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Sample records for vitro stability pharmacokinetics

  1. Pharmacokinetic profile of the microtubule stabilizer patupilone in tumor-bearing rodents and comparison of anti-cancer activity with other MTS in vitro and in vivo.

    Science.gov (United States)

    O'Reilly, Terence; Wartmann, Markus; Brueggen, Joseph; Allegrini, Peter R; Floersheimer, Andreas; Maira, Michel; McSheehy, Paul M J

    2008-11-01

    Patupilone is a microtubule stabilizer (MTS) currently in clinical development. Here, we evaluate the anti-cancer activity in vitro and in vivo in comparison to paclitaxel and describe the pharmacokinetics (PK) of patupilone in tumor-bearing nude mice and rats. The potency in vitro of patupilone and two other MTS, paclitaxel and ixabepilone, was determined using human colon carcinoma cell lines with low (HCT-116, HT-29, RKO) and high (HCT-15) P-glycoprotein expression (P-gp), as well as two multi-drug resistance (MDR) model cell pairs, MCF7/ADR and KB-8511 cells and their respective drug-sensitive parental counterparts. The PK of patupilone was investigated in nude mice bearing HCT-15 or HT-29 xenografts and in rats bearing s.c. pancreatic CA20498 tumors or A15 glioma tumors. Anti-cancer activity in vivo was compared to that of paclitaxel using three different human tumor colon models. The retention and efficacy of patupilone was compared in small and large HT-29 xenografts whose vascularity was determined by non-invasive magnetic resonance imaging. Patupilone was highly potent in vitro against four different colon carcinoma cell lines including those showing multi-drug-resistance. In contrast, paclitaxel and ixabepilone displayed significantly reduced activity with markedly increased resistance factors. In both rats and mice, a single i.v. bolus injection of patupilone (1.5-4 mg/kg) rapidly distributed from plasma to all tissues and was slowly eliminated from muscle, liver and small intestine, but showed longer retention in tumor and brain with no apparent elimination over 24 h. Patupilone showed significant activity against three human colon tumor models in vivo, unlike paclitaxel, which only had activity against low P-gp expressing tumors. In HT-29 tumors, patupilone activity and retention were independent of tumor size, blood volume and flow. The high potency of patupilone, which is not affected by P-gp expression either in vitro or in vivo, and favorable PK

  2. In vitro metabolism and pharmacokinetic studies on methylone

    DEFF Research Database (Denmark)

    Pedersen, Anders Just; Petersen, Trine Hedebrink; Linnet, Kristian

    2013-01-01

    Abuse of the stimulant designer drug methylone (methylenedioxymethcathinone) has been documented in most parts of the world. As with many of the new designer drugs that continuously appear in the illicit drug market, little is known about the pharmacokinetics of methylone. Using in vitro studies...

  3. In vitro pharmacokinetics of anti-psoriatic fumaric acid esters

    Science.gov (United States)

    Litjens, Nicolle HR; van Strijen, Elisabeth; van Gulpen, Co; Mattie, Herman; van Dissel, Jaap T; Thio, H Bing; Nibbering, Peter H

    2004-01-01

    Background Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at in vitro conditions representing different body compartments. Results DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8. Conclusion Together, these in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the

  4. In vitro pharmacokinetics of sirolimus-coated stent for tracheal stenosis

    African Journals Online (AJOL)

    In vitro pharmacokinetics of sirolimus-coated stent for tracheal stenosis. Shanzuan Wang, Zhengxian Chen, Qunying Lin, Qingyu Lin, Yumei Geng, Suwang Wang. Abstract. Purpose: To investigate the in vitro pharmacokinetics of sirolimus-coated stent for tracheal stenosis. Methods: Naked nickel titanium alloy stent was ...

  5. Pharmacokinetics of trefoil peptides and their stability in gastrointestinal contents

    DEFF Research Database (Denmark)

    Kjellev, Stine; Vestergaard, Else Marie; Nexø, Ebba

    2007-01-01

    Trefoil factor family (TFF) peptides are considered promising for therapeutic use in gastrointestinal diseases, and there is a need to explore the fate of injected TFF and the stability of the peptides in the gastrointestinal tract. We studied the pharmacokinetics of intravenously (i.v.) administ...... a higher stability toward gastric acid and digestive enzymes than toward microbial degradation........v.) administered hTFF2 in mice and rats and of hTFF3 administered i.v., intramuscularly, intraperitoneally, and subcutaneously in mice, and estimated by ELISA the decay of the peptides added to rat and human gastrointestinal contents. We found that i.v. injected hTFF2 and hTFF3 were cleared from the circulation...... within 2-3h, exhibiting comparable pharmacokinetic profiles. In contents from the rat stomach, hTFF levels remained unchanged for up to 6 days. In the small and large intestine of rats, the hTFF levels decreased markedly after 4 and 1h, respectively. In small intestinal contents from humans, the levels...

  6. Preparation of finasteride capsules-loaded drug nanoparticles: formulation, optimization, in vitro, and pharmacokinetic evaluation.

    Science.gov (United States)

    Ahmed, Tarek A

    2016-01-01

    In this study, optimized freeze-dried finasteride nanoparticles (NPs) were prepared from drug nanosuspension formulation that was developed using the bottom-up technique. The effects of four formulation and processing variables that affect the particle size and solubility enhancement of the NPs were explored using the response surface optimization design. The optimized formulation was morphologically characterized using transmission electron microscopy (TEM). Physicochemical interaction among the studied components was investigated. Crystalline change was investigated using X-ray powder diffraction (XRPD). Crystal growth of the freeze-dried NPs was compared to the corresponding aqueous drug nanosuspension. Freeze-dried NPs formulation was subsequently loaded into hard gelatin capsules that were examined for in vitro dissolution and pharmacokinetic behavior. Results revealed that in most of the studied variables, some of the quadratic and interaction effects had a significant effect on the studied responses. TEM image illustrated homogeneity and shape of the prepared NPs. No interaction among components was noticed. XRPD confirmed crystalline state change in the optimized NPs. An enhancement in the dissolution rate of more than 2.5 times from capsules filled with optimum drug NPs, when compared to capsules filled with pure drug, was obtained. Crystal growth, due to Ostwald ripening phenomenon and positive Gibbs free energy, was reduced following lyophilization of the nanosuspension formulation. Pharmacokinetic parameters from drug NPs were superior to that of pure drug and drug microparticles. In conclusion, freeze-dried NPs based on drug nanosuspension formulation is a successful technique in enhancing stability, solubility, and in vitro dissolution of poorly water-soluble drugs with possible impact on the drug bioavailability.

  7. Application of in silico, in vitro and preclinical pharmacokinetic data for the effective and efficient prediction of human pharmacokinetics.

    Science.gov (United States)

    Grime, Kenneth H; Barton, Patrick; McGinnity, Dermot F

    2013-04-01

    In the present age of pharmaceutical research and development, focused delivery of decision making data is more imperative than ever before. Resulting from several years' success, failure and consequential learning, this article also proffers advice and guidance on which in vitro and in vivo experiments to perform to facilitate efficient and cost-effective pursuit of candidate drugs with acceptable human pharmacokinetic profiles. Predictive in silico models are important in directing design toward compounds with the highest probability of having suitable DMPK properties rather than in predicting human pharmacokinetics per se, and the value and utility of such approaches are reviewed with the intention of providing direction to DMPK scientists. Relating to absorption, distribution, elimination and effective half-life, strategies are described to provide direction in commonly encountered scenarios.

  8. Enhanced Oral Bioavailability of Efavirenz by Solid Lipid Nanoparticles: In Vitro Drug Release and Pharmacokinetics Studies

    Directory of Open Access Journals (Sweden)

    Praveen Kumar Gaur

    2014-01-01

    Full Text Available Solid lipid nanoparticle is an efficient lipid based drug delivery system which can enhance the bioavailability of poorly water soluble drugs. Efavirenz is a highly lipophilic drug from nonnucleoside inhibitor category for treatment of HIV. Present work illustrates development of an SLN formulation for Efavirenz with increased bioavailability. At first, suitable lipid component and surfactant were chosen. SLNs were prepared and analyzed for physical parameters, stability, and pharmacokinetic profile. Efavirenz loaded SLNs were formulated using Glyceryl monostearate as main lipid and Tween 80 as surfactant. ESLN-3 has shown mean particle size of 124.5±3.2 nm with a PDI value of 0.234, negative zeta potential, and 86% drug entrapment. In vitro drug release study has shown 60.6–98.22% drug release in 24 h by various SLN formulations. Optimized SLNs have shown good stability at 40°C ± 2°C and 75±5% relative humidity (RH for 180 days. ESLN-3 exhibited 5.32-fold increase in peak plasma concentration (Cmax⁡ and 10.98-fold increase in AUC in comparison to Efavirenz suspension (ES.

  9. Predicting Pharmacokinetic Stability by Multiple Oral Administration of Atypical Antipsychotics

    Science.gov (United States)

    Aoki, Kazuo; Sakiyama, Yojiro; Ohnishi, Takashi; Sugita, Makoto

    2013-01-01

    Lower fluctuation, i.e., lower peak-to-trough plasma-concentration variation at steady-state pharmacokinetics, has several advantages for the treatment of schizophrenia with antipsychotics. The reduction of peak concentration can decrease the risk of dose-dependent side effects, such as extrapyramidal symptom and somnolence, and by contrast the increase in trough concentration can decrease the incidence of lack of efficacy due to subtherapeutic drug concentration. Using a one-compartment simulation technique with pharmacokinetic parameters of each atypical antipsychotic collected from package inserts, the fluctuation index was calculated. Among the antipsychotics, the indices varied from 0.018 to 1.9, depending on dosing regimens, formulations and several pharmacokinetic properties. The order of simulated fluctuation index is active-moiety aripiprazole (b.i.d.) blonanserin (b.i.d.)

  10. [Pharmacokinetics of Curcumin Ethosomes in Rats in vitro].

    Science.gov (United States)

    Zhao, Jing; Li, Yuan; Shi, Ming-Xin; Wang, Xue; Zhang, Jing-Qing

    2017-03-01

    To study the oral phamacokinetics of curcumin ethosomes in rats. Pharmacokinetics parameters were detected by DAS 2.1.1 software analysis through data of blood concentrations harvested from HPLC after oral administration of curcumin ethosomes in rats. Analyzed by non-compartmental method, the area under concentration-time curve from 0 to last time [AUC(0-72h)] of curcumin ethosomes was 1.6 times larger than that of free curcumin, the peak concentration (C max) of curcumin ethosomes was 1.5 times higher than that of free curcumin, the relative bioavailability of curcumin ethosomes was 152.2%. The 90% confidential interval of AUC(0-72 h)was 102.2%-128.5%, which was not in standard interval of bioequialence. Analyzed by compartmental method, the AUC(0-72 h)of curcumin ethosomes was 1.4 times larger than that of free curcumin and the relative bioavailability of curcumin ethosomes was 128.2%. The curcumin ethosomes can enhance bioavailability, which has a bioinequivalence with free curcumin.

  11. Stability of alginate microbead properties in vitro

    Science.gov (United States)

    Moya, Monica L.; Morley, Michael; Khanna, Omaditya; Opara, Emmanuel C.

    2013-01-01

    Alginate microbeads have been investigated clinically for a number of therapeutic interventions, including drug delivery for treatment of ischemic tissues, cell delivery for tissue regeneration, and islet encapsulation as a therapy for type I diabetes. The physical properties of the microbeads play an important role in regulating cell behavior, protein release, and biological response following implantation. In this research alginate microbeads were synthesized, varying composition (mannuronic acid to guluronic acid ratio), concentration of alginate and needle gauge size. Following synthesis, the size, volume fraction, and morphometry of the beads were quantified. In addition, these properties were monitored over time in vitro in the presence of varying calcium levels in the microenvironment. The initial volume available for solute diffusion increased with alginate concentration and mannuronic (M) acid content, and bead diameter decreased with M content but increased with needle diameter. Interestingly, microbeads eroded completely in saline in less than 3 weeks regardless of synthesis conditions much faster than what has been observed in vivo. However, microbead stability was increased by the addition of calcium in the culture medium. Beads synthesized with low alginate concentration and high G content exhibited a more rapid change in physical properties even in the presence of calcium. These data suggest that temporal variations in the physical characteristics of alginate microbeads can occur in vitro depending on synthesis conditions and microbead environment. The results presented here will assist in optimizing the design of the materials for clinical application in drug delivery and cell therapy. PMID:22350778

  12. Atorvastatin calcium loaded chitosan nanoparticles: in vitro evaluation and in vivo pharmacokinetic studies in rabbits

    Directory of Open Access Journals (Sweden)

    Abdul Baquee Ahmed

    2015-06-01

    Full Text Available In this study, we prepared atorvastatin calcium (AVST loaded chitosan nanoparticles to improve the oral bioavailability of the drug. Nanoparticles were prepared by solvent evaporation technique and evaluated for its particle size, entrapment efficiency, zeta potential, in vitro release and surface morphology by scanning electron microscopy (SEM. In addition, the pharmacokinetics of AVST from the optimized formulation (FT5 was compared with marketed immediate release formulation (Atorva(r in rabbits. Particle size of prepared nanoparticles was ranged between 179.3 ± 7.12 to 256.8 ± 8.24 nm with a low polydispersity index (PI value. Zeta potential study showed that the particles are stable with positive values between 13.03 ± 0.32 to 46.90 ± 0.49 mV. FT-IR studies confirmed the absence of incompatibility of AVST with excipient used in the formulations. In vitro release study showed that the drug release was sustained for 48 h. Results of pharmacokinetics study showed significant changes in the pharmacokinetic parameter (2.2 fold increase in AUC of the optimized formulation as compared to marketed formulation (Atorva(r. Thus, the developed nanoparticles evidenced the improvement of oral bioavailability of AVST in rabbit model.

