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1.
Anticancer Res ; 40(2): 689-694, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014909

RESUMO

BACKGROUND/AIM: Piperine, a major alkaloid of the fruit of black pepper plants, selectively inhibits the growth of triple-negative breast cancer cells but its lipophilicity restricts possible clinical application. This study therefore determined the feasibility of encapsulating piperine in nanoparticles (NPs) to increase its solubility in an aqueous environment. MATERIALS AND METHODS: Piperine-loaded biodegradable methoxy poly(ethylene glycol)-poly(lactic-co-glycolic) acid copolymer-based NPs were produced by single emulsion solvent extraction and thin-film hydration. Growth and viability of triple-negative breast cancer (TNBC) cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Annexin-V-FLUOS/propidium iodide staining, respectively. RESULTS: Thin-film hydration was superior to single emulsion solvent extraction, yielding piperine-loaded NPs with an average size of 50 nm. Piperine-loaded NPs inhibited TNBC cell growth and induced apoptosis while sparing normal fibroblasts. CONCLUSION: It is feasible to deliver a cytotoxic concentration of piperine to TNBC cells via NPs with the potential for improved bioavailability and solubility in biological fluids.


Assuntos
Alcaloides/administração & dosagem , Benzodioxóis/administração & dosagem , Nanopartículas/administração & dosagem , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Alcaloides/química , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Benzodioxóis/química , Linhagem Celular Tumoral , Emulsões/administração & dosagem , Emulsões/química , Feminino , Humanos , Nanopartículas/química , Piperidinas/química , Poliésteres/administração & dosagem , Poliésteres/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Alcamidas Poli-Insaturadas/química , Neoplasias de Mama Triplo Negativas/patologia
2.
Expert Rev Clin Pharmacol ; 13(2): 79-84, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31937172

RESUMO

Introduction: Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep, hypnagogic hallucinations, and sleep paralysis. Pitolisant is a first-in-class drug acting on histamine 3 receptors and indicated for the treatment of narcolepsy. This article aims to review pitolisant.Areas covered: In this paper the chemical properties, mechanism of action, pharmacokinetics, clinical efficacy and safety of pitolisant was introduced, and the development course of drugs for treating narcolepsy is also briefly described. We performed a systematic review of the literature using PubMed and the following keywords were used: 'pitolisant' and 'narcolepsy', 'cataplexy' and 'excessive daytime sleepiness' and 'histamine 3 receptor'.Expert opinion: Pitolisant is a histamine 3 receptor antagonist/inverse agonist. It can activate histamine release in the brain and enhances wakefulness. Clinical studies showed that pitolisant significantly decreased excessive daytime sleepiness and cataplexy rate versus placebo. Pitolisant was well tolerated, common adverse reactions were headache, insomnia, nausea, and anxiety.


Assuntos
Narcolepsia/tratamento farmacológico , Piperidinas/administração & dosagem , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Cataplexia/tratamento farmacológico , Cataplexia/fisiopatologia , Agonismo Inverso de Drogas , Agonistas dos Receptores Histamínicos/administração & dosagem , Agonistas dos Receptores Histamínicos/efeitos adversos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/efeitos adversos , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Narcolepsia/fisiopatologia , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Receptores Histamínicos H3/metabolismo
3.
Nat Commun ; 11(1): 74, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900393

RESUMO

Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Quinase do Linfoma Anaplásico/genética , Apoptose/efeitos dos fármacos , Carbazóis/administração & dosagem , Rearranjo Gênico/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piperidinas/administração & dosagem , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Quinase do Linfoma Anaplásico/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/fisiopatologia , Inibidores de Proteínas Quinases/administração & dosagem , Fatores de Transcrição/genética
4.
PLoS One ; 14(12): e0226255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31851711

