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1.
Proc Natl Acad Sci U S A ; 117(43): 26955-26965, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33037151

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2-infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Hidroxicloroquina/uso terapêutico , Pirazinas/uso terapêutico , Amidas/farmacocinética , Animais , Chlorocebus aethiops , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cricetinae , Modelos Animais de Doenças , Transmissão de Doença Infecciosa/prevenção & controle , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Hidroxicloroquina/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pirazinas/farmacocinética , SARS-CoV-2 , Resultado do Tratamento , Células Vero , Carga Viral/efeitos dos fármacos , Tratamento Farmacológico da COVID-19
2.
Bioorg Med Chem ; 28(23): 115797, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33075682

RESUMO

In order to identify anti-tubercular agents with a novel scaffold, commercial libraries of small organic compounds were screened against a fluorescent strain of Mycobacterium tuberculosis H37Rv, using a dual phenotypic assay. Compounds were assessed against bacteria replicating in broth medium, as well as inside macrophages, and thienothiazolocarboxamide (TTCA) scaffold was identified as hit in both assays, with submicromolar inhibitory concentrations. Derivatives of TTCA were further synthesized and evaluated for their inhibitory effects on M.tuberculosis H37Rv. In the present study we report the structure-activity relationship of these TTCA derivatives. Compounds 28, 32 and 42 displayed good anti-tubercular activities, as well as favorable ADME and PK properties. Compound 42 exhibited excellent oral bioavailability in mice with high distribution to lungs, within 1 h. It was found to be efficacious in a dose dependent manner in a murine model of M. tuberculosis infection. Hence, compound 42 is now under evaluation as a potential lead candidate for treatment of tuberculosis.


Assuntos
Amidas/química , Antituberculosos/química , Tiazóis/química , Amidas/farmacocinética , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Feminino , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microssomos/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose/patologia
3.
Planta Med ; 85(6): 491-495, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30754052

RESUMO

Aegeline is claimed to be a biologically active constituent of Aegle marmelos. Preclinical studies have reported possible therapeutic potential for aegeline against obesity and diabetes. In recent years, aegeline has been added to several weight loss products. However, the consumption of aegeline-containing supplements such as OxyELITE Pro and VERSA-1 has been linked to multiple cases of acute and chronic liver failure. This study was carried out to evaluate the pharmacokinetics and tissue distribution of aegeline in ND4 mice. Two doses of aegeline, a human equivalent dose (1×) 30 mg/kg and a 10× dose (300 mg/kg), were orally administered to the mice, and blood and tissue samples were collected over 8 h. The quantitative analysis of plasma and tissue homogenates (liver, kidney, and brain) was done by UHPLC-QTOF to determine aegeline concentrations. The peak plasma level of aegeline was achieved at a Tmax of 0.5 h, indicating its rapid absorption from the gastrointestinal tract. Aegeline was not detected in the plasma at 8 h after oral administration, with a half-life of 1.4 ± 0.01 and 1.3 ± 0.07 h for the 30 and 300 mg/kg doses, respectively. The half-life of aegeline in the liver was 1.2 h and 1.7 h for 30 and 300 mg/kg doses, respectively, with a Tmax of 1.9 h, which indicates relatively fast elimination of aegeline from the liver.


Assuntos
Amidas/farmacocinética , Administração Oral , Amidas/administração & dosagem , Animais , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Masculino , Camundongos , Distribuição Tecidual
4.
J Med Chem ; 62(1): 378-384, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30350962

RESUMO

A scaffold hopping exercise from a monocyclic mGlu2 NAM with poor rodent PK led to two novel heterobicyclic series of mGlu2 NAMs based on either a functionalized pyrazolo[1,5- a]pyrimidine-5-carboxamide core or a thieno[3,2- b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu2 NAM potency, selectivity (versus mGlu3 and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.