  13. Elucidation of arctigenin pharmacokinetics after intravenous and oral administrations in rats: integration of in vitro and in vivo findings via semi-mechanistic pharmacokinetic modeling.

    Science.gov (United States)

    Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

    2014-11-01

    Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max, K m, and Clint of 47.5 ± 3.4 nmol/min/mg, 204 ± 22 μM, and 233 ± 9 μl/min/mg with intestinal microsomes and 2.92 ± 0.07 nmol/min/mg, 22.7 ± 1.2 μM, and 129 ± 4 μl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r (2) > 0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses.

  14. In vitro simulation of in vivo pharmacokinetic model with intravenous administration via flow rate modulation.

    Science.gov (United States)

    Chen, Yuan-Cheng; Liang, Wang; Hu, Jia-Li; He, Gao-Li; Wu, Xiao-Jie; Liu, Xiao-Fang; Zhang, Jing; Hu, Xue-Qian

    2015-02-01

    The aim of this paper was to propose a method of flow rate modulation for simulation of in vivo pharmacokinetic (PK) model with intravenous injection based on a basic in vitro PK model. According to the rule of same relative change rate of concentration per unit time in vivo and in vitro, the equations for flow rate modulation were derived using equation method. Four examples from literature were given to show the application of flow rate modulation in the simulation of PK model of antimicrobial agents in vitro. Then an experiment was performed to confirm the feasibility of flow rate modulation method using levo-ornidazole as an example. The accuracy and precision of PK simulations were evaluated using average relative deviation (ARD), mean error and root mean squared error. In vitro model with constant flow rate could mimic one-compartment model, while the in vitro model with decreasing flow rate could simulate the linear mammillary model with multiple compartments. Zero-order model could be simulated using the in vitro model with elevating flow rate. In vitro PK model with gradually decreasing flow rate reproduced the two-compartment kinetics of levo-ornidazole quite well. The ARD was 0.925 % between in vitro PK parameters and in vivo values. Results suggest that various types of PK model could be simulated using flow rate modulation method without modifying the structure. The method provides uniform settings for the simulation of linear mammillary model and zero-order model based on in vitro one-compartment model, and brings convenience to the pharmacodynamic study.

  15. Evaluation of the transport, in vitro metabolism and pharmacokinetics of Salvinorin A, a potent hallucinogen.

    Science.gov (United States)

    Teksin, Zeynep S; Lee, Insong J; Nemieboka, Noble N; Othman, Ahmed A; Upreti, Vijay V; Hassan, Hazem E; Syed, Shariq S; Prisinzano, Thomas E; Eddington, Natalie D

    2009-06-01

    Salvinorin A is an unregulated potent hallucinogen isolated from the leaves of Salvia divinorum. It is the only known non-nitrogenous kappa-opioid selective agonist, and rivals synthetic lysergic acid diethylamide (LSD) in potency. The objective of this study was to characterize the in vitro transport, in vitro metabolism, and pharmacokinetic properties of Salvinorin A. The transport characteristics of Salvinorin A were assessed using MDCK-MDR1 cell monolayers. The P-glycoprotein (P-gp) affinity status was assessed by the P-gp ATPase assay. In vitro metabolism studies were performed with various specific human CYP450 isoforms and UGT2B7 to assess the metabolic characteristics of Salvinorin A. Cohorts (n = 3) of male Sprague Dawley rats were used to evaluate the pharmacokinetics and brain distribution of Salvinorin A (10 mg/kg, intraperitoneal (i.p.) over a 240-min period. A validated UV-HPLC and LC/MS/MS method was used to quantify the hallucinogen concentrations obtained from the in vitro and in vivo studies, respectively. Salvinorin A displayed a high secretory transport in the MDCK-MDR1 cells (4.07 +/- 1.34 x 10(-)5 cm/s). Salvinorin A also stimulated the P-gp ATPase activity in a concentration (5 and 10 microM)-dependent manner, suggesting that it may be a substrate of (P-gp). A significant decrease in Salvinorin A concentration ranging from 14.7 +/- 0.80% to 31.1 +/- 1.20% was observed after incubation with CYP2D6, CYP1A1, CYP2C18, and CYP2E1, respectively. A significant decrease was also observed after incubation with UGT2B7. These results suggest that Salvinorin A maybe a substrate of UGT2B7, CYP2D6, CYP1A1, CYP2E1, and CYP2C18. The in vivo pharmacokinetic study showed a relatively fast elimination with a half-life (t1/2) of 75 min and a clearance (Cl/F) of 26 L/h/kg. The distribution was extensive (Vd of 47.1 L/kg); however, the brain to plasma ratio was 0.050. Accordingly, the brain half-life was relatively short, 36 min. Salvinorin A is rapidly eliminated

  16. Aerosol Route to Administer Teicoplanin in Mechanical Ventilation: In Vitro Study, Lung Deposition and Pharmacokinetic Analyses in Pigs.

    Science.gov (United States)

    Guillon, Antoine; Mercier, Emmanuelle; Lanotte, Philippe; Haguenoer, Eve; Darrouzain, François; Barc, Céline; Sarradin, Pierre; Si-Tahar, Mustapha; Heuzé-Vourc'h, Nathalie; Diot, Patrice; Vecellio, Laurent

    2015-08-01

    Glycopeptides given intravenously achieve low airway concentrations. Nebulization of teicoplanin may be an efficient way of delivering a high concentration of this antibiotic to the lung. This multistep study assessed the feasibility of teicoplanin nebulization during mechanical ventilation by evaluating: the stability of its antibiotic effect; epithelial tolerance; lung deposition and systemic absorption in ventilated pigs. Nebulized and non-nebulized teicoplanin activity was tested on Staphylococcus aureus cultures. The cytotoxic effect of teicoplanin on human respiratory epithelial cells was assessed by measuring lactate dehydrogenase activity released, cell viability, and transepithelial electrical resistance. Volume median diameter of particles of nebulized teicoplanin was measured by laser diffraction during mechanical ventilation. The deposited mass of teicoplanin nebulized with a vibrating mesh nebulizer in ventilated piglets was assessed by scintigraphy. Blood pharmacokinetics of teicoplanin administered either intravenously or by nebulization was compared. No decrease of antibiotic activity was observed after nebulization. In vitro cytotoxicity of teicoplanin was only observed with 1000 times the dose recommended for intravenous administration. Volume median diameter of particles was 2.5±0.1 μm. Of the initial nebulizer charge of teicoplanin, 24±7% was present in the lungs of ventilated pigs after the nebulization. Amount absorbed in blood was low (3.4%±0.9%) after nebulization, and blood stream elimination half-life value was 25.4 h. Teicoplanin was administered efficiently by nebulization during mechanical ventilation, without any effect on its pharmacological properties or any cytotoxicity. The pharmacokinetic parameters are promising in view of its time-dependent killing process. All the results of our multi-step study highlighted the potential of teicoplanin to be nebulized during mechanical ventilation.

  17. The effects of delta1-cortienic acid on skin blanching, pharmacokinetics and stability of loteprednol etabonate.

    Science.gov (United States)

    Wu, W M; Bodor, E T; Howes, J; Bodor, N

    2012-05-01

    The effect of delta1-cortienic acid (delta1-CA) on human skin blanching activity of the soft corticosteroid, loteprednol etabonate (LE), has been studied. Ten volunteers had applied to their forearms a dose of LE ranging from 0.1 to 1 mM, or LE from 0.1 to 1 mM in combination with 2-times the concentration of delta1-CA (0.2 - 2mM). The results indicate that delta1-CA increased LE's effect on human vasoconstriction/skin blanching activity, both in the intensity and duration. This enhancing effect of delta1-CA was also observed in other blanching studies with other corticosteroids, such as hydrocortisone. The enhancement may occur through the displacement of LE bound to transcortin (also known as corticosteroid-binding globulin, or CBG) by delta1-CA as delta1-CA has a higher affinity for CBG than that for glucocorticoid receptor (GR), resulting in more free-LE to act on GR, and increased skin blanching. In rat studies, intravenous injection of delta1-CA (5-50 mg/kg) did not affect the pharmacokinetics of LE (5 mg/kg), indicating that delta1-CA is safe for combined use with LE. In stability studies, the presence of delta1-CA at the same concentrations as LE in aqueous suspension (0.1 and 0.2%) significantly increased the stability of LE. Thus, the combination of delta1-CA with LE serves an enhancing and stabilizing role while not impacting the pharmacokinetic properties of LE.

  18. Pharmacokinetics and pharmacodynamics of antibiotics in biofilm infections of Pseudomonas aeruginosa in vitro and in vivo

    DEFF Research Database (Denmark)

    Hengzhuang, Wang; Høiby, Niels; Ciofu, Oana

    2014-01-01

    Although progress on biofilm research has been obtained during the past decades, the treatment of biofilm infections with antibiotics remains a riddle. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of an antimicrobial agent provide important information helping to establish an effici......Although progress on biofilm research has been obtained during the past decades, the treatment of biofilm infections with antibiotics remains a riddle. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of an antimicrobial agent provide important information helping to establish...... an efficient dosing regimen and to minimize the development of antimicrobial tolerance and resistance in biofilm infections. Unfortunately, most previous PK/PD studies of antibiotics have been done on planktonic cells, and extrapolation of the results on biofilms is problematic as bacterial biofilms differ...... from planktonic grown cells in the growth rate, gene expression, and metabolism. Here, we set up several protocols for the studies of PK/PD of antibiotics in biofilm infections of P. aeruginosa in vitro and in vivo. It should be underlined that none of the protocols in biofilms have yet been...

  19. Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

    OpenAIRE

    Jie Li; Xin Li; Yu-Shan Ren; Yuan-Yuan Lv; Jun-Sheng Zhang; Xiao-Li Xu; Xian-Zhen Wang; Jing-Chun Yao; Gui-Min Zhang; Zhong Liu

    2017-01-01

    Although arctigenin (AG) has diverse bioactivities, such as anti-oxidant, anti-inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro. In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK) profiles of AG with different drug-delivery manners, including ...

  20. Simultaneous assessment of absorption characteristics of coumarins from Angelicae Pubescentis Radix: In vitro transport across Caco-2 cell and in vivo pharmacokinetics in rats after oral administration.

    Science.gov (United States)

    Yang, Yan-Fang; Zhang, Lei; Zhang, You-Bo; Yang, Xiu-Wei

    2017-08-15

    Angelicae Pubescentis Radix (APR), a well-known traditional Chinese medicine, is widely used for the treatments of rheumatism and headache for centuries. To assess the absorption characteristics of coumarins from APR, a sensitive and reliable UPLC-MS/MS method was established for the simultaneous determination of sixteen coumarins from APR, including psoralen, xanthotoxin, bergapten, bergaptol, isoimperatorin, imperatorin, columbianetin, columbianetin acetate, columbianadin, oxypeucedanin hydrate, angelol B, umbelliferone, scopoletin, osthole, meranzin hydrate and nodakenetin. The specificity, linearity, sensitivity, precision, accuracy, recovery, matrix effect and stability of the method were all validated to be satisfactory. The method was then applied to the in vitro transport of APR extract (APRE) across human intestinal epithelial Caco-2 cell and in vivo pharmacokinetics in rats after oral administration of APRE. All of the tested coumarins were well or moderately absorbed across Caco-2 monolayers, and could be quickly absorbed into rat blood circulation after oral administration. Columbianetin was the most easily absorbed compound across Caco-2 cell, and also had extremely highest plasma concentration in vivo. Excellent correlation between in vitro absorption across Caco-2 cell monolayers and in vivo pharmacokinetics of coumarins from APRE was well verified. The results provided valuable information for the overall absorption characteristics of the coumarins from APR, as well as for its further studies of in vivo active substances in the further. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. In Vitro Pharmacokinetic/Pharmacodynamic Modeling of Voriconazole Activity against Aspergillus Species in a New In Vitro Dynamic Model

    Science.gov (United States)

    Al-Saigh, R.; Elefanti, A.; Velegraki, A.; Zerva, L.

    2012-01-01

    The pharmacodynamics (PD) of voriconazole activity against Aspergillus spp. were studied using a new in vitro dynamic model simulating voriconazole human pharmacokinetics (PK), and the PK-PD data were bridged with human drug exposure to assess the percent target (near-maximum activity) attainment of different voriconazole dosages. Three Aspergillus clinical isolates (1 A. fumigatus, 1 A. flavus, and 1 A. terreus isolate) with CLSI MICs of 0.5 mg/liter were tested in an in vitro model simulating voriconazole PK in human plasma with Cmax values of 7, 3.5, and 1.75 mg/liter and a t1/2 of 6 h. The area under the galactomannan index-time curve (AUCGI) was used as the PD parameter. In vitro PK-PD data were bridged with population human PK of voriconazole exposure, and the percent target attainment was calculated. The in vitro PK-PD relationship of fAUC0-24-AUCGI followed a sigmoid pattern (global R2 = 0.97), with near-maximum activities (10% fungal growth) observed at an fAUC0-24 (95% confidence interval [CI]) of 18.9 (14.4 to 23.1) mg · h/liter against A. fumigatus, 26.6 (21.1 to 32.9) mg · h/liter against A. flavus, and 36.2 (27.8 to 45.7) mg · h/liter against A. terreus (F test; P voriconazole dosages was 24% (11 to 45%), 80% (32 to 97%), and 93% (86 to 97%) for A. fumigatus, 12% (5 to 26%), 63% (17 to 93%), and 86% (73 to 94%) for A. flavus, and 4% (2 to 11%), 36% (6 to 83%), and 68% (47 to 83%) for A. terreus. Based on the in vitro exposure-effect relationships, a standard dosage of voriconazole may be adequate for most patients with A. fumigatus but not A. flavus and A. terreus infections, for which a higher drug exposure may be required. This could be achieved using a higher voriconazole dosage, thus highlighting the usefulness of therapeutic drug monitoring in patients receiving a standard dosage. PMID:22869563

  2. Stabilization of resveratrol in blood circulation by conjugation to mPEG and mPEG-PLA polymers: investigation of conjugate linker and polymer composition on stability, metabolism, antioxidant activity and pharmacokinetic profile.

