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1.
Purpose The objective of this work was to investigate the influence of various preparation and formulation parameters on the in vitro and in vivo release of bupivacaine hydrochloride from an injectable in situ forming microparticle system (ISM).
Methods The in vitro drug release of ISM was investigated as a function of various formulation and process parameters and was compared to the
drug release from in situ forming implants and conventional microparticles. In vivo studies were carried out in male Sprague–Dawley rats.
Results Upon contact with an aqueous medium, the internal polymer phase of the ISM system solidified and formed microparticles. The
initial drug release from ISM systems was reduced with decreasing polymer phase/external oil phase ratio. An advantage of
the ISM system compared to in situ implant systems was the significantly reduced burst effect, resulting in drug release profiles comparable to microparticles
prepared by conventional methods. The in vivo drug release studies were in good agreement with the in vitro drug release. With the ISM system, the analgesic effect of the bupivacaine hydrochloride was prolonged when compared to the
injection of a drug solution or drug-polymer solution.
Conclusions ISM are an attractive alternative for parenteral drug delivery systems. 相似文献
2.
Purpose The efflux transporter, P-glycoprotein (P-gp), located in the brush-border membrane of intestinal absorptive cells, reduces the bioavailability of a wide range of orally administered drugs. Using P-gp inhibitors in transport experiments in Caco-2 cell monolayers is widely accepted as an efficient way to estimate the contribution of P-gp to the intestinal absorption of drugs. However, there still remain some arguments that the inhibitors might affect the function of other proteins. Multidrug resistance 1 gene (MDR1) specifically inhibited Caco-2 cells were constructed, therefore, as a better in vitro evaluation system of intestinal drug absorption.Methods The effective sites of RNAi were selected using siRNA libraries and single siRNAs and MDR1 stable knockdown Caco-2 cells were constructed using a tRNAval-shRNA expression vector.Results In siRNA stably expressed Caco-2 cells, the expression level of MDR1 was reduced at mRNA and protein levels. Transcellular transport studies using digoxin revealed that the P-gp function was suppressed completely, similar to that in verapamil-treated cells.Conclusions MDR1 stable knockdown Caco-2 cells were successfully constructed by RNAi technology. This will consequently allow the development of a selection system for candidate drugs with improved absorption properties. 相似文献
3.
Kim SH Kim SH Yoon HJ Shin DH Park SS Kim YS Park JS Jee YK 《European journal of clinical pharmacology》2011,67(2):121-127
Purpose
It has been suggested that drug-metabolizing enzymes might play important roles in the development of anti-tuberculosis drug (ATD)-induced maculopapular eruption (MPE), as in ATD-induced hepatitis. We investigated the associations between the genetic polymorphisms of drug-metabolizing enzymes and ATD-induced MPE. 相似文献4.
Saijie Zhu Minghuang Hong Lihong Zhang Guotao Tang Yanyan Jiang Yuanying Pei 《Pharmaceutical research》2010,27(1):161-174
Purpose
To investigate the effects of PEGylation degree and drug conjugation style on the in vitro and in vivo behavior of PEGylated polyamidoamine (PAMAM) dendrimers-based drug delivery system. 相似文献5.
Purpose
Multidrug resistance-associated protein 2 (MRP2/ABCC2) is an efflux pump that removes drugs and chemicals from cells. We sought to characterize the expression, trafficking and in vitro activity of seven single nucleotide polymorphisms (SNPs) in the ABCC2 gene.Methods
ABCC2 SNPs were generated using site-directed mutagenesis and stably expressed in Flp-In HEK293 cells, which allows targeted insertion of transgenes within the genome. Total and cell surface expression of MRP2 as well as accumulation of substrates (calcein AM and 5(6)-carboxy-2′,7′-dichlorofluorescein diacetate, CDCF) were quantified in cells or inverted membrane vesicles expressing wild-type (WT) or variant forms.Results
The cell surface expression of the C-24T-, G1249A-, G3542T-, T3563A-, C3972T- and G4544A-MRP2 variants was similar to WT-MRP2. While expression was similar, transport of calcein AM was enhanced in cells expressing the G3542T-, T3563A-, C3972T-, and G4544A-MRP2 variants. By comparison, cells expressing the C2366T-MRP2 variant had 40–50% lower surface expression, which increased the accumulation of calcein AM up to 3-fold. Accumulation of CDCF in inverted membrane vesicles expressing the C2366T-MRP2 variant was also reduced by 50%. In addition, the G1249A-MRP2 variant had decreased transport of CDCF.Conclusions
Taken together, these data demonstrate that genetic variability in the ABCC2 gene influences the in vitro expression, trafficking, and transport activity of MRP2.6.