RESUMO

BACKGROUND: Confounding by disease severity is an issue in pharmacoepidemiology studies of rheumatoid arthritis (RA), due to channeling of sicker patients to certain therapies. To address the issue of limited clinical data for confounder adjustment, a patient-level prediction model to differentiate between patients prescribed and not prescribed advanced therapies was developed as a surrogate for disease severity, using all available data from a US claims database. METHODS: Data from adult RA patients were used to build regularized logistic regression models to predict current and future disease severity using a biologic or tofacitinib prescription claim as a surrogate for moderate-to-severe disease. Model discrimination was assessed using the area under the receiver (AUC) operating characteristic curve, tested and trained in Optum Clinformatics® Extended DataMart (Optum) and additionally validated in three external IBM MarketScan® databases. The model was further validated in the Optum database across a range of patient cohorts. RESULTS: In the Optum database (n = 68,608), the AUC for discriminating RA patients with a prescription claim for a biologic or tofacitinib versus those without in the 90 days following index diagnosis was 0.80. Model AUCs were 0.77 in IBM CCAE (n = 75,579) and IBM MDCD (n = 7,537) and 0.75 in IBM MDCR (n = 36,090). There was little change in the prediction model assessing discrimination 730 days following index diagnosis (prediction model AUC in Optum was 0.79). CONCLUSIONS: A prediction model demonstrated good discrimination across multiple claims databases to identify RA patients with a prescription claim for advanced therapies during different time-at-risk periods as proxy for current and future moderate-to-severe disease. This work provides a robust model-derived risk score that can be used as a potential covariate and proxy measure to adjust for confounding by severity in multivariable models in the RA population. An R package to develop the prediction model and risk score are available in an open source platform for researchers.


Assuntos
Artrite Reumatoide/fisiopatologia , Bases de Dados Factuais , Revisão da Utilização de Seguros , Antirreumáticos/administração & dosagem , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Índice de Gravidade de Doença
6.
AIDS Rev ; 21(3): 126-134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31532397

RESUMO

Persistent coinfection with the hepatitis B/D viruses (HDV) represents the most severe form of viral hepatitis. Hepatitis D often leads to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The current treatment options are limited as only pegylated interferon-alpha (PEG-IFNa) has efficacy against HDV. However, treatment response is still unsatisfactory with 25-40% HDV RNA suppression after 1-2 years. In addition, late HDV RNA relapses have been described during long-term follow-up. Fortunately, new treatment options for patients with chronic hepatitis delta are now on the horizon. The hepatocyte entry inhibitor bulevirtide (formerly myrcludex B) and the farnesyl transferase inhibitor lonafarnib are currently explored in patients with chronic hepatitis delta in Phase 3 clinical studies. The nucleic acid inhibitor REP-2139-Ca and PEG-IFN-lambda are studied in Phase 2 trials. We here summarize data on the efficacy of these new antiviral drugs and the existing safety data on the treatment of HDV infection.


Assuntos
Antivirais/administração & dosagem , Hepatite D/tratamento farmacológico , Interferon-alfa/administração & dosagem , Lipopeptídeos/administração & dosagem , Ácidos Nucleicos/administração & dosagem , Piperidinas/administração & dosagem , Polímeros/administração & dosagem , Piridinas/administração & dosagem , Antivirais/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Coinfecção/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Hepatite B Crônica/tratamento farmacológico , Vírus Delta da Hepatite/efeitos dos fármacos , Humanos , Interferon-alfa/efeitos adversos , Lipopeptídeos/efeitos adversos , Ácidos Nucleicos/efeitos adversos , Piperidinas/efeitos adversos , Polímeros/efeitos adversos , Piridinas/efeitos adversos , Recidiva , Resultado do Tratamento
7.
BMC Complement Altern Med ; 19(1): 235, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477089

RESUMO

BACKGROUND: Oxyresveratrol is a major bioactive component derived from the heartwood of Artocarpus lacucha. This compound exerts several biological activities, including neuroprotective effects in vitro and in vivo. However, there is limited pharmacokinetic information on this compound, especially its distribution in neuronal tissue and its route of excretion. The aim of this study was to investigate the pharmacokinetic profiles of oxyresveratrol alone and in combination with piperine as a bioenhancer in rats. METHODS: Male Wistar rats were administered with oxyresveratrol 10 mg/kg, oxyresveratrol 10 mg/kg plus piperine 1 mg/kg via intravenous or oxyresveratrol 100 mg/kg, oxyresveratrol 100 mg/kg plus piperine 10 mg/kg via oral gavage. Plasma, internal organs, urine, and feces were collected. Determination of the oxyresveratrol concentration in biological samples was performed by liquid chromatography tandem mass spectrometry. RESULTS: The combination with piperine had shown a significantly higher maximum concentration in plasma approximately 1500 µg/L within 1-2 h after oral dosing, and could increase oral bioavailability of oxyresveratrol approximately 2-fold. Oxyresveratrol could widely distributed most of the internal organs with a tissue to plasma ratio of 10-100 fold within 5 min after dosing. Urinary excretion of oxyresveratrol glucuronide was the major route of excretion after administration of oxyresveratrol alone and in combination with piperine. CONCLUSION: The addition of piperine could enhance some of the pharmacokinetic properties of oxyresveratrol via both intravenous and oral administration. This pharmacokinetic information will be useful for appropriate strategies to develop oxyresveratrol as a phytopharmaceutical product.