Assuntos
Amidas/química , Sistema Nervoso Central/metabolismo , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Amidas/metabolismo , Amidas/farmacocinética , Animais , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Concentração Inibidora 50 , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Pirazóis/química , Piridinas/química , Pirimidinas/química , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 28(22): 3549-3553, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30301676

RESUMO

The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and function of T-helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, RORγt is an attractive drug target for such Th17-mediated autoimmune diseases. A structure-activity relationship (SAR) study of lead compound 1 yielded a novel series of RORγt inhibitors, represented by compound 6. Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable RORγt inhibitor 25, which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.


Assuntos
Amidas/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Administração Oral , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Doenças Autoimunes/tratamento farmacológico , Sítios de Ligação , Ligação Competitiva , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Interleucina-17/metabolismo , Interleucina-23/farmacologia , Camundongos , Simulação de Dinâmica Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica , Ratos , Pele/efeitos dos fármacos , Pele/metabolismo , Relação Estrutura-Atividade , Células Th17/citologia , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
6.
Bioorg Med Chem Lett ; 27(22): 4999-5001, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29037946

RESUMO

This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M4 PAM activity in most M4 PAMs to date, within the thieno[2,3-b]pyridine core, as the ß-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M4 PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core.


Assuntos
Amidas/química , Receptor Muscarínico M4/metabolismo , Regulação Alostérica , Amidas/síntese química , Amidas/farmacocinética , Animais , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Ligação Proteica , Piridinas/química , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M4/química , Relação Estrutura-Atividade
7.
J Alzheimers Dis ; 60(3): 783-794, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28922150

RESUMO

Ceramide levels are increased in blood and brain tissue of Alzheimer's disease (AD) patients. Since the ceramide transporter protein (CERT) is the only known protein able to mediate non-vesicular transfer of ceramide between organelle membranes, the modulation of CERT function may impact on ceramide accumulation. The competitive CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12) interferes with ceramide trafficking. To understand the role of ceramide/CERT in AD, HPA-12 can be a useful tool to modulate ceramide trafficking. Here we first report the synthesis and in vitro properties of HPA-12 radiolabeled with fluorine-18 and present preliminary in vitro and in vivo positron emission tomography (PET) imaging and biodistribution data. In vitro results demonstrated that the fluorination did not alter the biological properties of HPA-12 since the [fluorine-19]HPA-12, interferes with 5-DMB-ceramide trafficking in HeLa cells. Radiolabeled HPA-12, [fluorine-18]HPA-12, was obtained with a radiochemical yield of 90% and a specific activity of 73 MBq/µmol. PET imaging on wild-type mice showed hepatobiliary clearance and a brain uptake on the order of 0.3 standard uptake value (SUV) one hour post injection. Furthermore, the biodistribution data showed that after removal of the blood by intracardial perfusion, radioactivity was still measurable in the brain demonstrating that the [fluorine-18]HPA-12 crosses the blood brain barrier and is retained in the brain.


Assuntos
Amidas , Encéfalo/diagnóstico por imagem , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Amidas/síntese química , Amidas/química , Amidas/farmacocinética , Animais , Encéfalo/metabolismo , Ceramidas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Halogenação , Células HeLa , Humanos , Masculino , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Proteínas Serina-Treonina Quinases/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética
8.
Bioorg Med Chem Lett ; 27(21): 4858-4866, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28958625

RESUMO

Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu5 NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu5 NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu5 versus DAT.


Assuntos
Amidas/química , Receptor de Glutamato Metabotrópico 5/metabolismo , Regulação Alostérica , Amidas/farmacocinética , Amidas/farmacologia , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cães , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Concentração Inibidora 50 , Células Madin Darby de Rim Canino , Camundongos , Microssomos Hepáticos/metabolismo , Piridinas/química , Ratos , Receptor de Glutamato Metabotrópico 5/química , Relação Estrutura-Atividade , Triazóis/química
9.
Drug Des Devel Ther ; 11: 1941-1949, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28721013