    Science.gov (United States)

    Siddalingappa, Basavaraj; Benson, Heather A E; Brown, David H; Batty, Kevin T; Chen, Yan

    2015-01-01

    Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); α-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa), Resveratrol-PEG ether (2 and 5 kDa) displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resveratrol.

  3. Stabilization of resveratrol in blood circulation by conjugation to mPEG and mPEG-PLA polymers: investigation of conjugate linker and polymer composition on stability, metabolism, antioxidant activity and pharmacokinetic profile.

    Directory of Open Access Journals (Sweden)

    Basavaraj Siddalingappa

    Full Text Available Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h. Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol succinylamide resveratrol (MeO-PEGN-Succ-RSV (2 and 20 kDa; MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV (2 kDa; α-methoxy poly(ethylene glycol-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV (2 and 6.6kDa were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa, Resveratrol-PEG ether (2 and 5 kDa displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC, slower clearance and smaller volume of distribution, compared to resveratrol.

  4. Stabilization of Resveratrol in Blood Circulation by Conjugation to mPEG and mPEG-PLA Polymers: Investigation of Conjugate Linker and Polymer Composition on Stability, Metabolism, Antioxidant Activity and Pharmacokinetic Profile

    Science.gov (United States)

    Siddalingappa, Basavaraj; Benson, Heather A. E.; Brown, David H.; Batty, Kevin T.; Chen, Yan

    2015-01-01

    Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); α-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa), Resveratrol-PEG ether (2 and 5 kDa) displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resveratrol. PMID:25799413

  5. The In Vitro Stability of Circulating Tumour DNA.

    Science.gov (United States)

    Henao Diaz, Emanuela; Yachnin, Jeffrey; Grönberg, Henrik; Lindberg, Johan

    2016-01-01

    DNA from apoptotic cancer cells, present in the circulation, has the potential to facilitate genomic profiling and disease monitoring. However, only low fractions of total cell-free DNA originates from cancer cells, limiting the applicability of circulating tumour DNA (ctDNA). Optimal sample processing is consequently of uttermost importance. Therefore, we evaluated the in vitro stability of ctDNA. Blood was collected in 10 ml EDTA or Streck tubes. Three conditions (EDTA and Streck tubes in room temperature, EDTA tubes at five degrees) and four time points (plasma harvested from blood aliquots of each 10 ml tube in a time series up to 24 h) were investigated. Each condition was evaluated in five metastatic prostate cancer patients. Subsequently, three additional patients were collected enabling investigation of the in vitro stability in EDTA tubes up to 48 h. The in vitro stability of ctDNA was interrogated by low-pass whole genome sequencing which allows for the identification of somatic copy-number alterations (CNAs). In silico simulations demonstrated that non-parametric testing could detect a 1% contamination by white blood cell DNA. Mutational profiling was performed by targeted, in-solution based hybridization capture and subsequent sequencing. The allelic fraction of individual mutations was used as an estimate of the in vitro stability. Somatic CNAs were detected in all patients. Surprisingly, the ctDNA levels at zero hours were not significantly different to 24 or 48 hour in vitro incubation in any investigated condition. Subsequently, mutational profiling corroborated the conclusions from the CNA analysis. The stability of ctDNA simplifies logistics without the requirement of immediate processing or applying fixatives to prevent white blood cell lysis.

  6. Blood concentrations of acrylonitrile in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling.

    Science.gov (United States)

    Takano, Ryohji; Murayama, Norie; Horiuchi, Kana; Kitajima, Masato; Kumamoto, Masatoshi; Shono, Fumiaki; Yamazaki, Hiroshi

    2010-11-01

    The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for acrylonitrile in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a prior previously developed PBPK model in rats. The model basically consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for acrylonitrile. Evaluation of a previous rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after oral treatment with acrylonitrile (30 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of acrylonitrile in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. Acrylonitrile was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for acrylonitrile is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses. Copyright © 2010 Elsevier Inc. All rights reserved.

  7. Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data.

    Science.gov (United States)

    Abdel-Tawab, Mona; Werz, Oliver; Schubert-Zsilavecz, Manfred

    2011-06-01

    Non-steroidal anti-inflammatory drug (NSAID) intake is associated with high prevalence of gastrointestinal or cardiovascular adverse effects. All efforts to develop NSAIDs that spare the gastrointestinal tract and the cardiovasculature are still far from achieving a breakthrough. In the last two decades, preparations of the gum resin of Boswellia serrata (a traditional ayurvedic medicine) and of other Boswellia species have experienced increasing popularity in Western countries. Animal studies and pilot clinical trials support the potential of B. serrata gum resin extract (BSE) for the treatment of a variety of inflammatory diseases like inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and asthma. Moreover, in 2002 the European Medicines Agency classified BSE as an 'orphan drug' for the treatment of peritumoral brain oedema. Compared to NSAIDs, it is expected that the administration of BSE is associated with better tolerability, which needs to be confirmed in further clinical trials. Until recently, the pharmacological effects of BSE were mainly attributed to suppression of leukotriene formation via inhibition of 5-lipoxygenase (5-LO) by two boswellic acids, 11-keto-β-boswellic acid (KBA) and acetyl-11-keto-β-boswellic acid (AKBA). These two boswellic acids have also been chosen in the monograph of Indian frankincense in European Pharmacopoiea 6.0 as markers to ensure the quality of the air-dried gum resin exudate of B. serrata. Furthermore, several dietary supplements advertise the enriched content of KBA and AKBA. However, boswellic acids failed to inhibit leukotriene formation in human whole blood, and pharmacokinetic data revealed very low concentrations of AKBA and KBA in plasma, being far below the effective concentrations for bioactivity in vitro. Moreover, permeability studies suggest poor absorption of AKBA following oral administration. In view of these results, the previously assumed mode of action - that is, 5-LO inhibition - is

  8. Design, in vitro release characterization and pharmacokinetics of novel controlled release pellets containing levodropropizine.

    Science.gov (United States)

    Cao, Qing-Ri; Piao, Yong-Nan; Choi, Jae-Seung; Liu, Yan; Yang, Mingshi; Cui, Jing-Hao

    2014-05-01

    This study was performed to investigate the in vitro release characteristics of levodropropizine (LDP) from novel dual-coated sustained release (SR) pellets, and evaluate the pharmacokinetics of a novel controlled release (CR) preparation composed of the dual-coated SR pellets and immediate release (IR) LDP pellets. The dual-coated SR pellets composed of a drug-loaded nonpareil core, a sub-coating layer (HPMC 6cps) and an SR-coating layer (Aquacoat® ECD, Eudragit® RS 30D or Kollicoat® SR 30D) were prepared by a bottom-spray fluidized bed-coating method. The drug release from the dual-coated SR pellets coated with Aquacoat® ECD followed a zero-order profile in water, and the drug release was not affected by the coating level of the sub-coating layer and stable under the accelerated storage condition (40 °C, 75% RH) for 6 months. The CR preparation showed significantly decreased values of maximum drug concentration (Cmax) and elimination rate (K) than the reference product (LEVOTUS® SYR) but the similar bioavailability (F = 95.43%). The novel CR preparation presents promising delivery of LDP with an immediate and sustained release manner, with similar clinical effect as the commercial IR product.

  9. Sustained-release of caffeine from a polymeric tablet matrix: An in vitro and pharmacokinetic study

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Donna [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117597 (Singapore); Zhao Bin [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117597 (Singapore); Moochhala, Shabbir [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117597 (Singapore)]. E-mail: mshabbir@dso.org.sg; Yang Yiyan [Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, 04-01, The Nanos, Singapore 138669 (Singapore)

    2006-07-25

    Caffeine is utilized as a stimulant to impart a desired level of alertness during certain working hours. Usually, a single dose of caffeine induces 2-3 h of alertness coupled with side effects whereas a longer effect of 8-12 h is very useful for both daily life and military action. Thus, there is a need to deliver the stimulant continuously to an individual at one time to impart an increased level of alertness for the period stated after administration. This study aimed to design a polymeric microparticle system for sustained delivery of caffeine using a polymeric matrix. Poly(ethylene oxide) (PEO) was used as the erodible matrix material and the caffeine polymeric tablets were fabricated by compression using a Graseby Specac hydraulic press. In vitro release profiles as well as the pharmacokinetics studies data were obtained. Caffeine tablets fabricated using various polymers showed a high initial burst release type profile as compared to the caffeine-PEO-tablet. The PK studies showed sustained delivery of caffeine resulted in two expected phenomena: a reduction in the initial high rate of caffeine release (burst release) as well as a reduction in the change in caffeine concentration in the systemic circulation. A simple two-component system for sustained-release caffeine formulation therefore has been achieved.

  10. Pharmacokinetics and correlation between in vitro release and in vivo absorption of bio-adhesive pellets of panax notoginseng saponins.

    Science.gov (United States)

    Li, Ying; Zhang, Yun; Zhu, Chun-Yan

    2017-02-01

    The present study was designed to prepare and compare bio-adhesive pellets of panax notoginseng saponins (PNS) with hydroxy propyl methyl cellulose (HPMC), chitosan, and chitosan : carbomer, explore the influence of different bio-adhesive materials on pharmacokinetics behaviors of PNSbio-adhesive pellets, and evaluate the correlation between in vivo absorption and in vitro release (IVIVC). In order to predict the in vivo concentration-time profile by the in vitro release data of bio-adhesive pellets, the release experiment was performed using the rotating basket method in pH 6.8 phosphate buffer. The PNS concentrations in rat plasma were analyzed by HPLC-MS-MS method and the relative bioavailability and other pharmacokinetic parameters were estimated using Kinetica4.4 pharmacokinetic software. Numerical deconvolution method was used to evaluate IVIVC. Our results indicated that, compared with ordinary pellets, PNS bio-adhesive pellets showed increased oral bioavailability by 1.45 to 3.20 times, increased Cmax, and extended MRT. What's more, the release behavior of drug in HPMC pellets was shown to follow a Fickian diffusion mechanism, a synergetic function of diffusion and skeleton corrosion. The in vitro release and the in vivo biological activity had a good correlation, demonstrating that the PNS bio-adhesive pellets had a better sustained release. Numerical deconvolution technique showed the advantage in evaluation of IVIVC for self-designed bio-adhesive pellets with HPMC. In conclusion, the in vitro release data of bio-adhesive pellets with HPMC can predict its concentration-time profile in vivo. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

  11. Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings.

    Science.gov (United States)

    Li, Jie; Li, Xin; Ren, Yu-Shan; Lv, Yuan-Yuan; Zhang, Jun-Sheng; Xu, Xiao-Li; Wang, Xian-Zhen; Yao, Jing-Chun; Zhang, Gui-Min; Liu, Zhong

    2017-01-01

    Although arctigenin (AG) has diverse bioactivities, such as anti-oxidant, anti-inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro. In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK) profiles of AG with different drug-delivery manners, including intravenous (i.v), hypodermic injection (i.h), and sublingual (s.l) administration. The data shows that AG exhibited a strong absorption capacity in both rats and beagle dogs (absorption rate 100%), and a strong elimination ability (t1/2 beagle dog (25.9 ± 3.24%) > rat (15.7 ± 9%) > monkey (3.69 ± 0.12%). This systematic investigation of pharmacokinetic profiles of arctigenin (AG) in vivo and in vitro is worthy of further exploration.

  12. Biotransformation and in vivo stability of protein biotherapeutics: impact on candidate selection and pharmacokinetic profiling.

    Science.gov (United States)

    Hall, Michael P

    2014-11-01

    Historically, since the metabolism of administered peptide/protein drugs ("biotherapeutics") has been expected to undergo predictable pathways similar to endogenous proteins, comprehensive biotherapeutic metabolism studies have not been widely reported in the literature. However, since biotherapeutics have rapidly evolved into an impressive array of eclectic modalities, there has been a shift toward understanding the impact of metabolism on biotherapeutic development. For biotherapeutics containing non-native chemical linkers and other moieties besides natural amino acids, metabolism studies are critical as these moieties may impart undesired toxicology. For biotherapeutics that are composed solely of natural amino acids, where end-stage peptide and amino acid catabolites do not generally pose toxicity concerns, the understanding of biotherapeutic biotransformation, defined as in vivo modifications such as peripherally generated intermediate circulating catabolites prior to end-stage degradation or elimination, may impact in vivo stability and potency/clearance. As of yet, there are no harmonized methodologies for understanding biotherapeutic biotransformation and its impact on drug development, nor is there clear guidance from regulatory agencies on how and when these studies should be conducted. This review provides an update on biotherapeutic biotransformation studies and an overview of lessons learned, tools that have been developed, and suggestions of approaches to address issues. Biotherapeutic biotransformation studies, especially for certain modalities, should be implemented at an early stage of development to 1) understand the impact on potency/clearance, 2) select the most stable candidates or direct protein re-engineering efforts, and 3) select the best bioanalytical technique(s) for proper drug quantification and subsequent pharmacokinetic profiling and exposure/response assessment. Copyright © 2014 by The American Society for Pharmacology and

  13. Hydroxymethylation of DNA influences nucleosomal conformation and stability in vitro.

    Science.gov (United States)

    Mendonca, Agnes; Chang, En Hyung; Liu, Wenjie; Yuan, Chongli

    2014-11-01

    Hydroxymethylation of DNA at the C5 position of cytosine (5hmC) is recognized as an important epigenetic mark. The molecular role of 5hmC in gene regulation, however, is not well understood. We studied the effects of 5-hydroxymethylation (5hmC) on nucleosome properties in vitro using a combination of biochemical and fluorescence assays. Competitive reconstitution was used to evaluate the effect of 5hmC on nucleosome formation. The effects of 5hmC on nucleosome compactness and stability were characterized using FRET assays. These findings have also been compared with another important epigenetic mark, the cytosine methylation (5mC) of DNA. We observed that hydroxymethylation increases the binding affinity of DNA for the histone octamer. The formed nucleosome exhibits slightly different conformations based on the sequence and epigenetic context of DNA. DNA hydroxymethylation decreases the stability of formed nucleosomes in salt-induced dissociation processes. DNA containing 5hmC is more likely to be incorporated into nucleosomes. Once formed, the 5hmC nucleosomes might be in an open and transcriptionally active state due to the weakened interaction of hydroxymethylated DNA with the H2A-H2B dimers. Our results reveal the effect of 5hmC on regulating nucleosome compactness and stability in vitro. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. In Vitro Dissolution and In Vivo Bioavailability of Six Brands of Ciprofloxacin Tablets Administered in Rabbits and Their Pharmacokinetic Modeling

    Directory of Open Access Journals (Sweden)

    Sahar Fahmy

    2014-01-01

    Full Text Available This study was undertaken to assess the in vitro dissolution and in vivo bioavailability of six brands of ciprofloxacin oral tablets available in the UAE market using rabbits. The in vitro dissolution profiles of the six ciprofloxacin products were determined using the USP dissolution paddle method. Pharmacokinetic modeling using compartmental and noncompartmental analysis was done to determine the pharmacokinetic parameters of ciprofloxacin after single-dose oral administration. In vitro release study revealed that the amount of ciprofloxacin released in 20 minutes was not less than 80% of the labeled amount which is in accordance with the pharmacopoeial requirements. All tested products are considered to be very rapid dissolving except for formulae A and D. Ciprofloxacin plasma concentration in rabbits was best fitted to a two-compartment open model. The lowest bioavailability was determined to be for product A (93.24% while the highest bioavailability was determined to be for product E (108.01%. Postmarketing surveillance is very crucial to ensure product quality and eliminating substandard products to be distributed and, consequently, ensure better patient clinical outcome. The tested ciprofloxacin generic products distributed in the UAE market were proven to be of good quality and could be used interchangeably with the branded ciprofloxacin product.

