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1.
PLoS One ; 15(8): e0236297, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32780750

RESUMO

Naproxen is a widely used non-steroidal anti-inflammatory drug for the control of postoperative inflammatory signs and symptoms in dentistry. Its association with esomeprazole has been widely studied and has yielded good results for the control of acute pain, even with the delayed absorption of naproxen owing to the presence of esomeprazole. To further understand the absorption, distribution, and metabolism of this drug alone and in combination with esomeprazole, we will analyze the pharmacokinetic parameters of naproxen and its major metabolite, 6-O-desmethylnaproxen, in saliva samples. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method for the simultaneous determination of naproxen and 6-O-desmethylnaproxen in saliva will be developed and validated. Sequential saliva samples from six patients will be analyzed before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6 8, 11, 24, 48, 72, and 96 h after the ingestion of one naproxen tablet (500 mg) and esomeprazole-associated naproxen tablets (500 + 20 mg), at two different times. After liquid-liquid extraction with ethyl acetate and HCl, the samples will be analyzed using an 8040 Triple Quadrupole Mass Spectrometer (Shimadzu, Kyoto, Japan). Separation of naproxen and its major metabolic products will be performed using a Shim-Pack XR-ODS 75Lx2.0 column and C18 pre-column (Shimadzu, Kyoto, Japan) at 40°C using a mixture of methanol and 10 mM ammonium acetate (70:30, v/v) with an injection flow of 0.3 mL/min. The total analytical run time will be 5 min. The detection and quantification of naproxen and its metabolite will be validated, which elucidate the pharmacokinetics of this drug, thereby contributing to its proper prescription for the medical and dental interventions that cause acute pain.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Monitoramento de Medicamentos/métodos , Esomeprazol/farmacocinética , Naproxeno/análogos & derivados , Saliva/química , Administração Oral , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Esomeprazol/administração & dosagem , Esomeprazol/isolamento & purificação , Feminino , Absorção Gastrointestinal , Humanos , Masculino , Metanol/química , Pessoa de Meia-Idade , Naproxeno/administração & dosagem , Naproxeno/isolamento & purificação , Naproxeno/farmacocinética , Dor Processual/tratamento farmacológico , Reprodutibilidade dos Testes , Comprimidos , Espectrometria de Massas em Tandem/métodos , Adulto Jovem
2.
Food Chem ; 331: 127279, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32563800

RESUMO

Stability of protein-polyphenol aggregate particles, created by complexing polyphenols from blueberry and muscadine grape pomaces with a rice-pea protein isolate blend, was evaluated in an in vitro gastrointestinal model. Recovery index (RI; % total phenolics present post-digestion) was 69% and 62% from blueberry and muscadine grape protein-polyphenol particles, compared to 23% and 31% for the respective pomace extracts. Anthocyanins RI was 52% and 42% from particles (6% and 13% from pomace extracts), and proanthocyanidins RI was 77% and 73% from particles (25% and 14% from pomace extracts), from blueberry and grape, respectively. Protein-polyphenol particle digests retained 1.5 to 2-fold higher antioxidant capacity and suppressed the expression of pro-inflammatory cytokines, iNOS, IL6, and IL1ß, compared to unmodified extract digests, which only suppressed IL6. Protein-polyphenol particles as a delivery vehicle in foods may confer better stability during gastrointestinal transit, allow protected polyphenols to reach the gut microbiota, and preserve polyphenol bioactivity.


Assuntos
Mirtilos Azuis (Planta)/química , Polifenóis/farmacocinética , Vitis/química , Animais , Antocianinas/análise , Anti-Inflamatórios não Esteroides/farmacocinética , Antioxidantes/análise , Digestão , Indústria de Processamento de Alimentos , Frutas/química , Camundongos , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Proteínas de Vegetais Comestíveis/química , Proantocianidinas/análise , Células RAW 264.7
3.
Xenobiotica ; 50(11): 1332-1340, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32432967