RESUMO

PURPOSE: Barrier properties of the skin and physicochemical properties of drugs are the main factors for the delivery of local anesthetic molecules. The present work evaluates the anesthetic efficacy of drug-loaded nanocarrier (NC) systems for the delivery of local anesthetic drug, ropivacaine (RVC). METHODS: In this study, transcriptional transactivator peptide (TAT)-decorated RVC-loaded NCs (TAT-RVC/NCs) were successfully fabricated. Physicochemical properties of NCs were determined in terms of particle size, zeta potential, drug encapsulation efficiency, drug-loading capacity, stability, and in vitro drug release. The skin permeation of NCs was examined using a Franz diffusion cell mounted with depilated mouse skin in vitro, and in vivo anesthetic effect was evaluated in mice. RESULTS: The results showed that TAT-RVC/NCs have a mean diameter of 133.2 nm and high drug-loading capacity of 81.7%. From the in vitro skin permeation results, it was observed that transdermal flux of TAT-RVC/NCs was higher than that of RVC-loaded NCs (RVC/NCs) and RVC injection. The evaluation of in vivo anesthetic effect illustrated that TAT-RVC/NCs can enhance the transdermal delivery of RVC by reducing the pain threshold in mice. CONCLUSION: These results indicate that TAT-decorated NCs systems are useful for overcoming the barrier function of the skin, decreasing the dosage of RVC and enhancing the anesthetic effect. Therefore, TAT-decorated NCs can be used as an effective transdermal delivery system for local anesthesia.


Assuntos
Amidas/administração & dosagem , Amidas/farmacologia , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacologia , Portadores de Fármacos , Nanoestruturas , Pele , Transativadores/farmacologia , Administração Cutânea , Amidas/farmacocinética , Anestesia Local/métodos , Anestésicos Locais/farmacocinética , Animais , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Técnicas In Vitro , Medição da Dor/efeitos dos fármacos , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Ropivacaina , Absorção Cutânea
10.
Medicine (Baltimore) ; 96(1): e5735, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28072713

RESUMO

Complex regional pain syndrome (CRPS) is characterized by severe and chronic pain, but the pathophysiology of this disease are not clearly understood. The primary aim of our case-control study was to explore neuroinflammation in patients with CRPS using positron emission tomography (PET), with an 18-kDa translocator protein specific radioligand [C]-(R)-PK11195. [C]-(R)-PK11195 PET scans were acquired for 11 patients with CRPS (30-55 years) and 12 control subjects (30-52 years). Parametric image of distribution volume ratio (DVR) for each participant was generated by applying a relative equilibrium-based graphical analysis. The DVR of [C]-(R)-PK11195 in the caudate nucleus (t(21) = -3.209, P = 0.004), putamen (t(21) = -2.492, P = 0.022), nucleus accumbens (t(21) = -2.218, P = 0.040), and thalamus (t(21) = -2.395, P = 0.026) were significantly higher in CRPS patients than in healthy controls. Those of globus pallidus (t(21) = -2.045, P = 0.054) tended to be higher in CRPS patients than in healthy controls. In patients with CRPS, there was a positive correlation between the DVR of [C]-(R)-PK11195 in the caudate nucleus and the pain score, the visual analog scale (r = 0.661, P = 0.026, R = 0.408) and affective subscales of McGill Pain Questionnaire (r = 0.604, P = 0.049, R = 0.364). We demonstrated that neuroinflammation of CRPS patients in basal ganglia. Our results suggest that microglial pathology can be an important pathophysiology of CRPS. Association between the level of caudate nucleus and pain severity indicated that neuroinflammation in this region might play a key role. These results may be essential for developing effective medical treatments.


Assuntos
Gânglios da Base/diagnóstico por imagem , Síndromes da Dor Regional Complexa/diagnóstico por imagem , Síndromes da Dor Regional Complexa/metabolismo , Inflamação/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tálamo/diagnóstico por imagem , Adulto , Amidas/farmacocinética , Gânglios da Base/metabolismo , Estudos de Casos e Controles , Núcleo Caudado/diagnóstico por imagem , Núcleo Caudado/metabolismo , Feminino , Globo Pálido/diagnóstico por imagem , Globo Pálido/metabolismo , Humanos , Inflamação/metabolismo , Isoquinolinas/farmacocinética , Masculino , Pessoa de Meia-Idade , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/metabolismo , Medição da Dor , Projetos Piloto , Putamen/diagnóstico por imagem , Putamen/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Tálamo/metabolismo
11.
BMC Complement Altern Med ; 16: 177, 2016 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-27296455

