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1.
The drug release characteristics of beads made of poly(methyl vinyl ether-co-maleic acid) using Zn2+ as the crosslinking agent were investigated with respect to the influence of microwave irradiation. The beads were prepared by an extrusion method with sodium diclofenac as a model water-soluble drug. They were subjected to microwave irradiation at 80 W for 5 and 20 min, and at 300 W for 1 min 20 s and 5 min 20 s. The profiles of drug dissolution, drug content, drug–polymer interaction and polymer–polymer interaction were determined by dissolution testing, drug content assay, differential scanning calorimetry and Fourier transform infrared spectroscopy. Treatment of beads by microwave at varying intensities of irradiation can aid to retard the drug release with a greater reduction extent through treating the beads for a longer duration of irradiation. The treatment of beads by microwave induced the formation of multiple polymeric domains of great strength and extent of polymer–polymer and drug–polymer interaction. The release of drug from beads was retarded via the interplay of OH, NH, CH, (CH2)n and CO functional groups of these domains, and was mainly governed by the state of polymer relaxation of the matrix unlike that of the untreated beads of which the release of drug was effected via drug diffusion and polymer relaxation. In comparison to Ca2+ crosslinked matrix which exhibited inconsistent drug release retardation behavior under the influence of microwave, the extent and rate of drug released from the Zn2+ crosslinked beads were greatly reduced by microwave and the release of drug from these beads was consistently retarded in response to both high and low intensity microwaves.  相似文献   

2.
Localized and sustained delivery of anti-cancer agents to the tumor site has great potential for the treatment of solid tumors. A chitosan–egg phosphatidylcholine (chitosan–ePC) implant system containing PLA-b-PEG/PLA nanoparticles has been developed for the delivery of paclitaxel to treat ovarian cancer. Production of volumes of ascites fluid in the peritoneal cavity is a physical manifestation of ovarian cancer. In vitro release studies of paclitaxel from the implant were conducted in various fluids including human ascites fluid. A strong correlation (r2 = 0.977) was found between the release of paclitaxel in ascites fluid and PBS containing lysozyme (pH 7.4) at 37 °C. The drug release mechanism for this system was proposed based on swelling, degradation and morphology data. In addition, in vitro release of paclitaxel was found to be a good indicator of the in vivo release profile (correlation between release rates: r2 = 0.965). Release of paclitaxel was found to be sustained over a four-week period following implantation of the chitosan–ePC system into the peritoneal cavity of healthy Balb/C mice. Also, the concentrations of paclitaxel in both plasma and tissues (e.g. liver, kidney and small intestine) were found to be relatively constant.  相似文献   

3.
In the present work the interaction between chitosan hydrochloride (HCS) and two different types of mucin – one obtained from bovine submaxillary glands and the other from porcine stomach – was investigated. Two hydration media were tested: distilled water and 0.1 M HCl. Intrinsic viscosity, which provides information about polymeric chain conformation, was assessed in both media for HCS and bovine submaxillary mucin. Changes in the specific viscosity of HCS–mucin mixtures were observed as a function of the polymer:mucin weight ratio. The formation of interaction products was indicated by a minimum in the specific viscosity. Such a minimum occurred at different polymer:mucin weight ratios depending on the hydration medium and mucin type. This suggested a different stoichiometry of interaction. Turbidimetric measurements were also effected in order to evidentiate the eventual precipitation of the polymer–mucin interaction products. While in distilled water the precipitation of the interaction product did occur, in acidic medium, although a minimum in specific viscosity was observed, no precipitate was formed. The two techniques employed, viscosimetric and turbidimetric, allowed us to investigate for both mucins the influence of hydration medium on the formation of the HCS–mucin interaction products and to conclude that a slightly acid–neutral pH favours the interaction between HCS and mucins.  相似文献   

