RESUMEN
Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly available, they are sometimes insufficient and can cause dangerous adverse effects. As yet reported, derivatives of pyrrolo[3,4-d]pyridazinone are potent COX-2 inhibitors with a COX-2/COX-1 selectivity index better than meloxicam. Considering that N-acylhydrazone (NAH) moiety is a privileged structure occurring in many promising drug candidates, we decided to introduce this pharmacophore into new series of pyrrolo[3,4-d]pyridazinone derivatives. The current paper presents the synthesis and in vitro, spectroscopic, and in silico studies evaluating the biological and physicochemical properties of NAH derivatives of pyrrolo[3,4-d]pyridazinone. Novel compounds 5a-c-7a-c were received with high purity and good yields and did not show cytotoxicity in the MTT assay. Their COX-1, COX-2, and 15-LOX inhibitory activities were estimated using enzymatic tests and molecular docking studies. The title N-acylhydrazones appeared to be promising dual COX/LOX inhibitors. Moreover, spectroscopic and computational methods revealed that new compounds form stable complexes with the most abundant plasma proteins-AAG and HSA, but do not destabilize their secondary structure. Additionally, predicted pharmacokinetic and drug-likeness properties of investigated molecules suggest their potentially good membrane permeability and satisfactory bioavailability.
Asunto(s)
Inhibidores de la Ciclooxigenasa , Hidrazonas , Inhibidores de la Lipooxigenasa , Piridazinas , Pirroles , Hidrazonas/síntesis química , Hidrazonas/química , Hidrazonas/farmacocinética , Hidrazonas/farmacología , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacocinética , Inhibidores de la Ciclooxigenasa/farmacología , Piridazinas/síntesis química , Piridazinas/química , Piridazinas/farmacocinética , Piridazinas/farmacología , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacocinética , Pirroles/farmacología , Humanos , Fibroblastos , Simulación por Computador , Permeabilidad de la Membrana Celular , Línea CelularRESUMEN
This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin.
Asunto(s)
Compuestos de Bencidrilo/farmacocinética , Glucósidos/farmacocinética , Glucuronosiltransferasa/metabolismo , Ácido Mefenámico/farmacocinética , Rifampin/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , UDP Glucuronosiltransferasa 1A9/metabolismo , Administración Oral , Adolescente , Antibióticos Antituberculosos/administración & dosificación , Antibióticos Antituberculosos/efectos adversos , Antibióticos Antituberculosos/farmacocinética , Área Bajo la Curva , Niño , Preescolar , Simulación por Computador , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/efectos adversos , Inhibidores de la Ciclooxigenasa/farmacocinética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Voluntarios Sanos/estadística & datos numéricos , Insuficiencia Hepática/tratamiento farmacológico , Humanos , Lactante , Recién Nacido , Masculino , Ácido Mefenámico/administración & dosificación , Ácido Mefenámico/efectos adversos , Modelos Biológicos , Valor Predictivo de las Pruebas , Insuficiencia Renal/tratamiento farmacológico , Rifampin/administración & dosificación , Rifampin/efectos adversosRESUMEN
The sodium-glucose cotransporter 2 inhibitor ertugliflozin is metabolized by the uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes UGT1A9 and UGT2B4/2B7. This analysis evaluated the drug-drug interaction (DDI) following co-administration of ertugliflozin with the UGT inhibitor mefenamic acid (MFA) using physiologically-based pharmacokinetic (PBPK) modeling. The ertugliflozin modeling assumptions and parameters were verified using clinical data from single-dose and multiple-dose studies of ertugliflozin in healthy volunteers, and the PBPK fraction metabolized assignments were consistent with human absorption, distribution, metabolism, and excretion results. The model for MFA was developed using clinical data, and in vivo UGT inhibitory constant values were estimated using the results from a clinical DDI study with MFA and dapagliflozin, a UGT1A9 and UGT2B4/2B7 substrate in the same chemical class as ertugliflozin. Using the verified compound files, PBPK modeling predicted an ertugliflozin ratio of area under the plasma concentration-time curves (AUCR ) of 1.51 when co-administered with MFA. ClinicalTrials.gov identifier: NCT00989079.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Inhibidores de la Ciclooxigenasa/farmacocinética , Glucuronosiltransferasa/metabolismo , Ácido Mefenámico/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Adulto , Área Bajo la Curva , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/metabolismo , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Masculino , Ácido Mefenámico/administración & dosificación , Ácido Mefenámico/metabolismo , Persona de Mediana Edad , Modelos Biológicos , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/metabolismo , UDP Glucuronosiltransferasa 1A9 , Uridina/metabolismoRESUMEN