RESUMO

Diclofenac is an extensively used nonsteroidal anti-inflammatory drug, but gastrointestinal liabilities and cardiovascular complications take the shine away from such a widely prescribed drug. On the other hand, rutin, a dietary bioflavonoid, has quite a few pharmacological attributes to improve the efficacy and reduce the dose-related toxicities of diclofenac through the intended food-drug/herb-drug interaction. The aim of the present research work was to investigate the role of rutin on pharmacokinetic modulation and the consequent efficacy of diclofenac. At first, pharmacodynamics and pharmacokinetics of diclofenac as alone and in the presence of rutin were investigated orally in a rat model. Then, mechanistic studies were performed to explain the effect of rutin on improvement in oral exposure as well as the efficacy of diclofenac using a battery of in-vitro/in-situ/in-vivo studies. Results displayed that rutin enhanced efficacy as well as oral bioavailability of diclofenac in rats. A marked increase in permeability of diclofenac by rutin was displayed that is linked to inhibition of Breast Cancer Resistance Protein (BCRP) transporters. There was no significant effect of rutin on the modulation of intestinal transit, CYP2C9 inhibition in human liver microsomes, and CYP2C9/CYP2C11 expression in rat liver tissues to boost the oral exposure of diclofenac. Rutin is found to be an inhibitor for BCRP transporters and can act as an oral bioavailability enhancer for a drug like diclofenac.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Diclofenaco/farmacocinética , Rutina/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Animais , Interações Medicamentosas , Ratos
4.
Artigo em Inglês | MEDLINE | ID: mdl-32278291

RESUMO

A fast off-line FPSE-HPLC-PDA method has been reported that allows simultaneous clean up and determination of six non-steroidal anti-inflammatory drugs (NSAIDs) in saliva samples from healthy volunteers. Particularly, furprofen, indoprofen, ketoprofen, fenbufen, flurbiprofen, and ibuprofen were chromatographically resolved. Benzyl paraben was chosen as the internal standard (BzPB, IS). These target compounds were successfully extracted from human saliva using fabric phase sorptive extraction (FPSE) and then analysed in the liquid chromatographic system by means of a short analytical column (Symmetry C18, 75 × 4.6 mm, 3.5 µm) using acetonitrile (AcN) and phosphate buffer (PBS, 30 mM; pH = 2.5) as the mobile phases. The method, validated through the calculation of all analytical parameters in accordance of International Guidelines, was applied to real saliva sample analysis collected from informed volunteers. The proposed approach that included the use of sol-gel polytetrahydrofuran (sol-gel PTHF) sorbent immobilized on cellulose support and C18 stationary phase used in HPLC, showed high potential as a fast tool for future clinical and forensic applications. The herein reported results encourage potential future application of FPSE in the forensic field. Furthermore, the FPSE membrane was tested in dried saliva spot mode (DSS) in order to check its potential use as a sampling device, also for forensic applications.


Assuntos
Anti-Inflamatórios não Esteroides/química , Flurbiprofeno/química , Fenilpropionatos/química , Saliva/química , Anti-Inflamatórios não Esteroides/farmacocinética , Celulose/química , Cromatografia Líquida de Alta Pressão , Feminino , Flurbiprofeno/farmacocinética , Humanos , Limite de Detecção , Masculino , Estrutura Molecular , Parabenos/normas , Fenilpropionatos/farmacocinética , Microextração em Fase Sólida
5.
Int J Clin Pharmacol Ther ; 58(6): 316-331, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32324130

RESUMO

OBJECTIVE: Naproxen sodium (NAPSO) is commonly used in a variety of pain conditions. There are several strengths of NAPSO available over the counter (OTC). Most published data are based on single or multiple doses using 220 mg, hence there is a need to assess the analgesic efficacy of other strengths of NAPSO used in the OTC setting. MATERIALS AND METHODS: We reviewed published and unpublished studies of naproxen (NAP) and NAPSO to establish the pharmacokinetic relationship between dosage, plasma concentration, and efficacy, and to compare the analgesic efficacy of NAPSO 220, 440, and 550 mg or NAP 500 mg versus placebo and active comparators. RESULTS: Increasing OTC doses of NAP are associated with linear pharmacokinetics, i.e., plasma levels of NAP increase proportionately with dosage. Accordingly, the therapeutic efficacy of higher doses of NAP or NAPSO is greater than lower doses. All OTC doses of NAP and NAPSO are significantly more effective than placebo. Higher strengths are as effective or more effective than lower strengths, and at least comparable to other active treatments. CONCLUSION: The pharmacokinetic linearity associated with NAP means that data on efficacy for the lower OTC doses of NAPSO can be extrapolated to the higher OTC doses. Thus, it is given that NAPSO 275 and 550 mg will be at least as effective as or superior to the lower doses of 220 and 440 mg.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Naproxeno/farmacocinética , Humanos , Medicamentos sem Prescrição/farmacocinética
6.
J Zoo Wildl Med ; 51(1): 53-58, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32212546