RESUMO

BACKGROUND: N-alkylamides (NAAs) are a large group of secondary metabolites occurring in more than 25 plant families which are often used in traditional medicine. A prominent active NAA is spilanthol. The general goal was to quantitatively investigate the gut mucosa and blood-brain barrier (BBB) permeability pharmacokinetic properties of spilanthol. METHODS: Spilanthes acmella (L.) L. extracts, as well as purified spilanthol were used to investigate (1) the permeation of spilanthol through a Caco-2 cell monolayer in vitro, (2) the absorption from the intestinal lumen after oral administration to rats, and (3) the permeation through the BBB in mice after intravenous injection. Quantification of spilanthol was performed using a validated bio-analytical UPLC-MS(2) method. RESULTS: Spilanthol was able to cross the Caco-2 cell monolayer in vitro from the apical-to-basolateral side and from the basolateral-to-apical side with apparent permeability coefficients Papp between 5.2 · 10(-5) and 10.2 · 10(-5) cm/h. This in vitro permeability was confirmed by the in vivo intestinal absorption in rats after oral administration, where an elimination rate constant ke of 0.6 h(-1) was obtained. Furthermore, once present in the systemic circulation, spilanthol rapidly penetrated the blood-brain barrier: a highly significant influx of spilanthol into the brains was observed with a unidirectional influx rate constant K1 of 796 µl/(g · min). CONCLUSIONS: Spilanthol shows a high intestinal absorption from the gut into the systemic circulation, as well as a high BBB permeation rate from the blood into the brain.


Assuntos
Amidas/farmacocinética , Barreira Hematoencefálica/metabolismo , Mucosa Intestinal/metabolismo , Extratos Vegetais/farmacocinética , Administração Oral , Amidas/administração & dosagem , Animais , Asteraceae/química , Transporte Biológico , Encéfalo/metabolismo , Células CACO-2 , Capilares/metabolismo , Células Endoteliais/metabolismo , Feminino , Humanos , Camundongos Endogâmicos ICR , Permeabilidade , Alcamidas Poli-Insaturadas , Ratos
12.
J Sep Sci ; 39(14): 2728-35, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27233468

RESUMO

A sensitive and selective ultra high performance liquid chromatography with tandem mass spectrometry method was established and validated for the simultaneous determination of hydroxy-α-sanshool, hydroxy-ß-sanshool, and hydroxy-γ-sanshool in rat plasma after the subcutaneous and intravenous administration of an extract of the pericarp of Zanthoxylum bungeanum Maxim. Piperine was used as the internal standard. The analytes were extracted from rat plasma by liquid-liquid extraction with ethyl acetate and separated on a Thermo Hypersil GOLD C18 column (2.1 mm × 50 mm, 1.9 µm) with a gradient elution system at a flow rate of 0.4 mL/min. The mobile phase consisted of acetonitrile/0.05% formic acid in water and the total analysis time was 4 min. Positive electrospray ionization was performed using multiple reaction monitoring mode for the analytes. The calibration curves of the three analytes were linear over the tested concentration range. The intra- and interday precision was no more than 13.6%. Extraction recovery, matrix effect, and stability were satisfactory in rat plasma. The developed and validated method was suitable for the quantification of hydroxy-α-sanshool, hydroxy-ß-sanshool, and hydroxy-γ-sanshool and successfully applied to a pharmacokinetic study of these analytes after subcutaneous and intravenous administration to rats.