Prostate-specific membrane antigen (PSMA)-targeted radioligands have been used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently, albumin-binding PSMA radioligands with enhanced blood circulation were developed to increase the tumor accumulation of activity. The present study aimed at the design, synthesis and preclinical evaluation of a novel class of PSMA-targeting radioligands equipped with ibuprofen as a weak albumin-binding entity in order to improve the pharmacokinetic properties. Methods: Four novel glutamate-urea-based PSMA ligands were synthesized with ibuprofen, conjugated via variable amino acid-based linker entities. The albumin-binding properties of the 177Lu-labeled PSMA ligands were tested in vitro using mouse and human plasma. Affinity of the radioligands to PSMA and cellular uptake and internalization was investigated using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor cells. The tissue distribution profile of the radioligands was assessed in biodistribution and imaging studies using PC-3 PIP/flu tumor-bearing nude mice. Results: The PSMA ligands were obtained in moderate yields at high purity (>99%). 177Lu-labeling of the ligands was achieved at up to 100 MBq/nmol with >96% radiochemical purity. In vitro assays confirmed high binding of all radioligands to mouse and human plasma proteins and specific uptake and internalization into PSMA-positive PC-3 PIP tumor cells. Biodistribution studies and SPECT/CT scans revealed high accumulation in PC-3 PIP tumors but negligible uptake in PC-3 flu tumor xenografts as well as rapid clearance of activity from background organs and tissues. 177Lu-Ibu-DAB-PSMA, in which ibuprofen was conjugated via a positively-charged diaminobutyric acid (DAB) entity, showed distinguished tumor uptake and the most favorable tumor-to-blood and tumor-to-kidney ratios. Conclusion: The high accumulation of activity in the tumor and fast clearance from background organs was a common favorable characteristic of PSMA radioligands modified with ibuprofen as albumin-binding entity. 177Lu-Ibu-DAB-PSMA emerged as the most promising candidate; hence, more detailed preclinical investigations with this radioligand are warranted in view of a clinical translation.
Asunto(s)
Albúminas/metabolismo , Antígenos de Superficie/farmacología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Glutamato Carboxipeptidasa II/farmacología , Ibuprofeno/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/secundario , Animales , Antígenos de Superficie/administración & dosificación , Antígenos de Superficie/metabolismo , Proteínas Portadoras/metabolismo , Línea Celular Tumoral/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/farmacocinética , Femenino , Glutamato Carboxipeptidasa II/administración & dosificación , Glutamato Carboxipeptidasa II/metabolismo , Humanos , Ibuprofeno/farmacocinética , Inyecciones Subcutáneas , Ligandos , Lutecio/metabolismo , Masculino , Ratones , Ratones Desnudos , Radioisótopos/metabolismo , Radiofármacos/farmacocinética , Albúmina Sérica Humana , Seroglobulinas , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto/estadística & datos numéricosRESUMEN
BACKGROUND: Preterm neonates are usually not part of a traditional drug development programme, however they are frequently administered medicines. Developing modelling and simulation tools, such as physiologically based pharmacokinetic (PBPK) models that incorporate developmental physiology and maturation of drug metabolism, can be used to predict drug exposure in this group of patients, and may help to optimize drug dose adjustment. OBJECTIVE: The aim of this study was to assess and verify the predictability of a preterm PBPK model using compounds that undergo diverse renal and/or hepatic clearance based on the knowledge of their disposition in adults. METHODS: A PBPK model was developed in the Simcyp Simulator V17 to predict the pharmacokinetics (PK) of drugs in preterm neonates. Drug parameters for alfentanil, midazolam, caffeine, ibuprofen, gentamicin and vancomycin were collated from the literature. Predicted PK parameters and profiles were compared against the observed data. RESULTS: The preterm PBPK model predicted the PK changes of the six compounds using ontogeny functions for cytochrome P450 (CYP) 1A2, CYP2C9 and CYP3A4 after oral and intravenous administrations. For gentamicin and vancomycin, the maturation of renal function was able to predict the exposure of these two compounds after intravenous administration. All PK parameter predictions were within a twofold error criteria. CONCLUSION: While the developed preterm model for the prediction of PK behaviour in preterm patients is not intended to replace clinical studies, it can potentially help with deciding on first-time dosing in this population and study design in the absence of clinical data.
