduladores de Tubulina/uso terapêutico , Adolescente , Febre/complicações , Heterozigoto , Humanos , Linfadenopatia/complicações , Masculino , Pescoço , Faringite/complicações , Pirina/genética , Recidiva , Estomatite Aftosa/complicações , Síndrome
9.
Arthritis Rheumatol ; 71(10): 1727-1732, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31008548

RESUMO

OBJECTIVE: Oral ulcers, the hallmark lesion of Behçet's disease (BD), can be disabling and resistant to conventional treatment, and there is a need for safe and effective treatment. We undertook this study to investigate the long-term safety and efficacy of ustekinumab therapy for BD-related oral ulcers that are resistant to colchicine. METHODS: This multicenter, prospective, open-label study included 30 patients who fulfilled the criteria of the International Study Group for BD and who were diagnosed as having active oral ulcers resistant to colchicine. Patients were treated subcutaneously with ustekinumab 90 mg at inclusion, at week 4, and then once every 12 weeks. Each patient was assessed longitudinally for the presence and number of oral ulcers, and median numbers of oral ulcers (with interquartile range [IQR]) were calculated. The primary efficacy end point was the proportion of patients at week 12 who experienced complete response, defined as having no oral ulcers. RESULTS: The median number of oral ulcers per patient during ustekinumab therapy was significantly lower at week 12 compared to baseline (0 [IQR 0-1] versus 2 [IQR 2-3]; P < 0.0001). Complete response was achieved in 60.0% and 88.9% of patients at weeks 12 and 24, respectively. The median Behçet's Syndrome Activity Score (in which higher scores indicate more active disease) was significantly lower at weeks 12 and 24 (17.5 [IQR 10-42.5] and 10 [IQR 8-11], respectively) versus baseline (70 [IQR 50-70]; P < 0.0001). After a median follow-up of 12 months (IQR 6-16 months), 26 patients (86.7%) were still receiving ustekinumab treatment. Reasons for ustekinumab discontinuation included BD flare (n = 3) and side effects (n = 1). Seven patients (23.3%) experienced adverse events, including headaches (n = 4) and asthenia (n = 2), with no serious side effects. CONCLUSION: Ustekinumab seems to be effective in treating BD-related oral ulcers that are resistant to treatment with colchicine.


Assuntos
Síndrome de Behçet/tratamento farmacológico , Úlceras Orais/tratamento farmacológico , Ustekinumab/uso terapêutico , Adulto , Astenia/induzido quimicamente , Colchicina/uso terapêutico , Feminino , Cefaleia/induzido quimicamente , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Falha de Tratamento , Resultado do Tratamento , Moduladores de Tubulina/uso terapêutico
10.
Rheumatol Int ; 39(6): 1107-1112, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30976833

RESUMO

Behçet's disease (BD) is a systemic vasculitis affecting prominently the veins, which is usually diagnosed in adulthood, but can occur in children younger than 16 years in about 4-26% of cases. The therapy is based on several immune-suppressive drugs; in case of inadequate control and/or complications, the biologic therapy with anti-TNF drugs has been successfully used in adults. Here, we reported one pediatric case of BD with systemic (persistent/recurrent high fever), skin and mucosal manifestations (recurrent aphthous stomatitis, anal/penile ulcers, erythema nodosum and papulo-pustules), that were unresponsive to the conventional treatment with steroids and colchicine; however, he was successfully treated with adalimumab. Compared to adult patients, the experience with adalimumab in the treatment of pediatric BD is very limited. Indeed, through a systematic search in the medical literature, we retrieved 4 case reports and 2 case series, describing BD pediatric patients treated with adalimumab, in addition to three clinical studies including some BD children. The analysis and discussion of these available clinical experiences may indicate adalimumab as an effective and safe option to treat several forms of BD, in addition to BD-related chronic uveitis.


Assuntos
Adalimumab/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , /uso terapêutico , Criança , Colchicina/uso terapêutico , Humanos , Masculino , Moduladores de Tubulina/uso terapêutico
11.
Future Oncol ; 15(14): 1641-1653, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30892083

RESUMO

Eribulin is a novel microtubule inhibitor with mitotic and nonmitotic mechanisms of action. Both pooled and subgroup analyses from large-scale Phase III clinical trials demonstrated that eribulin has substantial activity in patients with pretreated (anthracycline and a taxane) advanced or metastatic breast cancer. We review recent pharmacological and clinical findings pertaining to eribulin use in metastatic breast cancer - particularly highlighting eribulin in difficult-to-treat and aggressive disease, and safety data in specific patient populations. Additionally, recent advancements in our understanding of the mechanism of action of eribulin and potential future directions for its clinical development are discussed. Ongoing studies of eribulin in combination with immunotherapies and established cytotoxic agents may help shape the future landscape of breast cancer treatment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais , Neoplasias da Mama/etiologia , Neoplasias da Mama/mortalidade , Ensaios Clínicos como Assunto , Feminino , Furanos/administração & dosagem , Furanos/efeitos adversos , Genes erbB-2 , Humanos , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Metástase Neoplásica , Estadiamento de Neoplasias , Resultado do Tratamento , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/efeitos adversos
12.
PLoS One ; 14(3): e0213811, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30889194