4.
The effect of four formulation and processing variables, calcium concentration, drying condition, concentration of hardening agent and hardening time on the bead properties and the release characteristics of a model drug from calcium pectinate gel (CPG) beads were studied. A poorly soluble compound, indomethacin, was used as the model drug. The investigated variables affected the bead size, the entrapment efficiency and the release of indomethacin from CPG beads. Drug release was found to be a function of the formulation and processing variables. The slower drug release was achieved from the formulations with higher calcium concentration, higher concentration of hardening agent and longer hardening time. The drying condition, however, did not influence the drug release. The mechanism of indomethacin release from CPG beads followed the diffusion controlled model for an inert porous matrix. All drug release data fitted well to the Higuchi square root time expression.  相似文献   

5.
The aim of this study was to evaluate the possible interactions in the solid state between the thiazide diuretics: bendroflumethiazide (BFMT), hydroflumethiazide (HFMT) and hydrochlorothiazide (HCT) and polyvinylpyrrolidone (PVP) following processing. The glass transition temperatures (Tgs) of a range of binary co-spray-dried PVP–thiazide composites were determined and compared to the predictions of the Gordon–Taylor, Fox, Couchman–Karasz, Kwei and Schneider equations. The solid composites of the thiazide diuretics and PVP were prepared by a spray drying technique. Properties of composites were determined with the use of helium pycnometry and FTIR spectroscopy. For many systems studied the experimentally detected Tgs exhibited large positive deviations when compared with the values predicted by the Gordon–Taylor, Fox and Couchman–Karasz equations. The data was better fitted by the Schneider equation consistent with a drug–polymer interaction. FTIR analysis revealed that strong hydrogen bonding between the sulphonamide groups of the thiazide diuretics and the PVP molecule was responsible for the increase in the Tgs. Additionally, in the case of BFMT–PVP composites, an interaction between the phenyl group and polymer ring was apparent. Glass transition–composition behaviour for amorphous drug–PVP composites deviated from the predictions of the commonly used Gordon–Taylor equation. Deviations were consistent with interactions between the components in the amorphous mixtures. The Schneider equation may be successfully applied to fit the Tg-composition profiles obtained, where other models fail to give good predictions.  相似文献   

6.
Regulatory interest is increasing for drug transporters generally and P-glycoprotein (Pgp) in particular, primarily in the area of drug–drug interactions. To aid in both identifying and discharging the potential liabilities associated with drug–transporter interactions, the pharmaceutical industry has a growing requirement for routine and robust non-clinical assays. An assay was designed, optimised and validated to determine the in vitro inhibitory potency of new chemical entities (NCEs) towards human Pgp-mediated transport. [3H]-Digoxin was established as a suitable probe substrate by investigating its characteristics in the in vitro system (MDCKII-MDR1 cells grown in 24-multiwell inserts). The inhibitory potencies (apparent IC50) of known Pgp inhibitors astemizole, GF120918, ketoconazole, itraconazole, quinidine, verapamil and quinine were determined over at least a 1000-fold concentration range. Validation was carried out using manual and automatic techniques. [3H]-Digoxin was found to be stable and have good mass balance in the system. In contrast to [A → B] transport, [3H]-digoxin [B → A] transport rates were readily measured with good reproducibility. There was no evidence of saturation of transport up to 10 μM digoxin and 30 nM digoxin was selected for routine assay use, reflecting clinical therapeutic concentrations. IC50 values ranged over approximately 100-fold with excellent reproducibility. Results from manual and automated versions were in close agreement. This method is suitable for routine use to assess the in vitro inhibitory potency of NCEs on Pgp-mediated digoxin transport. Comparison of IC50 values against clinical interaction profiles for the probe inhibitors indicated the in vitro assay is predictive of clinical digoxin–drug interactions mediated via Pgp.  相似文献   