Assuntos
Amidas/farmacocinética , Anestésicos/farmacocinética , Zanthoxylum/química , Amidas/análise , Anestésicos/análise , Cromatografia Líquida de Alta Pressão , Extração Líquido-Líquido , Estrutura Molecular , Espectrometria de Massas em Tandem
13.
J Nutr ; 146(2): 437S-443S, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26764323

RESUMO

BACKGROUND: Alfrutamide and caffedymine are phenolic amides found in plants, including garlic and cocoa. However, the bioavailability of alfrutamide and caffedymine and their effects on cardiovascular diseases (CVDs), particularly via effects on P-selectin expression(PSE) and platelet-leukocyte aggregation (PLA), are unknown. OBJECTIVE: The objective of this study was to investigate the bioavailability of alfrutamide and caffedymine and their effects on PSE and PLA, which are frequently involved in the progression of CVDs. METHODS: Cyclooxygenase (COX) I and COX-II activities and cAMP were determined by using COX and cAMP kits. Bioavailability was determined by HPLC analysis of plasma samples from Swiss Webster mice orally administered alfrutamide and caffedymine (10 µg each). PSE and PLA were also measured by flow cytometry using blood samples from the same mice. RESULTS: At 0.05 µmol/L, alfrutamide and caffedymine inhibited COX-I and COX-II by 20-40% (P < 0.05) and 16-33% (P < 0.05), respectively, compared with the control. At 0.1 µmol/L, the 2 compounds also inhibited platelet PSE by 28% (P < 0.05) and 35% (P < 0.05), respectively, compared with the control. The ß2-adrenoceptor antagonists ICI118551 and butoxamine partially suppressed the inhibition of PSE by caffedymine, suggesting that ß2 receptors are involved in inhibition by caffedymine but not by alfrutamide. At the same concentration (0.1 µmol/L), however, these 2 compounds inhibited PLA by 24-32% (P < 0.05) compared with the control. In addition, mice administered caffedymine and alfrutamide orally (10 µg/35 g body weight) exhibited maximum concentrations >0.6 µmol/L and significant inhibition of PSE by 23-34% (P < 0.05) and PLA by 20-27% (P < 0.05) compared with control mice. CONCLUSIONS: These data show the adequate bioavailability of alfrutamide and caffedymine and their different mechanisms of suppressing PSE and PLA: alfrutamide exerts its effects only via COX inhibition, whereas caffedymine works through both COX inhibition and cAMP amplification.


Assuntos
Amidas/farmacologia , Ácidos Cumáricos/farmacologia , Alho/química , Leucócitos/metabolismo , Selectina-P/sangue , Fenóis/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tiramina/análogos & derivados , Amidas/sangue , Amidas/farmacocinética , Animais , Disponibilidade Biológica , Plaquetas/efeitos dos fármacos , Adesão Celular , Ácidos Cumáricos/sangue , Ácidos Cumáricos/farmacocinética , AMP Cíclico/metabolismo , Ciclo-Oxigenase 1/sangue , Ciclo-Oxigenase 2/sangue , Inibidores de Ciclo-Oxigenase/farmacologia , Masculino , Camundongos , Fenóis/sangue , Fenóis/farmacocinética , Extratos Vegetais/sangue , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologia , Tiramina/sangue , Tiramina/farmacocinética , Tiramina/farmacologia
14.
Bioorg Med Chem ; 23(18): 6185-94, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26299827

RESUMO

A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on µ and δ opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)propionamide and examined their biological activities at the µ and δ opioid receptors. In continuation of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the present design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed very good binding affinity and highly selective toward the µ opioid receptor. Among these, the lead ligand 20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the µ opioid receptor, as well as functional selectivity in GPI assays (55.20 ± 4.30 nM) and weak or no agonist activities in MVD assays. Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this compound 20 is required to enhance in vivo activity.


Assuntos
Amidas/química , Receptores Opioides/química , Amidas/síntese química , Amidas/farmacocinética , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Ligantes , Masculino , Antagonistas de Entorpecentes/síntese química , Antagonistas de Entorpecentes/química , Antagonistas de Entorpecentes/farmacocinética , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Receptores Opioides delta/química , Receptores Opioides delta/metabolismo , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo
15.
Bone Joint J ; 97-B(6): 734-40, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26033051

