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1.
AAPS PharmSciTech ; 21(5): 184, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632735

RESUMO

Fibromyalgia (FM) is a chronic disease that has as main characteristic generalized musculoskeletal pain, which can cause physical and emotional problems to patients. However, pharmacological therapies show side effects that hamper the adhesion to treatment. Given this, (-)-linalool (LIN), a monoterpene with several therapeutic properties already reported in scientific literature as anti-depressive, antinociceptive, anti-inflammatory, and antihyperalgesic also demonstrated therapeutic potential in the treatment of FM. Nevertheless, physicochemical limitations as high volatilization and poor water-solubility make its use difficult. In this perspective, this present research had performed the incorporation of LIN into polymeric nanocapsules (LIN-NC). Size, morphology, encapsulation efficiency, cytotoxicity, and drug release were performed. The antihyperalgesic effect of LIN-NC was evaluated by a chronic non-inflammatory muscle pain model. The results demonstrated that the polymeric nanocapsules showed particle size of 199.1 ± 0.7 nm with a PDI measurement of 0.13 ± 0.01. The drug content and encapsulation efficiency were 13.78 ± 0.05 mg/mL and 80.98 ± 0.003%, respectively. The formulation did not show cytotoxicity on J774 macrophages. The oral treatment with LIN-NC and free-LIN increased the mechanical withdrawal threshold on all days of treatment in comparison with the control group. In conclusion, LIN-NC is a promising proposal in the development of phytotherapy-based nanoformulations for future clinical applications.


Assuntos
Monoterpenos Acíclicos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Fibromialgia/tratamento farmacológico , Nanocápsulas , Polímeros/administração & dosagem , Monoterpenos Acíclicos/farmacocinética , Monoterpenos Acíclicos/uso terapêutico , Animais , Anti-Inflamatórios/farmacocinética , Liberação Controlada de Fármacos , Humanos , Tamanho da Partícula , Solubilidade
2.
Clin Immunol ; 218: 108517, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32585295

RESUMO

Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Betacoronavirus/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Citocinas/genética , Citocinas/imunologia , Cálculos da Dosagem de Medicamento , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/genética , Janus Quinase 1/imunologia , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos
3.
Phytomedicine ; 71: 153233, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32454348

RESUMO

BACKGROUND: Xanthohumol is known to exert anti-inflammatory properties but has poor oral bioavailability. Using advanced micellization technology, it has been possible to markedly enhance its bioavailability. PURPOSE: In the present study, we compared the chronic anti-inflammatory activities of native and micellar xanthohumol in the rat adjuvant arthritis model, using diclofenac as a reference drug. METHODS: Adjuvant arthritis was induced by injecting Freund's complete adjuvant into the right hind paw of rats and monitoring paw volume over 3 weeks. The drugs were given daily for 3 weeks, starting from the day of adjuvant inoculation. Serum was collected at the end of the experiment to measure inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. RESULTS: Micellar solubilized xanthohumol showed a better anti-inflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α, interleukin-6 and C-reactive protein, myloperoxidase and lipid peroxidation markers. CONCLUSION: The findings confirm that micellar solubilization of xanthohumol enhances its anti-inflammatory activity, probably as a result of improving its bioavailabilty. The solubilized xanthohumol may prove to be a promising adjuvant tool for anti-inflammatory treatment and a potential anti-inflammatory alternative to synthetic drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Propiofenonas/química , Propiofenonas/farmacologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Feminino , Flavonoides/farmacocinética , Adjuvante de Freund/efeitos adversos , Interleucina-6/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Micelas , Estresse Oxidativo/efeitos dos fármacos , Propiofenonas/farmacocinética , Ratos Wistar , Solubilidade , Fator de Necrose Tumoral alfa/metabolismo
4.
Phytother Res ; 34(7): 1696-1703, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32147925