RESUMO

Mavacoxib is a selective cyclooxygenase-2 nonsteroidal anti-inflammatory drug that has been used for management of osteoarthritis and other inflammatory conditions in dogs. The main advantage of mavacoxib over other nonsteroidal anti-inflammatory drugs is its longer plasma half-life, leading to decreased dosing frequency. This study determined the pharmacokinetics of mavacoxib in Caribbean flamingos (Phoenicopterus ruber ruber) after a single-dose oral administration of 6 mg/kg (n = 6). Plasma mavacoxib concentrations were determined using liquid chromatography with mass spectrometry, and pharmacokinetic analysis was performed using noncompartmental methods. Mean peak plasma concentration (Cmax) was (mean; range) 2.97 (2.19--4.06) µg/ml; mean time to peak plasma concentration (Tmax) was 18.68 (4.00-48.00) hr; mean area under the curve (AUC) was 455 (292-637) hr * µg/ml; and mean terminal half-life (T1/2) was 74.47 (49.57-161.43) hr. Based on the results of this study, mavacoxib dosed at 6 mg/kg orally in Caribbean flamingos reaches plasma concentrations above the therapeutic concentration established for dogs, but further studies are needed to determine appropriate dosing recommendations in flamingos.


Assuntos
Animais de Zoológico/metabolismo , Anti-Inflamatórios não Esteroides/farmacocinética , Aves/metabolismo , Pirazóis/farmacocinética , Administração Oral , Animais , Feminino , Masculino
7.
Bioanalysis ; 12(3): 175-189, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32052638

RESUMO

Aim: Metamizole is a frequently used antipyretic and analgesic prodrug, yet its pharmacokinetics has not been thoroughly studied in infants and with coadministered medications. Thus, an LC-MS/MS method was developed to quantify the four major metamizole metabolites in human plasma. Methodology: Pre- and postcolumn infusion was installed to enable robust analyte retention and electrospray ionization following deproteinization of plasma samples. Results: The method was linear (R > 0.996), accurate (93.1-106.0%) and precise (≤12.7%). Mean recovery was more than 91.8% and ion suppression less than 13.1% for all analytes. Pharmacokinetic profiles were reproducible after 4 years at -80°C except for the formylated metabolite (-22.2%). Conclusion: The method fulfilled pertinent criteria of validation guidelines and required only little sample volume. The method therefore qualifies for metamizole analyses in children.


Assuntos
Anti-Inflamatórios não Esteroides/sangue , Cromatografia Líquida/métodos , Dipirona/sangue , Plasma/química , Espectrometria de Massas em Tandem/métodos , Anti-Inflamatórios não Esteroides/farmacocinética , Dipirona/farmacologia , Humanos
8.
J Med Chem ; 63(2): 529-541, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31910011

RESUMO

Structure-activity relationships for a series of small-molecule thiophenes resulted in potent and selective antagonism of human Complement C3a receptor. The compounds are about 100-fold more potent than the most reported antagonist SB290157. A new compound JR14a was among the most potent of the new antagonists in vitro, assessed by (a) inhibition of intracellular calcium release (IC50 10 nM) induced in human monocyte-derived macrophages by 100 nM C3a, (b) inhibition of ß-hexosaminidase secretion (IC50 8 nM) from human LAD2 mast cells degranulated by 100 nM C3a, and (c) selectivity for human C3aR over C5aR. JR14a was metabolically stable in rat plasma and in rat liver microsomes and efficacious in rats when given orally to suppress rat paw inflammation, macrophage and mast cell activation, and histopathology induced by intraplantar paw administration of a C3aR agonist. Potent C3aR antagonists are now available for interrogating C3a receptor activation and suppressing C3aR-mediated inflammation in mammalian physiology and disease.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Arginina/análogos & derivados , Compostos Benzidrílicos/farmacologia , Complemento C3a , Receptores de Complemento/antagonistas & inibidores , Tiofenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Arginina/farmacocinética , Arginina/farmacologia , Compostos Benzidrílicos/farmacocinética , Cálcio/metabolismo , Hexosaminidases/metabolismo , Humanos , Macrófagos/efeitos dos fármacos , Mastócitos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Wistar , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/farmacocinética
9.
Pharm Res ; 37(1): 3, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823096