  15. Development of the isolated perfused porcine skin flap for in vitro studies of percutaneous absorption pharmacokinetics and cutaneous biotransformation

    Energy Technology Data Exchange (ETDEWEB)

    Carver, M.P.

    1988-01-01

    The isolated perfused porcine skin flap (IPPSF) has proven to be a valuable in vitro tool for studying the physiology and biochemistry of skin and for identifying biochemical and histological markers of direct cutaneous toxicity. The present experiments were undertaken for two purposes: (1) to develop a pharmacokinetic model, based on dermal penetration in the IPPSF, which is predictive of percutaneous absorption in vivo, and (2) to examine cutaneous biotransformation of the important agricultural poison parathion (P). Dosing solutions of {sup 14}C-radiolabelled compounds representing 3 chemical classes-organic acid/base (benzoic acid (B), caffeine (C)), organophosphate (OP) pesticides, and steroid hormones, were applied topically in ethanol at 40 {mu}m cm{sup {minus}2}, both in vivo and on the IPPSF. A 3-compartment pharmacokinetic model describing mass transfer from the surface (C{sub 1}), diffusion through epidermis and dermis (C{sub 2}), and transfer into the perfusate (C{sub 3}), was developed based on flux through the IPPSF from 0-8 hr. Model simulations were predictive of percutaneous absorption in vivo for the OP's and steroids. Modification of the basic 3-compartment model to account for fast and slow tissue-release processes (B) and for flux-dependent perfusage flow increases (C), provided excellent in vivo-in vitro correlation over all 7 compounds.

  16. Prediction of pharmacokinetic and toxicological parameters of a 4-phenylcoumarin isolated from geopropolis: In silico and in vitro approaches.

    Science.gov (United States)

    da Cunha, Marcos Guilherme; Franco, Gilson César Nobre; Franchin, Marcelo; Beutler, John A; de Alencar, Severino Matias; Ikegaki, Masaharu; Rosalen, Pedro Luiz

    2016-11-30

    In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy-mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/Percepta™ and MetaDrug™ software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array. CNM did not pass all parameters of Lipinski's rule of five, with a predicted low oral bioavailability and high plasma protein binding, but with good predicted blood brain barrier penetration. CNM was predicted to show low affinity to cytochrome P450 family members. Furthermore, the predicted Ames test indicated potential mutagenicity of CNM. Also, the probability of toxicity for organs and tissues was classified as moderate and high for liver and kidney, and moderate and low for skin and eye irritation, respectively. The PCR array analysis showed that CNM significantly upregulated about 7% of all DNA damage-related genes. By exploring the biological function of these genes, it was found that the predicted CNM genotoxicity is likely to be mediated by apoptosis. The predicted ADME/Tox profile suggests that external use of CNM may be preferable to systemic exposure, while its genotoxicity was characterized by the upregulation of apoptosis-related genes after treatment. The combined use of in silico and in vitro approaches to evaluate these parameters generated useful hypotheses to guide further preclinical studies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Establishing in vitro in vivo correlations to screen monoclonal antibodies for physicochemical properties related to favorable human pharmacokinetics.

    Science.gov (United States)

    Avery, Lindsay B; Wade, Jason; Wang, Mengmeng; Tam, Amy; King, Amy; Piche-Nicholas, Nicole; Kavosi, Mania S; Penn, Steve; Cirelli, David; Kurz, Jeffrey C; Zhang, Minlei; Cunningham, Orla; Jones, Rhys; Fennell, Brian J; McDonnell, Barry; Sakorafas, Paul; Apgar, James; Finlay, William J; Lin, Laura; Bloom, Laird; O'Hara, Denise M

    2017-12-22

    Implementation of in vitro assays that correlate with in vivo human pharmacokinetics (PK) would provide desirable preclinical tools for the early selection of therapeutic monoclonal antibody (mAb) candidates with minimal non-target-related PK risk. Use of these tools minimizes the likelihood that mAbs with unfavorable PK would be advanced into costly preclinical and clinical development. In total, 42 mAbs varying in isotype and soluble versus membrane targets were tested in in vitro and in vivo studies. MAb physicochemical properties were assessed by measuring non-specific interactions (DNA- and insulin-binding ELISA), self-association (affinity-capture self-interaction nanoparticle spectroscopy) and binding to matrix-immobilized human FcRn (surface plasmon resonance and column chromatography). The range of scores obtained from each in vitro assay trended well with in vivo clearance (CL) using both human FcRn transgenic (Tg32) mouse allometrically projected human CL and observed human CL, where mAbs with high in vitro scores resulted in rapid CL in vivo. Establishing a threshold value for mAb CL in human of 0.32 mL/hr/kg enabled refinement of thresholds for each in vitro assay parameter, and using a combinatorial triage approach enabled the successful differentiation of mAbs at high risk for rapid CL (unfavorable PK) from those with low risk (favorable PK), which allowed mAbs requiring further characterization to be identified. Correlating in vitro parameters with in vivo human CL resulted in a set of in vitro tools for use in early testing that would enable selection of mAbs with the greatest likelihood of success in the clinic, allowing costly late-stage failures related to an inadequate exposure profile, toxicity or lack of efficacy to be avoided.

  18. Prediction of Ketoconazole absorption using an updated in vitro transfer model coupled to physiologically based pharmacokinetic modelling.

    Science.gov (United States)

    Ruff, Aaron; Fiolka, Tom; Kostewicz, Edmund S

    2017-03-30

    The aim of this study was to optimize the in vitro transfer model and to increase its biorelevance to more accurately mimic the in vivo supersaturation and precipitation behaviour of weak basic drugs. Therefore, disintegration of the formulation, volumes of the stomach and intestinal compartments, transfer rate, bile salt concentration, pH range and paddle speed were varied over a physiological relevant range. The supersaturation and precipitation data from these experiments for Ketoconazole (KTZ) were coupled to physiologically based pharmacokinetic (PBPK) model using Stella® software, which also incorporated the disposition kinetics of KTZ taken from the literature, in order to simulate the oral absorption and plasma profile in humans. As expected for a poorly soluble weak base, KTZ demonstrated supersaturation followed by precipitation under various in vitro conditions simulating the proximal small intestine with the results influenced by transfer rate, hydrodynamics, volume, bile salt concentration and pH values. When the in vitro data representing the "average" GI conditions was coupled to the PBPK model, the simulated profiles came closest to the observed mean plasma profiles for KTZ. In line with the high permeability of KTZ, the simulated profiles were highly influenced by supersaturation whilst precipitation was not predicted to occur in vivo. A physiological relevant in vitro "standard" transfer model setup to investigate supersaturation and precipitation was established. For translating the in vitro data to the in vivo setting, it is important that permeability is considered which can be achieved by coupling the in vitro data to PBPK modelling. Copyright © 2016. Published by Elsevier B.V.

  19. In vitro/in vivo phototoxic risk assessments of griseofulvin based on photobiochemical and pharmacokinetic behaviors.

    Science.gov (United States)

    Seto, Yoshiki; Onoue, Satomi; Yamada, Shizuo

    2009-09-10

    The present investigation aims to establish efficacious screening strategy to clarify the phototoxic potential of pharmaceutical substances and its possible pathways by characterizing both photobiochemical properties and pharmacokinetic profiles. Photochemical behavior of griseofulvin, as model compounds, was evaluated by reactive oxygen species (ROS) assay, and the photogenotoxic potential was also assessed by DNA binding assay, DNA photocleavage assay, and atomic force microscopy. Pharmacokinetic (PK) study was also carried out after dermal and oral administration of griseofulvin in rats. ROS assay suggested the phototoxic potential of griseofulvin via type II photochemical pathways, and the photogenotoxic risk of griseofulvin was also proposed as evidenced by high affinity toward DNA and potent DNA photocleaving activity. PK profiling and in vivo phototoxicity testing demonstrated that a highly concentrated griseofulvin in the skin might cause phototoxic skin reactions in rats, whereas oral administration of griseofulvin in single dosing regimen (20mg/kg) resulted in 10(3)-fold less skin deposition than phototoxic skin concentration of griseofulvin. Upon these findings, the phototoxic potential of griseofulvin might not be severe at least in a single oral dosing regimen, whereas it might be phototoxic in dermal administration. The combination use of photobiochemical and pharmacokinetic data would be valuable to provide reliable prediction on phototoxic risk and possible toxic pathways of new drug entities in the early stage of drug discovery.

  20. Characterization of Pharmacokinetics in the Göttingen Minipig with Reference Human Drugs: An In Vitro and In Vivo Approach.

    Science.gov (United States)

    Lignet, Floriane; Sherbetjian, Eva; Kratochwil, Nicole; Jones, Russell; Suenderhauf, Claudia; Otteneder, Michael B; Singer, Thomas; Parrott, Neil

    2016-10-01

    This study aims to expand our understanding of the mechanisms of drug absorption, distribution, metabolism and excretion in the Göttingen minipig to aid a knowledge-driven selection of the optimal species for preclinical pharmaceutical research. The pharmacokinetics of seven reference compounds (antipyrine, atenolol, cimetidine, diazepam, hydrochlorothiazide, midazolam and theophylline) was investigated after intravenous and oral dosing in minipigs. Supportive in vitro data were generated on hepatocellularity, metabolic clearance in hepatocytes, blood cell and plasma protein binding and metabolism routes. Systemic plasma clearance for the seven drugs ranged from low (1.1 ml/min/kg, theophylline) to close to liver blood flow (37.4 ml/min/kg, cimetidine). Volume of distribution in minipigs ranged from 0.7 L/kg for antipyrine to 3.2 L/kg for hydrochlorothiazide. A gender-related difference of in vivo metabolic clearance was observed for antipyrine. The hepatocellularity for minipig was determined as 124 Mcells/g liver, similar to the values reported for human. Based on these data a preliminary in vitro to in vivo correlation (IVIVC) for metabolic clearance measured in hepatocytes was investigated. Metabolite profiles of diazepam and midazolam compared well between minipig and human. The results of the present study support the use of in vitro metabolism data for the evaluation of minipig in preclinical research and safety testing.

  1. Stability of acetaldehyde-derived DNA adduct in vitro.

    Science.gov (United States)

    Hori, Kimiko; Miyamoto, Shin'ichi; Yukawa, Yoshiyuki; Muto, Manabu; Chiba, Tsutomu; Matsuda, Tomonari

    2012-07-13

    Acetaldehyde (AA) derived from alcoholic beverages is a confirmed carcinogen for esophageal and head and neck cancers. AA forms various DNA adducts and is thought to play a crucial role in carcinogenesis. Transient DNA adducts are usually repaired, but the stability of AA-derived DNA adducts has not been elucidated. We investigated the stability of N(2)-ethylidene-2'-deoxyguanosine (N(2)-ethylidene-dG), a major AA-derived DNA adduct, in cultured cells. First, to determine the optimal concentration of AA for detecting N(2)-ethylidene-dG in cell culture, a dose-response study was performed using HL60 cells of the human promyelocytic leukemia cell line. An AA concentration ≥ 0.01% (1.8 mM) was required to detect N(2)-ethylidene-dG in vitro. We next examined the stability of N(2)-ethylidene-dG. After a 1 or 2h exposure to 0.01% of AA in a tightly sealed bottle, N(2)-ethylidene-dG content was measured by sensitive liquid chromatography tandem mass spectrometry immediately, 24h, and 48 h after exposure. After the 1h exposure, the mean (± SD) N(2)-ethylidene-dG contents were 12.1 ± 1.28, 8.20 ± 0.64, and 6.70 ± 0.52 adducts per 10(7) bases at each postexposure time. After the 2h exposure, N(2)-ethylidene-dG content increased to 21.4 ± 7.50, 10.5 ± 3.61, and 9.83 ± 3.90 adducts per 10(7) bases at each postexposure time. The half-life of this adduct was calculated as ∼35 h in independent experiments. These results indicate that AA exposure from daily alcohol consumption may cause DNA damage and may increase the risk of alcohol-related carcinogenesis. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Forecasting gastrointestinal precipitation and oral pharmacokinetics of dantrolene in dogs using an in vitro precipitation testing coupled with in silico modeling and simulation.