RESUMO

Cannabidiol (CBD) is a dietary supplement with numerous purported health benefits and an expanding commercial market. Commercially available CBD preparations range from tinctures, oils, and powders, to foods and beverages. Despite widespread use, information regarding bioavailability of these formulations is limited. The purpose of this study was to test the bioavailability of two oral formulations of CBD in humans and explore their potential acute anti-inflammatory activity. We conducted a pilot randomized, parallel arm, double-blind study in 10 healthy adults to determine differences in pharmacokinetics of commercially available water and lipid-soluble CBD powders. Participants consumed a single 30 mg dose, which is within the range of typical commercial supplement doses, and blood samples were collected over 6 hr and analyzed for CBD concentrations. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and T = 90 min, cultured and stimulated with bacterial lipopolysaccharide (LPS) to induce an inflammatory response. Cell supernatants were assayed for IL-10 and TNF, markers of inflammation, using enzyme-linked immunosorbent assays. The water-soluble powder had Cmax = 2.82 ng/ml, Tmax = 90 min, and was approximately ×4.5 more bioavailable than the lipid-soluble form. TNF was decreased in LPS-stimulated PBMCs collected 90 min after CBD exposure relative to cells collected at baseline. This study provides pilot data for designing and powering future studies to establish the anti-inflammatory potential and bioavailability of a larger variety of commercial CBD products consumed by humans.


Assuntos
Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Canabidiol/farmacocinética , Canabidiol/uso terapêutico , Administração Oral , Adulto , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Adulto Jovem
5.
J Med Chem ; 63(7): 3665-3677, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32162512

RESUMO

TWIK-related K+ (TREK) channels are potential analgesic targets. However, selective activators for TREK with both defined action mechanism and analgesic ability for chronic pain have been lacking. Here, we report (1S,3R)-3-((4-(6-methylbenzo[d]thiazol-2-yl)phenyl)carbamoyl)cyclopentane-1-carboxylic acid (C3001a), a selective activator for TREK, against other two-pore domain K+ (K2P) channels. C3001a binds to the cryptic binding site formed by P1 and TM4 in TREK-1, as suggested by computational modeling and experimental analysis. Furthermore, we identify the carboxyl group of C3001a as a structural determinant for binding to TREK-1/2 and the key residue that defines the subtype selectivity of C3001a. C3001a targets TREK channels in the peripheral nervous system to reduce the excitability of nociceptive neurons. In neuropathic pain, C3001a alleviated spontaneous pain and cold hyperalgesia. In a mouse model of acute pancreatitis, C3001a alleviated mechanical allodynia and inflammation. Together, C3001a represents a lead compound which could advance the rational design of peripherally acting analgesics targeting K2P channels without opioid-like adverse effects.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzotiazóis/uso terapêutico , Inflamação Neurogênica/tratamento farmacológico , Dor/tratamento farmacológico , Canais de Potássio de Domínios Poros em Tandem/agonistas , Analgésicos/metabolismo , Analgésicos/farmacocinética , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Benzotiazóis/metabolismo , Benzotiazóis/farmacocinética , Sítios de Ligação , Gânglios Espinais/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Pancreatite/tratamento farmacológico , Canais de Potássio de Domínios Poros em Tandem/química , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Ligação Proteica , Ratos Sprague-Dawley , Relação Estrutura-Atividade
6.
Artigo em Inglês | MEDLINE | ID: mdl-32036253

RESUMO

As a myricetin derivative, M10 is a potent agent of anti-chronic colonic inflammation. It has better activity than myricetin in preventing azoxymethane/dextran sulfate sodium - induced ulcerative colitis. Here, we introduce a sensitive quantification method based on ultra performance liquid chromatography-tandem mass spectrometry for the determination of M10-H and M10-Na in Wistar rat plasma. Samples were treated with L - ascorbic acid and phosphate buffer solution to maintain stability and with acetonitrile to remove the proteins in the plasma. The supernatant was separated with BEH C18 column and eluted with ultrapure water and acetonitrile both containing 0.1% formic acid. The detection was performed by a triple quadrupole mass spectrometer with positive electrospray ionization mode in multiple reactive monitoring. This method was validated for the carryover effect, selectivity, accuracy, precision, matrix effect, stability, and recovery. A linear correlation was established between concentration and response by the calibration curves over 10-2000 ng·mL-1 (r > 0.99). This method was applied to a pharmacokinetic study of intragastrical administration of M10-H and M10-Na in Wistar rats. In addition, the relative bioavailability of M10-H to M10-Na in Wistar rats was 60 ±â€¯19%, calculated by the ratio of area under concentration (AUC) of M10-H to M10-Na after intragastrical administration of a single dose (100 mg·kg-1 for M10-H and M10-Na, respectively) in Wistar rats.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Flavonoides/química , Flavonoides/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Feminino , Flavonoides/administração & dosagem , Limite de Detecção , Masculino , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
7.
AAPS PharmSciTech ; 21(3): 95, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32096106

