查看更多>>摘要：In this paper, the molecular dynamics as well as inter- and intramolecular interactions in the homogenous solid dispersions (SDs) of active pharmaceutical ingredient - probucol (PRO) with acetylated glucose (acGLU), acetylated sucrose (acSUC), and sucrose acetoisobutyrate (aibSUC), prepared in 5:1 molar ratio, have been investigated using broadband dielectric (BD) and Fourier transform infrared (FTIR) spectroscopy. Importantly, high pressure dielectric measurements revealed that as for neat PRO, a breakdown of the isochronal structural (alpha) and JG-beta exact superpositioning, due to increasing separation between both processes under compression, can also be detected in its mixtures with acetylated saccharides (acSACCHs). Furthermore, the analysis of temperature dependences of JG-beta-relaxation times for PRO and PRO-acSACCH SDs at selected isobaric conditions indicated the increase in the cooperativity of the secondary process (reflected in the value of the activation entropy, Delta S beta) at elevated pressure in all systems. The mere addition of the small amount of excipient to neat PRO (p = 0.1 MPa) resulted in a greater value of Delta S beta (it was the most noticeable in the case of aibSUC). Further FTIR studies carried out on the pressure densified glasses of PRO, and binary mixtures suggested that the observed changes in the cooperativity of the JG-beta-process, as well as the failure of the exact isochronal superpositioning of alpha- and JG-beta relaxation times, are due to varying H-bond pattern in the examined single- and two-component systems at high compression/in the presence of saccharide.
查看更多>>摘要：ZCY-15, N-(3,5-dimethyladamatan-1-yl)-N-(3-methylphenyl) urea, is a candidate compound synthesized from the memantine structure and has been shown to be remarkably effective in treating Alzheimer's disease. To elucidate the pharmacokinetics and tissue distribution of ZCY-15 in rats after oral and intravenous administration, a rapid and selective LC-MS/MS method was established for the determination of ZCY-15 in rat plasma and tissues. According to the dissolution characteristics, the plasma samples were prepared by acetonitrile protein precipitation and carbamazepine was selected as the internal standard (IS). After separation by gradient elution using Aqela Venusil ASB C8 (2.1 x 50 mm, 3 mu m), the pretreated samples were analyzed in MRM mode in positive ESI mode. The effective detection limit of this method was 1.95-1000 ngmL- 1. Tissue samples were collected from the heart, liver, spleen, lung, kidney, fat, muscle, brain, hippocampus, testicles or ovaries, large intestine, small intestine and stomach. The proposed method demonstrated fine precision and accuracy for analyzing ZCY15 in selected tissues within the concentration range of standard liquid chromatography-tandem mass spectrometry. The whole analysis time was 3.6 min per sample. After oral administration, the blood and tissue concentrations of ZCY-15 in female rats were significantly higher than those in male rats. The clearance rate of ZCY-15 in female rats was lower than that in male rats. The results confirmed that there were gender differences. It has been shown that ZCY-15 could pass through the blood-brain barrier and was highly concentrated in the hippocampus. We established the first bioanalytical method to quantify ZCY-15 in rodent bio-samples for ongoing pharmacokinetic and tissue distribution studies, and the results were expected to lay foundation for the subsequent studies.
Leow, Jacqueline Wen HuiVerma, Ravi KumarLim, Amos Boon HaoFan, Hao...