RESUMO

PURPOSE: Inhaled delivery of pirfenidone to the lungs of patients with idiopathic pulmonary fibrosis holds promise to eliminate oral-observed side effects while enhancing efficacy. This study aimed to comprehensively describe the pulmonary pharmacokinetics of inhaled aerosol pirfenidone in healthy adult sheep. METHODS: Pirfenidone concentrations were evaluated in plasma, lung-derived lymph and epithelial lining fluid (ELF) with data subjected to non-compartmental pharmacokinetic analysis. RESULTS: Compartmental pharmacokinetic evaluation indicated that a 49 mg lung-deposited dose delivered an ELF Cmax of 62 ± 23 mg/L, and plasma Cmax of 3.1 ± 1.7 mg/L. Further analysis revealed that plasma pirfenidone reached Tmax faster and at higher concentrations than in lymph. These results suggested inhaled pirfenidone was cleared from the alveolar interstitium via blood faster than the drug could equilibrate between the lung interstitial fluid and lung lymphatics. However, the data also suggested that a 'reservoir' of pirfenidone feeds into lung lymph at later time points (after it has largely been cleared from plasma), prolonging lung lymphatic exposure. CONCLUSIONS: This study indicates inhaled pirfenidone efficiently deposits in ELF and is cleared from the lungs by initial absorption into plasma, followed by later equilibrium with lung interstitial and lymph fluid.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Pulmão/metabolismo , Piridonas/farmacocinética , Administração por Inalação , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Feminino , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Linfa/metabolismo , Piridonas/administração & dosagem , Ovinos
10.
AAPS J ; 22(1): 3, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712917

RESUMO

Multiple approaches such as mathematical deconvolution and mechanistic oral absorption models have been used to predict in vivo drug dissolution in the gastrointestinal (GI) tract. However, these approaches are often validated by plasma pharmacokinetic profiles, but not by in vivo drug dissolution due to the limited data available regarding the local GI environment. It is also challenging to predict and validate in vivo dissolution in different regions of the GI tract (stomach, duodenum, jejunum, and ileum). In this study, the dynamic fluid compartment absorption and transport (DFCAT) model was used to predict the in vivo dissolution profiles of ibuprofen, which was administered as an 800-mg immediate-release tablet to healthy subjects, in different regions of the GI tract. The prediction was validated with concentration time-courses of ibuprofen (BCS class 2a) in different regions of the GI tract that we have obtained over the past few years. The computational model predicted that the dissolution of ibuprofen was minimal in the stomach (2%), slightly more in the duodenum (6.3%), and primarily dissolved in the jejunum (63%) and the ileum (25%). The detailed model prediction of drug dissolution in different regions of GI can provide a quantitative reference of in vivo dissolution that may provide valuable insight in developing in vitro tests for drug product optimization and quality.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Liberação Controlada de Fármacos , Ibuprofeno/farmacocinética , Absorção Intestinal , Modelos Teóricos , Administração Oral , Anti-Inflamatórios não Esteroides/administração & dosagem , Trato Gastrointestinal , Humanos , Ibuprofeno/administração & dosagem , Estudo de Prova de Conceito
11.
Int J Pharm ; 572: 118800, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678378

RESUMO

The aim of the present work was to develop compound transdermal patch containing teriflunomide (TEF) and ketoprofen (KTP) using permeation enhancement strategy; reveal the molecular mechanism by which Azone (AZ) promoted transdermal absorption of compound patch through the enhancement of drug-drug intermolecular interaction. The formulation was optimized using in vitro skin permeation study and confirmed with pharmacodynamics study, anti-inflammatory study and analgesics study. Enhanced drug-drug interaction by AZ was characterized using FT-IR, 13C NMR, molecular modeling and thermal analysis. The optimized formulation was composed of TEF (3%), KTP (2%), AZ (10%) and DURO-TAK® 87-4098 as adhesive matrix. The skin permeation amount of TEF-KTP combination was promoted by AZ about 1.9 times (594.2 ±â€¯46.8 µg/cm2) and 1.2 times (502.92 ±â€¯24.0 µg/cm2) compared with TEF-AZ and KTP-AZ individual patch. It was proved that the interaction between TEF and KTP via hydrogen bonding was further enhanced by AZ due to the increased molecular mobility of acrylate polymer (ΔTg = -17.7 °C), which was proved by FTIR and 13C NMR spectra. The enhanced drug-drug intermolecular interaction increased drug dispersed status and decreased the quantity of drug's hydrogen bonding site, thus increasing the drug release amount significantly. In conclusion, a compound transdermal patch containing KTP and TEF was developed successfully and a novel enhancement mechanism was clarified at molecular level, which provided reference for the development of novel compound transdermal patch.