RESUMO

Taking the articular and periarticular structures as a litmus test for gold-based nanoformulations, the potential of gold nanoparticles in protecting the normal physiological functions of these structures particularly in geriatric patients is one of the research areas of current interest. Aside from its use to make the traditional and fashionable ornaments for human usage, the gold metal is also known for its rich therapeutic activity. This is especially true when the gold is converted from its bulk form into nanosized form before its administering into the human body. Since it is the age of nanocomponents in medical and pharmaceutical research areas, this review is therefore mainly focused on nanoparticulate systems consisting of aurum. Accumulating research reports nevertheless show concrete evidence indicating the potential of gold-based nanoformulations to manage joint syndromes such as osteoarthritis and rheumatoid arthritis. This review embarks from preparation techniques and characterization methods to therapeutical application potentials of gold-based nanoformulations.


Assuntos
Cartilagem Articular/efeitos dos fármacos , Ouro/administração & dosagem , Ouro/química , Cápsula Articular/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Cartilagem Articular/metabolismo , Composição de Medicamentos/métodos , Ouro/farmacocinética , Humanos , Cápsula Articular/metabolismo
8.
Carbohydr Polym ; 230: 115625, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887856

RESUMO

A new positively charged nanoemulsion using quaternized chitosan (QCS) as a protective layer was developed to improve the stability and bioactivity of lipophilic active components. The anti-inflammatory Plai extract was chosen as both an active ingredient and an oil phase of the system. Compared with chitosan-coated nanoemulsion (NE2-CS) and uncoated nanoemulsion (NE1), the QCS coating could improve the stability of the Plai extract during 28 days. The particle size of NE1 increased from 141 nm to 202 nm after coating with QCS, whereas zeta potential changed from -22.03 mV for NE1 to 20.23 mV for NE2-QCS, confirming the presence of QCS. A clear improvement in anti-inflammatory, anti-cancer, and transdermal properties of Plai extract was verified for NE2-QCS, which could be due to the NEs' fineness and the permanent positive charge of the protective layer. Therefore, we suggested that QCS-coated NEs can be used as an effective transdermal delivery system for lipophilic active components.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antineoplásicos/administração & dosagem , Quitosana/análogos & derivados , Nanopartículas/química , Extratos Vegetais/administração & dosagem , Absorção Cutânea , Zingiberaceae/química , Anti-Inflamatórios/farmacocinética , Antineoplásicos/farmacocinética , Linhagem Celular , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Emulsões/química , Humanos , Extratos Vegetais/farmacocinética , Eletricidade Estática
9.
Pharm Res ; 37(3): 44, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31993760

RESUMO

PURPOSE: This prospective study aimed to evaluate the effects of genetic polymorphisms in sulindac-related metabolizing enzyme genes including FMO3 and AOX1 on the population pharmacokinetics of sulindac in 58 pregnant women with preterm labor. METHODS: Plasma samples were collected at 1.5, 4, and 10 h after first oral administration of sulindac. Plasma concentrations of sulindac and its active metabolite (sulindac sulfide) were determined, and pharmacokinetic analysis was performed with NONMEM 7.3. RESULTS: The mean maternal and gestational ages at the time of dosing were 32.5 ± 4.4 (range, 20-41) years and 27.4 ± 4.4 (range, 16.4-33.4) weeks, respectively. In the population pharmacokinetic analysis, one depot compartment model of sulindac with absorption lag time best described the data. The metabolism of sulindac and sulindac sulfide was described using Michaelis-Menten kinetics. In stepwise modeling, gestational age impacted volume of distribution (Vc), and FMO3 rs2266782 was shown by the Michaelis constant to affect conversion of sulindac sulfide to sulindac (KM32); these were retained in the final model. CONCLUSIONS: Genetic polymorphisms of FMO3 and AOX1 could affect the pharmacokinetics of sulindac in women who undergo preterm labor. The results of this study could help clinicians develop individualized treatment plans for administering sulindac.