Asunto(s)
Alfentanilo/farmacocinética , Gentamicinas/farmacocinética , Recién Nacido/metabolismo , Midazolam/farmacocinética , Vancomicina/farmacocinética , Administración Intravenosa , Administración Oral , Alfentanilo/administración & dosificación , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Cafeína/administración & dosificación , Cafeína/farmacocinética , Simulación por Computador , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/farmacocinética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP3A/metabolismo , Femenino , Gentamicinas/administración & dosificación , Edad Gestacional , Humanos , Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/farmacocinética , Ibuprofeno/administración & dosificación , Ibuprofeno/farmacocinética , Recién Nacido/fisiología , Riñón/metabolismo , Hígado/metabolismo , Masculino , Tasa de Depuración Metabólica/fisiología , Midazolam/administración & dosificación , Modelos Biológicos , Narcóticos/administración & dosificación , Narcóticos/farmacocinética , Valor Predictivo de las Pruebas , Nacimiento Prematuro , Vancomicina/administración & dosificaciónRESUMEN
Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug (NSAID) commonly used in the treatment of pain, fever and inflammation. However, the administration of IBU in its free carboxylic acid form is strongly dependent on its limited solubility in aqueous solution. This mandates for an increased drug concentration to reach the therapeutic window, and promotes the alternative use of IBU sodium salt, even if this latter form poses significant constraints in terms of tunable release due to its uncontrolled and rapid diffusion. A potential solution is represented by oral administration through physical encapsulation of ibuprofen in designed carriers, despite this route limits the application of this therapeutic agent. In this work, we propose the covalent tethering of ibuprofen to a hydrogel matrix via esterification reaction. Exploiting the cleavability of the ester bond under physiological conditions, we propose a controlled drug delivery system where the whole drug payload can be released, thus overcoming the questioned aspects of over-dosage and solubility-dependent administration. In particular, we tested the biological activity of cleaved ibuprofen in terms of cyclooxygenase inhibition, reporting that chemical tethering did not alter the efficiency of the NSAID. Moreover, due to the sol-gel transition of the hydrogel matrix, these ibuprofen-functionalized hydrogels could be used as injectable tools in several clinical scenarios, performing a localized drug release and opening advanced avenues for in situ treatments.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacocinética , Portadores de Fármacos/química , Hidrogeles/química , Ibuprofeno/farmacocinética , Resinas Acrílicas/química , Administración Oral , Línea Celular Tumoral , Inhibidores de la Ciclooxigenasa/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Liberación de Fármacos , Pruebas de Enzimas , Humanos , Ibuprofeno/administración & dosificación , Glicoles de Propileno/química , Prostaglandina-Endoperóxido Sintasas/metabolismo , Sefarosa/química , SolubilidadRESUMEN
Cyclooxygenase-2 (COX-2) is involved in the inflammatory response, and its recurrent overexpression in cancers as well as in neurodegenerative disorders has made it an important target for therapy. For this reason, noninvasive imaging of COX-2 expression may represent an important diagnostic tool. In this work, a COX-2 inhibitor analogue, VA426 [1-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-5-(4-(methylsulfonil)phenyl)-1H-pyrrole], was synthesized and radiolabelled with the 11C radioisotope. The ex vivo biodistribution profile of 11C-VA426 was evaluated in the brain and periphery of healthy rats and mice and in brain and periphery of inflammation models, based on the administration of LPS. 11C-VA426 synthesis with the tBuOK base showed optimal radiochemical yield (15 ± 2%) based on triflate activity, molar activity (range 37-148 GBq/µmol), and radiochemical purity (>95%). Ex vivo biodistribution studies showed a fast uptake of radioactivity but a rapid washout, except in regions expressing COX-2 (lungs, liver, and kidney) both in rats and in mice, with maximum values at 30 and 10 minutes p.i., respectively. LPS administration did not show significant effect on radioactivity accumulation. Celecoxib competition experiments performed in rats and mice treated with LPS produced a general target unrelated reduction of radioactivity concentration in all peripheral tissues and brain areas examined. Finally, in agreement with the negative results obtained from biodistribution experiments, radiometabolites analysis revealed that 11C-VA426 is highly unstable in vivo. This study indicates that the compound 11C-VA426 is not currently suitable to be used as radiopharmaceutical for PET imaging. This family of compounds needs further implementation in order to improve in vivo stability.
Asunto(s)
Radioisótopos de Carbono , Ciclooxigenasa 2/análisis , Inhibidores de la Ciclooxigenasa , Marcaje Isotópico/métodos , Radiofármacos/síntesis química , Animales , Biotransformación , Celecoxib/farmacología , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacocinética , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Inflamación/inducido químicamente , Inflamación/diagnóstico por imagen , Ligandos , Lipopolisacáridos/toxicidad , Hígado/metabolismo , Masculino , Ratones , Especificidad de Órganos , Tomografía de Emisión de Positrones , Radiofármacos/química , Radiofármacos/farmacocinética , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Global prevalence of the severe periodontitis is at the alarming stage and its association with the systemic complications is highly evident which cannot be neglected. An insight into the pathophysiology of the periodontitis reveals that the promising amelioration could only be envisaged with the 4-D/multi-pronged approach of combining antibiotic along with the host modulating agents. The complications of the disease itself suggest that the use of antibiotic alone is not able to cater the symptoms completely. There is a need of other host modulatory agents too, such as Cyclo-oxygenase -II (COX II) enzyme inhibitors, Matrix metalloproteinase's (MMPs) inhibitors and osteo-integrating agents. Also, there is an unmet need of singular treatment modality through which all these agents can be sequentially and directly delivered into the periodontal cavity. The current hypothesis takes it a step forward wherein an antibiotic is combined with other three host modulatory agents in a singular drug delivery system. The encapsulation of multiple therapeutic agents with controlled release would therefore allow for reduced drug dose thus minimizing side effects; contributing to enhanced patient compliance and treatment efficacy. Hence this approach can be presented as a 4-D/multi-pronged approach for circumvention of periodontitis.