RESUMO

PURPOSE: To investigate the potential of colchicine to improve bleb function after trabeculectomy. METHODS: To find the maximum usable colchicine concentration, an ocular irritation study was performed with the Draize test at concentrations of 0.001%, 0.01% and 0.1%. Additionally, the synergistic effect of topical colchicine instillation and MMC application to surgical site was evaluated in a rabbit model by measuring changes after trabeculectomy in intraocular pressure (IOP) and bleb morphology score at 3, 7, 14, 21, 28, 35, 42, and 49 days. RESULTS: Experiments with a rabbit model of trabeculectomy showed that 0.04% MMC plus 0.01% colchicine was more effective than saline and 0.04% MMC alone in maintaining IOP reduction at days 7-49 (P < 0.01 at all time points) and day 49 (P < 0.05), respectively, while 0.04% MMC alone was more effective than saline only at days 7-35 (P < 0.05 at all time points). 0.04% MMC plus 0.01% colchicine and 0.04% MMC alone were more effective than saline at preserving bleb score at days 7-21 and 35-49 (P < 0.05 at all time points) and at days 7-35 (P < 0.05 at all time points), respectively. CONCLUSION: Colchicine may be a promising adjuvant for strengthening the effect of MMC and improving the survival of the filtering bleb in trabeculectomy.


Assuntos
Vesícula/tratamento farmacológico , Colchicina/uso terapêutico , Oftalmopatias/tratamento farmacológico , Mitomicina/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Trabeculectomia/métodos , Alquilantes/uso terapêutico , Animais , Vesícula/fisiopatologia , Vesícula/cirurgia , Quimioterapia Combinada , Oftalmopatias/cirurgia , Masculino , Neovascularização Patológica/cirurgia , Coelhos , Moduladores de Tubulina/uso terapêutico
14.
Eur J Med Chem ; 170: 73-86, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30878833

RESUMO

The colchicine binding site of tubulin is an attractive molecular target domain for cancer therapies. However, there was no FDA approved drug for targeting colchicine domain. Our previous crystallography discovered that a potential binding site of αT5 loop-αH7 nearby colchicine domain was beneficial for introducing affinity fragment. In this work, benzo heterocycles (i.e., indole, indazole and quinoline) with the high affinity ability of αT5 loop-αH7 were chosen as affinity fragment to modify the molecule structure of podophyllotoxin for improving the tubulin binding affinity. 4ß-NH-(benzo heterocycles)-4-desoxy-podophyllotoxin were synchronously located at α/ß interface of tubulin through providing affinity fragment to αT5 loop-αH7 (i.e., α178Ser, α182Val, α241Phe) and colchicine domain (i.e., ß241Cys, ß124ASP). 4ß-NH-(6″-aminoindole)-4-desoxy-podophyllotoxin not only exhibited nanomolar antitumor potency in vitro but also destroyed solid tumor growth without lethal toxicity in vivo. The correctness of rational drug design was strictly demonstrated by bioactivity test.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Colchicina/metabolismo , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/uso terapêutico , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Desenho de Drogas , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Podofilotoxina/uso terapêutico , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico
15.
BMJ Case Rep ; 12(2)2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30824470

RESUMO

Postcardiac injury syndrome (PCIS) is a rare condition that is considered to have a trauma-induced autoimmune mechanism triggered by damage to pericardial and/or pleural tissues. We report a case of PCIS accompanied by systemic oedema after thymectomy. A 73-year-old woman was referred to our hospital for dyspnoea and oedema, 9 months after thymectomy. Evaluation revealed the presence of pericardial effusion, pleural effusion and systemic oedema. Differential diagnosis included constrictive pericarditis (secondary to tuberculosis), serositis caused by collagen disease and malignancy. Detailed investigations led to the diagnosis of PCIS, which was successfully treated with prednisolone. This report focuses on the diagnostic approach to PCIS. Since it took time to make a final diagnosis in our patient, we analysed several past case reports and series to determine the cause of the delay in diagnosis.