11页
查看更多>>摘要：Extrahepatic CYP2J2 metabolism of arachidonic acid (AA) to bioactive regioisomeric epoxyeicosatrienoic acids (EETs) is implicated in both physiological and pathological conditions. Here, we aimed to characterize atypical substrate inhibition kinetics of this endogenous metabolic pathway and its reversible inhibition by xenobiotic inhibitors when AA is used as the physiologically-relevant substrate vis-`a-vis conventional probe substrate astemizole (AST). As compared to typical Michaelis-Menten kinetics observed for AST, complete substrate inhibition was observed for CYP2J2 metabolism of AA to 14,15-EET whereby velocity of the reaction declined significantly at concentrations of AA above 20-30 mu M with an estimated substrate inhibition constant (Ks) of 31 mu M. In silico sequential docking of two AA substrates to orthosteric (OBS) and adjacent secondary binding sites (SBS) within a 3-dimensional homology model of CYP2J2 revealed favorable and comparable binding poses of glide-scores -3.1 and -3.8 respectively. Molecular dynamics (MD) simulations ascertained CYP2J2 conformational stability with dual AA substrate binding as time-dependent root mean squared deviation (RMSD) of protein C alpha atoms and ligand heavy atoms stabilized to a plateau in all but one trajectory (n=6). The distance between heme-iron and omega 6 (C14, C15) double bond of AA in OBS also increased from 7.5 +/- 1.4 ?, to 8.5 +/- 1.8 ?, when CYP2J2 was simulated with only AA in OBS versus the presence of AA in both OBS and SBS (p<0.001), supporting the observed in vitro substrate inhibition phenomenon. Poor correlation was observed between inhibitory constants (Ki) determined for a panel of nine competitive and mixed mode xenobiotic inhibitors against CYP2J2 metabolism of AA as compared to AST, whereby 4 out of 9 drugs had a greater than 5-fold difference between Ki values. Nonlinear Eadie-Hofstee plots illustrated that complete substrate inhibition of CYP2J2 by AA was not attenuated even at high concentrations of xenobiotic inhibitors which further corroborates that CYP2J2 may accommodate three or more ligands simultaneously. In light of the atypical kinetics, our results highlight the importance of using physiologically-relevant substrates in in vitro enzymatic inhibition assays for the characterization of xenobiotic-endobiotic interactions which is applicable to other complex endogenous metabolic pathways beyond CYP2J2 metabolism of AA to EETs. The accurate determination of Ki would further facilitate the association of xenobiotic-endobiotic interactions to observed therapeutic or toxic outcomes.
查看更多>>摘要：Ophthalmic drug delivery via eye drops is inefficient because only about 1-5% of the drug permeates the cornea during the short residence time of a few minutes. Contact lenses are receiving considerable attention for delivering ophthalmic drugs because of higher bioavailability and the possibility of sustained release from hour to days, and possibly longer. The drug release durations from contact lenses are typically measured in vitro and it is challenging to relate the in vitro release to in vivo release, particularly for hydrophobic drugs which may not exhibit sink release in vitro and in vivo. The in vitro release can be fitted to diffusion equation to determine the partition coefficient and diffusivity, which can then be utilized to model in vivo release. The Higuchi equation is frequently used to model the short time release from a contact lens to determine diffusivity with the implicit assumption that the release is under sink conditions and the starting concentration in the lens was uniform. Both conditions may be violated when measuring release of hydrophobic drugs from contact lenses because the diffusivity and partition coefficient, and also the time needed for equilibrium are not known a priori. Here we develop a method to use the data for both loading and release of cyclosporine, which is a common hydrophobic ophthalmic drug, to determine the partition coefficient and diffusivity. The proposed approach does not require sink conditions and also does not require the lens to be fully equilibrated during loading, which may take almost a month for lenses considered here. The model is based on solving the diffusion equation in the gel along with a mass balance in the fluid. The model equations are solved numerically by finite difference. When the value of partition coefficient is high, such as it is for cyclosporine, the dynamic data is only sensitive to a ratio of partition coefficient and diffusivity, and this ratio had to first be determined from the loading data. Then the two unknown parameters were obtained by minimizing the error between the model prediction and experimental data. The method was used to determine D and K for several silicone hydrogel formulations with varying ratio of hydrogel and silicone fractions.