Asunto(s)
Antibacterianos/uso terapéutico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Periodontitis/tratamiento farmacológico , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/uso terapéutico , Celecoxib/administración & dosificación , Celecoxib/uso terapéutico , Terapia Combinada , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/farmacocinética , Doxiciclina/administración & dosificación , Doxiciclina/uso terapéutico , Esquema de Medicación , Sinergismo Farmacológico , Quimioterapia Combinada , Durapatita/administración & dosificación , Durapatita/uso terapéutico , Encía/fisiología , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/administración & dosificación , Inhibidores de la Metaloproteinasa de la Matriz/farmacocinética , Minociclina/administración & dosificación , Minociclina/uso terapéutico , Modelos Biológicos , Oseointegración/efectos de los fármacos , Periodoncia/métodos , Periodontitis/cirugía , Regeneración , Trastornos Relacionados con SustanciasRESUMEN
Objective: In this study, we aimed to develop a candidate modifited polymeric nanoparticle (NP) system that will kill cancer cells by facilitated to apoptosis and also reduce pain. Significance: The primary goal of treatment, especially for metastatic cancers, is to control the growth of the cancer and to alleviate the symptoms. Pain is one of the commonest symptoms of cancer. In cancer treatment, directing cancer cells to death while simultaneously relieving pain will be a new approach. Methods: Chitosan-modified PLGA NPs were prepared using an nanoprecipitation technique. The NPs were loaded with flurbiprofen and decorated with folic acid. STAT3-siRNA was adsorbed to these polymeric NPs using antisense technology. Results: The NPs were small in size (176.9-220.3 nm) with positive zeta potential (+14.1 mV to +27.2 mV). They had high loading capacity and prolonged release properties over 144 hours. Cytotoxicity studies performed with siRNA showed effective electrostatic interaction due to the positively charged NPs. Folic acid facilitated entry into cancer cells and helped to kill them. Conclusion: The formulation we developed is a potential carrier system for both treatment of cancer and prevention of pain, especially for metastatic cancers.
Asunto(s)
Antineoplásicos/administración & dosificación , Dolor en Cáncer/prevención & control , Inhibidores de la Ciclooxigenasa/administración & dosificación , Portadores de Fármacos/química , Flurbiprofeno/administración & dosificación , Neoplasias/tratamiento farmacológico , ARN Interferente Pequeño/administración & dosificación , Animales , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Dolor en Cáncer/etiología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quitosano/química , Inhibidores de la Ciclooxigenasa/farmacocinética , Flurbiprofeno/farmacocinética , Ácido Fólico/administración & dosificación , Ácido Fólico/farmacocinética , Humanos , Ratones , Nanopartículas/química , Neoplasias/complicaciones , Neoplasias/patología , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , ARN Interferente Pequeño/genética , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/genéticaRESUMEN
Indications for aspirin during pregnancy are a matter of debate and there is a recent trend to an extended prescription and an overuse of aspirin in pregnancy. Aspirin is efficient in secondary prevention of preeclampsia essentially in patients with a personal history of preeclampsia. The effect of aspirin on platelet aggregation and on the TXA2/PGI2 balance is dose-dependent. The optimum dosage, from 75mg/day to 150mg/day, needs to be determined. Fetal safety data at 150mg/day are still limited. The efficacy of aspirin seems to be subject to a chronobiological effect. It is recommended to prescribe an evening or bedtime intake. Aspirin, in primary prevention of preeclampsia, given to high-risk patients identified in the first trimester by screening tests, seems to reduce the occurrence of early-onset preeclampsia. Nevertheless, there are insufficient data for the implementation of such screening procedures in practice.
