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1.
Pharmaceutics ; 13(3)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799884

RESUMO

Supinoxin is a novel anticancer drug candidate targeting the Y593 phospho-p68 RNA helicase, by exhibiting antiproliferative activity and/or suppression of tumor growth. This study aimed to characterize the in vitro and in vivo pharmacokinetics of supinoxin and attempt physiologically based pharmacokinetic (PBPK) modeling in rats. Supinoxin has good permeability, comparable to that of metoprolol (high permeability compound) in Caco-2 cells, with negligible net absorptive or secretory transport observed. After an intravenous injection at a dose range of 0.5-5 mg/kg, the terminal half-life (i.e., 2.54-2.80 h), systemic clearance (i.e., 691-865 mL/h/kg), and steady state volume of distribution (i.e., 2040-3500 mL/kg) of supinoxin remained unchanged, suggesting dose-independent (i.e., dose-proportional) pharmacokinetics for the dose ranges studied. After oral administration, supinoxin showed modest absorption with an absolute oral bioavailability of 56.9-57.4%. The fecal recovery following intravenous and oral administration was 16.5% and 46.8%, respectively, whereas the urinary recoveries in both administration routes were negligible. Supinoxin was mainly eliminated via NADPH-dependent phase I metabolism (i.e., 58.5% of total clearance), while UDPGA-dependent phase II metabolism appeared negligible in the rat liver microsome. Supinoxin was most abundantly distributed in the adipose tissue, gut, and liver among the nine major tissues studied (i.e., the brain, liver, kidneys, heart, lungs, spleen, gut, muscles, and adipose tissue), and the tissue exposure profiles of supinoxin were well predicted with physiologically based pharmacokinetics.

2.
Pharmaceutics ; 13(3)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800741

RESUMO

Rivaroxaban (RXB), a novel oral anticoagulant that directly inhibits factor Xa, is a poorly soluble drug belonging to Biopharmaceutics Classification System (BCS) class II. In this study, a hot-melt extruded amorphous solid dispersion (HME-ASD) containing RXB is prepared by changing the drug:polymer ratio (Polyvinylpyrrolidione-vinyl acetate 64, 1:1-1:4) and barrel temperature (200-240 °C), fixed at 20% of Cremophor® RH 40 and 15 rpm of the screw speed, using the hot-melt extruding technique. This study evaluates the solubility, dissolution behavior, and bioavailability for application to oral drug delivery and optimizes the formulation of rivaroxaban amorphous solid dispersion (RXB-ASD). Based on a central composite design, optimized RXB-ASD (PVP VA 64 ratio 1:4.1, barrel temperature 216.1 °C, Cremophor® RH 40 20%, screw speed 15 rpm) showed satisfactory results for dependent variables. An in vitro drug dissolution study exhibited relatively high dissolution in four media and achieved around an 80% cumulative drug release in 120 min. Optimized RXB-ASD was stable under the accelerated condition for three months without a change in crystallinity and the dissolution rate. A pharmacokinetic study of RXB-ASD in rats showed that the absorption was markedly increased in terms of rate and amount, i.e., the systemic exposure values, compared to raw RXB powder. These results showed the application of quality by design (QbD) in the formulation development of hot-melt extruded RXB-ASD, which can be used as an oral drug delivery system by increasing the dissolution rate and bioavailability.