    Science.gov (United States)

    Kambayashi, Atsushi; Dressman, Jennifer B

    2017-10-01

    The aim of the current research was to determine the precipitation kinetics of dantrolene sodium using canine biorelevant in vitro testing and to model the precipitation kinetics by appropriately coupling the data with an in silico tool adapted for dogs. The precipitation profiles of dantrolene sodium solutions were obtained with the in vitro paddle apparatus at a revolution rate of 50rpm. The in silico prediction tool was designed using STELLA software and the predicted plasma concentration profiles of dantrolene using the in vitro precipitation data were compared with the observed in vivo pharmacokinetics in beagle dogs. The plasma profiles of dantrolene, which served as a model weakly acidic drug which precipitates in the upper gastrointestinal tract, was successfully predicted using the in vitro precipitation testing coupled with the in silico modeling and simulation approach. The approach was subsequently used to forecast the effect of pharmaceutical excipients (HPMC/PG) on the ability of the drug to supersaturate in the gut and the resulting pharmacokinetics. The agreement of the simulated pharmacokinetics with the observed values confirms the ability of canine biorelevant media to predict oral performance of enhanced dosage forms in dogs. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Evaluation of Isolated Fractions of Aloe vera Gel Materials on Indinavir Pharmacokinetics: In vitro and in vivo Studies.

    Science.gov (United States)

    Wallis, Lonette; Malan, Maides; Gouws, Chrisna; Steyn, Dewald; Ellis, Suria; Abay, Efrem; Wiesner, Lubbe; Otto, Daniel P; Hamman, Josias

    2016-01-01

    Aloe vera is a plant with a long history of traditional medicinal use and is consumed in different products, sometimes in conjunction with prescribed medicines. A. vera gel has shown the ability to modulate drug absorption in vitro. The aim of this study was to fractionate the precipitated polysaccharide component of A. vera gel based on molecular weight and to compare their interactions with indinavir pharmacokinetics. Crude polysaccharides were precipitated from a solution of A. vera gel and was fractionated by means of centrifugal filtration through membranes with different molecular weight cut-off values (i.e. 300 KDa, 100 KDa and 30 KDa). Marker molecules were quantified in the aloe leaf materials by means of nuclear magnetic resonance spectroscopy and the average molecular weight was determined by means of gel filtration chromatography linked to multi-angle-laser-light scattering and refractive index detection. The effect of the aloe leaf materials on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers as well as indinavir metabolism in LS180 cells was measured. The bioavailability of indinavir in the presence and absence of the aloe leaf materials was determined in Sprague-Dawley rats. All the aloe leaf materials investigated in this study reduced the TEER of Caco-2 cell monolayers, inhibited indinavir metabolism in LS 180 cells to different extents and changed the bioavailability parameters of indinavir in rats compared to that of indinavir alone. These indinavir pharmacokinetic modulation effects were not dependent on the presence of aloverose and also not on the average molecular weight of the isolated fractions.

  4. In vitro and in vivo anticancer activities of synthetic (-)-laulimalide, a marine natural product microtubule stabilizing agent.

    Science.gov (United States)

    Liu, Junke; Towle, Murray J; Cheng, Hongsheng; Saxton, Philip; Reardon, Cathy; Wu, Jiayi; Murphy, Erin A; Kuznetsov, Galina; Johannes, Charles W; Tremblay, Martin R; Zhao, Hongjuan; Pesant, Marc; Fang, Francis G; Vermeulen, Mary W; Gallagher, Brian M; Littlefield, Bruce A

    2007-01-01

    Laulimalide is a cytotoxic natural product isolated from marine sponges. It is structurally distinct from taxanes. However, like paclitaxel, laulimalide binds to tubulin and enhances microtubule assembly and stabilization. It exhibits potent inhibition of cellular proliferation with IC50 values in the low nM range against numerous cancer cell lines. In contrast to paclitaxel, however, laulimalide is also very potent against multidrug-resistant (MDR) cancer cell lines which overexpress P-glycoprotein (PgP). It has unique structural and biological properties, and attempts at synthesis have attracted considerable effort in recent years, resulting in more than ten published total syntheses. Despite this extensive attention, there have been no reported in vivo evaluations of laulimalide to date, probably due to the structural complexity of laulimalide and the scarcity of natural material. In our studies to explore the therapeutic potential of laulimalide, a total synthesis capable of producing gram quantities of laulimalide was designed, which enabled both in vitro and in vivo evaluation. Our in vitro results with synthetic material confirmed the previous reports that laulimalide is a mitotic blocker that can inhibit the growth of a variety of both non-MDR and MDR human cancer cell lines. However, despite demonstrating promise in cell-based and pharmacokinetic studies, laulimalide exhibited only minimal tumor growth inhibition in vivo and was accompanied by severe toxicity and mortality. The unfavorable efficacy to toxicity ratio in vivo suggests that laulimalide may have limited value for development as a new anticancer therapeutic agent.

  5. Aqueous Stability and Oral Pharmacokinetics of Meloxicam and Carprofen in Male C57BL/6 Mice

    Science.gov (United States)

    Ingrao, Joelle C; Johnson, Ron; Tor, Elizabeth; Gu, Yu; Litman, Marcus; Turner, Patricia V

    2013-01-01

    We found that carprofen and meloxicam under 3 environmental conditions (ambient dark, ambient light, and 4 °C) remained stable for at least 7 d. We then evaluated the oral pharmacokinetics of meloxicam (20 mg/kg) and carprofen (10 mg/kg) in male C57BL/6 mice after oral gavage or administration in the drinking water. Mice did not drink meloxicam-medicated water but readily consumed carprofen-medicated water, consuming an average of 14.19 mL carprofen-medicated water per 100 g body weight daily; mice drank more during the dark phase than during the light phase. Plasma analyzed by HPLC (meloxicam) and tandem mass spectrometry (carprofen) revealed that the peak meloxicam and carprofen concentrations were 16.7 and 20.3 μg/mL and occurred at 4 and 2 h after oral gavage, respectively. Similar blood levels were achieved after 12 h access to the carprofen-medicated water bottle. At 24 h after oral gavage, the drugs were not detectable in plasma. Meloxicam plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.4 mg/L × h, 7.4 h, 0.36 L/kg, and 0.125 mL/h × kg, respectively. Carprofen plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.8 mg/L × h, 7.4 h, 0.42 L/kg, and 0.062 mL/h × kg, respectively. No gross or microscopic evidence of toxicity was seen in any mouse. Our findings indicate that carprofen can be administered in drinking water to mice and that medicated water bottles should be placed 12 to 24 h prior to painful procedures. PMID:24041210

  6. Aqueous stability and oral pharmacokinetics of meloxicam and carprofen in male C57BL/6 mice.

    Science.gov (United States)

    Ingrao, Joelle C; Johnson, Ron; Tor, Elizabeth; Gu, Yu; Litman, Marcus; Turner, Patricia V

    2013-09-01

    We found that carprofen and meloxicam under 3 environmental conditions (ambient dark, ambient light, and 4 °C) remained stable for at least 7 d. We then evaluated the oral pharmacokinetics of meloxicam (20 mg/kg) and carprofen (10 mg/kg) in male C57BL/6 mice after oral gavage or administration in the drinking water. Mice did not drink meloxicam-medicated water but readily consumed carprofen-medicated water, consuming an average of 14.19 mL carprofen-medicated water per 100 g body weight daily; mice drank more during the dark phase than during the light phase. Plasma analyzed by HPLC (meloxicam) and tandem mass spectrometry (carprofen) revealed that the peak meloxicam and carprofen concentrations were 16.7 and 20.3 μg/mL and occurred at 4 and 2 h after oral gavage, respectively. Similar blood levels were achieved after 12 h access to the carprofen-medicated water bottle. At 24 h after oral gavage, the drugs were not detectable in plasma. Meloxicam plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.4 mg/L × h, 7.4 h, 0.36 L/kg, and 0.125 mL/h × kg, respectively. Carprofen plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.8 mg/L × h, 7.4 h, 0.42 L/kg, and 0.062 mL/h × kg, respectively. No gross or microscopic evidence of toxicity was seen in any mouse. Our findings indicate that carprofen can be administered in drinking water to mice and that medicated water bottles should be placed 12 to 24 h prior to painful procedures.

  7. Topical formulations containing finasteride. Part I: in vitro permeation/penetration study and in vivo pharmacokinetics in hairless rat.

    Science.gov (United States)

    Monti, Daniela; Tampucci, Silvia; Burgalassi, Susi; Chetoni, Patrizia; Lenzi, Carla; Pirone, Andrea; Mailland, Federico

    2014-08-01

    In hair follicle (Hf) cells, the type-2 5-α-reductase enzyme, implicated in androgenetic alopecia, is selectively inhibited by finasteride (FNS). Because an effective topical formulation to deliver FNS to Hf is currently unavailable, this investigation aimed at evaluating in vitro FNS skin permeation and retention through and into hairless rat and human abdominal skin. Four hydroxypropyl chitosan (HPCH)-based formulations (P-08-012, P-08-016, P-08-063, and P-08-064) and one anhydrous formulation without HPCH (P-10-008) were tested. The pharmacokinetics in plasma and skin after application of P-08-016 or P-10-008 on dorsal rat skin with single and repeated doses was investigated. P-08-016 performed the best in driving FNS to the reticular dermis without producing a high transdermal flux. Neither the in vivo single nor the repeated dose experiments produced plasma levels of FNS and no differences were found between formulations concerning skin retention. No increase in the amount of drug retained in the skin was obtained with the repeated dose experiment. In conclusion, the HPCH-based formulation P-08-016 might represent an alternative to systemic therapy for its ability to promote a cutaneous depot of FNS in the region of hair bulbs, minimizing systemic absorption even after repeated treatments. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  8. In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases.

    Science.gov (United States)

    Huang, Liyue; Be, Xuhai; Berry, Loren; Moore, Earl; Janosky, Brett; Wells, Mary; Pan, Wei-Jian; Zhao, Zhiyang; Lin, Min-Hwa Jasmine

    2011-05-01

    AMG 900 is a small molecule being developed as an orally administered, highly potent, and selective pan-aurora kinase inhibitor. The aim of the investigations was to characterize in vitro and in vivo pharmacokinetic (PK) properties of AMG 900 in preclinical species. AMG 900 was rapidly metabolized in liver microsomes and highly bound to plasma proteins in the species tested. It was a weak Pgp substrate with good passive permeability. AMG 900 exhibited a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 h. AMG 900 was well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake had an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans were predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibited acceptable PK properties in preclinical species and was predicted to have low clearance in humans. AMG 900 is currently in Phase I clinical testing as a treatment for solid tumours. Preliminary human PK results appear to be consistent with the predictions.

  9. Loratadine bioavailability via buccal transferosomal gel: formulation, statistical optimization, in vitro/in vivo characterization, and pharmacokinetics in human volunteers.

    Science.gov (United States)

    Elkomy, Mohammed H; El Menshawe, Shahira F; Abou-Taleb, Heba A; Elkarmalawy, Marwa H

    2017-11-01

    Loratadine (LTD) is an antihistaminic drug that suffers limited solubility, poor oral bioavailability (owing to extensive first-pass metabolism), and highly variable oral absorption. This study was undertaken to develop and statistically optimize transfersomal gel for transbuccal delivery of LTD. Transfersomes bearing LTD were prepared by conventional thin film hydration method and optimized using sequential Quality-by-Design approach that involved Placket-Burman design for screening followed by constrained simplex-centroid design for optimization of a Tween-80/Span-60/Span-80 mixture. The transferosomes were characterized for entrapment efficiency, particle size, and shape. Optimized transferosomes were incorporated in a mucoadhesive gel. The gel was characterized for rheology, ex vivo permeation across chicken pouch buccal mucosa, in vitro release, and mucoadhesion. Pharmacokinetic behavior of LTD formulations was investigated in healthy volunteers following administration of a single 10-mg dose. Optimal transferosomes characterized by submicron size (380 nm), spherical shape and adequate loading capacity (60%) were obtained by using quasi-equal ratio surfactant mixture. In terms of amount permeated, percentage released, and mucoadhesion time, the transferosomal gel proved superior to control, transferosome-free gel. Bioavailability of the transferosomal gel was comparable to Claritin® oral tablets. However, inter-individual variability in Cmax and AUC was reduced by 76 and 90%, respectively, when the buccal gel was used. Linear Correlation of in vitro release with in vivo buccal absorption fractions was established with excellent correlation coefficient (R2>0.97). In summary, a novel buccal delivery system for LTD was developed. However, further clinical investigation is warranted to evaluate its therapeutic effectiveness and utility.

  10. Atrial natriuretic peptide-Fc, ANP-Fc, fusion proteins: semisynthesis, in vitro activity and pharmacokinetics in rats.

    Science.gov (United States)

    Mezo, Adam R; McDonnell, Kevin A; Low, Susan C; Song, Jeff; Reidy, Tom J; Lu, Qi; Amari, John V; Hoehn, Todd; Peters, Robert T; Dumont, Jennifer; Bitonti, Alan J

    2012-03-21

    Atrial natriuretic peptide (ANP) may be a useful molecule for the treatment of cardiovascular diseases due to its potent natriuretic effects. In an effort to prolong the short in vivo half-life of ANP, fusions of the peptide to the Fc domain of IgG were generated using a semisynthetic methodology. Synthetic ANP peptides were synthesized with thioesters at either the N- or C-termini of the peptide and subsequently linked to the N-terminus of recombinantly expressed Fc using native chemical ligation. The linker length between the ANP and Fc moieties was varied among 2, 11, or 16 amino acids. In addition, either one ("monomeric") or two ("dimeric") ANP peptides were linked to Fc to study whether this modification had an effect on in vitro activity and/or in vivo half-life. The various constructs were studied for in vitro activity using a cell-based cGMP assay. The ANP-Fc fusion constructs were between 16- and ∼375-fold weaker than unconjugated ANP in this assay, and a trend was observed where the most potent conjugates were those with longer linkers and in the dimeric configuration. The pharmacokinetics of several constructs were assessed in rats, and the half-life of the ANP-Fc's were found to be approximately 2 orders of magnitude longer than that of the unconjugated peptide. There was no significant difference in terminal half-life between the monomeric and dimeric constructs (2.8-5.5 h), but a trend was observed where the C(max) of the monomeric constructs was approximately 3-fold higher than that of the dimeric constructs, although the origin of this effect is not understood. These novel ANP-Fc fusion constructs hold promise for future therapeutic application in the treatment of cardiovascular diseases.