Asunto(s)
Aspirina/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Preeclampsia/prevención & control , Aspirina/administración & dosificación , Aspirina/efectos adversos , Aspirina/farmacocinética , Fenómenos Cronobiológicos , Contraindicaciones de los Medicamentos , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/efectos adversos , Inhibidores de la Ciclooxigenasa/farmacocinética , Inhibidores de la Ciclooxigenasa/uso terapéutico , Utilización de Medicamentos , Diagnóstico Precoz , Femenino , Enfermedades Fetales/inducido químicamente , Francia/epidemiología , Humanos , Tamizaje Masivo , Metaanálisis como Asunto , Placenta/metabolismo , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/farmacocinética , Preeclampsia/diagnóstico , Preeclampsia/epidemiología , Embarazo , Complicaciones del Embarazo/inducido químicamente , Primer Trimestre del Embarazo , Prevención Primaria , Antagonistas de Prostaglandina/administración & dosificación , Antagonistas de Prostaglandina/efectos adversos , Antagonistas de Prostaglandina/farmacocinética , Antagonistas de Prostaglandina/uso terapéutico , Factores de Riesgo , Prevención SecundariaRESUMEN
Use of the human volunteers in bioequivalence studies is being discouraged by the Food and drug administration after the introduction of biowaiver approaches. In-vitro in-vivo correlation (IVIVC) with the level A is accepted for the registration of new molecules. In the present study deconvolution technique with numeric approaches was applied after compressing and in vitro validating the 100mg Nimesulide immediate, intermediate and slow release tablets. Single centered, crossover, randomized study was conducted in four phases with a two-week washout period to obtain the plasma drug concentration data after administrating test and reference products in male healthy volunteers. KineticaTM 4.4.1 (Thermoelectron corp, USA) was used for the calculation of two ways ANOVA with 90% CI from both log transformed and non- transformed data and Phoenix WinNonlin 7 and it's IVIVC toolkit version 7.0 was used for the application of numeric approaches of IVIVC. Results revealed that the individual internal percentage prediction error for AUCinf and Cmax were found to be < 15% while their average values were < 10% in all medium. Numeric values of % PE at pH 6.8 and pH 7.4 (50 rpm in USP II and 100 rpm in USP I and II apparatus) were found to be (2.5842, 2.9789 and, 7.1732; 7.0944, 2.4721 and 4.350) for AUCinf and (2.5842, 0.5736 and 4.6928; 5.6214, 3.0551 and -2.4711) values for Cmax respectively. The low values of prediction errors demonstrate that the correlation model is projecting the in vivo response of each formulation. Percentage External error (% PE) was not required because individual values of percentage internal error (%PE) of Cmax and AUClast were not >15. In order to predict point to point correlation between fraction drug dissolved and drug absorbed, their mean r2 value was found to be > 0.9112 which showed a linear correlation in slightly alkaline pH.
Asunto(s)
Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/farmacocinética , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Adolescente , Adulto , Estudios Cruzados , Preparaciones de Acción Retardada , Liberación de Fármacos , Humanos , Masculino , Comprimidos , Equivalencia Terapéutica , Adulto JovenRESUMEN
While cyclooxygenase inhibitors have been the most common medications used to facilitate earlier closure of patent ductus arteriosus in preterm infants, adverse effects and variable efficacy have highlighted a need for alternative options. Acetaminophen facilitates ductal closure via an alternate pathway of prostaglandin inhibition. Despite treatment with high doses, toxicity is uncommon in preterm infants, possibly due to immature hepatic metabolism. Pooled data from randomized clinical trials of early treatment demonstrate that acetaminophen has similar efficacy as cyclooxygenase inhibitors for PDA closure with a favorable side effect profile and without any apparent increase in adverse neonatal outcomes. Acetaminophen may therefore be an ideal first-line agent among moderately and extremely preterm infants, though there is a paucity of data from controlled trials regarding its use in infants at the border of viability (gestation age ≤25 weeks). Evidence from clinical studies of limited quality supports acetaminophen treatment as rescue therapy for infants with persistent PDA after unsuccessful cyclooxygenase inhibitor treatment, including those being considered for surgical ligation.
Asunto(s)
Acetaminofén/uso terapéutico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Conducto Arterioso Permeable/tratamiento farmacológico , Hemodinámica/efectos de los fármacos , Recien Nacido Prematuro , Acetaminofén/farmacocinética , Acetaminofén/farmacología , Inhibidores de la Ciclooxigenasa/farmacocinética , Inhibidores de la Ciclooxigenasa/farmacología , Conducto Arterioso Permeable/fisiopatología , Medicina Basada en la Evidencia , Humanos , Recien Nacido Extremadamente Prematuro , Recién Nacido de Bajo Peso , Recién Nacido , Estudios Observacionales como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Cardiovascular diseases (CVDs) are becoming major contributors to the burden of disease due to genetic and environmental factors. Despite current standard oral care, cardiovascular risk remains relatively high. A triple antiplatelet therapy with a cyclooxygenase-1 (COX-1) inhibitor, a P2Y12 receptor antagonist, and a protease-activated receptor-1 (PAR-1) antagonist has been established in the secondary prevention of atherothrombosis in patients with acute myocardial infraction and in those with peripheral artery disease. However, due to the combinatorial use of three different drugs, patients receiving this triple therapy are exposed to enhanced risk of bleeding. Conforming to polypharmacology principles, the discovery of a single compound that can simultaneously block the three platelet activation pathways (PAR-1, P2Y12, and COX-1) is of importance. Natural products have served as an inexhaustible source of bioactive compounds presenting a diverse pharmaceutical profile, including anti-inflammatory, antioxidant, anticancer, and antithrombotic activity. Indeed, principal component analysis indicated that natural products have the potential to inhibit the three aforementioned pathways, though existed reports refer to single inhibition mechanism on specific receptor(s) implicated in platelet activation. We thus set out to explore possibilities that take advantage of this potential of natural products and shape the basis to produce novel compounds that could simultaneously target PAR-1, P2Y12, and COX-1 platelet activation pathways. Polyunsaturated fatty acids (PUFAs) have multiple effects leading to improvements in blood pressure and cardiac function and arterial compliance. A promising approach to achieve the desirable goal is the bioconjugation of natural products with PUFAs. Herein, we describe the principles that should be followed to develop molecular hybrids bearing triple antiplatelet activity profile.