3.
Pharmacol Res ; 165: 105423, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33434621

RESUMO

Brain derived neurotrophic factor (BDNF) promotes maturation of dopaminergic (DAergic) neurons in the midbrain and positively regulates their maintenance and outgrowth. Therefore, understanding the mechanisms regulating the BDNF signaling pathway in DAergic neurons may help discover potential therapeutic strategies for neuropsychological disorders associated with dysregulation of DAergic neurotransmission. Because estrogen-related receptor gamma (ERRγ) is highly expressed in both the fetal nervous system and adult brains during DAergic neuronal differentiation, and it is involved in regulating the DAergic neuronal phenotype, we asked in this study whether ERRγ ligand regulates BDNF signaling and subsequent DAergic neuronal phenotype. Based on the X-ray crystal structures of the ligand binding domain of ERRγ, we designed and synthesized the ERRγ agonist, (E)-4-hydroxy-N'-(4-(phenylethynyl)benzylidene)benzohydrazide (HPB2) (Kd value, 8.35 µmol/L). HPB2 increased BDNF mRNA and protein levels, and enhanced the expression of the BDNF receptor tropomyosin receptor kinase B (TrkB) in human neuroblastoma SH-SY5Y, differentiated Lund human mesencephalic (LUHMES) cells, and primary ventral mesencephalic (VM) neurons. HPB2-induced upregulation of BDNF was attenuated by GSK5182, an antagonist of ERRγ, and siRNA-mediated ERRγ silencing. HPB2-induced activation of extracellular-signal-regulated kinase (ERK) and phosphorylation of cAMP-response element binding protein (CREB) was responsible for BDNF upregulation in SH-SY5Y cells. HPB2 enhanced the DAergic neuronal phenotype, namely upregulation of tyrosine hydroxylase (TH) and DA transporter (DAT) with neurite outgrowth, both in SH-SY5Y and primary VM neurons, which was interfered by the inhibition of BDNF-TrkB signaling, ERRγ knockdown, or blockade of ERK activation. HPB2 also upregulated BDNF and TH in the striatum and induced neurite elongation in the substantia nigra of mice brain. In conclusion, ERRγ activation regulated BDNF expression and the subsequent DAergic neuronal phenotype in neuronal cells. Our results might provide new insights into the mechanism underlying the regulation of BDNF expression, leading to novel therapeutic strategies for neuropsychological disorders associated with DAergic dysregulation.

4.
Biomed Pharmacother ; 133: 111041, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378949

RESUMO

Poly (ADP-ribose) polymerase 1 (PARP1)-dependent cell death in the retinal pigment epithelium (RPE) is implicated in dry age-related macular degeneration (AMD). Although PARP1 inhibitors are available for treating dry AMD, their delivery route is not ideal for patients. The aim of this study was to test the efficacy of a novel PARP1-inhibitory compound (PIC) in vitro and in vivo. This study presents PIC, a novel small molecule, with superior efficacy to PARP1 inhibitors in the market. PIC demonstrated a distinctive inhibitory profile against PARP isotypes than the FDA-approved PARP1 inhibitors. PIC inhibited PARP1 activation at an IC50 of 0.41 ± 0.15 nM in an enzyme-based assay in vitro and at IC50 and EC50 in ARPE-19 cells of 0.11 ± 0.02 nM and 0.22 ± 0.02 nM, respectively, upon H2O2 insult. PIC also moderated mitochondrial fission and depolarization and maintained cellular energy levels under oxidative stress in ARPE-19 cells. Furthermore, PIC demonstrated good corneal penetration in a rat model, presenting PIC as a promising candidate for eye drop therapeutics for dry AMD. When PIC was administered as an eye drop formulation, RPE morphology was preserved, maintaining the thickness of the outer nuclear layers under sodium iodate (SI) treatment in rats. In SI-treated rabbits, eye drop administration of PIC also retained the structural and functional integrity when analyzed using funduscopy and electroretinogram. Collectively, our data portray PIC as an attractive treatment measure for dry AMD.


Assuntos
Degeneração Macular/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Administração Oftálmica , Animais , Antioxidantes/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Humanos , Iodatos , Degeneração Macular/induzido quimicamente , Degeneração Macular/enzimologia , Degeneração Macular/patologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Absorção Ocular , Soluções Oftálmicas , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Coelhos , Ratos Sprague-Dawley , Epitélio Pigmentado da Retina/enzimologia , Epitélio Pigmentado da Retina/patologia
5.
Nanoscale Res Lett ; 15(1): 133, 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32572634