Assuntos
Aldeído Oxidase/genética , Anti-Inflamatórios/farmacocinética , Trabalho de Parto Prematuro/metabolismo , Oxigenases/genética , Polimorfismo Genético/fisiologia , Sulindaco/farmacocinética , Adulto , Aldeído Oxidase/metabolismo , Feminino , Genótipo , Idade Gestacional , Humanos , Modelos Biológicos , Oxigenases/metabolismo , Gravidez , Estudos Prospectivos , Transdução de Sinais , Sulindaco/análogos & derivados , Sulindaco/metabolismo
10.
J Nanobiotechnology ; 18(1): 17, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964393

RESUMO

This study aimed to develop a new colon-targeted drug delivery system via the preparation of ternary nanocomposite carriers based on organic polymer, aminoclay and lipid vesicles. Budesonide (Bud), an anti-inflammatory drug was chosen as a model drug and encapsulated into three different formulations: liposome (Bud-Lip), aminoclay-coated liposome (AC-Bud-Lip), and Eudragit® S100-aminoclay double coated liposome (EAC-Bud-Lip). The formation of the aminoclay-lipid vesicle nanocomposite was confirmed by energy dispersive X-ray spectrum, transmission electron microscopy, and Fourier-transform infrared spectroscopy. All formulations were produced with a high encapsulation efficiency in a narrow size distribution. Drug release from EAC-Bud-Lip was approximately 10% for 2-h incubation at pH 1.2, implying the minimal drug release in acidic gastric condition. At pH 7.4, EAC-Bud-Lip underwent significant size reduction and exhibited drug release profiles similar to that from AC-Bud-Lip, implying the pH-dependent removal of the outer coating layer. Compared to free Bud solution, EAC-Bud-Lip achieved a higher drug uptake in Caco-2 cells and exhibited a stronger inhibition of TNF-α and IL-6 secretion in LPS-stimulated Raw264.7 cells. Furthermore, a bio-distribution study in mice demonstrated that Eudragit® S100-aminoclay dual coating led to a higher colonic distribution with a longer residence time, which correlated well with the delayed systemic drug exposure in rats. Taken together, the present study suggests that the ternary nanocomposite carrier consisting of Eudragit® S100, aminoclay, and lipid vesicle might be useful as an effective colon-targeted drug delivery system.


Assuntos
Anti-Inflamatórios/química , Budesonida/química , Argila/química , Colo/metabolismo , Lipídeos/química , Lipossomos/química , Nanocompostos/química , Animais , Anti-Inflamatórios/farmacocinética , Budesonida/farmacocinética , Células CACO-2 , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Interleucina-6/metabolismo , Masculino , Camundongos , Ácidos Polimetacrílicos/química , Células RAW 264.7 , Ratos Sprague-Dawley , Solubilidade , Propriedades de Superfície , Distribuição Tecidual , Fator de Necrose Tumoral alfa/metabolismo
11.
J Med Chem ; 63(3): 1032-1050, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31904232

RESUMO

Activation of prostanoid EP2 receptor exacerbates neuroinflammatory and neurodegenerative pathology in central nervous system diseases such as epilepsy, Alzheimer's disease, and cerebral aneurysms. A selective and brain-permeable EP2 antagonist will be useful to attenuate the inflammatory consequences of EP2 activation and to reduce the severity of these chronic diseases. We recently developed a brain-permeable EP2 antagonist 1 (TG6-10-1), which displayed anti-inflammatory and neuroprotective actions in rodent models of status epilepticus. However, this compound exhibited moderate selectivity to EP2, a short plasma half-life in rodents (1.7 h) and low aqueous solubility (27 µM), limiting its use in animal models of chronic disease. With lead-optimization studies, we have developed several novel EP2 antagonists with improved water solubility, brain penetration, high EP2 potency, and selectivity. These novel inhibitors suppress inflammatory gene expression induced by EP2 receptor activation in a microglial cell line, reinforcing the use of EP2 antagonists as anti-inflammatory agents.


Assuntos
Anti-Inflamatórios/farmacologia , Indóis/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Linhagem Celular , Doenças do Sistema Nervoso Central/metabolismo , Humanos , Indóis/síntese química , Indóis/farmacocinética , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacocinética , Solubilidade , Relação Estrutura-Atividade , Água/química
12.
J Med Chem ; 63(3): 1397-1414, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31934767

RESUMO

Colony-stimulating factor 1 receptor (CSF-1R) is involved in inflammatory disorders as well as in many types of cancer. Based on high-throughput screening and docking results, we performed a detailed structure-activity-relationship study, leading to the discovery of a new series of compounds with nanomolar IC50 values against CSF-1R without the inhibition of fibroblast growth factor receptors. One of the most promising hits, compound 29, potently inhibited CSF-1R kinase with an IC50 value of 0.7 nM, while it showed no inhibition to the same family member FMS-like tyrosine kinase 3. Compound 29 displayed excellent anti-inflammatory effects against RAW264.7 macrophages indicated by significant inhibition against the activation of the CSF-1R pathway with low cytotoxicity. In addition, compound 29 exhibited strong in vivo anti-inflammatory efficacy alongside favorable drug characteristics. This novel compound 29 may serve as a new drug candidate with promising applications in inflammatory disorders.