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Plaquetas , Ciclooxigenasa 1 , Inhibidores de la Ciclooxigenasa , Ácidos Grasos Insaturados , Plasma/química , Inhibidores de Agregación Plaquetaria , Receptor PAR-1/antagonistas & inhibidores , Receptores Purinérgicos P2Y12 , Plaquetas/química , Plaquetas/metabolismo , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacocinética , Inhibidores de la Ciclooxigenasa/farmacología , Evaluación Preclínica de Medicamentos/métodos , Estabilidad de Medicamentos , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/farmacocinética , Ácidos Grasos Insaturados/farmacología , Humanos , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacología , Antagonistas del Receptor Purinérgico P2Y/química , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Antagonistas del Receptor Purinérgico P2Y/farmacología , Receptor PAR-1/metabolismoRESUMEN
Cancer is one of the leading causes of death worldwide. Chemotherapy and radiotherapy are the conventional primary treatments for cancer patients. However, most of cancer cells develop resistance to both chemotherapy and radiotherapy after a period of treatment, besides their lethal side-effects. This motivated investigators to seek more effective alternatives with fewer side-effects. In the last few years, resveratrol, a natural polyphenolic phytoalexin, has attracted much attention due to its wide biological effects. In this concise review, we highlight the role of resveratrol in the prevention and therapy of cancer with particular focus on colorectal and skin cancer. Also, we discuss the molecular mechanisms underlying its chemopreventive and therapeutic activity. Finally, we highlight the problems associated with the clinical application of resveratrol and how attempts have been made to overcome these drawbacks.
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Anticarcinógenos/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/prevención & control , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/prevención & control , Estilbenos/uso terapéutico , Animales , Anticarcinógenos/farmacocinética , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Autofagia , Inhibidores de la Ciclooxigenasa/farmacocinética , Inhibidores de la Ciclooxigenasa/uso terapéutico , Femenino , Humanos , Inflamasomas , Masculino , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Metástasis de la Neoplasia , Ratas , Resveratrol , Sesquiterpenos , Estilbenos/farmacocinética , FitoalexinasRESUMEN
PURPOSE: Intravitreal delivery of non-steroidal anti-inflammatory drugs could be an effective way to treat macular edema caused by posterior segment inflammation. In this study, we evaluated the intravitreal bioavailability and anti-inflammatory efficacy of flurbiprofen in rabbit eyes. METHODS: For pharmacokinetics, 0.1 ml of 7.66 mg/ml flurbiprofen solution was injected intravitreally and vitreous drug levels were analyzed at specific time points using LC-MS technique. For efficacy, 100 ng lipopolysaccharide of E.coli was injected intravitreally in rabbits to induce inflammation. The animals were separated in three groups and received intraocular flurbiprofen, dexamethasone and PBS to serve as control. Complete ocular examination and total cell count in aqueous fluid were determined to evaluate the extent of inflammation. Eyes were then enucleated for histopathology analysis. The efficacy in the uveitis model was determined by clinical signs of inflammation, total leukocyte count and histology findings. RESULTS: No adverse events were observed during pharmacokinetic assessment. No signs of inflammation, hemorrhage or retina detachment were detected. The recovery of flurbiprofen from vitreous samples was 92.6%. The half-life of flurbiprofen was estimated to be 1.92 h with an elimination constant rate (K) of 0.36. Treatment with intraocular injections of flurbiprofen and dexamethasone significantly reduced total leukocyte count in a manner comparable to dexamethasone [reduction of 96.84% (p < 0.05) and 97.44% (p < 0.05), respectively]. Histologic studies demonstrated significantly less signs of ocular inflammation after flurbiprofen injection compared to control eyes. CONCLUSIONS: Flurbiprofen is effective in suppressing inflammation in this experimental uveitis model. In our experimental setting, intravitreal flurbiprofen seem to have a therapeutic result comparable to dexamethasone. However, the half-life of the drug remains short, necessitating further research to prolong its presence in the vitreous cavity.