查看更多>>摘要：Panax Notoginseng Saponins (PNS) has been widely used in the prevention and treatment of cardiovascular and cerebrovascular diseases such as myocardial infarction, heart failure and cerebral infarction. However, oral administration of PNS showed low bioavailability because of its instability and poor membrane permeability in the gastrointestinal tract. Here, lipoprotein-inspired hybrid nanoparticles of PNS-Lecithin-Zein (PLZ-NPs) were prepared by using a simple phase separation method, which possessed a core-shell structure, where zein was used as protein part to replace the animal origin protein to increase the resistance to acid and enzymes while lecithin was used as the lipid composition to improve the oral absorption of PNS as well as to increase the drug loading capacity of PNS into the nanocarriers. The results of stability test showed that PLZ-NPs had robust enzymolysis resistance ability for acid and digestive enzymes of gastrointestinal environments. The fluorescent resonance energy transfer (FRET) assay confirmed the ability of LZ-NPs to be intactly absorbed by Caco-2 cell monolayer. Cell transport studies demonstrated that the permeability of PLZ-NPs in Caco-2/HT29-MTX co-culture cell model was 1.5-fold that of PNS. Meanwhile, the single-pass intestinal perfusion assay proved the absorption parameter Peff of PLZ-NPs was 1.75 and 1.80 times higher than that of PNS in the ileum and jejunum, respectively. Finally, the in vivo pharmacokinetic experiment showed that the relative oral bioavailability of PLZ-NPs was 1.71-fold that of free PNS in SD rat. In summary, the employment of the Lecithin/Zein hybrid nanoparticles could be considered as a promising approach for PNS analogues.
查看更多>>摘要：BackgroundThe totality of bacteria, protozoa, viruses and fungi that lives in the human body is called microbiota. Human microbiota specifically colonizes the skin, the respiratory and urinary tract, the urogenital tract and the gastrointestinal system. This study focuses on the intestinal microbiota to explore the drug-microbiota relationship and, therefore, how the drug bioavailability changes in relation to the microbiota biodiversity to identify more personalized therapies, with the minimum risk of side effects. MethodsTo achieve this goal, we developed a new mathematical model with two compartments, the intestine and the blood, which takes into account the colonic mucosal permeability variation - measured by Ussing chamber system on human colonic mucosal biopsies - and the fecal microbiota composition, determined through microbiota 16S rRNA sequencing analysis. Both of the clinical parameters were evaluated in a group of Irritable Bowel Syndrome patients compared to a group of healthy controls. Key ResultsThe results show that plasma drug concentration increases as bacterial concentration decreases, while it decreases as intestinal length decreases too. ConclusionsThe study provides interesting data since in literature there are not yet mathematical models with these features, in which the importance of intestinal microbiota, the "forgotten organ", is considered both for the subject health state and in the nutrients and drugs metabolism.
Garcia, Monica C.Eberhardt, NataliaSanmarco, Liliana M.Ponce, Nicolas E....
10页
查看更多>>摘要：Benznidazole (BZ) is a first-line drug for the treatment of Chagas disease; however, it presents several disadvantages that could hamper its therapeutic success. Multiparticulate drug delivery systems (MDDS) are promising carriers to improve the performance of drugs. We developed BZ-loaded MDDS intended for improving Chagas disease therapy. To assess their efficacy and safety, Trypanosoma (T) cruzi infected BALB/c mice were orally treated with free BZ or BZ-MDDS at different regimens (doses of 50 and 100 mg/kg/day, administered daily or at 2- or 5-days intervals) and compared with infected non-treated (INT) mice. At 100 mg/kg/day, independent of the administration regimen, both treatments were able to override the parasitemia, and at 50 mg/ kg/day significantly reduced it compared to INT mice. BZ-MDDS at a dose of 100 mg/kg/day administered every 5 days (BZ-MDDS 100-13d) induced the lowest cardiac parasite load, indicating an improved efficacy with lower total dose of BZ when loaded to the MDDS. Reactive oxygen species produced by leukocytes were higher in INT and mice treated with BZ at 50 mg/kg/day compared to 100 mg/kg/day, likely because of persistent infection. BZ-MDDS treatments markedly reduced heart and liver injury markers compared to INT mice and those receiving the standard treatment. Therefore, BZ-MDDS exhibited enhanced activity against T. cruzi infection even at lower doses and reduced administration frequency compared to free BZ while increasing the treatment safety. They likely avoid undesired side effects of BZ by keeping a sustained concentration, avoiding plasmatic drug peaks. BZMDDS evidenced significant improvements in experimental Chagas disease treatment and can be considered as a potential improved therapeutic alternative against this illness.