Purpose
We developed simulation and modeling methods to predict the in vivo pharmacokinetic profiles of acyclovir, following escalating oral doses of valacyclovir, in wildtype and Pept1 knockout mice. We also quantitated the contribution of specific intestinal segments in the absorption of valacyclovir in these mice.Methods
Simulations were conducted using a mechanistic advanced compartmental absorption and transit (ACAT) model implemented in GastroPlus?. Simulations were performed for 3 h post-dose in wildtype and Pept1 knockout mice following single oral doses of 10, 25, 50 and 100 nmol/g valacyclovir, and compared to experimentally observed plasma concentration-time profiles of acyclovir.Results
Good fits were obtained in wildtype and Pept1 knockout mice. Valacyclovir was primarily absorbed from duodenum (42%) and jejunum (24%) of wildtype mice, with reduced uptake from ileum (3%) and caecum/colon (1%), for a total of 70% absorption. In contrast, the absorption of valacyclovir in Pept1 knockout mice was slow and sustained throughout the entire intestinal tract in which duodenum (4%), jejunum (14%), ileum (10%) and caecum/colon (12%) accounted for a total of 40% absorption.Conclusion
The ACAT model bridged the gap between in situ and in vivo experimental findings, and facilitated our understanding of the complicated intestinal absorption processes of valacyclovir.7.
8.
Feighery LM Cochrane SW Quinn T Baird AW O'Toole D Owens SE O'Donoghue D Mrsny RJ Brayden DJ 《Pharmaceutical research》2008,25(6):1377-1386
Purpose To examine whether myosin light chain kinase (MLCK) inhibitors can reduce intestinal epithelial permeability increases in vitro.
Materials and Methods Isolated rat, mouse and human colonic tissue mucosae and Caco-2 monolayers were exposed to cytochalasin D (cD) and sodium
caprate (C10), in the absence and presence of the MLCK inhibitors, ML-9 and D PIK. Transepithelial electrical resistance (TEER) and Papp
of [14C]-mannitol or FITC-dextran 4000 (FD-4) were measured. Western blots were used to measure MLC phosphorylation.
Results Increases in Papp of [14C]-mannitol and decreases in TEER were induced by tight junction openers. These changes were attenuated by ML-9. D-PIK offset
the FD-4 Papp increase induced by C10 in Caco-2 only, while ML-9 and PIK inhibited MLC directly. cD induced constriction of peri-junctional actin in Caco-2 monolayers,
but this was prevented by ML-9. Although mannitol fluxes across colonic mucosae from dextran-sulphate (DSS)-treated mice were
higher than control, they were not ameliorated by either ML-9 or PIK in vitro.
Conclusions ML-9 inhibits paracellular permeability increases in several intestinal epithelial models. D-PIK reduced stimulated paracellular
fluxes in Caco-2 monolayers, but not in tissue. Pre-established increases were not modified by two MLCK inhibitors in a mouse
model of IBD. 相似文献
9.
Genetic polymorphisms in the coding exons of the CYP1A1 gene were analyzed in 100 Koreans. Three types of CYP1A1 polymorphisms, specifically G134A, G184C and A2455G, were identified with allelic frequencies of 18, 3, and 16%, respectively, and no linkage was observed among them. The novel G184C polymorphism identified in this study was associated with the mutation of an alanine residue at position 62 to proline. Other earlier-reported polymorphisms in the coding region of CYP1A1 were not detected.Abbreviations CYP Cytochrome P450 - PCR Polymerase chain reaction 相似文献
10.
Ying Zhao Desheng Zhai Hui He Tingting Li Xijing Chen Hui Ji 《European journal of clinical pharmacology》2009,65(6):579-584
Purpose Our objective was to study the effects of polymorphic the CYP3A5 (allele *1 and *3), MDR1 [single nucleotide polymorphisms (SNPs) G2677T, C3435T] and CACNA1C (SNPs rs2239128, rs2239050, rs2238032) genes on nimodipine oral disposition and response in healthy Chinese subjects.