Assuntos
Traumatismos Cardíacos/complicações , Traumatismos Cardíacos/diagnóstico , Timectomia/efeitos adversos , Idoso , Anti-Inflamatórios/uso terapêutico , Aspirina/uso terapêutico , Colchicina/uso terapêutico , Diagnóstico Tardio , Diagnóstico Diferencial , Ecocardiografia , Feminino , Traumatismos Cardíacos/tratamento farmacológico , Traumatismos Cardíacos/etiologia , Humanos , Derrame Pericárdico/diagnóstico por imagem , Derrame Pericárdico/tratamento farmacológico , Derrame Pericárdico/etiologia , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/tratamento farmacológico , Derrame Pleural/etiologia , Prednisolona/uso terapêutico , Síndrome , Tomografia Computadorizada por Raios X , Moduladores de Tubulina/uso terapêutico
16.
Clin Rheumatol ; 38(3): 921-926, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30706291

RESUMO

INTRODUCTION: Familial Mediterranean fever (FMF) is characterized by self-limiting fever episodes usually accompanied by serositis, arthralgia, and arthritis. Functional gastrointestinal disorders (FGIDs) are diseases in which brain-gut axis and low-grade inflammation take part in pathogenesis. We aimed to study the FGIDs frequencies and possible risk factors for FGIDs in children with FMF. METHOD: This case-control study included 103 children with FMF followed up between July 2016 and July 2018 and 100 healthy controls. Age, gender, disease characteristics, and MEFV gene results were recorded retrospectively. Laboratory parameters were obtained at the time of study enrollment. Diagnosis of FGIDs was assessed with Rome IV criteria. RESULTS: The mean age at study enrollment was 12.58 ± 3.79 and 9.71 ± 3.59 years in FMF and healthy control groups, respectively. Overall FGID frequency was 39.8% (n = 41) in FMF patients and 19% (n = 19) in the control group. Functional dyspepsia and irritable bowel syndrome (particularly constipation predominant subtype) rates were statistically higher in the FMF group. In detail, genotype, age at onset, symptoms, colchicine duration, and colchicine responses did not differ between FMF patients in regard to having FGIDs. CONCLUSIONS: This study showed that children with FMF may predispose to pain predominant FGIDs. We also suggest that FGIDs should be considered in FMF patients suffering recurrent abdominal pain episodes unaccompanied by APR elevation, which can be also named as incomplete FMF attacks.


Assuntos
Febre Familiar do Mediterrâneo/epidemiologia , Gastroenteropatias/epidemiologia , Dor Abdominal/epidemiologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Colchicina/uso terapêutico , Constipação Intestinal/epidemiologia , Diarreia/epidemiologia , Dispepsia/epidemiologia , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Humanos , Síndrome do Intestino Irritável/epidemiologia , Masculino , Moduladores de Tubulina/uso terapêutico
17.
Cardiovasc Intervent Radiol ; 42(5): 685-692, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30719539

RESUMO

PURPOSE: To investigate the efficacy of paclitaxel drug-eluting balloons (PEB) versus standard balloon angioplasty (BA) in stenosis of native hemodialysis arteriovenous fistulas (AVFs). MATERIALS AND METHODS: A total of 96 patients with ESRD (mean ± SD age 57.0 ± 9.1 years, 63.5% were males) who underwent endovascular treatment with PEB angioplasty (n = 32) and BA (n = 64) for a dysfunctional native AVF were included. Clinical success, complications, primary patency and postoperative recurrence parameters were recorded in each group. RESULTS: Primary patency rate at 6 months was significantly higher in PEB than in BA group (96.9 vs. 20.3%, p < 0.001), while the two groups had similar primary patency rates at 9 months (66.8 vs. 50.0%) and 12 months (6.3% for each). No significant difference was noted between PEB and BA groups in terms of the rate (21.9% and. 31.3%), time (median 220 vs. 152.5 days) and reasons (reocclusion in 18.8 vs. 28.1%) for dysfunction recurrence as well as the number of recurrent treatments. AVF dysfunction recurrence was more likely in younger age AVF (median 4 vs. 23 months, p < 0.001 in PEB, and 8.5 vs. 20.5 months p = 0.001 in SBA) and in AVF ≤ 6 months in both SBA and PEB groups (71.4 vs. 12.0%, p = 0.005 in PEB, 40.0 vs. 2.3%, p < 0.001). CONCLUSION: In conclusion, our findings emphasize favorable safety and efficacy of PEB and BA in the management of dysfunctional hemodialysis AVFs with similar rates of post-PTA recurrence of AVF dysfunction. Nonetheless, there was a nonsignificant tendency for lower rate and a delay for recurrent dysfunction in patients treated with PEB and a significant association younger AVF age with an increased risk of post-PTA recurrence of AVF dysfunction. LEVEL OF EVIDENCE: 3, Retrospective cohort study.