Assuntos
Alcaloides , Benzodioxóis , Piperidinas , Extratos Vegetais , Alcamidas Poli-Insaturadas , Estilbenos , Administração Intravenosa , Administração Oral , Alcaloides/administração & dosagem , Alcaloides/sangue , Alcaloides/farmacocinética , Alcaloides/urina , Animais , Artocarpus , Benzodioxóis/administração & dosagem , Benzodioxóis/sangue , Benzodioxóis/farmacocinética , Benzodioxóis/urina , Interações de Medicamentos , Masculino , Piperidinas/administração & dosagem , Piperidinas/sangue , Piperidinas/farmacocinética , Piperidinas/urina , Extratos Vegetais/administração & dosagem , Extratos Vegetais/sangue , Extratos Vegetais/farmacocinética , Extratos Vegetais/urina , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/sangue , Alcamidas Poli-Insaturadas/farmacocinética , Alcamidas Poli-Insaturadas/urina , Ratos , Ratos Wistar , Estilbenos/administração & dosagem , Estilbenos/sangue , Estilbenos/farmacocinética , Estilbenos/urina
9.
Int J Neurosci ; 129(12): 1203-1212, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31393204

RESUMO

Purpose of the study: Kaempferol (KM) is a flavonoid found in plant-derived foods and medicinal plants. Recently, it is well established that KM plays a protective role to develop Alzheimer's disease. The current study aimed at evaluating the effect of intracerebroventricular micro-injection of KM on memory retention of passive avoidance learning (MRPAM) and identifying the potentially related cholinergic mechanisms (ChMs) in rats. Materials and methods: In the current study, male Wistar rats randomly divided into control, vehicle and KM (10, 20 and 40 µg/rat) groups. Moreover, MRPAM was evaluated by shuttle box test. The role of ChM was studied using non-selective and selective acetylcholine antagonists (scopolamine [SCN], 4-DAMP and methoctramine [MN], respectively) as well as pirenzepine (PZ) in combination with KM. Results: The employment of KM (40 µg/rat) improved the SCN-induced memory impairment in MRPAM. Co-treatment with KM (40 µg/rat) plus 4-DAMP significantly increased the step-through latency (STL, P < 0.05; 167 ± 28 s) and decreased the total dark chamber (TDC, P < 0.05; 121 ± 31 s) compared with those of the 4-DAMP group (STL: 75 ± 13 s; TDC: 178 ± 46 s). Co-treatment with KM (40 µg/rat) plus PZ attenuated STL, and also increased TDC (P < 0.01; 220 ± 28 s) compared with those of the PZ group. Co-treatment with KM (10 and 20 µg/rat) and MN increased STL (P < 0.05), and deceased TDC compared with those of the MN group (P < 0.01). Conclusions: Totally, the results of the present study showed that cholinergic system may be involved in improving effect of KM on SCN-induced memory impairment.


Assuntos
Acetilcolina/fisiologia , Aprendizagem da Esquiva/efeitos dos fármacos , Antagonistas Colinérgicos/administração & dosagem , Quempferóis/administração & dosagem , Memória/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Animais , Aprendizagem da Esquiva/fisiologia , Diaminas/administração & dosagem , Injeções Intraventriculares , Masculino , Memória/fisiologia , Microinjeções , Piperidinas/administração & dosagem , Pirenzepina/administração & dosagem , Ratos Wistar , Escopolamina/administração & dosagem
10.
BMC Neurol ; 19(1): 191, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409292

RESUMO

BACKGROUND: We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine. METHODS: SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Study drug was to be taken within 4 h (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2 h and took a second dose 2-24 h post-first dose) or recurrence (patient pain-free at 2 h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24 h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan. RESULTS: The proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2 h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p > 0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2 h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p > 0.05); MBS free, 71% vs 41% (p = 0.02); pain relief, 77% vs 52% (p = 0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo. CONCLUSIONS: A second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo. TRIAL REGISTRATION: SAMURAI ( NCT02439320 ) [April 2015]. SPARTAN ( NCT02605174 ) [May 2016].