Assuntos
Alquinos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Alquinos/síntese química , Alquinos/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Feminino , Inflamação/induzido quimicamente , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Células RAW 264.7 , Ratos Sprague-Dawley , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade
13.
FASEB J ; 34(2): 1996-2010, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31907999

RESUMO

Despite the use of antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments, that is, HIV-1-associated neurocognitive disorders remain prevalent potentially due to persistent viral replication, production of viral proteins, associated brain inflammation or in certain instances, antiretroviral neurotoxicity. Cellular targets in the brain include microglia which in response to infection release inflammatory markers and viral proteins. Evidence suggests that PPARγ agonists exert anti-inflammatory properties in neurological disorders. However, these agonists namely, thiazolidinediones have limited use in the clinic due to reported adverse side effects. INT131 is a novel non-thiazolidinedione compound that belongs to a new class of drugs known as selective PPARγ modulators. INT131 is considered to have a safer profile; however, its neuroprotective role in vivo is not known.The goal of this study was to examine the effect of INT131 in the context of EcoHIV-induced inflammation in vitro, in primary cultures of mouse glial cells and in vivo, in a mouse model of EcoHIV-associated brain inflammation, as well as characterize its pharmacokinetic properties and brain penetration. In primary cultures of glial cells and in the in vivo mouse model, EcoHIV exposure resulted in a significant elevation of inflammatory markers such as TNFα, IL-1ß, CCL3, and C3 which were attenuated with INT131 treatment. Pharmacokinetic analyses revealed that INT131 penetrates into the brain with a brain to blood partition ratio Kp value of 8.5%. Overall, this is the first report to demonstrate that INT131 could be a potential candidate for the treatment of HIV-1-associated brain inflammation.


Assuntos
Anti-Inflamatórios , Infecções por HIV/tratamento farmacológico , HIV-1/metabolismo , Transtornos Neurocognitivos/tratamento farmacológico , PPAR gama/agonistas , Quinolinas , Sulfonamidas , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/patologia , HIV-1/genética , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Transtornos Neurocognitivos/genética , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/patologia , Neuroglia/patologia , PPAR gama/genética , PPAR gama/metabolismo , Quinolinas/farmacocinética , Quinolinas/farmacologia , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia
14.
Chem Biol Interact ; 315: 108851, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31614129

RESUMO

BACKGROUND: Currently, few herbal pharmacokinetic (PK) parameters have been applied successfully for therapeutic monitoring because of the complexity of consistency when there are multiple chemicals and efficacies. PURPOSE: The present study aims to evaluate the herbal PK properties by investigating the PK parameters of the 8 absorbed bioactive compounds (ABCs), which can represent its parent herbal holistic efficacy, to achieve a PK therapeutic monitoring of herbs. METHOD: First, we tested the hypothesis that the antidepressant and prokinetic effects and related anti-inflammation and anti-oxidation activity (APIO) by Fructus aurantii-Magnolia Bark (FM) formula are related to 8 compounds according to the absorbable evidence and the determined contents. Subsequently, stable and representative APIO from 8ABCs allowed us to develop a sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of 8 compounds following the oral administration of FM decoction (20 g/kg) in rats. RESULT: 8 compounds either including Meranzin hydrate (MH) or MH alone almost identically (8 compounds: 91.62-108.82%)or nearly(MH: 65.38-88.41%) replicated the parent formula FM in terms of efficacy for inducing APIO. CONCLUSION: This unifying strategy shows how multi-herb formulas pharmacokinetic therapeutic monitoring can be achieved by the method we established.