Assuntos
Analgésicos/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Experimental/prevenção & controle , Azepinas/administração & dosagem , Crotonatos/administração & dosagem , Cetoprofeno/administração & dosagem , Dor/prevenção & controle , Absorção Cutânea/efeitos dos fármacos , Toluidinas/administração & dosagem , Adesivo Transdérmico , Ácido Acético , Administração Cutânea , Analgésicos/química , Analgésicos/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Artrite Experimental/induzido quimicamente , Azepinas/química , Crotonatos/química , Crotonatos/farmacocinética , Combinação de Medicamentos , Composição de Medicamentos , Interações Medicamentosas , Liberação Controlada de Fármacos , Adjuvante de Freund , Ligação de Hidrogênio , Cetoprofeno/química , Cetoprofeno/farmacocinética , Masculino , Camundongos , Dor/induzido quimicamente , Permeabilidade , Coelhos , Ratos , Toluidinas/química , Toluidinas/farmacocinética
12.
AAPS PharmSciTech ; 20(8): 322, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650263

RESUMO

The objectives of this work were to prepare a 5 wt% lidocaine-diclofenac ionic liquid drug-loaded gelatin/poly(vinyl alcohol) transdermal patch using a freeze/thaw method and to evaluate its physicochemical properties, in vitro release of lidocaine and diclofenac, and stability test. The lidocaine-diclofenac ionic liquid drug was produced by the ion pair reaction between the hydrochloride salts of lidocaine and the sodium salts of diclofenac. The thermal properties of the final drug product were significantly changed from the primary drugs. The ionic liquid drug could be dissolved in water and mixed in a polymer solution. The resulting transdermal patch was then exposed to 10 cycles of freezing and thawing preparation at - 20°C for 8 h and at 25°C for 4 h, respectively. As a result, it was found that the lidocaine-diclofenac ionic liquid drug-loaded transdermal patch showed good physicochemical properties and could feasibly be used in pharmaceutical applications. The lidocaine-diclofenac ionic liquid drug was not affected by the properties of the transdermal patch due to the lack of chemical interaction between polymer base and drug. The high drug release values of both lidocaine and diclofenac were controlled by the gelatin/poly(vinyl alcohol) transdermal patch. The patch showed good stability over the study period of 3 months when kept at 4°C or under ambient temperature.


Assuntos
Diclofenaco/farmacocinética , Gelatina/farmacocinética , Líquidos Iônicos/farmacocinética , Lidocaína/farmacocinética , Álcool de Polivinil/farmacocinética , Adesivo Transdérmico , Administração Cutânea , Anestésicos Locais/química , Anestésicos Locais/farmacocinética , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Diclofenaco/química , Combinação de Medicamentos , Liberação Controlada de Fármacos , Congelamento , Gelatina/química , Líquidos Iônicos/química , Lidocaína/química , Álcool de Polivinil/química
13.
Int J Pharm ; 572: 118723, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31628978

RESUMO

5-aminosalicylic acid (5-ASA) is the most widely used drug for the treatment of ulcerative colitis. The benefits of targeted delivery of 5-ASA to the large intestine are well known, resulting in reduced systemic absorption and increased local concentrations at the disease site. In the present study, a 5-ASA colon delivery system based on the time-dependent strategy, exploiting the relatively consistent small intestinal transit time (SITT), was manufactured and evaluated in vitro as well as in vivo. The system was obtained by successive spray-coating of an immediate-release tablet core with low-viscosity HPMC and Eudragit® L. The enteric film was effective in preventing release during the acidic stage of the in vitro test, while the HPMC coating brought about reproducible lag phases prior to release in phosphate buffer medium. A γ-scintigraphy investigation pointed out that, following administration to fasted and fed volunteers, disintegration of the units never occurred prior to colon arrival. In all cases, a lag time preceded the appearance of the drug and its N-acetyl metabolite in the bloodstream, which was found to correlate with the time of disintegration in a linear mode. The plasma levels of the drug and metabolite as well as their cumulative urinary recovery were relatively low with respect to those reported when 5-ASA is delivered to the small bowel.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Colo/metabolismo , Sistemas de Liberação de Medicamentos , Mesalamina/administração & dosagem , Administração Oral , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/urina , Estudos Cross-Over , Liberação Controlada de Fármacos , Jejum/metabolismo , Humanos , Masculino , Mesalamina/sangue , Mesalamina/farmacocinética , Mesalamina/urina , Pessoa de Meia-Idade , Cintilografia , Adulto Jovem
14.
Skin Pharmacol Physiol ; 32(6): 318-327, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31614350