Assuntos
Benzamidas/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Agonistas do Receptor de Serotonina/administração & dosagem , Adulto , Benzamidas/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Recidiva , Agonistas do Receptor de Serotonina/efeitos adversos
11.
Indian J Ophthalmol ; 67(9): 1400-1404, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31436181

RESUMO

Purpose: With increasing environmental pollution, the incidence of allergic conjunctivitis is increasing. Newer anti-allergic medications with combined anti-histaminic and mast cell stabilization action can help reducing the use of topical steroids for milder form of disease. There is no study directly comparing olopatadine (0.1%), bepotastine (1.5%), and alcaftadine (0.25%) for mild to moderate allergic conjunctivitis cases. Hence, we decided to methodically study the efficacy of three topical medications. Methods: Prospective, observer-masked clinical trial enrolled 45 patients with 15 patients in each of the three groups. Patients with mild to moderate allergic conjunctivitis were sequentially assigned to respective groups, and relief of symptoms and signs were noted upto 1-month follow-up. Results: All three topical medications faired almost equally in resolving symptoms of the patients with mild to moderate allergic conjunctivitis, and most of them reported complete relief after 1 week of use of medication. Few cases with limbal or palpebral papillae reported symptomatic relief after use of medication, but the resolution of these signs was not noted in all three groups. Conclusion: We concluded similar efficacy of three medications in relieving symptoms and inefficacy in regressing palpebral and limbal papillae in cases of allergic conjunctivitis.


Assuntos
Benzazepinas/administração & dosagem , Conjuntivite Alérgica/tratamento farmacológico , Imidazóis/administração & dosagem , Cloridrato de Olopatadina/administração & dosagem , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Adolescente , Adulto , Antialérgicos/administração & dosagem , Criança , Túnica Conjuntiva/patologia , Conjuntivite Alérgica/diagnóstico , Conjuntivite Alérgica/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Humanos , Masculino , Soluções Oftálmicas , Estudos Prospectivos , Método Simples-Cego , Resultado do Tratamento , Adulto Jovem
12.
BMJ Case Rep ; 12(8)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466953

RESUMO

Ovarian cancer is the second the most common gynaecological malignancy in developed countries. 70% of patients relapse in the first 3 years following debulking surgery and first-line chemotherapy. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor which uses the concept of synthetic lethality in the presence of a mutation in the breast cancer susceptibility gene (BRCA), and is now recommended as maintenance treatment in patients with platinum-sensitive relapse of ovarian cancer. It has been shown to increase progression-free survival. We present a case of a 68-year-old woman with brain metastases from high-grade serous ovarian cancer who has remained free of disease progression for longer than 17 months with niraparib use as maintenance treatment after second-line chemotherapy.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Cistadenocarcinoma Seroso/tratamento farmacológico , Indazóis/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Piperidinas/administração & dosagem , Idoso , Cistadenocarcinoma Seroso/patologia , Intervalo Livre de Doença , Feminino , Humanos , Indazóis/uso terapêutico , Quimioterapia de Manutenção , Gradação de Tumores , Neoplasias Ovarianas/patologia , Piperidinas/uso terapêutico , Resultado do Tratamento
13.
Eur J Pharm Sci ; 137: 104988, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31291598