RESUMO

Oleanolic acid has been used only as a subsidiary agent in cosmetic products. The aim of the study is to show the effect of oleanolic acid as an active ingredient for the alleviation of wrinkles in humans and to develop a polymeric micelle formulation that enables poorly soluble oleanolic acid to be used as a main ingredient in cosmetic products for reducing wrinkles. The solubility of oleanolic acid was evaluated in solubilizers, surfactants, and polymers. The particle sizes and shapes of polymeric micelles containing oleanolic acid were evaluated by electrophoretic light scattering spectrophotometer and scanning electron cryomicroscopy. Encapsulation efficiency and skin permeation were measured by HPLC. Stability of the polymeric micelles stored at 40 °C for 3 months was evaluated by visual observation, particle size measurement, and oleanolic acid content measurement. Polymeric micelles in final product ampoule form were applied around the eyes of 23 female subjects for 8 weeks. Five skin parameters were evaluated by optical profilometry every 4 weeks for 8 weeks. In addition, professionals made visual observations of the skin and a human skin irritation study was conducted. Polymeric micelles of oleanolic acid with a particle size of less than 100 nm were prepared using Capryol 90® and poloxamer. The skin permeation rate of the oleanolic acid in the polymeric micelles was higher than that in the other solutions made of oleanolic acid dispersed in 2 different surfactants. No significant changes in particle size, color, or oleanolic acid content were observed, and the polymeric micelles stored at 40 °C for 3 months did not undergo phase separation. After 8 weeks of application, skin irritation had not developed and all five parameters evaluated by optical profilometry as well as the visual evaluation scores were significantly improved. This study showed that the polymeric micelles of oleanolic acid prepared in this study were stable and effective at alleviating wrinkles in humans as the principal active ingredient. Based on these findings, it is expected that polymeric micelles of oleanolic acid can be widely used in cosmetic applications.

6.
J Pharm Biomed Anal ; 179: 112987, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31761376

RESUMO

Motolimod (VTX-2337) is an agonist of toll-like receptor 8. In this study, a novel and sensitive liquid chromatography-tandem mass spectrometry method was developed for quantifying motolimod in rat plasma and subsequently used in a pharmacokinetic study. Proteins were precipitated from plasma samples using acetonitrile prior to the analysis. GS-9620 was used as an internal standard. High-performance liquid chromatography was performed using a Spursil C18-EP column (3 µm, 50 × 2.1 mm). Aqueous ammonium formate and acetonitrile were used as the mobile phase. Motolimod was detected using an electrospray ionization interface under multiple reaction monitoring conditions in the positive ion mode. The developed method produced a linear correlation over a concentration range of 1-1000 ng/mL (r = 0.9944). Intra- and inter-day precision values ranged from 4.8%-10.7% (the lower limit of quantification precision value was 16.3 %), whereas intra- and inter-day accuracy values ranged from 0.3%-9.1 %. The mean recovery of motolimod from rat plasma was 109.4 %. Additionally, motolimod was found to be stable under various conditions (three freeze-thaw cycles, 6-h storage at room temperature, short- and long-term stability tests, and processing). The developed method was successfully used in a pharmacokinetic study in rats. Motolimod showed non-linear pharmacokinetics following its intravenous administration to rats at 0.6-6 mg/kg. Additionally, very low exposure (<1 %) was obtained following oral administration of the drug to rats. The results also showed that motolimod has a low metabolic stability in the liver microsomes and exhibits extensive binding to the plasma proteins.

7.
J Adv Vet Anim Res ; 6(4): 481-485, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31819875

RESUMO

Objective: We performed a randomized two-way crossover study to evaluate the pharmacokinetic profiles of two high-dose ascorbic acid (AA) after IV infusion in healthy beagle dogs. Materials and Methods: The dogs were administered IV AA at two doses of 1.5 and 3 gm/kg for 4 h, and the AA concentration in plasma and urine pH was measured before and after administration. Results: The plasma concentrations of AA in both groups peaked 3 h after administration. Among the two groups, the urine pH was not significantly different (p = 0.1299-0.7944). High-dose IV AA did not induce serious adverse events in dogs. Conclusion: The results of this study suggest that the high dose of AA which reaches the therapeutic dose for cancer and supports the safety of high-dose IV AA in dogs.

8.
Chem Commun (Camb) ; 55(70): 10424-10427, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31407744

RESUMO

The development of sensitive and reliable fluorescent probes for the early diagnosis of Alzheimer's disease (AD) is highly challenging and plays an important role in achieving effective treatments. Herein, we designed and synthesized an indole-based fluorophore for TTR in human plasma, an important hallmark of AD pathogenesis. This robust and simple fluorescent method allows quantification of TTR in the complex biological matrix.