Assuntos
Anti-Inflamatórios/farmacocinética , Antidepressivos/farmacocinética , Antioxidantes/farmacocinética , Medicamentos de Ervas Chinesas/química , Magnolia/química , Casca de Planta/química , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cumarínicos/farmacocinética , Medicamentos de Ervas Chinesas/farmacocinética , Frutas/química , Cinética , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos
15.
Ophthalmic Res ; 63(1): 41-49, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31112980

RESUMO

PURPOSE: This study was aimed at determining the intraocular pharmacokinetics based on molecular physicochemical properties in a rabbit model. METHODS: The entire dataset was obtained from previous literature, and research articles regarding 70 molecular compounds were investigated. The intravitreal half-lives in rabbit eyeballs of 22 macromolecules and 48 micromolecules were analyzed. Multiple linear regression analysis was carried out with non-collinear independent variables (molecular weight [MW] and lipophilicity) influencing intravitreal half-lives. The best-fit equations were selected based on the correlation coefficients and goodness-of-fit statistics. RESULTS: The best-fit models obtained from the entire dataset, macromolecules, and micromolecules suggest the correlation between molecular physicochemical properties (MW and lipophilicity) and intravitreal half-life. Exclusion of outlier molecules (amphotericin B and foscarnet) leads to a better-fit correlation. MW is the definite single factor affecting intravitreal half-lives of macromolecules (Log t1/2 = 0.148 + 0.370 Log MW, R2 = 0.769), while both MW and lipophilicity influence the intraocular pharmacokinetics of micromolecules (Log t1/2 = -1.213 + 0.762 Log MW - 0.115 Log p, R2 = 0.554). CONCLUSION: The present study indicates that intravitreal half-life could be predicted based on molecular physicochemical properties (MW and lipophilicity). Also, increasing MW while reducing lipophilicity would be a reliable method for prolonging the intravitreal half-life of small chemical drugs, while MW is the single major determinant for large biologic drugs.


Assuntos
Inibidores da Angiogênese/farmacocinética , Anti-Infecciosos/farmacocinética , Anti-Inflamatórios/farmacocinética , Peso Molecular , Preparações Farmacêuticas/metabolismo , Corpo Vítreo/metabolismo , Animais , Injeções Intravítreas , Modelos Animais , Coelhos , Análise de Regressão
17.
Biomed Res Int ; 2019: 4568039, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781615

RESUMO

Chemical structures derived from marine foods are highly diverse and pharmacologically promising. In particular, chitooligosaccharides (COS) present a safe pharmacokinetic profile and a great source of new bioactive polymers. This review describes the antioxidant, anti-inflammatory, and antidiabetic properties of COS from recent publications. Thus, COS constitute an effective agent against oxidative stress, cellular damage, and inflammatory pathogenesis. The mechanisms of action and targeted therapeutic pathways of COS are summarized and discussed. COS may act as antioxidants via their radical scavenging activity and by decreasing oxidative stress markers. The mechanism of COS antidiabetic effect is characterized by an acceleration of pancreatic islets proliferation, an increase in insulin secretion and sensitivity, a reduction of postprandial glucose, and an improvement of glucose uptake. COS upregulate the GLUT2 and inhibit digestive enzyme and glucose transporters. Furthermore, they resulted in reduction of gluconeogenesis and promotion of glucose conversion. On the other hand, the COS decrease inflammatory mediators, suppress the activation of NF-κB, increase the phosphorylation of kinase, and stimulate the proliferation of lymphocytes. Overall, this review brings evidence from experimental data about protective effect of COS.


Assuntos
Anti-Inflamatórios , Quitina/análogos & derivados , Depuradores de Radicais Livres , Hipoglicemiantes , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Quitina/farmacocinética , Quitina/uso terapêutico , Depuradores de Radicais Livres/farmacocinética , Depuradores de Radicais Livres/uso terapêutico , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Transportador de Glucose Tipo 2/metabolismo , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico
18.
Int J Pharm ; 572: 118839, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31715359

RESUMO

This study intended to investigate the in vivo pulmonary fate of intratracheally dosed nanosuspensions of fluticasone propionate (FP). Three FP suspensions, including a microsuspension and two nanosuspensions with different dissolution profiles, were prepared and they exhibited comparable aerodynamic performances after nebulization via a jet nebulizer. Following intratracheal administration to rats, the microsuspension underwent extensive mucociliary clearance, leading to a limited absorption time whereas the nanosuspensions decreased the mucociliary clearance and allowed dissolution rate-limiting and extended pulmonary absorption, resulting in prolonged pulmonary retention and long-acting anti-inflammatory efficacy in a lipopolysaccharide induced lung injury model. Delaying the FP dissolution of a nanosuspension by phospholipid coating increased AUC value in lung tissues to 1.72-fold of a conventional nanosuspension, but led to a decreased pharmacological efficacy. This study demonstrated that inhalable nanosuspensions were a feasible means for the sustained pulmonary delivery of FP and the local anti-inflammatory efficacy was highly dependent on the dissolution profiles.