7.
The aim of this work was to prepare lectin-conjugated chitosan–Ca–alginate microparticles (MPs) loaded with acid-resistant particles of 5-fluorouracil (5-FU) for efficient local treatment of colon cancer. MPs were prepared by a novel one-step spray-drying technique and after wheat germ agglutinin (WGA) conjugation, they were characterized for size, swelling behavior, surface charge, entrapment efficiency and in vitro drug release. Prepared particles were spherical, with 6.73 μg/mg of WGA conjugated onto their surface. The size and zeta potential increased after conjugation, from 6.6 to 14.7 μm and from 9.6 to 15.3 mV, while drug encapsulation was 75.6 and 72.8%, respectively after conjugation. The swelling behavior of beads was mainly determined by properties of the cross-linked chitosan–alginate network. In vitro drug release studies carried out in simulated in vivo conditions with respect to pH, confirmed the potential of the particles to release the drug in a controlled manner. Also, the drug release was not significantly affected by WGA conjugation. The retention of biorecognitive activity of WGA after covalent coupling to MPs was confirmed by haemagglutination test. Functionalized MPs showed excessive mucoadhesiveness in vitro, due to the positive surface charge, pH-dependent swelling of the matrix and lectin–sugar recognition.  相似文献   

8.
Semi-micro column high-performance liquid chromatographic method with ultraviolet detection for the determination of triazolam (TZ) in rat plasma and brain microdialysate is described. The separation was achieved on a 250×1.5 mm, i.d. C18 column and the column effluent was monitored at 222 nm. The detection limits at a signal-to-noise ratio of 3 obtained using spiked plasma and artificial cerebrospinal fluid were 2.1 and 0.7 ng/ml, respectively. The method was applied to drug–drug interaction study of TZ with itraconazole (ITZ). The peak concentration (Cmax) and the area under the curve (AUC) of TZ in brain microdialysate after simultaneous administration of TZ (2.5 mg/kg, intravenously (i.v.)) and ITZ (25 mg/kg, p.o.) to rats increased 3.4-folds (P<0.001) and 2.9-folds (P<0.001), respectively, compared to those of TZ alone. Also, the AUC of TZ in plasma increased 2.6-folds and remarkable delay in its elimination half-life (t1/2) was observed. The concentrations of TZ in brain microdialysate and plasma were also measured after single administration of TZ (2.5 mg/kg, i.v.) to rats pretreated with daily administration of ITZ (25 mg/kg, p.o.) once a day for a week. There was no significant difference in TZ's Cmax in both ITZ treatments (P>0.2) however its t1/2 after the daily pretreatment with ITZ was significantly increased (P<0.05). In plasma, the AUC of TZ after daily pretreatment of ITZ was lower than the single combined treatment, but significantly different from TZ's AUC in the absence of ITZ (P<0.05). As a result, single simultaneous administration of TZ with ITZ and single administration of TZ after daily pretreatment with ITZ to rats, ITZ seriously interfered with the pharmacokinetic parameters of TZ in plasma and brain micodialysate.  相似文献   

9.
The aim of the present work was to investigate the influence of polymer concentration and polymer:mucin weight ratio on chitosan–mucin interaction, assessed by means of viscosimetric measurements. Two hydration media, distilled water and 0.1 M HCl, were used. Chitosan solutions were prepared at concentrations greater than the characteristic entanglement concentration and mixed with increasing amounts of porcine gastric mucin. Viscosity measurements were performed on the polymer–mucin mixtures and on polymer and mucin solutions having the same concentrations as in the mixtures. The flow curves were fitted according to a modified form of Cheng–Evans equation in order to obtain the relevant model parameters: low shear viscosity η0 and high shear viscosity η, indexes of the sample structure at rest and upon high shear, respectively. The formation of chitosan–mucin interaction products was determined on the basis of the changes in η0 and η of the mixtures as a function of polymer:mucin weight ratio. Rheological synergism parameter was also calculated. The results obtained suggest that two different types of rheological interaction occur between chitosan and mucin in both media, depending on polymer concentration and polymer:mucin weight ratio: one is characterized by a minimum in viscosity and occurs at higher polymer:mucin weight ratio, the other one produces a positive rheological synergism and is observed in presence of an excess of mucin. Only the last one causes a ‘strengthening’ of the mucoadhesive interface and it is responsible for the mucoadhesive joint. This hypothesis is confirmed by tensile stress measurements performed on HCS solutions in presence of mucin dispersions at different concentrations.  相似文献   