RESUMO

Piperine, an alkaloid from black pepper, has demonstrated beneficial effects in central nervous system, especially in epilepsy control. However, its therapeutic application remains limited due to the low aqueous solubility of piperine. Thus, the present study aimed to formulate piperine into a more solubilized form to enhance its oral bioavailability and facilitate its development as a potential anti-epileptic treatment. The nanoprecipitation method was applied to prepare piperine nanoparticles, which were then examined under transmission electron microscopy. A spherical nanosized particle was obtained with small particle size (average particle size 130.20 ±â€¯1.57 nm), narrow size distribution (polydispersity index 0.195 ±â€¯0.002) and efficient entrapment (entrapment efficiency 92.2 ±â€¯2.5%). Compared with the unformulated piperine, nanosized piperine had a much faster dissolution rate with 3 times higher accumulated drug release after 24 h. After oral administration at 3.5 mg/kg in rats, the nanosized piperine formulations could improve its oral bioavailability by 2.7-fold with 16 times higher concentrations in brain at 10 h postdosing. Moreover, the piperine nanoparticles exhibited effective protection against pentylenetetrazol-induced seizures in both zebrafish and mice. In summary, the present study provided a simple formulation strategy for oral administration of piperine to overcome its limitation in water solubility. The developed formulations could effectively enhance oral bioavailability of piperine with promising anti-epileptic effect, which could be applied as a potential therapy in epilepsy control.


Assuntos
Alcaloides/administração & dosagem , Anticonvulsivantes/administração & dosagem , Benzodioxóis/administração & dosagem , Epilepsia/tratamento farmacológico , Nanopartículas/administração & dosagem , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Administração Oral , Alcaloides/química , Alcaloides/farmacocinética , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Benzodioxóis/química , Benzodioxóis/farmacocinética , Disponibilidade Biológica , Liberação Controlada de Fármacos , Embrião não Mamífero , Masculino , Camundongos , Nanopartículas/química , Piperidinas/química , Piperidinas/farmacocinética , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/farmacocinética , Ratos Sprague-Dawley , Distribuição Tecidual , Peixe-Zebra
14.
Immunol Med ; 42(2): 84-93, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31318324

RESUMO

Atopic dermatitis (AD) is the most common inflammatory skin disease driven by both terminal keratinocyte differentiation defects and type 2 immune responses, and this condition causes psychological and social morbidity. Although patients with severe AD require systemic immunotherapy, conventional agents including ciclosporin could not be used for several years due to side effects such as nephrotoxicity, hypertension and long-term risks of malignancy. It is well known that dupilumab, which blocks receptor binding of both IL-4 and IL-13, is remarkably efficacious in the treatment of AD. We have entered a new era when many novel topical and systemic agents that may have great potential in AD treatment are emerging through clinical trials. The purpose of this article is to summarize the efficacy and safety of the current topical and systemic therapies in AD by reviewing recently published papers regarding phase II/III clinical trials. It is revealed that topical phosphodiesterase 4 inhibitors and Janus kinase (JAK) inhibitors are promising treatments for AD. Moreover, systemic therapies such as biologics targeting IL-13 and oral JAK inhibitors show strong efficacy in AD.


Assuntos
Dermatite Atópica/tratamento farmacológico , Inibidores de Janus Quinases/administração & dosagem , Inibidores da Fosfodiesterase 4/administração & dosagem , Acrilamidas/administração & dosagem , Administração Tópica , Anticorpos Monoclonais Humanizados/administração & dosagem , Produtos Biológicos/administração & dosagem , Compostos de Boro/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Dermatite Atópica/etiologia , Dermatite Atópica/imunologia , Humanos , Imunoterapia , Interleucina-13 , Terapia de Alvo Molecular , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Resorcinóis/administração & dosagem , Estilbenos/administração & dosagem , Canais de Cátion TRPV/antagonistas & inibidores
15.
Artigo em Chinês | MEDLINE | ID: mdl-31262109