RESUMO

Only limited data are available regarding the infiltration of local anaesthetic for total hip arthroplasty (THA), and no studies were performed for THA using the anterior approach. In this prospective, randomised placebo-controlled study we investigated the effect of both standard and reverse infiltration of local anaesthetic in combination with the anterior approach for THA. The primary endpoint was the mean numeric rating score for pain four hours post-operatively. In addition, we recorded the length of hospital stay, the operating time, the destination of the patient at discharge, the use of pain medication, the occurrence of side effects and pain scores at various times post-operatively. Between November 2012 and January 2014, 75 patients were included in the study. They were randomised into three groups: standard infiltration of local anaesthetic, reversed infiltration of local anaesthetic, and placebo. There was no difference in mean numeric rating score for pain four hours post-operatively (p = 0.87). There were significantly more side effects at one and eight hours post-operatively in the placebo group (p = 0.02; p = 0.03), but this did not influence the mobilisation of the patients. There were no differences in all other outcomes between the groups. We found no clinically relevant effect when the infiltration of local anaesthetic with ropivacaine and epinephrine was used in a multimodal pain protocol for THA using the anterior approach.


Assuntos
Amidas/farmacocinética , Anestesia Local , Anestésicos Locais/farmacocinética , Artroplastia de Quadril/métodos , Dor Pós-Operatória/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/reabilitação , Epinefrina/farmacocinética , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ropivacaina
16.
Bioorg Med Chem Lett ; 25(8): 1736-1741, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25800115
17.
Eur J Ophthalmol ; 25(4): 352-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25588594

RESUMO

PURPOSE: Dexmedetomidine can prolong the duration of local anesthetics, but the effect of retrobulbar dexmedetomidine on the potency of ropivacaine for retrobulbar block has not been investigated. Our study was designed to determine the effect of retrobulbar dexmedetomidine on ropivacaine for retrobulbar block in children. METHODS: A group of 90 children aged 10-16 years scheduled for vitreoretinal surgery who received retrobulbar block were randomly assigned to 1 of 3 groups: group L (retrobulbar ropivacaine), group LD1 (ropivacaine plus 0.5 µg.kg-1 dexmedetomidine), or group LD2 (ropivacaine plus 1 µg.kg-1 dexmedetomidine). The minimum local anesthetic concentration (MLAC) was determined according to a Dixon-Massey protocol. The primary endpoint of the study was MLAC. Secondary outcomes were duration of postoperative analgesia, postoperative pain scores, dexmedetomidine side effects, and time to hospital discharge. RESULTS: The MLAC values of retrobulbar ropivacaine were 0.314%, 0.259%, and 0.246% in groups L, LD1, and LD2, respectively. The median (interquartile range) durations of analgesia in the postoperative period were 66 (54-117), 89 (40-157), and 168 (120-194) minutes in groups L, LD1, and LD2, respectively (L vs LD1 or LD2, p<0.05). Wake-up time was significantly increased in groups LD1 and LD2. CONCLUSIONS: Retrobulbar dexmedetomidine reduces the MLAC values of ropivacaine and improves postoperative analgesia in children without any neurologic side effects.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Amidas/farmacocinética , Analgesia , Anestésicos Locais/farmacocinética , Dexmedetomidina/farmacologia , Bloqueio Nervoso/métodos , Cirurgia Vitreorretiniana , Adolescente , Anestesia Local , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Órbita , Dor Pós-Operatória , Ropivacaina
18.
Eur J Nucl Med Mol Imaging ; 42(3): 503-11, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25351507