10.
The aim of this work was to assess the effectiveness and actual advantages of the microwave (MW) technology for preparing ternary complexes of ketoprofen (Keto) with β-cyclodextrin (β-Cd) or methylated-β-cyclodextrin (Meβ-Cd) and phosphatidylcholine (EPC3) with respect to conventional preparation methods, such as co-grinding and sealed-heating. The products obtained with the different techniques were characterized by differential scanning calorimetry (DSC), X-ray powder diffractometry, FT-IR spectroscopy and dissolution studies. For each method, the influence of different experimental conditions on the physical–chemical properties of the final products has been also investigated. DSC analysis was used to monitor physical stability of ternary complexes during 2 years storage under ambient conditions. MW irradiation resulted to be a rapid and very convenient preparation technique. In fact, it was more effective than the considered conventional methods, enabling obtainment in shorter times of products with better performance. In particular, the Keto–Meβ-Cd–EPC3 product prepared by MW treatment at 750 W for 10 min allowed achievement of about 80% of drug dissolution after 60 min, in comparison with the 50% and 63% values obtained for the corresponding products prepared by 30-min co-grinding or 60-min sealed-heating. Moreover, such ternary products were more effective in improving drug dissolution than the corresponding Keto–Meβ-Cd systems. Furthermore, the MW treatment at such irradiation energy enabled obtainment of totally dehydrated samples, which maintained unchanged solid-state characteristics and showed no susceptibility to ambient humidity after 2 years storage at ambient temperature. Therefore, MW-treated Keto–Meβ-Cd–EPC3 systems can be successfully used for formulation of tablets with enhanced drug dissolution behaviour.  相似文献   

11.
Inhibition of P-glycoprotein (PGP) resulting from the co-administration of substrate drugs represents a potential source of drug–drug interactions. Although in vitro screens can readily identify such interactions, the accuracy with which they mimic interactions in tissues or their value in predicting interactions in vivo is unresolved. This was addressed for the model PGP substrate digoxin by comparing the modulation of its permeability across Caco-2 cells and ex vivo human and rodent intestine by drugs for which pharmacokinetic data on interactions with digoxin in man is available. All five compounds (talinolol, omeprazole, verapamil, quinidine, cyclosporin) dose-dependently increased absorptive (A–B) digoxin permeability with maximal increases of 2.2–4.5-fold across Caco-2. Quantitatively similar increases were observed in ex vivo human and mouse intestine and studies in mdr1a(−/−) intestine confirmed that these interactions are mediated solely by PGP. In vitro changes in digoxin permeability were qualitative indicators of the increase in digoxin Cmax for these compounds in man, although accounting for the luminal drug concentrations expected for a given oral dose was a critical consideration. Based on a limited dataset these data suggest that Caco-2 accurately mimics intestinal digoxin interactions and may be useful in predicting the threshold dose at which interactions become clinically significant. Further studies across a wider range of drugs are needed to determine the broader applicability of in vitro data for quantitative prediction of clinical drug interactions.  相似文献   

12.
Doxorubicin was chemically conjugated to acrylated chitosan in order to obtain sustained-release profiles of doxorubicin from thermo-responsive and photo-crosslinkable hydrogels. Chitooligosaccharide was acrylated with glycidyl methacrylate and subsequently conjugated to doxorubicin via an amide linkage. A mixture of doxorubicin–chitosan conjugates, acrylated Pluronic, and doxorubicin formed physical gels at 37 °C. Photo-irradiation was subsequently performed to chemically crosslink the physical hydrogel at 37 °C. Chitooligosaccharide–doxorubicin conjugates in the doxorubicin hydrogels significantly reduced burst release of free doxorubicin from doxorubicin hydrogels compared hydrogels without the conjugates. Upon incubating doxorubicin hydrogels at 37 °C, chitosan–doxorubicin conjugates were confirmed to be degraded into more hydrophilic oligomers by reversed-phase chromatography. In vitro cytotoxicity assay using released media from doxorubicin hydrogels showed that degraded chitosan–doxorubicin had cytotoxicity comparable to free doxorubicin. Athymic nude mice bearing human lung adenocarcinoma were subjected to intra-tumoral injections of physical hydrogels. After photo-crosslinking injected hydrogels using surgical catheters, tumor sizes, body weights, and survivals were measured for 1 month. Released media from doxorubicin hydrogels exerted similar cytotoxicities to free doxorubicin, and the tumor volume was significantly reduced for 1 month compared to other samples. Thus, doxorubicin hydrogels containing doxorubicin conjugates can be employed as a novel injectable anti-cancer drug aiming to achieve sustained release of doxorubicin for several weeks against solid tumors.  相似文献   