Assuntos
Doença de Alzheimer/diagnóstico , Corantes Fluorescentes/química , Pré-Albumina/metabolismo , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/metabolismo , Humanos , Limite de Detecção , Espectrometria de Fluorescência
9.
Clin Pharmacol ; 11: 51-56, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936756

RESUMO

Purpose: The purpose of this study was to investigate the effects of the type of formulation on the efficacy of warfarin. Materials and methods: The electronic medical records of patients with cerebral infarction, who were administered tablet or powder formulations of warfarin from 2013-2015, were retrospectively analyzed. Clinical data, changes in the international normalized ratio (INR), the warfarin dose, and the time to reach the plasma warfarin concentration that could induce an adverse effect, such as bleeding, were evaluated. Coefficients of variation of INR and of the warfarin dose, as well as the warfarin sensitivity index (WSI), were used to evaluate the INR stability. Statistical analysis of the data was performed using a independent t-test. Additionally, survival analysis was performed. Results: The data showed that 57 and 137 patients were administered warfarin as powder and tablet formulations, respectively. We noted that INR, WSI, and INR/dose × body weight differed significantly between the two groups of patients. The median survival times to reach the plasma warfarin concentration that could induce adverse effects were 3.6 and 4.2 days of treatment with the powder and tablet formulations, respectively. The efficacy of warfarin was higher when the drug was administered as a powder than when it was administered as a tablet. Conclusion: The findings of this study indicate that INR should be carefully monitored in the first 4 days of warfarin administration as a powder formulation.

10.
J Vet Intern Med ; 33(2): 531-535, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30548689

RESUMO

BACKGROUND: Although the demand for esomeprazole is increasing in veterinary medicine, the pharmacokinetics (PK) and pharmacodynamics of esomeprazole have been described in only a few studies. OBJECTIVE: To determine the PK of 0.5 and 1 mg/kg esomeprazole administered IV q12h and to investigate its effects on intragastric pH in healthy dogs. ANIMALS: Six adult Beagles. METHODS: Open-label, randomized, and crossover design. The dogs received 0.5 or 1 mg/kg esomeprazole IV q12h for 48 hours. Plasma concentrations of esomeprazole were measured by high-performance liquid chromatography-tandem mass spectrometry. Intragastric pH was determined using the Bravo pH monitoring system and recorded as mean percentage time (MPT) for which pH was ≥3 and ≥4 for 24 hours in each group. RESULTS: The peak plasma concentration and area under the curve from the time of dosing to the last measurable concentration in the 1 mg/kg group were higher than those in the 0.5 mg/kg group. However, when the dosage normalized, intergroup differences were not significant. The MPTs for which intragastric pH was ≥3 and ≥4 for 48 hours were 88% ± 7% and 81% ± 9% for the 0.5 mg/kg group and 90% ± 9% and 85% ± 11% for the 1 mg/kg group, respectively, with no significant intergroup differences. CONCLUSIONS AND CLINICAL IMPORTANCE: The pharmacokinetic parameters and acid suppressant effect for 0.5 and 1 mg/kg esomeprazole were not significantly different. Furthermore, the efficacy of esomeprazole 0.5 mg/kg IV q12h was sufficient to increase intragastric pH in Beagles.


Assuntos
Antiulcerosos/farmacologia , Cães/metabolismo , Esomeprazol/farmacologia , Animais , Antiulcerosos/administração & dosagem , Antiulcerosos/farmacocinética , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/veterinária , Estudos Cross-Over , Cães/sangue , Relação Dose-Resposta a Droga , Esomeprazol/administração & dosagem , Esomeprazol/farmacocinética , Ácido Gástrico/metabolismo , Determinação da Acidez Gástrica/veterinária , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Injeções Intravenosas/veterinária , Distribuição Aleatória
11.
J Pharm Biomed Anal ; 164: 590-597, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30469108