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Endoftalmitis/complicaciones , Flurbiprofeno/farmacocinética , Edema Macular/tratamiento farmacológico , Cuerpo Vítreo/metabolismo , Animales , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/farmacocinética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Endoftalmitis/tratamiento farmacológico , Endoftalmitis/metabolismo , Flurbiprofeno/administración & dosificación , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/etiología , Oftalmoscopía , Segmento Posterior del Ojo , Conejos , Resultado del Tratamiento , Cuerpo Vítreo/patologíaRESUMEN
L-type amino acid transporter 1 (LAT1) is selectively expressed in the blood-brain barrier (BBB) and brain parenchyma. This transporter can facilitate brain delivery of neuroprotective agents and additionally give opportunity to minimize systemic exposure. Here, we investigated structure-pharmacokinetics relationship of five newly synthesized LAT1-utilizing prodrugs of the cyclooxygenase inhibitor, ketoprofen, in order to identify beneficial structural features of prodrugs to achieve both targeted brain delivery and low peripheral distribution of the parent drug. Besides, we studied whether pharmacokinetics and bioconversion of LAT1-utilizing prodrugs in vivo can be predicted in early stage experiments. To achieve these goals, we compared the in vitro brain uptake mechanism of prodrugs, rate of BBB permeation of compounds using in situ perfusion technique, their systemic pharmacokinetics and release of parent drug in brain, plasma and liver of mice. The results revealed that both excellent LAT1-binding ability and transporter utilization in vitro can be achieved by conjugating the parent drug to aromatic amino acids such as phenylalanine in comparison to prodrugs with an aliphatic promoiety. The presence of an aromatic promoiety directly conjugated in meta- or para-position to ketoprofen led to LAT1-utilizing prodrugs capable of delivering the parent drug into the brain with higher unbound brain to plasma ratio and reduced liver exposure than with ketoprofen itself. In contrast, the prodrugs with aliphatic promoieties and with an additional carbon attached between the parent drug and phenylalanine aromatic ring did not enhance brain delivery of ketoprofen. Furthermore, we have devised a screening strategy to pinpoint successful candidates at an early stage of development of LAT1-utilizing prodrugs. The screening approach demonstrated that early stage experiments could not replace pharmacokinetic studies in vivo due to the lack of prediction of the intra-brain/systemic distribution of the prodrugs as well as the release of the parent drug. Overall, this study provides essential knowledge required for improvement of targeted brain delivery and reduction of systemic exposure of drugs via the LAT1-mediated prodrug approach.
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Encéfalo/metabolismo , Sistemas de Liberación de Medicamentos , Cetoprofeno/administración & dosificación , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Aminoácidos Aromáticos/química , Animales , Barrera Hematoencefálica/metabolismo , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacocinética , Humanos , Cetoprofeno/química , Cetoprofeno/farmacocinética , Hígado/metabolismo , Masculino , Ratones , Profármacos , Distribución TisularRESUMEN
The mechanism of action of low-dose aspirin in the prevention of colorectal cancer (CRC) remains largely hypothetical. We aimed to compare the effects of low-dose aspirin (100 mg/day for 7 days) given to 40 individuals undergoing CRC screening on the extent of cyclooxygenase (COX)-1 acetylation at serine-529 (AceCOX-1), in blood platelets vs. colorectal mucosa, at 7 (group 1) and 24 h (group 2) after dosing. A significantly (P < 0.01) lower %AceCOX-1 was detected in colonic and rectal mucosa (average 64%) vs. platelets (average 75%) in both groups. This effect was associated with an average 46% (P < 0.01) and 35% (P < 0.05) reduction in prostaglandin (PG) E2 levels and phosphorylated S6 (p-S6) levels, respectively. Rectal mucosal levels of p-S6/S6 significantly (P < 0.01) correlated with PGE2 . These findings demonstrate that low-dose aspirin produces long-lasting acetylation of COX-1 and downregulation of p-S6 in human colorectal mucosa, an effect that may interfere with early colorectal carcinogenesis.