13.
We have previously shown that a single i.p. injection of nitrosomethylurea (NMU) in 3-day-old rats orally treated with the pesticide mancozeb (MZ), the flavonoid quercetin (Q) or in combination (MZ-Q) induces hyperplasia, atypical acinar cell proliferation and carcinoma in situ (CIS) in the pancreas. This work studies the effect of oral administration of phenobarbital (PB) on this model of pancreatic carcinogenesis. The animals were fed on a diet supplemented by MZ or/and Q from the 10th day of pregnancy, thorough lactation and as pups after weaning until being sacrificed at week 24. Saline injection with non-supplemented diet was used for the control group (SAL). The experimental groups were (1) SAL (control), (2) SAL-PB, (3) NMU, (4) NMU-PB, (5) MZ-NMU, (6) MZ-NMU-PB, (7) Q-NMU, (8) Q-NMU-PB, (9) MZ-Q-NMU and (10) MZ-Q-NMU-PB. Acinar cell hyperplasia was found in all groups of NMU-treated rats. Dysplastic foci (DYS) were seen in groups 3–10 at the following percentages: 19, 48, 71, 27, 71, 35, 100 and 30, respectively. CIS were recorded in groups 4 to 10 at percentages: 4, 36, 13, 11, 0, 16, 5, respectively. Conclusion: Although PB, Q or MZ given alone enhance DYS lesions in NMU-treated rats, the MZ/Q/PB combined treatments may increase (mainly in males) or decrease (mainly in female) the DYS and CIS proportion. Because PB, MZ and Q influence P450 enzymes, we suggest that these enzymes play a role in the carcinogenesis process.  相似文献   

14.
Clozapine is often used in combination with other medications. To date, there has been no comprehensive review of drug–drug interactions involving clozapine. This review summarizes published reports of suspected drug–drug interactions, and assesses their clinical significance. A computerized search was conducted using MEDLINE (1975–1996) to retrieve all reports of adverse events associated with the concurrent use of clozapine and other agents. Forty-three reports involving 19 different drugs were evaluated. Clozapine appeared to be involved in pharmacokinetic and pharmacodynamic interactions when prescribed concurrently with most major classes of therapeutic agents. In general, the addition of other medications with similar pharmacological effects or side-effects to clozapine may enhance these effects in an additive or possibly synergistic manner. The selective serotonin reuptake inhibitor fluvoxamine was involved in the most thoroughly documented pharmacokinetic interactions, while a number of reports were found implicating various benzodiazepines in apparent pharmacodynamic interactions. No clozapine–drug combination is absolutely contraindicated, but some members of a given therapeutic class may pose less risk than others when used concurrently with clozapine. © 1997 John Wiley & Sons, Ltd.  相似文献   