RESUMO

The antioxidant enzyme human extracellular superoxide dismutase (SOD3) is a promising biopharmaceutical candidate for the treatment of various diseases. To support the early development of SOD3 as a biopharmaceutical, a simple, sensitive, and rapid liquid chromatography tandem mass spectrometry procedure was developed and validated for the determination of SOD3 levels in the plasma of ICR mice. After purification with Ni-NTA magnetic beads and digestion with trypsin, SOD3 signature peptides and internal standard signature peptide (ISP) were separated via high performance liquid chromatography using a Zorbax C18 column (2.1 × 50 mm, 3.5 µm) and a mobile phase consisting of 10 mM ammonium formate, 0.1% formic acid, and acetonitrile. The analyte and ISP were detected via a tandem mass spectrometer in electrospray ionization and multiple reaction monitoring modes to select both the signature peptide for SOD3 at m/z 669 to 969 and the ISP at m/z 655 to 941 in the positive ion mode. The calibration curves were linear (r > 0.99) between 5 and 1000 µg/mL with a lower limit of quantification of 5 µg/mL. The relative standard deviation ranged from 3.08 to 8.84% while the relative error ranged from -0.13 to -9.56%. This method was successfully applied to a preclinical pharmacokinetic study of SOD3 in male ICR mice.


Assuntos
Produtos Biológicos/farmacocinética , Fracionamento Químico/métodos , Superóxido Dismutase/farmacocinética , Animais , Produtos Biológicos/sangue , Fracionamento Químico/instrumentação , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Células HEK293 , Humanos , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Peptídeos/sangue , Peptídeos/isolamento & purificação , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/sangue , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacocinética , Padrões de Referência , Reprodutibilidade dos Testes , Organismos Livres de Patógenos Específicos , Espectrometria de Massas por Ionização por Electrospray/instrumentação , Espectrometria de Massas por Ionização por Electrospray/métodos , Superóxido Dismutase/administração & dosagem , Superóxido Dismutase/sangue , Superóxido Dismutase/isolamento & purificação , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
12.
J Nanosci Nanotechnol ; 19(2): 634-639, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30360134

RESUMO

The aim of this work was to prepare and assess a self-nanoemulsifying drug delivery system (SNEDDS) containing water-insoluble orlistat that was used for the inhibition of lipase activity in gastrointestinal lumen. The pseudo-ternary phase diagram, composed of orlistat and medium chain triglycerides (MCT) as oil phase and Cremophor EL as surfactant, was made for the confirmation of giving SNEDDS preconcentrate. The physical state, particle size dispersed in water, dissolution and lipase inhibition of SNEDDS preconcentrates were investigated. The appointed SNEDDS preconcentrates in the pseudo-ternary phase diagram showed no endothermic peak of orlistat and a liquid state. The particle sizes of SNEDDS dispersed with water were uniform and in the range of <200 nm. In the dissolution test, the liquid SNEDDS preconcentrate and solid state mixture exhibited 90.89±2.03% versus 22.42±3.71% at 60 min., respectively, whereas the raw orlistat showed no significant dissolution rate. The SNEDDS preconcentrate showed a lipase inhibition of 92.42±1.58% until 60 min., with no significant inhibition activity of orlistat. Therefore, the SNEDDS preconcentrate presented in this work solubilized orlistat and increased its dissolution rate, and resulted in sufficient inhibitory action on lipase.

13.
Exp Eye Res ; 180: 8-17, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30500363

RESUMO

Receptor interacting protein kinase 1 (RIPK1) plays a key role in necroptosis, which is a type of programmed necrosis that is involved in ocular diseases, including glaucoma and dry age-related macular degeneration (AMD). We previously introduced RIPK1-inhibitory compound (RIC), which has biochemical characteristics and a mode of action that are distinct from those of the prototype RIPK1 inhibitor necrostatin-1. The intraperitoneal administration of RIC exerts a protective effect on retinal ganglion cells against a glaucomatous insult. In this study, we examined the protective effect of RIC on retinal pigment epithelium (RPE) against sodium iodate (SI) insult, which is associated with dry AMD pathogenesis. The eye drop administration of RIC that reached on the retina prevented RPE loss in SI-induced retinal degeneration. RIC consistently demonstrated retinal protection in the funduscopy and electroretinogram analyses in SI-injected rabbits and iodoacetic acid-treated mini-pigs. Moreover, the in vivo protective effects of RIC were superior to those of ACU-4429 and doxycycline, which are other medications investigated in clinical trials for the treatment of dry AMD, and RIC did not induce retinal toxicity following topical administration in rats. Collectively, RIC displayed excellent retinal penetration and prevented retinal degeneration in the pathogenesis of dry AMD with a high in vivo efficacy.