RESUMO

Objective: There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib,a novel multitargeted receptor tyrosine kinase inhibitor, has previously shown antitumor activity in phase Ⅱ studies of patients with advanced MTC. This study was to evaluate the efficacy and the safety of vandetanib on advanced MTC. Methods: This study was an open, international multi-center phase Ⅲ clinical trial and the study number was NCT01298323. The single-center study was a sub-group analysis of the international study, which was conducted on 9 pathologically confirmed advanced MTC patients by Cancer Hospital Chinese Academy of Medical Sciences between March 2012 and October 2017. Vandetanib (300 mg) was orally administered daily till death or withdrawal. The efficacy was evaluated according to RECIST criteria and the adverse events were evaluated according to NCI criteria. Results: The objective response rate was 3/9,and the disease control rate was 4/9. The median progression-free survival was 44 months. All patients who had the elevated levels of calcitonin (CTN) and carcino-embryonic antigen (CEA) before treatment began to show the decreases in the level of CTN and CEA after 3 months and later showed again the increases in the levels of both tumor markers with tumor progression. By ROC curve analysis, CTN was of statistically significance(P<0.05, 95%CI 0.558-0.834), but CEA was not(P>0.05). Adverse events were generally mild (grade 1 or 2),including hypertension (9 cases),skin rash (9 cases), and diarrhea (6 cases). Two patients developed grade 3 elevation of serum glutamate pyruvate transaminase and one patient developed grade 3 elevation of drug-related bowel disease. No grade 4 drug-related adverse event occurred. Conclusions: Vandetanib is effective and well tolerated for patients with locally advanced or metastatic MTC who have no chance for surgery. This indicates the increase of CTN is clinically relevant to disease progression, but the number of patients are extremely low, and, therefore further research is needed. Long-term use of vandetanib may cause resistance.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Medular/tratamento farmacológico , Piperidinas/administração & dosagem , Quinazolinas/administração & dosagem , Neoplasias da Glândula Tireoide/tratamento farmacológico , Administração Oral , Carcinoma Medular/patologia , Humanos , Neoplasias da Glândula Tireoide/patologia , Resultado do Tratamento
16.
Lancet ; 394(10200): 737-745, 2019 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-31311674

RESUMO

BACKGROUND: Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine. METHODS: In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual. FINDINGS: Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3â€ˆ× the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2â€ˆ× the upper limit of normal were reported. Treated participants reported no serious adverse events. INTERPRETATION: In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns. FUNDING: Biohaven Pharmaceuticals.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Administração Sublingual , Adulto , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Comprimidos/administração & dosagem
17.
J Cutan Pathol ; 46(11): 872-877, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31254410

RESUMO

Cutaneous immune-related adverse events (irAEs) are a known consequence of immune checkpoint inhibitor (ICI) therapy and may exhibit a spectrum of morphologic features both clinically and histologically. Lichenoid dermatitis associated with ICI therapy (LD-ICI) is the most frequently encountered histopathologic type of irAE biopsied by dermatologists. There is frequent clinical and histologic overlap between irAEs and several reactive and neoplastic dermatologic disorders; thus, clinical information is essential. LD-ICI with histologic, immunohistochemical, and molecular features typical of mycosis fungoides (MF) are unique. Here, we report a patient who developed LD-ICI with MF-like morphologic features with monoclonal T-cell receptor gene rearrangement on consecutive biopsies during ICI therapy. The development of monoclonal LD-ICI is important for clinicians and pathologists to recognize in patients receiving ICI therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Erupção por Droga , Erupções Liquenoides , Pele , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Erupção por Droga/metabolismo , Erupção por Droga/patologia , Humanos , Erupções Liquenoides/induzido quimicamente , Erupções Liquenoides/metabolismo , Erupções Liquenoides/patologia , Masculino , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Pele/metabolismo , Pele/patologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Vemurafenib/administração & dosagem , Vemurafenib/efeitos adversos
18.
Mater Sci Eng C Mater Biol Appl ; 102: 45-52, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147016

RESUMO

Tyrosinase inhibitors could effectively limit the activity of tyrosinase in melanocytes to reduce the excessive synthesis and deposition of melanin. However, low skin permeability and lacking in targeting greatly restricted their application. Herein, ZnO quantum dots were synthesized by gel-sol method and grafted with BQ-788, which have been employed as transdermal and targeting carrier to delivery ellagic acid to melanocytes. Ellagic acid loaded ZnO quantum dots with the size distribution of around 9 nm could targetedly bind to melanocytes and enter the melanocytes by endocytosis within 1 h. The ellagic acid release behavior was controlled by the decreasing of pH via the rapid dissolution of ZnO. When the concentration of BQ-788/EA@ZnO was 12.5 µg/mL, the inhibition rate on tyrosinase activity and melanin deposition were up to 44.23 ±â€¯4.97% and 37.50 ±â€¯5.23%, respectively. In view of their good biocompatibility, they were of great potential in clinically external application for tyrosinase inhibition.