  11. In vivo pharmacokinetics and in vitro antifungal activity of iodiconazole, a new triazole, determined by microdialysis sampling.

    Science.gov (United States)

    Sun, Ning; Xie, Ying; Sheng, Chunquan; Cao, Yongbing; Zhang, Wannian; Chen, Hongzhuan; Fan, Guorong

    2013-03-01

    In this study, the distribution of a new triazole drug, iodiconazole, in rat dermal interstitial fluid and blood was investigated by double-site microdialysis following dermal administration. It was demonstrated that well-calibrated microdialysis sampling in rats could be used to assess the percutaneous penetration kinetics of iodiconazole cream. Iodiconazole penetrated rapidly and cleared slowly from the dermis. The ratio of area under the concentration-time curve in dermis (AUC(dermis)) to that in blood (AUC(blood)) was close to 20, which meant that the free iodiconazole concentration had a higher distribution in the target tissue. Subsequently, the in vitro antifungal activities of iodiconazole were evaluated and were compared with those of fluconazole, itraconazole, ketoconazole, miconazole and terbinafine. Iodiconazole exhibited broad spectrum and potent activity against 12 kinds of clinically pathogenic fungi. The drug concentration percentage inhibition curves versus time of iodiconazole against the tested fungi elucidated the two-dimensional relationship (concentration-effect) following drug administration, indicating that the percentage inhibition (%) of iodiconazole compared with the drug-free control in dermal dialysate were all >90% in the 900-min sampling time following dermal administration. Moreover, integration of in vivo pharmacokinetic data with the in vitro minimum inhibitory concentration (MIC) provided iodiconazole AUC/MIC ratios in rat dermis and blood of 347.7h and 18.8h, respectively, with an iodiconazole cream (2%) dosage of 0.033 g/cm² (3 cm×5 cm). These findings show a reservoir effect in the skin following topical application. Iodiconazole topical cream may be a future alternative for treatment of dermatophytosis in humans. Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  12. A Diffusion-Based and Dynamic 3D-Printed Device That Enables Parallel in Vitro Pharmacokinetic Profiling of Molecules.

    Science.gov (United States)

    Lockwood, Sarah Y; Meisel, Jayda E; Monsma, Frederick J; Spence, Dana M

    2016-02-02

    The process of bringing a drug to market involves many steps, including the preclinical stage, where various properties of the drug candidate molecule are determined. These properties, which include drug absorption, distribution, metabolism, and excretion, are often displayed in a pharmacokinetic (PK) profile. While PK profiles are determined in animal models, in vitro systems that model in vivo processes are available, although each possesses shortcomings. Here, we present a 3D-printed, diffusion-based, and dynamic in vitro PK device. The device contains six flow channels, each with integrated porous membrane-based insert wells. The pores of these membranes enable drugs to freely diffuse back and forth between the flow channels and the inserts, thus enabling both loading and clearance portions of a standard PK curve to be generated. The device is designed to work with 96-well plate technology and consumes single-digit milliliter volumes to generate multiple PK profiles, simultaneously. Generation of PK profiles by use of the device was initially performed with fluorescein as a test molecule. Effects of such parameters as flow rate, loading time, volume in the insert well, and initial concentration of the test molecule were investigated. A prediction model was generated from this data, enabling the user to predict the concentration of the test molecule at any point along the PK profile within a coefficient of variation of ∼ 5%. Depletion of the analyte from the well was characterized and was determined to follow first-order rate kinetics, indicated by statistically equivalent (p > 0.05) depletion half-lives that were independent of the starting concentration. A PK curve for an approved antibiotic, levofloxacin, was generated to show utility beyond the fluorescein test molecule.

  13. In vitro - In vivo metabolism and pharmacokinetics of picroside I and II using LC-ESI-MS method.

    Science.gov (United States)

    Upadhyay, Dilawar; Anandjiwala, Sheetal; Padh, Harish; Nivsarkar, Manish

    2016-07-25

    Picroside I and II, iridoid glycosides, are the major active markers of roots and rhizomes of Picrorhiza kurroa (family: Scrophulariaceae). The rhizomes of P. kurroa have been traditionally used to treat worms, constipation, low fever, scorpion sting, asthma and ailments affecting the liver. Various Ayurvedic and herbal preparations are available in the market which contains P. kurroa e.g. Arogyavadhini vati, Tiktadi kwath, Picrolax capsules and suspension. These preparations are used without any significant pharmacokinetics data. Previously, we have reported that oral bioavailability of picroside I and II is low. Most of the iridoid glycosides are primarily metabolized by intestinal microbial flora. So, it is necessary to determine the metabolic profile of picroside I and II and check the correlation with lower bioavailability. Therefore, this study was designed to check metabolic (in vitro and in vivo) profile along with pharmacokinetic profile of picroside I and II. For this, a sensitive and selective LC-ESI-MS method was developed and validated for simultaneous determination of picroside I and II in rat plasma. Chromatographic separations were performed on C18 column. The mobile phase consisted of acetonitrile: 10 mM ammonium acetate buffer [90:10 v/v], pH 3.5. In-vitro Metabolic study was performed on rat liver microsomes and primary hepatocytes. In-vivo pharmacokinetic and metabolic profile of picroside I and II was generated after oral administration of Kutkin (mixture of picroside I and II) to Sprague-Dawley rats. Various pharmacokinetic parameters viz. Cmax, Tmax, AUC(0-t) were determined. In metabolic study, eight metabolites of picroside I and six metabolites of picroside II were identified in vitro, out of which four metabolites for each picroside I and picroside II were identified in vivo. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

    Directory of Open Access Journals (Sweden)

    Jie Li

    2017-06-01

    Full Text Available Although arctigenin (AG has diverse bioactivities, such as anti-oxidant, anti-inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro. In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK profiles of AG with different drug-delivery manners, including intravenous (i.v, hypodermic injection (i.h, and sublingual (s.l administration. The data shows that AG exhibited a strong absorption capacity in both rats and beagle dogs (absorption rate < 1 h, a high absorption degree (absolute bioavailability > 100%, and a strong elimination ability (t1/2 < 2 h. The tissue distributions of AG at different time points after i.h showed that the distribution of AG in rat tissues is rapid (2.5 h to reach the peak and wide (detectable in almost all tissues and organs. The AG concentration in the intestine was the highest, followed by that in the heart, liver, pancreas, and kidney. In vitro, AG were incubated with human, monkey, beagle dog and rat liver microsomes. The concentrations of AG were detected by UPLC-MS/MS at different time points (from 0 min to 90 min. The percentages of AG remaining in four species’ liver microsomes were human (62 ± 6.36% > beagle dog (25.9 ± 3.24% > rat (15.7 ± 9% > monkey (3.69 ± 0.12%. This systematic investigation of pharmacokinetic profiles of arctigenin (AG in vivo and in vitro is worthy of further exploration.

  15. Ocular melanin binding of drugs: in vitro binding studies combined to a pharmacokinetic model

    OpenAIRE

    Rimpelä, Anna-Kaisa

    2014-01-01

    Lääkeaineet voivat kerääntyä pigmentoituneisiin kudoksiin sitoutumalla solujen sisältämään melaniinipigmenttiin. Melaniini vaikuttaa lääkeaineen farmakokinetiikkaan toimimalla varastona, josta lääkeaine annostelun päättymisen jälkeen vapautuu. Sitoutuminen voi myös aiheuttaa haittoja suuren paikallisen pitoisuuden vuoksi. Tämä tutkimus käsittelee silmän melaniinia. Kirjallisuuskatsauksessa tutustutaan tavallisimpiin melaniinisitoutumisen tutkimusmenetelmiin ja painotetaan in vitro sitoutumisk...

  16. Preparation, In Vitro Characterization, and In Vivo Pharmacokinetic Evaluation of Respirable Porous Microparticles Containing Rifampicin

    Science.gov (United States)

    Kundawala, Aliasgar; Patel, Vishnu; Patel, Harsha; Choudhary, Dhaglaram

    2014-01-01

    Abstract This study aimed to prepare and evaluate rifampicin microparticles for the lung delivery of rifampicin as respirable powder. The microparticles were prepared using chitosan by the spray-drying method and evaluated for aerodynamic properties and pulmonary drug absorption. To control the drug release, tripoly-phosphate in different concentrations 0.6, 0.9, 1.2, and 1.5 was employed to get a sustained drug release profile. The microparticles were evaluated for drug loading, % entrapment efficiency, tapped density, morphological characteristics, and in vitro drug release studies. Aerosol properties were determined using the Andersen cascade impactor. Porous microparticles with particle sizes (d0.5) less than 10 μm were obtained. The entrapment of rifampicin in microparticles was up to 72%. In vitro drug release suggested that the crosslinked microparticles showed sustained release for more than 12 hrs. The drug release rate was found to be decreased as the TPP concentration was increased. The microparticles showed a fine particle fraction in the range of 55–63% with mass median aerodynamic diameter (MMAD) values below 3 μm. The in vivo pulmonary absorption of the chitosan microparticles suggested a sustained drug release profile up to 72 hrs with an elimination rate of 0.010 per hr. The studies revealed that the spray-dried porous microparticles have suitable properties to be used as respirable powder in rifampicin delivery to the lungs. PMID:25853075

  17. In vitro antioxidant and membrane stabilization activities of the fruit ...

    African Journals Online (AJOL)

    The crude, partitioned extracts (n-hexane, chloroform and ethyl acetate) and seven pooled column chromatographic fractions were used for MSA (in vitro), using indomethacin and hypotonic solution as positive and negative controls. The total phenolic content (TPC) and antioxidant activity were determined. Phytochemical ...

  18. High drug payload curcumin nanosuspensions stabilized by mPEG-DSPE and SPC: in vitro and in vivo evaluation.

    Science.gov (United States)

    Hong, Jingyi; Liu, Yingying; Xiao, Yao; Yang, Xiaofeng; Su, Wenjing; Zhang, Mingzhu; Liao, Yonghong; Kuang, Haixue; Wang, Xiangtao

    2017-11-01

    Curcumin (CUR) is a promising drug candidate based on its broad bioactivities and good antitumor effect, but the application of CUR is potentially restricted because of its poor solubility and bioavailability. This study aims at developing a simple and effective drug delivery system for CUR to enhance its solubility and bioavailability thus to improve its antitumor efficacy. Curcumin nanosuspensions (CUR-NSps) were prepared by precipitation-ultrasonication method using mPEG2000-DSPE and soybean lecithin as a combined stabilizer. CUR-NSps with a high drug payload of 67.07% were successfully prepared. The resultant CUR-NSps had a mean particle size of 186.33 ± 2.73 nm with a zeta potential of -19.00 ± 1.31 mV. In vitro cytotoxicity assay showed that CUR-NSps exhibited enhanced cytotoxicity compared to CUR solution. The pharmacokinetics results demonstrated that CUR-NSps exhibited a significantly greater AUC0-24 and prolonged MRT compared to CUR injections after intravenous administration. In the biodistribution study, CUR-NSps demonstrated enhanced biodistribution compared with CUR injections in liver, spleen, kidney, brain, and tumor. The CUR-NSps also showed improved antitumor therapeutic efficacy over the injections (70.34% versus 40.03%, p drug formulation for intravenous administration of CUR for the treatment of cancer.

  19. In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA.

    Science.gov (United States)

    Kevin, Richard C; Lefever, Timothy W; Snyder, Rodney W; Patel, Purvi R; Fennell, Timothy R; Wiley, Jenny L; McGregor, Iain S; Thomas, Brian F

    2017-01-01

    CUMYL-PICA [1-pentyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide] and 5F-CUMYL-PICA [1-(5-fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide] are recently identified recreationally used/abused synthetic cannabinoids, but have uncharacterized pharmacokinetic profiles and metabolic processes. This study characterized clearance and metabolism of these compounds by human and rat liver microsomes and hepatocytes, and then compared these parameters with in vivo rat plasma and urine sampling. It also evaluated hypothermia, a characteristic cannabimimetic effect. Incubation of CUMYL-PICA and 5F-CUMYL-PICA with rat and human liver microsomes suggested rapid metabolic clearance, but in vivo metabolism was prolonged, such that parent compounds remained detectable in rat plasma 24 h post-dosing. At 3 mg/kg (intraperitoneally), both compounds produced moderate hypothermic effects. Twenty-eight metabolites were tentatively identified for CUMYL-PICA and, coincidentally, 28 metabolites for 5F-CUMYL-PICA, primarily consisting of phase I oxidative transformations and phase II glucuronidation. The primary metabolic pathways for both compounds resulted in the formation of identical metabolites following terminal hydroxylation or dealkylation of the N-pentyl chain for CUMYL-PICA or of the 5-fluoropentyl chain for 5F-CUMYL-PICA. These data provide evidence that in vivo elimination of CUMYL-PICA, 5F-CUMYL-PICA and other synthetic cannabinoids is delayed compared to in vitro modeling, possibly due to sequestration into adipose tissue. Additionally, the present data underscore the need for careful selection of metabolites as analytical targets to distinguish between closely related synthetic cannabinoids in forensic settings.

  20. Ceftriaxone pharmacokinetic properties during continuous veno-veno haemofiltration using an in vitro adult, paediatric and neonatal model.