Assuntos
Modelos Animais de Doenças , Atrofia Geográfica/prevenção & controle , Substâncias Protetoras/uso terapêutico , Proteína Serina-Treonina Quinases de Interação com Receptores/uso terapêutico , Células Ganglionares da Retina/efeitos dos fármacos , Administração Oftálmica , Animais , Eletrorretinografia , Atrofia Geográfica/induzido quimicamente , Atrofia Geográfica/patologia , Iodatos/toxicidade , Masculino , Oftalmoscopia , Éteres Fenílicos/uso terapêutico , Propanolaminas/uso terapêutico , Coelhos , Ratos , Ratos Sprague-Dawley , Degeneração Retiniana/prevenção & controle
14.
Int J Nanomedicine ; 13: 7095-7106, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464461

RESUMO

Background: The present study aimed to develop orlistat-loaded solid self-nanoemulsifying drug delivery system preconcentrate (SSP) with the minimum use of lipid excipients for the enhanced solubility, in vitro dissolution, lipase inhibition, and in vivo performance. Materials and methods: In the screening of solubilizing vehicles, Solutol HS15 and Lauroglycol 90 were selected as the surfactant and oil phase, respectively. A pseudo-ternary phase diagram composed of Solutol HS15, Lauroglycol 90, and orlistat as an anti-obesity agent and lipid component was constructed, and the SSP regions were confirmed in terms of the particle size distribution in water, melting point by differential scanning calorimetry, and crystallinity by X-ray diffraction. Results: Physicochemical interaction between Solutol HS15 and orlistat resulted in SSP with various melting points in the range of 26°~33°C. The representative maximum orlistat-loaded SSP (orlistat/Solutol HS15/Lauroglycol 90=55/40/5, weight ratio) showed the melting point of 32.23°C and constructed uniform nanoemulsion with the particle size of 141.7±1.1 nm dispersed in water. In the dissolution test at pH 1.2 without any detergent, the SSP reached 98.12%±0.83% until 45 minutes, whereas raw orlistat showed no significant dissolution rate. The dissolution samples containing SSP showed a lipase inhibition of 90.42%±1.58% within 45 minutes. In terms of the reduction level of fat absorption in rats, the intake group of SSP gave a significantly higher fat excretion into stool than the one observed in the raw orlistat group (P<0.05). Conclusion: In conclusion, the suggested novel SSP formulation would be an effective and promising candidate for the treatment of obesity.


Assuntos
Sistemas de Liberação de Medicamentos , Emulsões/química , Nanopartículas/química , Orlistate/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Excipientes/química , Fezes/química , Lipase/metabolismo , Lipídeos/química , Masculino , Óleos/química , Orlistate/administração & dosagem , Orlistate/química , Tamanho da Partícula , Transição de Fase , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química , Sus scrofa , Temperatura de Transição , Difração de Raios X
15.
BMC Vet Res ; 14(1): 291, 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30249242

RESUMO

BACKGROUND: Sildenafil citrate, a highly selective phosphodiesterase type 5 inhibitor, is used to treat pulmonary hypertension (PH) in veterinary medicine. The objective of this study was to investigate pharmacokinetic profiles by oral administration of orally disintegrating film (ODF) and film coated tablet (FCT) formulations and rectal administration of ODF formulation in healthy dogs. Twelve healthy beagle dogs were administered four separate doses of sildenafil: FCT formulation 2 mg/kg orally, ODF formulation 2 mg/kg orally, ODF formulation 2 mg/kg rectally, and ODF formulation 10 mg/kg rectally. For 24 hours following administration, blood samples were collected and the plasma concentrations of sildenafil were assayed by liquid chromatography-tandem mass spectrometry. RESULTS: There were no significant differences in all the pharmacokinetic parameters between FCT and ODF formulations when administrated orally. Cmax at the time of rectal administration was lower when the same dose was given as that orally administered. No serious systemic adverse events (AEs) were observed. CONCLUSIONS: These findings suggest that sildenafil ODF formulation can be used as an alternative to FCT formulation in the treatment of canine PH patients; additionally, rectal administration of sildenafil ODF may be a beneficial treatment option for canine patients who are unable to receive medication orally.