Methods Pharmacokinetics and pharmacodynamics data were obtained from a bioequivalence study, and the same 20 subjects were genotyped
for CYP3A, MDR1 and CACNA1C. An additional 41 healthy Chinese subjects were recruited to obtain an indication of the distribution of CACNA1C polymorphisms in the Chinese population. Racial differences in the frequency of CACNA1C alleles were assessed. The phenotype differences between genotypes were analyzed.
Results The allelic frequencies of rs2239050 and rs2238032 in our Chinese cohort were different from those in a Caucasian population
(p < 0.01). Subjects with mutant alleles (*3/*3) of the CYP3A5 gene had a decreased oral clearance of nimodipine, with a higher lnCmax or compared with those subjects with the heterozygote (*1/*3) or wild type (*1/*1) gene. The CACNA1C rs2239128 C and rs2239050 G SNPs were associated with a stronger efficacy compared with their respective alleles, rs2239128
T and rs2239050 C. MDR1 polymorphisms showed no significance in terms of nimodipine disposition.
Conclusions The polymorphic CYP3A5 (allele *1 and *3) and CACNA1C genes have effects on nimodipine oral disposition and response in healthy Chinese subjects. The homozygous variant of CYP3A5 (*3/*3) was associated with significantly increased nimodipine exposure. CACNA1C SNPs rs2239128 C and rs2239050 G were associated with a stronger efficacy. 相似文献
11.
Purpose
To determine the in vitro sub-cellular localization and in vivo efficacy of chitosan/GMO nanostructures containing paclitaxel (PTX) compared to a conventional PTX treatment (Taxol®).Methods
The sub-cellular localization of coumarin-6 labeled chitosan/GMO nanostructures was determined by confocal microscopy in MDA-MB-231 cells. The antitumor efficacy was evaluated in two separate studies using FOX-Chase (CB17) SCID Female-Mice MDA-MB-231 xenograph model. Treatments consisted of intravenous Taxol® or chitosan/GMO nanostructures with or without PTX, local intra-tumor bolus of Taxol® or chitosan/GMO nanostructures with or without PTX. The tumor diameter and animal weight was monitored at various intervals. Histopathological changes were evaluated in end-point tumors.Results
The tumor diameter increased at a constant rate for all the groups between days 7-14. After a single intratumoral bolus dose of chitosan/GMO containing PTX showed significant reduction in tumor diameter on day 15 when compared to control, placebo and intravenous PTX administration. The tumor diameter reached a maximal decrease (4-fold) by day 18, and the difference was reduced to approximately 2-fold by day 21. Qualitatively similar results were observed in a separate study containing PTX when administered intravenously.Conclusion
Chitosan/GMO nanostructures containing PTX are safe and effective administered locally or intravenously. Partially supported by DOD Award BC04566412.
Rezvan Yazdian-Robati Mohammad Ramezani Seyed Hamid Jalalian Khalil Abnous Seyed Mohammad Taghdisi 《Pharmaceutical research》2016,33(9):2289-2297
Purpose
The clinical use of Epirubicin (Epi), as an anthracycline drug, is limited because of its cardiotoxicity. Here, an Epirubicin (Epi)-modified polyvalent aptamer system (MPAS) conjugate was developed for the treatment of both murine colon carcinoma cells (C26) and breast cancer cells (MCF-7).Methods
Epi-MPAS conjugate formation was evaluated by fluorometric analysis. Release profiles of Epi from the developed conjugate were analyzed at pHs 5.4 and 7.4. For MTT assay (cytotoxic study) C26 and MCF-7 (target cells) and CHO cells (Chinese hamster ovary cell, nontarget) were treated with Epi, MPAS and Epi-MPAS conjugate. Internalization was assessed by fluorescence imaging and flow cytometry analysis. The designed conjugate was used for prohibition of tumor growth in vivo.Results
Release of Epi from the Epi-MPAS conjugated was pH-dependent (more release at pH 5.5). Flow cytometry analysis and MTT assay showed that Epi-MPAS conjugate could significantly enhance the cellular uptake of Epi and increase its cytotoxicity in target cells as compared with non-targeted cell (CHO). Additionally, this complex could efficiently prohibit the tumor growth in vivo.Conclusion
In conclusion, the developed drug delivery system had the characteristics of efficient Epi loading, pH-dependent drug release and tumor targeting in vitro and in vivo.13.