    Science.gov (United States)

    Harvey, B; Johnson, T N; Yeomanson, D; Mulla, H; Mayer, A P

    2014-01-01

    During continuous venoveno haemofiltration (CVVH), extracorporeal drug clearance is dependant on blood flow, ultrafiltration rate, albumin binding, and the drug's molecular weight and volume of distribution. Drug doses are adjusted assuming reduced drug clearance by the renal system and CVVH. High volume haemofiltration, pre-dilution and different filter membranes can greatly alter drug clearance. Consequently, assessing the adequacy of cephalosporin dosing during CVVH is complex; under- or overdosing may occur. We studied the pharmacokinetic properties of ceftriaxone during CVVH in vitro. Renaflow filters were used to model 6, 20 and 50 kg patients. Each circuit and reservoir was prepared with a known volume of Hartmann's solution, human albumin solution 4.5% or blood. Pump speed and exchange rate were standardised for weight. Haemosol BO was used as the replacement fluid with 70% pre-dilution. Following paired sampling from the circuit and ultrafiltrate fluid, ceftriaxone was injected into the circuit. Paired samples were taken up to 720 minutes. Ceftraxione concentrations were determined using high performance liquid chromatography (HPLC). Maximum circuit concentrations (Cmax) at 2 minutes for albumin were 3.5, 2.65 and 4.85 mg/l, for blood were 4.5, 6.5 and 5.55 mg/l and for Hartmann's were 1.65, 2.95 and 3.65 mg/l for 6 kg, 20 kg and 50 kg models. The sieving coefficients (Sc) from blood (ratio of mean concentrations in the ultrafiltrate/circuits samples) were 0.31 and 0.51 with T1/2 (the half life) 62 and 20 minutes in the 6 kg and the 20 kg circuits, respectively. The data suggest in an in vitro model of ceftriaxone is rapidly cleared during CVVH. Albumin circuits had the lowest Sc and longest terminal T1/2, reflecting protein binding of the drug and suggest ceftriaxone clearance may be more rapid in hypoalbuminaemic patients. The Cmax was lower in the Hartmann circuits, possibly reflecting precipitation of the drug with calcium in this solution.

  1. Reconstituted collagen fibrils. Fibrillar and molecular stability of the collagen upon maturation in vitro.

    OpenAIRE

    Danielsen, C.C.

    1984-01-01

    During the maturation in vitro of reconstituted collagen fibrils prepared from rat skin, the mechanical and thermal stability of collagen increased and the pepsin-solubility decreased. At the same time a larger fraction of the pepsin-soluble collagen attained a lower molecular thermal stability that resulted in a biphasic thermal transition of the soluble collagen. Type-I collagen, with a similar biphasic thermal transition, was isolated from acid-insoluble rat skin collagen.

  2. Colour stability of laminate veneers: an in vitro study.

    Science.gov (United States)

    Turgut, Sedanur; Bagis, Bora

    2011-12-01

    Obtaining a perfect aesthetic, especially with the translucent porcelain laminate veneers; shade of the porcelain, type of the resin cement and their long term colour stability are important factors to achieve aesthetic success. The purpose of the study was to assess the effect of different resin cement systems and UV ageing on the colour of full ceramic laminates with different shades. 392 discs were made with A1, A3, HO and HT shades of IPS e.max Press with 0.5mm thickness. Different shades of light cured Variolink Veneer, Ivoclar Vivadent (+3, MO, -3); Rely X Veneer, 3M ESPE (A1, A3, White Opaque, Translucent); and dual cured Maxcem Elite, Kerr (White, Yellow, White Opaque, Clear); and Variolink II, Ivoclar Vivadent (White Opaque, Translucent) resin cements were applied on the porcelain discs with a thickness of 0.1mm. Colour differences of the porcelain substructures after cementation and 300 h (150 kJ/m(2)) of UV ageing test, were examined with a colorimeter (Shade Eye Ex, Shofu, Japan). The results were analysed statistically with Wilcoxon signed-rank and Kruskal-Wallis test. The mean values of L*, a*, and b* were also compared using Paired Sample t-test. Spearman's Rank Correlation test was used to analyse the correlation between ceramics with resin-cemented ceramics after ageing. The data analyses were evaluated at a significance level of p resin cements, which were polymerized beneath the porcelain substructure with 0.5mm thickness. Although statistically significant differences were observed for all specimens, the magnitudes of the mean colour differences were at an acceptable perception level and were considered clinically acceptable (ΔEResin cements and ageing process influence the colour of porcelain laminate veneers. Cementation of laminates with either dual or light-cure resin cements does not effect the long term colour stability differently. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Stability and in vitro metabolism of dipeptide model prodrugs with affinity for the oligopeptide transporter

    DEFF Research Database (Denmark)

    Lepist, E I; Kusk, T; Larsen, D H

    2000-01-01

    -Glu(OBzl)-Ala and Asp(OBzl)-Sar in aqueous solution and in relevant biological media and to compare these results with those of our previous study of D-Asp(OBzl)-Ala. Furthermore, the resulting aqueous stability and in vitro metabolism data are related to our previous affinity data to evaluate if Glu-Sar, D...

  4. In vitro lipid digestion of chitin nanocrystal stabilized o/w emulsions

    NARCIS (Netherlands)

    Tzoumaki, M.V.; Moschakis, T.; Scholten, E.; Biliaderis, C.G.

    2013-01-01

    Chitin nanocrystals (ChN) have been shown to form stable Pickering emulsions. These oil-in-water emulsions were compared with conventional milk (whey protein isolate, WPI, and sodium caseinate, SCn) protein-stabilized emulsions in terms of their lipid digestion kinetics using an in vitro enzymatic

  5. In vitro color stability of provisional restorative materials

    Directory of Open Access Journals (Sweden)

    Hamid Jalali

    2012-01-01

    Aims: The purpose of this study was to investigate the effect of tea on provisional restorative materials. Setting and Design: This study was designed to measure the degree of color change of three acrylic resin provisional materials, before and after immersion in artificial saliva and artificial saliva-tea solution for 2 and 4 weeks. Materials and Methods : Three types of acrylic provisional materials (duralay, tempron, acropars TRP, were studied. Twenty disks (20±0.1 mm by 2±0.05 mm were fabricated from each material. Specimens were polished with acrylic bur using pumice and diamond polishing paste. Base line color was measured using a spectrophotometer. Ten disks were stored in artificial saliva and 10 were stored in a solution of artificial saliva and tea at room temperature. Color measurements were made after 2 and 4 weeks of immersion. Statistical analysis used: Differences in color changes were compared by two way ANOVA, across the six groups, followed by a Turkey-Kramer′s multiple comparison test. Results: For specimens immersed in artificial saliva, the color change of methyl methacrylate materials; duralay (ΔE=4.94 and tempron (ΔE=6.54, was significantly more than butyl methacrylate material; acropars (ΔE=4.10. After immersion in an artificial saliva- tea solution, tempron exhibited less color change (ΔE=8.50 compared to duralay (ΔE=10.93 and acropars (ΔE=15.64. Conclusion: Color stability of methyl methacrylate is higher than butyl methacrylates so if provisional materials are used for extended periods of time; tempron is preferred.

  6. Physicochemical, pharmacokinetic, efficacy and toxicity profiling of a potential nitrofuranyl methyl piperazine derivative IIIM-MCD-211 for oral tuberculosis therapy via in-silico-in-vitro-in-vivo approach.

    Science.gov (United States)

    Magotra, Asmita; Sharma, Anjna; Singh, Samsher; Ojha, Probir Kumar; Kumar, Sunil; Bokolia, Naveen; Wazir, Priya; Sharma, Shweta; Khan, Inshad Ali; Singh, Parvinder Pal; Vishwakarma, Ram A; Singh, Gurdarshan; Nandi, Utpal

    2017-11-21

    Recent tuberculosis (TB) drug discovery programme involve continuous pursuit for new chemical entity (NCE) which can be not only effective against both susceptible and resistant strains of Mycobacterium tuberculosis (Mtb) but also safe and faster acting with the target, thereby shortening the prolonged TB treatments. We have identified a potential nitrofuranyl methyl piperazine derivative, IIIM-MCD-211 as new antitubercular agent with minimum inhibitory concentration (MIC) value of 0.0072 μM against H37Rv strain. Objective of the present study is to investigate physicochemical, pharmacokinetic, efficacy and toxicity profile using in-silico, in-vitro and in-vivo model in comprehensive manner to assess the likelihood of developing IIIM-MCD-211 as a clinical candidate. Results of computational prediction reveal that compound does not violate Lipinski's, Veber's and Jorgensen's rule linked with drug like properties and oral bioavailability. Experimentally, IIIM-MCD-211 exhibits excellent lipophilicity that is optimal for oral administration. IIIM-MCD-211 displays evidence of P-glycoprotein (P-gp) induction but no inhibition ability in rhodamine cell exclusion assay. IIIM-MCD-211 shows high permeability and plasma protein binding based on parallel artificial membrane permeability assay (PAMPA) and rapid equilibrium dialysis (RED) model, respectively. IIIM-MCD-211 has adequate metabolic stability in rat liver microsomes (RLM) and favourable pharmacokinetics with admirable correlation during dose escalation study in Swiss mice. IIIM-MCD-211 has capability to appear into highly perfusable tissues. IIIM-MCD-211 is able to actively prevent progression of TB infection in chronic infection mice model. IIIM-MCD-211 shows no substantial cytotoxicity in HepG2 cell line. In acute toxicity study, significant increase of total white blood cell (WBC) count in treatment group as compared to control group is observed. Overall, amenable preclinical data make IIIM-MCD-211 ideal

  7. Development of a Physiologically Relevant Population Pharmacokinetic in Vitro-in Vivo Correlation Approach for Designing Extended-Release Oral Dosage Formulation.

    Science.gov (United States)

    Kim, Tae Hwan; Shin, Soyoung; Bulitta, Jürgen B; Youn, Yu Seok; Yoo, Sun Dong; Shin, Beom Soo

    2017-01-03

    Establishing a level A in vitro-in vivo correlation (IVIVC) for a drug with complex absorption kinetics is challenging. The objective of the present study was to develop an IVIVC approach based on population pharmacokinetic (POP-PK) modeling that incorporated physiologically relevant absorption kinetics. To prepare three extended release (ER) tablets of loxoprofen, three types of hydroxypropyl methylcellulose (HPMC 100, 4000, and 15000 cps) were used as drug release modifiers, while lactose and magnesium stearate were used as the diluent and lubricant, respectively. An in vitro dissolution test in various pH conditions showed that loxoprofen dissolution was faster at higher pH. The in vivo pharmacokinetics of loxoprofen was assessed following oral administration of the different loxoprofen formulations to Beagle dogs (n = 22 in total). Secondary peaks or shoulders were observed in many of the individual plasma concentration vs time profiles after ER tablet administration, which may result from secondary absorption in the intestine due to a dissolution rate increase under intestinal pH compared to that observed at stomach pH. In addition, in vivo oral bioavailability was found to decrease with prolonged drug dissolution, indicating site-specific absorption. Based on the in vitro dissolution and in vivo absorption data, a POP-PK IVIVC model was developed using S-ADAPT software. pH-dependent biphasic dissolution kinetics, described using modified Michaelis-Menten kinetics with varying Vmax, and site-specific absorption, modeled using a changeable absorbed fraction parameter, were applied to the POP-PK IVIVC model. To experimentally determine the biphasic dissolution profiles of the ER tablets, another in vitro dissolution test was conducted by switching dissolution medium pH based on an in vivo estimate of gastric emptying time. The model estimated, using linear regression, that in vivo initial maximum dissolution rate (Vmax(0)in vivo) was highly correlated (r2 > 0

  8. Hot melt extruded Aprepitant-Soluplus solid dispersion: preformulation considerations, stability and in vitro study.

    Science.gov (United States)

    Penumetcha, Sai Sumana; Gutta, Lakshmi Narayana; Dhanala, Harish; Yamili, Satyanarayana; Challa, Swetha; Rudraraju, Sneha; Rudraraju, Soumya; Rudraraju, Varma

    2016-10-01

    Solubility limitation of BCS class II drugs pose challenges to in vitro release. To investigate the miscibility of Aprepitant (APR) and Soluplus(®) (SOL) for hot melt extrusion (HME) viability and improved in vitro release of APR. Solubility parameters of APR and SOL from group contribution methods were evaluated. Heat-cool-heat differential scanning calorimetry (DSC) scans were assessed for determining the glass forming ability (GFA) and glass stability (GS) of APR. An optimum HME temperature was selected based on melting point depression in physical mixtures. Moisture sorption isotherms were collected using a dynamic vapor sorption (DVS) analyzer at 25 °C. A 1:4 APR:SOL physical mixture was extruded in a co-rotating 12 mm twin screw extruder and in vitro release was assessed in fasted state simulated intestinal fluid (FaSSIF) with 0.25% SLS. Extrudates were analyzed using TGA, DSC, XRD and FTIR. APR was classified as a class II glass former. APR and SOL had composition dependent miscibility based on Gibb's free energy of mixing. Extrudate prepared using HME had an amorphous as well as a crystalline phase that showed good stability in accelerated stability conditions. Smaller particle size extrudates exhibited a higher % moisture uptake and in vitro release compared to larger particle size extrudates. Enhanced in vitro release of APR from extrudates was attributed to amorphization of APR, solubilization as well as crystal growth inhibition effect of SOL due to H-bond formation with APR. A solid dispersion of APR with improved in vitro release was successfully developed using HME technology.

  9. Synergistic killing by meropenem and colistin combination of carbapenem-resistant Acinetobacter baumannii isolates from Chinese patients in an in vitro pharmacokinetic/pharmacodynamic model.