Assuntos
Cães/metabolismo , Inibidores da Fosfodiesterase 5/farmacocinética , Citrato de Sildenafila/farmacocinética , Administração Oral , Administração Retal , Animais , Área Sob a Curva , Estudos Cross-Over , Relação Dose-Resposta a Droga , Masculino , Inibidores da Fosfodiesterase 5/administração & dosagem , Citrato de Sildenafila/administração & dosagem , Comprimidos
16.
Pharmaceutics ; 10(3)2018 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-29966249

RESUMO

Raloxifene hydrochloride (RLH) was formulated into a pH-modified supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) to increase drug solubility and dissolution rate. Optimal formulations of pH-modified S-SMEDDSs were developed by incorporating hydroxypropyl-cellulose-L as a precipitation inhibitor and phosphoric acid as a pH modifier (an acidifier). RLH was dissolved to greater extents by all pH-modified S-SMEDDSs compared with non-pH-modified S-SMEDDSs. In particular, phosphoric acid afforded greater drug dissolution than did the other acidifiers tested, perhaps because phosphoric acid better controlled the pH. More than 50% of the RLH was released from the pH-modified S-SMEDDS at pH 2.5 compared with only ~5% of the drug into aqueous buffer (pH 1.2 or 6.8) after dissolution of a conventional tablet. pH-modified S-SMEDDSs with a hydrophilic polymer and phosphoric acid improved the dissolution behavior of a drug exhibiting poor aqueous solubility.

17.
Eur J Med Chem ; 148: 397-409, 2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29477073

RESUMO

Autotaxin (ATX) is a potential target for the treatment of various cancers. A new series of ATX inhibitors was rationally designed and synthesized based on our previous study. Biological evaluation and structure-activity relationship (SAR) of this series are discussed. Among fourteen synthesized derivatives, six compounds (2, 3, 4, 12, 13 and 14) exhibited enhanced ATX inhibitory activities with IC50 values in the low nanomolar range. Molecular interactions of all the synthesized compounds within the active site of ATX were studied through molecular docking studies. Herein, we describe our lead optimization efforts that resulted in the identification of a potent ATX inhibitor (compound 4 with IC50 = 1.23 nM, FS-3 and 2.18 nM, bis-pNPP). Furthermore, pharmacokinetic properties of this most promising compound are profiled.


Assuntos
Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/química , Antineoplásicos/química , Domínio Catalítico , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Ligação Proteica , Relação Estrutura-Atividade
18.
Xenobiotica ; 48(8): 831-838, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28803538

RESUMO

1. We characterized the pharmacokinetics of tafamidis, a novel drug to treat transthyretin-related amyloidosis, in rats after intravenous and oral administration at doses of 0.3-3 mg/kg. In vitro Caco-2 cell permeability and liver microsomal stability, as well as in vivo tissue distribution and plasma protein binding were also examined. 2. After intravenous injection, systemic clearance (CL), volumes of distribution at steady state (Vss) and half-life (T½) remained unaltered as a function of dose, with values in the ranges of 6.41-7.03 mL/h/kg, 270-354 mL/kg and 39.5-46.9 h, respectively. Following oral administration, absolute bioavailability was 99.7-104% and was independent of doses from 0.3 to 3 mg/kg. In the urine and faeces, 4.36% and 48.9% of tafamidis, respectively, were recovered. 3. Tafamidis was distributed primarily in the liver and not in the brain, kidney, testis, heart, spleen, lung, gut, muscle, or adipose tissue. Further, tafamidis was very stable in rat liver microsomes, and its plasma protein binding was 99.9%. 4. In conclusion, tafamidis showed dose-independent pharmacokinetics with intravenous and oral doses of 0.3-3 mg/kg. Tafamidis undergoes minimal first-pass metabolism, distributes mostly in the liver and plasma, and appears to be eliminated primarily via biliary excretion.