Jin Guan Liying Zhou Yusheng Pan Haitao Han Hongtao Xu Weisan Pan 《Pharmaceutical research》2010,27(1):105-114
Purpose
The purpose of this paper is to develop a novel gastro-retentive osmotic pump capsule using asymmetric membrane technology. 相似文献14.
Jasmine A. Luzum Kevin M. Sweet Philip F. Binkley Tara J. Schmidlen Joseph P. Jarvis Michael F. Christman Wolfgang Sadee Joseph P. Kitzmiller 《Pharmaceutical research》2017,34(8):1615-1625
Purpose
This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure.Methods
Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n?=?65) or metoprolol (n?=?33).Results
CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02–0.75] p?=?0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84–10.30] p?=?0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200 mg/day).Conclusion
Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.15.
Maren I. Blonk Nathalie van der Velde Patricia M. L. A. van den Bemt Ron H. N. van Schaik Tischa J. M. van der Cammen 《International journal of clinical pharmacy》2010,32(1):26
Objective The objective of this study is to investigate the association between CYP2D6*4, CYP3A5*3 and ABCB1 3435T polymorphisms and drug-related falls. Method Multivariate logistic regression was performed in an existing database in order to study the association between falls history and CYP2D6*4, CYP3A5*3, ABCB1 3435T polymorphisms in patients using fall-risk-increasing CYP2D6, CYP3A5 and P-glycoprotein (gene product of ABCB1) substrates. Results No statistically significant increased fall risk was found in ‘poor metabolizers’ compared to ‘extensive’ and ‘intermediate metabolizers’ using fall-risk-increasing CYP2D6 substrates (Odds ratio (OR) = 2.2; 95% confidence interval (CI) 0.2–25.0), CYP3A5 substrates (OR = 0.9; 95% CI 0.2–3.3) and P-glycoprotein substrates (OR = 2.1; 95% CI 0.2–17.2). Conclusion The hypothesis that ‘poor metabolizers’ have an increased fall risk was not confirmed. A larger study population is needed to confirm the potential association that was seen between CYP2D6*4 and ABCB1 3435T polymorphisms and drug-related falls. 相似文献
16.
Purpose The objectives of the study was to develop a dissolution test method that can be used to predict the oral absorption of montelukast
sodium, and to establish an in vitro/in vivo correlation (IVIVC) using computer simulations.
Methods Drug solubility was measured in different media. The dissolution behaviour of montelukast sodium 10 mg film coated tablets
was studied using the flow-through cell dissolution method following a dynamic pH change protocol, as well as in the USP Apparatus
2. Computer simulations were performed using GastroPlus™. Biorelevant dissolution media (BDM) prepared using bile salts and
lecithin in buffers was used as the dissolution media, as well as the USP simulated intestinal fluid (SIF) pH 6.8 and blank
FaSSIF pH 6.5. Dissolution tests in the USP Apparatus 2 were performed under a constant pH condition, while the pH range used
in the flow through cells was pH 2.0 to 7.5. The in vitro data were used as input functions into GastroPlus™ to simulate the in vivo profiles of the drug.
Results The solubility of montelukast sodium was low at low pH, but increased as the pH was increased. There was no significant difference
in solubility in the pH range of 5.0 to 7.5 in blank buffers, but the drug solubility was higher in biorelevant media compared
with the corresponding blank buffers at the same pH. Using the flow through cells, the dissolution rate was fast in simulated
gastric fluid containing 0.1% SLS. The dissolution rate slowed down when the medium was changed to FaSSIF pH 6.5 and increased
when the medium was changed to FaSSIF medium at pH 7.5. In the USP Apparatus 2, better dissolution was observed in FaSSIF
compared with the USP buffers and blank FaSSIF with similar pH values. Dissolution was incomplete with less than 10% of the
drug dissolved in the USP-SIF, and was practically non existent in blank FaSSIF pH 6.5. The in vitro results of the dynamic dissolution test were able to predict the clinical data from a bioavailability study best.