Assuntos
Anti-Inflamatórios/administração & dosagem , Fluticasona/administração & dosagem , Lesão Pulmonar/tratamento farmacológico , Nanopartículas , Administração por Inalação , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Área Sob a Curva , Preparações de Ação Retardada , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Fluticasona/farmacocinética , Fluticasona/farmacologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nebulizadores e Vaporizadores , Ratos , Ratos Wistar , Suspensões , Distribuição Tecidual
19.
AAPS PharmSciTech ; 20(8): 320, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646399

RESUMO

The in vitro drug release in an aqueous medium is a critical performance metric for a sustained release drug product. During long-term release studies, drugs may degrade in the release medium, and such degradation can lead to errors in drug release quantitation. Using dexamethasone as a model drug and LC-MS/MS methods employing dexamethasone-d4 as an internal standard, this study identified that dexamethasone can degrade into 13 major degradation products in phosphate buffered saline (PBS) as a function of time, temperature (25, 37, and 45°C), and light exposure. A putative scheme for dexamethasone degradation pathways in PBS has been proposed. In proof-of-concept studies, the analytical method was used to quantitate dexamethasone and its degradation products during in vitro release studies with sustained release dexamethasone-poly(D,L-lactide-co-glycolide) (PLGA) implants incubated in phosphate buffer saline (PBS). Further, mathematical approaches were developed to estimate drug release from implants after accounting for drug degradation in PBS. The LC-MS/MS analytical method and the mathematical approaches developed could be used for assessing the stability and/or release of dexamethasone during manufacturing, storage, and use of various dosage forms.


Assuntos
Anti-Inflamatórios/farmacocinética , Dexametasona/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Água/metabolismo , Anti-Inflamatórios/administração & dosagem , Cromatografia Líquida/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Dexametasona/administração & dosagem , Implantes de Medicamento , Liberação Controlada de Fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Espectrometria de Massas em Tandem/métodos
20.
J Dermatol ; 46(12): 1141-1152, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31631377

RESUMO

Guselkumab, an interleukin-23 blocker, was superior to placebo and adalimumab and well-tolerated in phase 3 psoriasis studies (VOYAGE 1 and VOYAGE 2). This analysis evaluated the consistency of response in the Asian subpopulation in VOYAGE 1 and VOYAGE 2. Study designs were identical through week 24; patients were randomized to guselkumab, placebo, or adalimumab. Investigator's Global Assessment (IGA), Psoriasis Area and Severity Index (PASI), safety, and pharmacokinetic and immunogenicity data from VOYAGE 1 and VOYAGE 2 were pooled and compared by race (Asian, n = 199; non-Asian, n = 1630). At week 16, treatment differences between guselkumab and placebo were 78.2 (95% confidence interval [CI], 66.9-89.6) and 76.4 (95% CI, 72.7-80.2) percentage points for IGA 0/1 (score of 0 or 1) and 70.1 (95% CI, 60.0-80.1) and 68.5 (95% CI, 64.9-72.2) percentage points for PASI 90 (≥90% improvement) in the Asian and non-Asian populations, respectively. Treatment differences between guselkumab and adalimumab were 31.1 (95% CI, 17.7-44.6) and 16.1 (95% CI, 11.2-21.0) percentage points for IGA 0/1 and 24.9 (95% CI, 9.4-40.5) and 23.2 (95% CI, 17.7-28.6) percentage points for PASI 90 in the Asian and non-Asian populations, respectively. Similar results were observed at week 24. Safety was generally similar between populations and among treatment groups. Median serum guselkumab concentrations over time were comparable between the populations. Comparable responses between the Asian and non-Asian populations in this analysis suggest that the overall efficacy, safety, and the resulting benefit/risk analyses from VOYAGE 1 and VOYAGE 2 are applicable to Asian populations.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Psoríase/tratamento farmacológico , Adalimumab/farmacocinética , Adalimumab/uso terapêutico , Adulto , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacocinética , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Interleucina-23/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade
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