Assuntos
Ácido Elágico/química , Inibidores Enzimáticos/farmacologia , Melanócitos/enzimologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Pontos Quânticos/química , Óxido de Zinco/química , Administração Cutânea , Adulto , Materiais Biocompatíveis/farmacologia , Células Cultivadas , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Humanos , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Monofenol Mono-Oxigenase/metabolismo , Oligopeptídeos/síntese química , Oligopeptídeos/química , Piperidinas/síntese química , Piperidinas/química , Pontos Quânticos/ultraestrutura , Tirosina/metabolismo , Óxido de Zinco/síntese química
19.
Pharmacol Res Perspect ; 7(3): e00477, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31164986

RESUMO

Vandetanib and pazopanib are clinically available, multi-targeted inhibitors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. Short-term VEGF receptor inhibition is associated with hypertension in 15%-60% of patients, which may limit the use of these anticancer therapies over the longer term. To evaluate the longer-term cardiovascular implications of treatment, we investigated the "on"-treatment (21 days) and "off"-treatment (10 days) effects following daily administration of vandetanib, pazopanib, or vehicle, in conscious rats. Cardiovascular variables were monitored in unrestrained Sprague-Dawley rats instrumented with radiotelemetric devices. In Study 1, rats were randomly assigned to receive either daily intraperitoneal injections of vehicle (volume 0.5 mL; n = 5) or vandetanib 25 mg/kg/day (volume 0.5 mL; n = 6). In Study 2, rats received either vehicle (volume 0.5 mL; n = 4) or pazopanib 30 mg/kg/day (volume 0.5 mL; n = 7), dosed once every 24 hours for 21 days. All solutions were in 2% Tween, 5% propylene glycol in 0.9% saline solution. Vandetanib caused sustained increases in mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared to baseline and vehicle. Vandetanib also significantly altered the circadian cycling of MAP, SBP, and DBP. Elevations in SBP were detectable 162 hours after the last dose of vandetanib. Pazopanib also caused increases in MAP, SBP, and DBP. However, compared to vandetanib, these increases were of slower onset and a smaller magnitude. These data suggest that the cardiovascular consequences of vandetanib and pazopanib treatment are sustained, even after prolonged cessation of drug treatment.


Assuntos
Hipertensão/induzido quimicamente , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Quinazolinas/efeitos adversos , Sulfonamidas/efeitos adversos , Animais , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Esquema de Medicação , Humanos , Masculino , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Quinazolinas/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagem
20.
Pharmacol Res Perspect ; 7(3): e00480, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31164987

RESUMO

N-methyl-d-aspartate receptors (NMDAR) are widely expressed in the brain. GluN2B subunit-containing NMDARs has recently attracted significant attention as potential pharmacological targets, with emphasis on the functional properties of allosteric antagonists. We used primary cultures from chicken embryo forebrain (E10), expressing native GluN2B-containing NMDA receptors as a novel model system. Comparing the inhibition of calcium influx by well-known GluN2B subunit-specific allosteric antagonists, the following rank order of potency was found: EVT-101 (EC 50 22 ± 8 nmol/L) > Ro 25-6981 (EC 50 60 ± 30 nmol/L) > ifenprodil (EC 50 100 ± 40 nmol/L) > eliprodil (EC 50 1300 ± 700 nmol/L), similar to previous observations in rat cortical cultures and cell lines overexpressing chimeric receptors. The less explored Ro 04-5595 had an EC 50 of 186 ± 32 nmol/L. Venturing to explain the differences in potency, binding properties were further studied by in silico docking and molecular dynamics simulations using x-ray crystal structures of GluN1/GluN2B amino terminal domain. We found that Ro 04-5595 was predicted to bind the recently discovered EVT-101 binding site, not the ifenprodil-binding site. The EVT-101 binding pocket appears to accommodate more structurally different ligands than the ifenprodil-binding site, and contains residues essential in ligand interactions necessary for calcium influx inhibition. For the ifenprodil site, the less effective antagonist (eliprodil) fails to interact with key residues, while in the EVT-101 pocket, difference in potency might be explained by differences in ligand-receptor interaction patterns.


Assuntos
Imidazóis/administração & dosagem , Piperidinas/administração & dosagem , Prosencéfalo/citologia , Piridazinas/administração & dosagem , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Células Cultivadas , Embrião de Galinha , Células HEK293 , Humanos , Imidazóis/química , Imidazóis/farmacologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fenóis/administração & dosagem , Fenóis/química , Fenóis/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Domínios Proteicos , Piridazinas/química , Piridazinas/farmacologia , Ratos
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