Conclusions Dynamic dissolution testing using the flow through cell seems to be a powerful tool to establish in vitro/in vivo correlations for poorly soluble drugs as input function into GastroPlus. 相似文献
17.
Summary
Purpose: DDB (dimethyl-4,4′-dimethoxy-5,6,5′6′-dimethylene dioxybiphenyl-2,2′-dicarboxylate) is a synthetic hepatoprotectant which
has been widely used to treat chronic viral hepatitis B patients in China for more than 20 years. In this study, we evaluated
DDB as a multidrug resistance (MDR) chemosensitizing agent.
Methods: A panel of sensitive and resistant cancer cell lines were treated with various concentration of DDB, and the effect on chemosensitivity
and accumulation of anticancer drugs; promotion of apoptosis and P-glycoprotein (P-gp) expression were determined by MTT (Dimethyl
thiazolyl-2,5-diphenyltetrazolium bromide) assay, fluorospectrometry and flow cytometry respectively. Drug resistance reversal
activity of DDB was also examined in BALB/c nude mice bearing both acquired MDR human nasopharyngeal carcinoma KBv200 and
parental KB xenografts. The effect of DDB on the pharmacokinetics of Dox and hematological toxicity induced by Dox was measured
in ICR and C57/BL mice, respectively.
Results: DDB at nontoxic concentrations of 12.5, 25 and 50 μM partly reversed the resistance to vincristine, doxorubicin, paclitaxel
in acquired MDR breast carcinoma MCF-7/Adr cells, KBv200 and intrinsic MDR human hepatocarcinoma Bel7402 cells, whereas no chemosensitizing effect of DDB was observed in sensitive KB and MCF-7 cells. DDB increased the intracellular
accumulation of doxorubicin and inhibited surface P-gp expression in MCF-7/Adr cells. Furthermore, it was found that DDB promoted
doxorubicin-induced apoptosis of Bel7402 cells through enhanced caspase-3 activation. Co-administration of DDB at 300 and 500 mg/kg orally to nude mice increased
the antitumor activity of vincristine to KBv200 xenografts without a significant increase in toxicity. In contrast, Co-administration
of DDB did not inhibit the growth of KB xenografts. DDB also markedly reduced the decrease of leukocytes in doxorubicin-treated
C57/BL mice. Co-administration of DDB increased Dox concentration in ICR mice bearing S180 sarcoma, but no pharmacokinetical
interaction with Dox was observed.
Conclusion: These results indicate that DDB has MDR reversal activity by inhibiting P-gp and when used in combination with anti-cancer
drugs, it could potentially be used as a clinical treatment for P-gp-mediated MDR cancers. 相似文献
18.
19.
Gökalp O Gunes A Cam H Cure E Aydın O Tamer MN Scordo MG Dahl ML 《European journal of clinical pharmacology》2011,67(12):1223-1229
Aim
To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas. 相似文献20.
PURPOSE: This work evaluated gelatin microparticles and biodegradable composite scaffolds for the controlled release of vascular endothelial growth factor (VEGF) in vitro and in vivo. METHODS: Gelatin crosslinking, VEGF dose, and buffer type were investigated for their effects on VEGF release. Release was also evaluated from microparticles confined within porous polymer scaffolds (composites). In vitro and in vivo studies were conducted using radiolabeled VEGF. RESULTS: The effect of VEGF dose on its fractional release from gelatin microparticles in vitro was minimal, but the addition of collagenase to the buffer resulted in a higher cumulative release of VEGF. Gelatin crosslinking extent was a significant factor on release from both microparticles alone and composite scaffolds in vitro and in vivo. VEGF bioactivity from composite scaffolds in vitro was maintained above 90% of the expected bioactivity over 14 days. CONCLUSIONS: VEGF release kinetics were dependent on the extent of gelatin crosslinking and were characteristic of the specific growth factor due to the effects of growth factor size, charge, and conformation on its complexation with gelatin. These studies demonstrate the utility of gelatin microparticles and their composite scaffolds as delivery vehicles for the controlled release of VEGF for tissue engineering applications. 相似文献