RESUMO

BACKGROUND AND AIM: Since the pharmacological effects of diclofenac (DF) are short-lived because of its short half-life, prolongation of the pharmacological effect in a topical formulation is needed for more appropriate clinical use. For the enhancement of dermal accumulation and prolongation of the pharmacological effect of drugs, the aim of this study was to develop a simple gel formulation containing an ion-pair complex of DF and phenylephrine (PHE), which induce constriction of the vascular smooth muscles. MATERIALS AND METHODS: The ion-pair complex was prepared by mixing sodium DF and an ethanolic solution of PHE. The formed complex was characterized by powder X-ray diffraction (PXRD) and Fourier-transform infrared (FT-IR) spectroscopy. The ion-pair complex for the gel formulation was prepared by mixing an equimolar concentration of 50% 1,3-butylene glycol and distilled aqueous solution of 2% xanthan gum, which was characterized by proton nuclear magnetic resonance (1H-NMR). Skin permeation and accumulation of DF and PHE were evaluated by in vitro and in vivo studies. RESULTS: From the results of PXRD and FT-IR, it was suggested that new crystalline peaks formed by the ion-pair complex and their complex interacted with the carboxyl group in DF and the amino group in PHE. In the gel formulation, the ion-pair complexes were detected by 1H-NMR. The ion-pair complex enhanced the accumulation of DF in the skin in the in vitro study. On the other hand, PHE accumulation in the dermis increased with the ion-pair complex, as exhibited by the in vivo study. CONCLUSION: A new gel formulation containing the ion-pair complex of DF and PHE was developed, which improved the accumulation of DF in skin.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Diclofenaco/administração & dosagem , Portadores de Fármacos/administração & dosagem , Fenilefrina/administração & dosagem , Vasoconstritores/administração & dosagem , Administração Cutânea , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Diclofenaco/química , Diclofenaco/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Feminino , Géis , Técnicas In Vitro , Masculino , Fenilefrina/química , Fenilefrina/farmacocinética , Difração de Pó , Espectroscopia de Prótons por Ressonância Magnética , Ratos Wistar , Pele/metabolismo , Absorção Cutânea/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Suínos , Porco Miniatura , Vasoconstritores/química , Vasoconstritores/farmacocinética , Difração de Raios X
15.
J Dairy Sci ; 102(12): 11465-11469, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31629517

RESUMO

Flunixin is a nonsteroidal anti-inflammatory drug and the most commonly prescribed analgesic in cattle in the United States. Recently, the US Food and Drug Administration (FDA) approved a transdermal formulation of flunixin for control of pyrexia associated with bovine respiratory disease and the control of pain associated with foot rot. The transdermal formulation is not currently approved for use in lactating dairy cattle in the United States, but extra-label use in dairy cattle is permissible under US regulations. The objectives of this study were to determine the pharmacokinetics in milk of dairy cows treated with transdermal flunixin and determine an appropriate withdrawal time for milk. Ten lactating Holstein cows were enrolled into the study in mid lactation. Following treatment, cows were milked 3 times per day through 144 h. Milk samples were collected for drug analysis using ultra-high-pressure liquid chromatography coupled with a triple quadrupole mass spectrometer. The geometric mean maximum concentration for flunixin in milk was 0.010 µg/mL and was 0.061 µg/mL for the active metabolite, 5-hydroxyflunixin. The geometric mean terminal half-life was 20.71 h for flunixin and 22.62 h for 5-hydroxyflunixin. Calculations to approximate a withdrawal time in milk following transdermal flunixin administration were accomplished using a statistical tolerance limit procedure. This analysis indicated that it would be prudent to observe a withdrawal period of 96 h following the last treatment. This is more than twice as long as the labeled withdrawal period of 36 h following use of the injectable formulation. The withdrawal period suggested by this work should be applied carefully, as this study was not conducted under the full quality control practices required by the US FDA for a full drug approval study. Caution should be taken when applying this withdrawal time to diseased animals, animals that are milked with different milking frequencies, and those in different stages of production as these have all been shown to affect drug depletion from milk.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Clonixina/análogos & derivados , Leite/metabolismo , Administração Cutânea , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Bovinos , Cromatografia Líquida de Alta Pressão , Clonixina/administração & dosagem , Clonixina/metabolismo , Clonixina/farmacocinética , Feminino , Lactação , Espectrometria de Massas
16.
J Photochem Photobiol B ; 199: 111619, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31622787