15.
16.
The Tris(hydroxymethyl)aminomethane (TRIS) salt of a substituted 5,6,7,8-tetrahydro-1,8-naphthyridine compound (I) in a mannitol-based formulation was stressed at various conditions. Liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) analyses of the stressed samples revealed that oxidation and dimerization were the primary degradation pathways for this compound. 1H- and 13C-nuclear magnetic resonance (NMR) spectroscopy were used to characterize the isolated dimers. The aromatized degradate, N-oxide, amide, and three dimeric products were all confirmed by either LC/MS using authentic standards or NMR spectroscopy. In general, the aromatized product was always the primary degradate produced under all stress conditions. When stressed at 80 °C, the TRIS counterion also underwent thermal degradation to yield formaldehyde in situ which reacted with the parent compound to form a unique methylene-bridged dimeric product and an N-formyl degradate. A minor condensation product between the compound I and the TRIS counterion was also detected in the 80 °C stressed samples. Under 40 °C/75% RH stress conditions, TRIS derived degradates were insignificant, while dimers formed by compound I became predominant. In addition, two hydroxylated products (7-OH and 5-OH) were also detected. Mechanisms for the formation of the oxidative and dimeric degradates were proposed.  相似文献   

17.
目的研究交联甲壳胺PEG尼莫地平(rosslinked chitosan PEG nimodipine,RCPN)缓释颗粒的性质及体外释药特性。方法采用乳化交联法制备交联甲壳胺PEG尼莫地平缓释颗粒;用红外光谱(IR)对其结构进行表征;扫描电子显微镜(SEM)观察颗粒形态及表面结构;考察颗粒的粒径分布、颗粒中药物含量测定及在不同介质中药物的释放。结果电镜扫描显示颗粒呈球形,表面圆整,个别表面有凹凸状;RCPN缓释颗粒平均粒径为1.20 mm;红外图谱显示甲壳胺的氨基和戊二醛的羰基发生反应生成Schiffs碱。该颗粒剂有缓释作用,释药特性符合Higuchi方程。结论以交联甲壳胺做为辅料制备的缓释颗粒在体外具有缓释作用。  相似文献   

18.
Abstract: A recently discovered neurotoxic compound, l–methyl–4–phenyl–l,2,3,6–tetrahydropyridine, has been found to cause a parkinsonian–like syndrome in man and monkey, but not in laboratory animals such as rat, mouse and guinea pig. MPTP seems to selectively destroy the melanin containing dopaminergic cells in pars compacta of substantia nigra. Lower mammalian species do not have melanin in these cells, which indicates that the presence of neuromelanin may be of importance for the development of MPTP–induced lesions. By means of whole–body autoradiography of 3H–MPTP in mice, accumulation and retention was observed in the dopaminergic pathways, in locus caeruleus and in structures in the medulla oblongata and spinal cord. A high uptake was also seen in melanin–containing tissues such as in the eyes of pigmented mice. MPTP has earlier been found to have high affinity in vitro for dopamine melanin, which is similar to the pigment in substantia nigra. The typical features of the MPTP–induced neurotoxicity with destruction of pigmented nerve cells and development of parkinsonism may be due to accumulation and retention of MPTP and its metabolites in these cells. In species with pigmented nerve cells, such as man and monkey, the accumulation may be much more pronounced because of the melanin affinity of MPTP and its metabolites  相似文献   

19.
The purpose of this study was to investigate the possibility to develop different levels of correlation between in vitro dissolution parameters and in vivo pharmacokinetic parameters for three rifampicin formulations. A level A correlation of in vitro release and in vivo absorption could be obtained for individual plasma level data by means of the Wagner and Nelson method. Linear correlation could be obtained when percent dose released in vitro was plotted vs percent dose absorbed in vivo with correlation coefficients between 0.954, 0.983 and 0.997 for the formulations studied. A second level correlation between mean in vitro dissolution time (MDT) and mean in vivo residence time (MRT) was performed with a correlation coefficient of 0.536, 0.420 and 0.335. Finally, it was also possible to establish a good in vitro–in vivo correlation when the T50%hrs (time taken to release 50% of rifampicin) in vitro and CmaxTmax or AUC in vivo were compared.  相似文献   

20.
Orteronel is a nonsteroidal, selective inhibitor of 17,20‐lyase that was recently in phase 3 clinical development as a treatment for castration‐resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm , respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50 > 100 µm ). Orteronel also does not exhibit time‐dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug–drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)‐warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration–time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a ‘non‐inhibitor’ and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. Copyright © 2014 John Wiley & Sons, Ltd.  相似文献   

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