查看更多>>摘要：Structural elucidation of small molecules only available in low quantity (nanogram) is one of the big advantages of the crystalline sponge method. The optimization of various soaking parameters is crucial for effective analyte absorption and repetitive positioning in the pores of the crystal. Time-consuming X-ray diffraction measurements are necessary for data collection and confirmation of successful guest inclusion. In this work, we report a screening method to select optimal soaking conditions without the need of single-crystal X-ray diffraction analysis for individual compounds and mixtures. 14 substances were chosen as test compounds. Parallel guest soaking of individual compounds and mixtures was conducted using various soaking conditions. After evaporation of solvent, excessive material was removed, and guest molecules released through dissolution of the framework. Liquid chromatography-tandem mass spectrometry allowed the estimation of analyte trapped in the pores and the selection of optimal soaking condition dependent on the highest amount of analyte to crystal size (affinity factor). The tool allowed subsequent crystallographic analysis of ten compounds with minimal experiment time. Additionally, a study to examine the lower limit of detection of the crystalline sponge method was conducted. Determination of two target analytes was possible using only 5 ng of sample. Our study shows the potential of an affinity screening to prioritize soaking parameters by estimation of the guest concentration in a single crystal for one or multiple target compounds within a short period of time.
Adel, Islam M.ElMeligy, Mohamed F.Abdelkhalek, AbdelFattah A.Elkasabgy, Nermeen A....
11页
查看更多>>摘要：The goal of this research was to evaluate the beneficial effects of topical curcumin loaded freeze-dried wafers in wound healing. Curcumin wafers were fabricated by cross-linking of chitosan with beta glycerophosphate under magnetic stirring. Composite wafers were prepared by the addition of sodium hyaluronate. Wafers were fabricated by freeze-drying technique. The resulted wafers were examined by naked eye and their dimensions were measured using a caliper. % Drug content, in-vitro release and % water uptake tests were conducted to characterize the fabricated wafers. Porosity testing, compressive mechanical behavior, morphological examination using scanning electron microscopy, thermal behavior using differential scanning calorimetry and Fourier transform infrared spectroscopy were all carried out on the optimized cross-linked wafers followed by their microbiological assays and cytotoxicity studies. The results showed that the optimized wafers possessed high water uptake capabilities while entertaining very high porosity levels (86-89%). Microbiological assay revealed the superiority of the selected curcumin wafers versus free curcumin in bacterial growth inhibition against Staphylococcus epidermidis and Staphylococcus aureus (MRSA) bacteria. The anti-inflammatory effects of the selected curcumin wafers were evaluated against pro-inflammatory cytokines. The results suggested that they were significantly better than free curcumin in lowering cytokines levels. To conclude, the obtained findings revealed that curcumin wafers offered a promising solution in the field of wound healing.
查看更多>>摘要：The inadequate bioavailability and toxicity potential of antiretroviral therapy limit their effectiveness in the complete eradication of HIV from viral reservoirs. The penetration of these drugs into the brain is challenging because of the unfavorable physicochemical properties required to cross the membranes, limiting the transport of the drugs. Thus, in the current study, the authors report a nanocarrier-based drug delivery of a highly hydrophobic drug to overcome the existing limitations of the conventional therapies. An explicitly simple approach was used to overcome the limitations of existing anti-HIV therapies. The monophasic hot homogenized solution of lipid, drug, and solubilizer was diluted with the predetermined hot surfactant solution followed by the ultrasonication to generate the polydisperse nanoparticles with the size range of 50-1000 nm. The anti-HIV1 potential of nanostructured lipid carriers of Etravirine on HIV-infected cell lines showed efficacy with an appreciable increase in the therapeutic index as compared with the plain drug. Further, the results obtained from confocal microscopy along with flow cytometry exhibited efficient uptake of the nanocarrier loaded with coumarin-6 in cells. The pharmacokinetics of Etravirine nanostructured carriers was significantly better in all aspects compared to the plain drug solution, which could be attributed to molecular dispersion in the lipid matrix of the nanocarrier. A significant enhancement of Etravirine concentration of several-fold was also observed in the liver, ovary, lymph node, and brain, respectively, as compared to plain drug solution when assessed by biodistribution studies in rats. In conclusion, ETR-NLC systems could serve as a promising approach for simultaneous multi-site targeting and could provide therapeutic benefits for the efficient eradication of HIV/AIDS infections.
NSTL
Elsevier