RESUMO

PURPOSE: Neuroinflammation plays a critical role in various neuropathological conditions, and hence there is renewed interest in the translocator protein (TSPO) as a biomarker of microglial activation and macrophage infiltration in the brain. This is reflected in the large amount of research conducted seeking to replace the prototypical PET radiotracer (11)C-R-PK11195 with a TSPO ligand with higher performance. Here we report the in vivo preclinical investigation of the novel TSPO tracer (18)F-GE-180 in a rat model of stroke. METHODS: Focal cerebral ischaemia was induced in Wistar rats by 60-min occlusion of the middle cerebral artery (MCAO). Brain damage was assessed 24 h after MCAO by T2 MRI. Rats were scanned with (11)C-R-PK11195 and (18)F-GE-180 5 or 6 days after MCAO. Specificity of binding was confirmed by injection of unlabelled R-PK11195 or GE-180 20 min after injection of (18)F-GE-180. In vivo data were confirmed by ex vivo immunohistochemistry for microglial (CD11b) and astrocytic biomarkers (GFAP). RESULTS: (18)F-GE-180 uptake was 24 % higher in the core of the ischaemic lesion and 18 % lower in the contralateral healthy tissue than that of (11)C-R-PK11195 uptake (1.5 ± 0.2-fold higher signal to noise ratio). We confirmed this finding using the simplified reference tissue model (BPND = 3.5 ± 0.4 and 2.4 ± 0.5 for (18)F-GE-180 and (11)C-R-PK11195, respectively, with R 1 = 1). Injection of unlabelled R-PK11195 or GE-180 20 min after injection of (18)F-GE-180 significantly displaced (18)F-GE-180 (69 ± 5 % and 63 ± 4 %, respectively). Specificity of the binding was also confirmed by in vitro autoradiography, and the location and presence of activated microglia and infiltrated macrophages were confirmed by immunohistochemistry. CONCLUSION: The in vivo binding characteristics of (18)F-GE-180 demonstrate a better signal to noise ratio than (11)C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in healthy tissue. These results provide evidence that (18)F-GE-180 is a strong candidate to replace (11)C-R-PK11195.


Assuntos
Amidas/farmacocinética , Carbazóis/farmacocinética , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Isoquinolinas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Animais , Encéfalo/diagnóstico por imagem , Proteínas de Transporte/metabolismo , Avaliação Pré-Clínica de Medicamentos , Masculino , Tomografia por Emissão de Pósitrons , Ratos , Ratos Wistar , Receptores de GABA-A/metabolismo , Distribuição Tecidual
19.
J Neurosurg Anesthesiol ; 27(1): 1-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24633212

RESUMO

BACKGROUND: The aim of this prospective, comparative, randomized study was to compare the inhalational anesthetics isoflurane, sevoflurane, and desflurane in pediatric patients undergoing craniotomy for excision of supratentorial tumors. We assessed early postoperative recovery outcome, intraoperative hemodynamics, and degree of brain swelling, as well as postoperative vomiting and shivering. METHODS: Sixty patients scheduled for supratentorial brain tumor excision, were randomly allocated into 1 of 3 groups (20 patients each); isoflurane, sevoflurane, and desflurane group. After IV induction of anesthesia, maintenance was achieved using the inhalational anesthetic according to the allocated group. Tracheal extubation time was the primary endpoint. The secondary endpoints included: emergence time and the interval time needed to reach Aldrete score ≥9, intraoperative degree of brain swelling, intraoperative heart rate and mean arterial blood pressure, as well as postoperative vomiting and shivering. RESULTS: The mean emergence time, extubation time, and the interval required to reach Aldrete score 9 were significantly shorter in the desflurane and sevoflurane groups than the isoflurane group. No statistically significant changes in the 3 groups regarding intraoperative brain swelling, hemodynamics, and postoperative shivering or vomiting were noted. CONCLUSIONS: Desflurane and sevoflurane can be used to facilitate early emergence from anesthesia in neurosurgical pediatric patients. Emergence times are shorter with desflurane or sevoflurane than with isoflurane. The patients who received desflurane or sevoflurane have similar intraoperative and postoperative incidence of adverse effects compared with those who received isoflurane. Thus, desflurane and sevoflurane can be considered as suitable for emergence in pediatric neurosurgical anesthesia.


Assuntos
Amidas , Anestesia Local/métodos , Anestésicos Inalatórios , Anestésicos Locais , Craniotomia/métodos , Isoflurano/análogos & derivados , Lidocaína , Éteres Metílicos , Bloqueio Nervoso/métodos , Couro Cabeludo , Adulto , Amidas/farmacocinética , Anestesia Geral , Anestésicos Inalatórios/farmacocinética , Anestésicos Locais/farmacocinética , Pressão Sanguínea/efeitos dos fármacos , Desflurano , Combinação de Medicamentos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Isoflurano/farmacocinética , Lidocaína/farmacocinética , Masculino , Éteres Metílicos/farmacocinética , Pessoa de Meia-Idade , Dor Pós-Operatória/epidemiologia , Ropivacaina , Sevoflurano , Vigília
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