RESUMO

Curcumin, a naturally derived polyphenolic compound has potent activities against cardiac disease like reducing hypertrophy, increasing antioxidant activity, maintaining hormone levels and blood pressure etc. Polymeric curcumin nanoparticles is a solemn concern nowadays in accordance to improve the beneficial properties of curcumin by diminishing its disadvantages like hydrophobic nature thereby results in maximum delivery of drug curcumin at the target. This study demonstrated the application of curcumin capped gold loaded poly (lactic-co-glycolic acid) nanoparticles (CAu-PLGA Nps) for the inhibition of cardiac hypertrophy by preserving myocardial functions of Wister rat model. Rat models were arbitrarily divided into five groups and observation period was 10 weeks; 1. Control 2. Enalopril (EP), an hypertropic agent induced group 3. EP and Curcumin (C) 4. EP and Curcumin capped gold (CAu) Nps and 5. EP and CAu-PLGA Nps injected group. CAu-PLGA Nps was first synthesized from double emulsion-solvent evaporation method and were characterized by its adoptable techniques such as FT-IR, XRD, SEM and TEM analysis. These analyses demonstrate the encapsulation of curcumin capped gold nanoparticles into PLGA there confirms the successful synthesis of CAu-PLGA Nps. Animals studies illustrates that the CAu-PLGA Nps has significantly produced cardiac anti-hypertrophy and drug delivery when compared to the other groups. CAu-PLGA Nps exhibit increased survival rate, improved cardiac functions like cardiac systolic and diastolic function, maintaining heart weight and left ventricle pressure at the controlled level. Beneficiary activities of CAu-PLGA Nps were associated with its cardiovascular functions like anti-inflammatory, antioxidant, controls cardiomycete growth, increased drug delivery, prevents accumulation of cholesterol and prevents myocardial infarction.


Assuntos
Anti-Inflamatórios não Esteroides/química , Cardiomegalia/tratamento farmacológico , Curcumina/química , Nanopartículas Metálicas/química , Nanocápsulas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Antioxidantes , Terapia Combinada/métodos , Curcumina/farmacocinética , Liberação Controlada de Fármacos , Emulsões/química , Ouro/química , Humanos , Masculino , Tamanho da Partícula , Fototerapia/métodos , Polimerização , Ratos , Solventes/química
17.
Pharm Dev Technol ; 24(10): 1278-1286, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31535942

RESUMO

Flurbiprofen (FB) is an effective nonsteroidal anti-inflammatory and BCS class II drug and its poor solubility plays a critical role in limiting its bioavailability. Nanosuspensions can be defined as nanosized colloidal dispersions of drug particles stabilized with stabilizers. The solubility of poor soluble drugs can be increased thanks to their small size and large surface area. The aim of this study is to optimize FB nanosuspensions. The formulations were stabilized with Plantacare 2000® as a surfactant using a combination of High Speed Homogenization (HSH) and High Pressure Homogenization techniques (HPH). We also investigated the effects of the critical process parameters (CPPs) of these techniques (homogenization speed & time for HSH and homogenization pressure & cycle for HPH) on three critical quality attributes of nanosuspensions, being the particle size (PS), polydispersity index (PDI) and zeta potential (ZP). After the optimization of HSH, the macrosuspension was transferred to a high pressure homogenizer. After producing FB nanosuspensions by the HPH technique, seven processes which comprise different homogenization pressures, or combinations and different cycles, were applied. Due to the combination of HSH and HPH techniques and the optimization of CPPs, an optimum formulation for a dermal application was found using a 33 full factorial design with these process parameters, and characterization studies were also performed.


Assuntos
Anti-Inflamatórios não Esteroides/química , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Flurbiprofeno/química , Nanopartículas/química , Pressão , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/normas , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Flurbiprofeno/farmacocinética , Flurbiprofeno/normas , Tamanho da Partícula , Permeabilidade , Ratos Wistar , Absorção Cutânea/efeitos dos fármacos , Propriedades de Superfície , Suspensões
18.
Drug Dev Ind Pharm ; 45(11): 1807-1820, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31489829

RESUMO

This study is using the targeted approach and anti-inflammatory action of the probiotic biomass to lessen the side effects of therapeutic agents of ulcerative colitis. The aim of the present study is to prepare mesalamine loaded eudragit S-100 with probiotic microparticles by spray drying method. The in-vitro release of the optimized formulation was 90.55 ± 2.42 in 24 hr, which display controlled drug release of mesalamine at a particular region. Mesalamine loaded eudragit S-100 with probiotic microparticles (F12) presented average particle size of 4.91 µm. The statistical analysis was done by one way ANOVA and then comparison test of Bonferroni was done and p values <.05 were considered as significant. The effects of spray dried microparticles over inflamed Caco-2 cell were also evaluated by determining the concentration of IL-8. From in-vivo study it was seen that pretreatment of mesalamine with probiotic prevents DNBS (Dinitrobenzenesulfonic acid) induced colitis in rats and represents protective action against ulcerative colitis because of its antioxidant and anti-inflammatory actions. The results give the foundation for a combination of targeted approach along with the anti-inflammatory potential of the probiotic which might help to decrease the problems which are seen with the traditional cure and management of ulcerative colitis.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Composição de Medicamentos/métodos , Mesalamina/administração & dosagem , Probióticos/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacocinética , Benzenossulfonatos/toxicidade , Células CACO-2 , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/patologia , Modelos Animais de Doenças , Portadores de Fármacos/química , Combinação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Lactobacillus acidophilus , Masculino , Mesalamina/efeitos adversos , Mesalamina/farmacocinética , Tamanho da Partícula , Ácidos Polimetacrílicos/química , Probióticos/farmacocinética , Ratos , Ratos Wistar
19.
J Vet Pharmacol Ther ; 42(6): 640-646, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435966