Assuntos
Angioplastia/métodos , Fístula Arteriovenosa/terapia , Paclitaxel/uso terapêutico , Diálise Renal/efeitos adversos , Grau de Desobstrução Vascular , Angioplastia com Balão/métodos , Fístula Arteriovenosa/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Moduladores de Tubulina/uso terapêutico
19.
Eur Urol Focus ; 5(2): 168-170, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30745118

RESUMO

One of the standard management options for high-risk localized prostate cancer is radiotherapy combined with long-term androgen deprivation therapy. Trials involving chemotherapy or next-generation hormone therapies in combination with a local treatment are ongoing for this specific subgroup.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Terapia Combinada/métodos , Neoplasias da Próstata/terapia , Radioterapia/métodos , Androstenos/administração & dosagem , Androstenos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Humanos , Masculino , Neoplasias da Próstata/patologia , Taxoides/administração & dosagem , Taxoides/uso terapêutico , Resultado do Tratamento , Moduladores de Tubulina/uso terapêutico
20.
JAMA Cardiol ; 4(4): 332-340, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30747949

RESUMO

Importance: In a recent meta-analysis of randomized clinical trials, femoropopliteal artery revascularization with paclitaxel drug-coated devices was associated with increased long-term all-cause mortality compared with non-drug-coated devices. However, to our knowledge, these findings have not been replicated in other data sources and may be subject to confounding from missing data associated with patient withdrawal and loss to follow-up. Objective: To evaluate differences in all-cause mortality between patients who were treated with drug-coated devices vs non-drug-coated devices for femoropopliteal artery revascularization. Design, Setting, and Participants: This nationwide, multicenter retrospective cohort study included 16 560 Centers for Medicare and Medicaid Services beneficiaries who were admitted for femoropopliteal artery revascularization from January 1, 2016, to December 31, 2016. All-cause mortality was analyzed through September 30, 2017. Exposures: Drug-coated devices (drug-eluting stent [DES] or drug-coated balloon [DCB]) compared with non-drug-coated devices (bare metal stent or uncoated percutaneous transluminal angioplasty balloon). Main Outcomes and Measures: The primary outcome was all-cause mortality analyzed through the end of follow-up. Results: Among 16 560 patients treated at 1883 hospitals, the mean (SD) age was 72.9 (11) years, 7734 (46.7%) were men, 12 232 (73.9%) were white, 8222 (49.7%) currently or had previously used tobacco, 9817 (59.3%) had diabetes, and 8450 (51.0%) had critical limb ischemia (CLI). Drug-coated devices were used in 5989 participants (36.2%). The median follow-up was 389 days (interquartile range, 277-508 days). Among all patients, treatment with drug-coated devices was associated with a lower cumulative incidence of all-cause mortality compared with treatment with non-drug-coated devices through 600 days postprocedure (32.5% vs 34.3%, respectively; log-rank P = .007). Similar survival trends were observed when treatment was stratified by using a DCB alone or DES with or without DCB. After multivariable adjustment, drug-coated devices were not associated with a difference in all-cause mortality compared with non-drug-coated devices (hazard ratio [HR], 0.97; 95% CI, 0.91-1.04; P = .43). These findings were consistent among those with CLI (HR, 0.93; 95% CI, 0.85-1.01; P = .09) or without CLI (HR, 0.94; 95% CI, 0.85-1.03; P = .20), and for those treated with DCB alone (HR, 0.94; 95% CI, 0.86-1.03; P = .17) or DES with or without DCB (HR, 0.97; 95% CI, 0.89-1.06; P = .48). Conclusions and Relevance: In this large nationwide analysis of Centers for Medicare and Medicaid Services beneficiaries, there was no evidence of increased all-cause mortality following femoropopliteal artery revascularization with drug-coated devices compared with non-drug-coated devices.


Assuntos
Angioplastia/instrumentação , Stents Farmacológicos/efeitos adversos , Mortalidade/tendências , Doença Arterial Periférica/terapia , Idoso , Idoso de 80 Anos ou mais , Angioplastia/métodos , Stents Farmacológicos/estatística & dados numéricos , Extremidades/irrigação sanguínea , Extremidades/patologia , Feminino , Artéria Femoral/patologia , Humanos , Masculino , Medicare/estatística & dados numéricos , Pessoa de Meia-Idade , Paclitaxel/uso terapêutico , Doença Arterial Periférica/mortalidade , Doença Arterial Periférica/patologia , Artéria Poplítea/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Resultado do Tratamento , Moduladores de Tubulina/uso terapêutico , Estados Unidos/epidemiologia
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