Assuntos
Neuropatias Amiloides Familiares , Benzoxazóis/farmacologia , Benzoxazóis/farmacocinética , Encéfalo/metabolismo , Fígado/metabolismo , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/metabolismo , Neuropatias Amiloides Familiares/patologia , Animais , Encéfalo/patologia , Células CACO-2 , Humanos , Fígado/patologia , Masculino , Microssomos Hepáticos/metabolismo , Microssomos Hepáticos/patologia , Especificidade de Órgãos , Ratos , Ratos Sprague-Dawley
19.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1061-1062: 123-127, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28734159

RESUMO

CKD-712 is a potential treatment for sepsis, as it exhibits protective effects against lipopolysaccharide-mediated platelet aggregation, inducible nitric oxide synthase expression, and cecum-ligation puncture-induced septic mortality in mice. In this study, we develop a rapid and sensitive LC-MS/MS method for determining CKD-712 in rat plasma. CKD-712 and papaverine hydrochloride (an internal standard) were analyzed using an LC-MS/MS system consisting of an Agilent HPLC system (HP-1100) equipped with an Atlantis HILIC Silica (2.1×50mm, 3µm) column and a API 4000 (Applied Biosystems/MDS Sciex, USA) in a positive ESI mode. We utilized multiple reaction monitoring (MRM) at m/z transitions of 306.2-164.0 to analyze CKD-712, and 340.3-202.1 m/z for IS, with a mobile phase of acetonitrile (0.025% trifluoroacetic acid):20mM ammonium acetate (94:6, v/v) at a flow rate of 0.25mL/min. The lower limit of quantification (LLOQ) was 5ng/mL, with a linearity ranging from 5 to 1000ng/mL (r>0.999). Validation parameters including specificity, precision, accuracy, matrix effect, recovery, dilution effect and stability results were well within acceptance criteria, and applied successfully on a pharmacokinetic study in rats.


Assuntos
Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Tetra-Hidroisoquinolinas/sangue , Tetra-Hidroisoquinolinas/farmacocinética , Animais , Estabilidade de Medicamentos , Feminino , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Reprodutibilidade dos Testes , Tetra-Hidroisoquinolinas/química
20.
J Pharm Biomed Anal ; 137: 90-95, 2017 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-28107689

RESUMO

Tafamidis is a first-in-class inhibitor of transthyretin amyloid fibril formation. It has been available in Argentina, Japan, and Mexico for the treatment of transthyretin amyloidosis in adult patients with early-stage symptomatic polyneuropathy. In this study, a rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for the assay of tafamidis in rat plasma. The method was also assessed for its applicability to pharmacokinetic studies in rats. Tafamidis was extracted from rat plasma by the liquid-liquid extraction method using hydrochloric acid and ethyl acetate. A reversed-phase C18 column and a mobile phase consisting of 10mM ammonium formate and acetonitrile were used to achieve chromatographic separation. The flow rate for the mobile phase was set at 0.3mL/min. Tafamidis and 2-CBC, which was used as the internal standard (IS), were analyzed by multiple reaction monitoring in negative ESI mode at m/z transitions of 305.4→261.4 for tafamidis and 271.7→227.8 for the IS. The lower limit of quantification of tafamidis was obtained as 3ng/mL, and the calibration curve was linear over a concentration range of 3-3000ng/mL (R2>0.99). The validation parameters investigated, which were specificity, precision, accuracy, matrix effect, recovery, and stability, were well within acceptable limits. The method was successfully used for the evaluation of the pharmacokinetics of tafamidis in rats.


Assuntos
Benzoxazóis/sangue , Benzoxazóis/farmacocinética , Cromatografia Líquida/métodos , Plasma/química , Espectrometria de Massas em Tandem/métodos , Animais , Benzoxazóis/química , Extração Líquido-Líquido/métodos , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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