RESUMO

Pharmacokinetic (PK) studies of oral firocoxib in large animal species have been limited to horses, preruminating calves, and adult camels. The aim of this study was to describe pharmacokinetics and bioavailability of firocoxib in adult goats. Ten healthy adult goats were administered 0.5 mg/kg firocoxib intravenously (i.v.) and per os (p.o.) in a randomized, crossover study. Plasma firocoxib concentrations were measured over a 96-hr period for each treatment using HPLC and mass spectrometry, and PK analysis was performed. The p.o. formulation reached mean peak plasma concentration of 139 ng/ml (range: 87-196 ng/ml) in 0.77 hr (0.25-2.00 hr), and half-life was 21.51 hr (10.21-48.32 hr). Mean bioavailability was 71% (51%-82%), indicative of adequate gastrointestinal absorption of firocoxib. There were no negative effects observed in any animal, and all blood work values remained within or very near reference range at the study's conclusion. Results indicate that oral firocoxib is well-absorbed and rapidly reaches peak plasma concentrations, although the concentration also decreased quickly prior to the terminal phase. The prolonged half-life may suggest tissue accumulation and higher plasma concentrations over time, depending on dosing schedule. Further studies to determine tissue residue depletion, pharmacodynamics, and therapeutic concentrations of firocoxib in goats are necessary.


Assuntos
4-Butirolactona/análogos & derivados , Anti-Inflamatórios não Esteroides/farmacocinética , Cabras/sangue , Sulfonas/farmacocinética , 4-Butirolactona/sangue , 4-Butirolactona/metabolismo , 4-Butirolactona/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/sangue , Área Sob a Curva , Estudos Cross-Over , Feminino , Cabras/metabolismo , Meia-Vida , Sulfonas/sangue , Sulfonas/metabolismo
20.
Drug Dev Ind Pharm ; 45(11): 1777-1787, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31418598

RESUMO

Development of extended release oral formulations of dexketoprofen trometamol (DT), a rapidly eliminated drug with high solubility, poses a great challenge especially when a portion of the dose is to be absorbed from the colon. In this study, site-specific release-retardant mini-matrix tablets (SSRRMTs) were developed and functionally coated with pH-responsive materials to achieve a site-specific delivery of DT at the duodenojejunal (DSRRMT) and ileocecal (ISRRMT) regions. Stomach-specific coated mini-tablets (SSCMTs) were manufactured for immediate release of about 16% of the daily dose of DT in the stomach. The SSCMT, DSRRMT, and ISRRMT were combined into a solid dosage form (C-SSRRMT tablets or capsules) to achieve the required linear release profile for once daily administration of DT. The SSRRMT and C-SSRRMT formulations were evaluated for the physical properties, in vitro-disintegration and in vitro dissolution and proved to be consistent with the pharmacopeial specifications. The in vitro release profiles of both C-SSRRMT tablets and capsules showed a constant release rate of about 6 mg/h and were similar to that of the theoretical target linear release profile. The pharmacokinetic study using human volunteers showed the bioequivalence of a single oral dose of C-SSRRMT capsules compared to three-successive oral doses of the immediate release market tablets with less ups and downs in the drug levels. The C-SSRRMT capsules formulation, may therefore, constitute an advance in the extended oral delivery of DT without the lack of efficacy and the adverse events frequently encountered in multiple daily dosing of the immediate release tablets.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Preparações de Ação Retardada/farmacocinética , Cetoprofeno/análogos & derivados , Trometamina/farmacocinética , Administração Oral , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Área Sob a Curva , Estudos Cross-Over , Preparações de Ação Retardada/administração & dosagem , Esquema de Medicação , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Voluntários Saudáveis , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Cetoprofeno/administração & dosagem , Cetoprofeno/farmacocinética , Masculino , Solubilidade , Comprimidos , Equivalência Terapêutica , Trometamina/administração & dosagem
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