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Aspirina , Plaquetas , Neoplasias Colorrectales , Ciclooxigenasa 1/metabolismo , Dinoprostona/biosíntesis , Mucosa Intestinal , Proteínas Quinasas S6 Ribosómicas/metabolismo , Acetilación/efectos de los fármacos , Aspirina/administración & dosificación , Aspirina/farmacocinética , Biopsia/métodos , Plaquetas/efectos de los fármacos , Plaquetas/enzimología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/prevención & control , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/enzimología , Masculino , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Resultado del TratamientoRESUMEN
The objective of the study was to establish the dose-response relationship for robenacoxib, a selective cyclooxygenase (COX)-2 inhibitor, in a urate crystal model of acute synovitis. In a randomized partial Latin square design trial, 12 beagle dogs were administered orally single doses of robenacoxib (0.5, 1, 2, 4 and 8 mg/kg), placebo and the positive control meloxicam (0.1 mg/kg), 3 h after injection of sodium urate crystals into a stifle joint. Dogs were assessed for weight bearing on a force plate and by subjective clinical orthopaedic observations. Robenacoxib produced dose-dependent improvement in weight bearing, and decreased pain on palpation and joint swelling, over the dose range 0.5-2 mg/kg with no further increase in effect over the range 2-8 mg/kg. For weight bearing on the force plate, the ED50 of robenacoxib was 0.6-0.8 mg/kg. The onset of action and time to peak effect of robenacoxib were faster (respectively, 2-2.5 h and 3-5 h) than for meloxicam (respectively, 3 h and 6 h). Robenacoxib significantly inhibited COX-2 at all doses, with dose-related activity. Robenacoxib did not inhibit COX-1 over the dose range 0.5-4 mg/kg, but produced transient inhibition at 8 mg/kg. In conclusion, oral administration of robenacoxib over the dose range 0.5-8 mg/kg demonstrated significant analgesic and anti-inflammatory efficacy in dogs.
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Difenilamina/análogos & derivados , Enfermedades de los Perros/inducido químicamente , Fenilacetatos/uso terapéutico , Rodilla de Cuadrúpedos/efectos de los fármacos , Sinovitis/veterinaria , Ácido Úrico/toxicidad , Administración Oral , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/sangre , Inhibidores de la Ciclooxigenasa/farmacocinética , Inhibidores de la Ciclooxigenasa/uso terapéutico , Difenilamina/sangre , Difenilamina/farmacocinética , Difenilamina/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Perros , Cojera Animal , Fenilacetatos/sangre , Fenilacetatos/farmacocinéticaRESUMEN
We have developed the convenient methods for synthesis of polyfluorosalicylic acids and their derivatives. For the first time the biological properties of polyfluorosalicylates were investigated in vitro (permeability through the biological membranes, COX-1 inhibitory action) and in vivo (anti-inflammatory, analgesic activities, acute toxicity). Molecular docking of polyfluorinated salicylates confirmed in vitro and in vivo experiments.
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Analgésicos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Inhibidores de la Ciclooxigenasa/uso terapéutico , Edema/tratamiento farmacológico , Salicilatos/uso terapéutico , Analgésicos/química , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacocinética , Inhibidores de la Ciclooxigenasa/farmacología , Femenino , Halogenación , Masculino , Simulación del Acoplamiento Molecular , Ratas Sprague-Dawley , Ratas Wistar , Salicilatos/química , Salicilatos/farmacocinética , Salicilatos/farmacología , OvinosRESUMEN
Despite aggressive treatment with radiation and combination chemotherapy following tumor resection, the 5-year survival rate for patients with head and neck cancer is at best only 50%. In this study, we examined the therapeutic potential of localized release of diclofenac from electrospun nanofibers generated from poly(D,L-lactide-co-glycolide) polymer. Diclofenac was chosen since anti-inflammatory agents that inhibit cyclooxygenase have shown great potential in their ability to directly inhibit tumor growth as well as suppress inflammation-mediated tumor growth. A mouse resection model of oral carcinoma was developed by establishing tumor growth in the oral cavity by ultrasound-guided injection of 1 million SCC-9 cells in the floor of the mouth. Following resection, mice were allocated into four groups with the following treatment: 1) no treatment, 2) implanted scaffolds without diclofenac, 3) implanted scaffolds loaded with diclofenac, and 4) diclofenac given orally. Small animal ultrasound and magnetic resonance imaging were utilized for longitudinal determination of tumor recurrence. At the end of 7 weeks following tumor resection, 33% of mice with diclofenac-loaded scaffolds had a recurrent tumor, in comparison to 90%-100% of the mice in the other three groups. At this time point, mice with diclofenac-releasing scaffolds showed 89% survival rate, while the other groups showed survival rates of 10%-25%. Immunohistochemical staining of recurrent tumors revealed a near 10-fold decrease in the proliferation marker Ki-67 in the tumors derived from mice with diclofenac-releasing scaffolds. In summary, the local application of diclofenac in an orthotopic mouse tumor resection model of oral cancer reduced tumor recurrence with significant improvement in survival over a 7-week study period following tumor resection. Local drug release of anti-inflammatory agents should be investigated as a therapeutic option in the prevention of tumor recurrence in oral squamous carcinoma.