    Science.gov (United States)

    Liu, Xiaofen; Zhao, Miao; Chen, Yuancheng; Bian, Xingchen; Li, Yunfei; Shi, Jun; Zhang, Jing

    2016-11-01

    Carbapenem-resistant Acinetobacter baumannii (CRAB) is an important clinical threat. Combination therapy that exerts a synergistic effect has become a potential solution to combat CRAB. However, choosing an optimal combination regimen is challenging. A dynamic in vitro pharmacokinetic/pharmacodynamic (PK/PD) model that can simulate the pharmacokinetic profiles of antibiotics provides a powerful tool to compare antibacterial responses to different clinical dosage regimens. In this study, the synergistic effect of the combination of meropenem and colistin was tested in 12 clinical CRAB isolates from Chinese patients using the chequerboard technique. The antibacterial effect was investigated in an in vitro PK/PD diffusion model by simulating different dosage regimens: meropenem monotherapy (0.5 g with 0.5-h infusion or 1 g with 3-h infusion); colistin monotherapy (fixed unbound concentration maintained at 0.25, 0.5 or 1 mg/L); and combination of meropenem and colistin. The chequerboard method showed that the combination of meropenem and colistin had synergistic effects against all 12 isolates, with fractional inhibitory concentration indices (FICIs) of ≤0.5. Moreover, the dynamic in vitro PK/PD model demonstrated that for clinical CRAB isolates with a meropenem MIC of 128 mg/L, the combination (meropenem 1 g with 3-h infusion combined with colistin maintained at 1 mg/L) could achieve 3.8 log10 killing after 24 h, whereas monotherapy was unable to provide such an antibacterial effect. Taken together, these results suggest that the combination of meropenem and colistin might be a promising therapy against CRAB. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  10. Investigating the impact of drug crystallinity in amorphous tacrolimus capsules on pharmacokinetics and bioequivalence using discriminatory in vitro dissolution testing and PBPK modeling and simulation.

    Science.gov (United States)

    Purohit, Hitesh S; Trasi, Niraj S; Sun, Dajun D; Chow, Edwin C Y; Wen, Hong; Zhang, Xinyuan; Gao, Yi; Taylor, Lynne S

    2017-12-28

    Delivering a drug in amorphous form in a formulated product is a strategy used to enhance the apparent solubility of a drug substance and its oral bioavailability. Drug crystallization in such products may occur during the manufacturing process or upon storage, reducing the solubility advantage of the amorphous drug. However, the impact of partial drug crystallization in the drug product on the resulting bioavailability and pharmacokinetics is unknown. In this study, dissolution testing of commercial tacrolimus capsules (which are formulated to contain amorphous drug), both fresh and those containing different amounts of crystalline drug, was conducted using both USP and non-compendial dissolution tests with different dissolution media and volumes. A physiologically based pharmacokinetic (PBPK) absorption model was developed to predict the impact of crystallinity extent on the oral absorption of the products and to evaluate the discriminatory ability of the different dissolution methods. Virtual bioequivalence simulations between partially crystallized tacrolimus capsules versus fresh Prograf or generic tacrolimus capsules were performed using the PBPK model and in vitro dissolution data of the various fresh and partially crystallized capsules under USP and non-compendial dissolution conditions. The results suggest that compendial dissolution tests may not be sufficiently discriminatory with respect to the presence of crystallinity in an amorphous formulation. Non-sink dissolution tests using lower dissolution volumes generate more discriminatory profiles that predict different pharmacokinetics of tacrolimus capsules containing different extents of drug crystallinity. In conclusion, the PBPK modeling approach can be used to assess the impact of partial drug crystallinity in the formulated product and to guide the development of appropriate dissolution methods. Copyright © 2017. Published by Elsevier Inc.

  11. Prediction of in-vivo pharmacokinetic profile for immediate and modified release oral dosage forms of furosemide using an in-vitro-in-silico-in-vivo approach.

    Science.gov (United States)

    Otsuka, Keiichi; Wagner, Christian; Selen, Arzu; Dressman, Jennifer

    2015-05-01

    To develop a physiologically based pharmacokinetic (PBPK) model for furosemide immediate release (IR) tablets and modified release (MR) capsules by coupling biorelevant dissolution testing results with pharmacokinetic (PK) and physiologic parameters, and to investigate the key factors influencing furosemide absorption using simulation approaches and the PBPK model. Using solubility, dissolution kinetics, gastrointestinal (GI) parameters and disposition parameters, a PBPK model for furosemide was developed with STELLA software. Solubility and dissolution profiles for both formulations were evaluated in biorelevant and compendial media. The simulated plasma profiles were compared with in-vivo profiles using point estimates of area under plasma concentration-time curve, maximal concentration after the dose and time to maximal concentration after the dose. Simulated plasma profiles of both furosemide IR tablets and MR capsules were similar to the observed in-vivo profile in terms of PK parameters. Sensitivity analysis of the IR tablet model indicated that both the gastric emptying and absorption rate have an influence on the plasma profile. For the MR capsules, the sensitivity analysis suggested that the release rate in the small intestine, gastric emptying and the absorption rate all have an influence on the plasma profile. A predictive model to describe both IR and MR dosage forms containing furosemide was attained. Because sensitivity analysis of the model is able to identify key factors influencing the plasma profile, this in-vitro-in-silico-in-vivo approach could be a useful tool for facilitating formulation development of drug products. © 2015 Royal Pharmaceutical Society.

  12. Targeting anti-apoptotic Bcl-2 by AT-101 to increase radiation efficacy: data from in vitro and clinical pharmacokinetic studies in head and neck cancer.

    Science.gov (United States)

    Zerp, Shuraila F; Stoter, T Rianne; Hoebers, Frank J P; van den Brekel, Michiel W M; Dubbelman, Ria; Kuipers, Gitta K; Lafleur, M Vincent M; Slotman, Ben J; Verheij, Marcel

    2015-07-30

    Pro-survival Bcl-2 family members can promote cancer development and contribute to treatment resistance. Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by overexpression of anti-apoptotic Bcl-2 family members. Increased levels of these anti-apoptotic proteins have been associated with radio- and chemoresistance and poor clinical outcome. Inhibition of anti-apoptotic Bcl-2 family members therefore represents an appealing strategy to overcome resistance to anti-cancer therapies. The aim of this study was to evaluate combined effects of radiation and the pan-Bcl-2 inhibitor AT-101 in HNSCC in vitro. In addition, we determined human plasma levels of AT-101 obtained from a phase I/II trial, and compared these with the effective in vitro concentrations to substantiate therapeutic opportunities. We examined the effect of AT-101, radiation and the combination on apoptosis induction and clonogenic survival in two HNSCC cell lines that express the target proteins. Apoptosis was assessed by bis-benzimide staining to detect morphological nuclear changes and/or by propidium iodide staining and flow-cytometry analysis to quantify sub-diploid apoptotic nuclei. The type of interaction between AT-101 and radiation was evaluated by calculating the Combination Index (CI) and by performing isobolographic analysis. For the pharmacokinetic analysis, plasma AT-101 levels were measured by HPLC in blood samples collected from patients enrolled in our clinical phase I/II study. These patients with locally advanced HNSCC were treated with standard cisplatin-based chemoradiotherapy and received dose-escalating oral AT-101 in a 2-weeks daily schedule every 3 weeks. In vitro results showed that AT-101 enhances radiation-induced apoptosis with CI's below 1.0, indicating synergy. This effect was sequence-dependent. Clonogenic survival assays demonstrated a radiosensitizing effect with a DEF37 of 1.3 at sub-apoptotic concentrations of AT-101. Pharmacokinetic analysis of

  13. Establishment and assessment of a novel in vitro bio-PK/PD system in predicting the in vivo pharmacokinetics and pharmacodynamics of cyclophosphamide.

    Science.gov (United States)

    Tong, Shanshan; Sun, Hong; Xue, Caifu; Chen, Hanmei; Liu, Jing; Yang, Huiying; Zhou, Ning; Xiang, Xiaoqiang; Cai, Weimin

    2017-06-06

    1. A novel bio-pharmacokinetic/pharmacodynamic (PK/PD) system was established and assessed in predicting the PK parameters and PD effects of the model drug cyclophosphamide (CP) considering the interrelationships between drug metabolism, pharmacological effects and dynamic blood circulation processes in vitro. 2. The system contains a peristaltic pump, a reaction chamber with rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogels, an effector cell chamber and a recirculating pipeline. The metabolism and pharmacological effects of CP (5, 10 and 20 mM) were measured by HPLC and MTT assay. A mathematical model based on mass balance was used to predict the in vitro clearance of CP. In vivo clearance of CP was estimated by in vitro to in vivo extrapolations (IVIVE) and simulations using Simcyp® software. 3. The predicted in vivo clearance of CP at concentrations of 5, 10 and 20 mM was 11.36, 10.12 and 10.68 mL/min/kg, respectively, within two-fold differences compared with the reported 11.1 mL/min/kg. The survival ratio of effector cells during the metabolism and circulation of CP was significantly enhanced. 4. This system may serve as an alternative approach to predict in vivo metabolism, pharmacological effects and toxicity of drugs, ensuring an efficient drug screening process.

  14. Cryptotanshinone-Loaded Cerasomes Formulation: In Vitro Drug Release, in Vivo Pharmacokinetics, and in Vivo Efficacy for Topical Therapy of Acne

    Directory of Open Access Journals (Sweden)

    Ting Zuo

    2016-12-01

    Full Text Available Cerasomes (CS, evolved from liposomes, are novel drug-delivery systems that have potential medical application as carriers for drugs or active ingredients. Although many studies have been conducted on the pharmaceutical and physicochemical properties of CS, the role of CS in influencing the in vivo plasma and topical pharmacokinetics and efficacy of topical drug delivery remain unclear. In this context, we chose cryptotanshinone (CTS as a model drug for the preparation of CTS-CS by means of the ethanol injection method to investigate their in vitro/in vivo drug-release behavior and in vivo efficacy. (1 In in vitro studies, CTS-CS gel was proven to be capable of achieving a higher permeation rate and significant accumulation in the dermis of isolated rat skin using Franz diffusion cells. (2 In in vivo studies, microdialysis experiments used to measure the plasma and topical pharmacokinetics demonstrated that the CS had a high drug concentration, short peak time, and slow elimination. Meanwhile, the plasma area under the concentration–time curve of CTS-CS gel was less than half that for the CTS gel in 12 h, which indicates that the drug bioavailability dramatically increased in the experiments. (3 In in vivo efficacy studies, we duplicated a rat acne model and performed antiacne efficacy experiments. The CTS-CS gel improved the antiacne efficacy compared to that of ordinary CTS gel. Moreover, it inhibited the expression of interleukin-1α and androgen receptors effectively. All of these results show that CTS-CS gel has significant potential for the treatment of acne induced by inflammation and excessive secretion of androgen, suggesting that CS formulations were designed as a good therapeutic option for skin disease.

  15. Development of an in vitro model to simulate the gastrointestinal digestion and absorption of stabilizing agents

    Directory of Open Access Journals (Sweden)

    Uberti Francesca

    2014-01-01

    Full Text Available Each step in the winemaking process must be carefully planned and controlled to optimize the quality of wine. Among others, tartaric stabilization is a critical step in enology, and although effective, the usual practices to solve it show some qualitative limitations, and important economical and environmental impacts. For the reasons reported above, the wine producers are searching for alternative practices, with particular interest in the area of organic products. Biopolymers are possible alternatives in this field. The selection, the characterization and the safety aspects of new biopolymers are the objectives of the European project STABIWINE (Use of biopolymers for sustainable stabilization of quality wines. The first group of biopolymers analyzed includes polyaminoacids and, in particular, polymers of L-aspartic acid (PAA, which can be used as enological additives for tartaric stabilization. In order to contribute in drafting the toxicological dossier, the metabolic fate of PAAs has been assessed by in vitro models, mimicking gastrointestinal digestion and absorption.

  16. Biomechanics of a Posterior Lumbar Motion Stabilizing Device: In Vitro Comparison to Intact and Fused Conditions.

    Science.gov (United States)

    Perez-Orribo, Luis; Zucherman, James F; Hsu, Kenneth Y; Reyes, Phillip M; Rodriguez-Martinez, Nestor G; Crawford, Neil R

    2016-01-01

    Nondestructive flexibility tests were performed in vitro, comparing multiple conditions of fixation in a single group of specimens. To compare the biomechanical behavior of the lumbar spine in the intact condition, after implanting a novel motion stabilizer, and after implanting a rigid fixator. Two specific scenarios that may benefit from dynamic lumbar stabilization are single-level moderate instability, where the stabilizing tissues are relatively incompetent, and juxta-level to fusion, where the last instrumented level requires intermediate stiffness ("topping off") to prevent transfer of high stresses from the stiffer fusion construct to the intact adjacent levels. Both scenarios were evaluated in vitro. Seven human cadaveric L2-S1 segments were tested (1) intact, (2) after moderate destabilization, (3) after 2-level hybrid posterior fixation, consisting of bilateral dynamic pedicle screws at L4 interconnected with rigid rods to standard pedicle screws at L5 and S1, (4) after 2-level rigid fixation, (5) after 1-level (L4-L5) dynamic fixation, and (6) after 1-level rigid fixation. In each condition, angular range of motion (ROM) and sagittal instantaneous axis of rotation (IAR) were assessed. In 1-level constructs, dynamic hardware allowed 104% of intact ROM, whereas rigid hardware allowed 49% of intact ROM. Relative to the intact, the IAR was shifted significantly farther posterior by rigid 1-level instrumentation than by dynamic 1-level instrumentation. In 2-level constructs, the dynamic level allowed significantly greater ROM than the rigid level in all directions but allowed significantly less ROM than the intact level in all directions except axial rotation. Dynamic instrumentation shifted the IAR less than rigid instrumentation, providing more favorable kinematics. This dynamic stabilizer provided 1-level ROM that was close to intact ROM during all loading modes in vitro. In the topping-off construct, the dynamic segment allowed intermediate ROM to give

  17. In vitro-in vivo correlations for nicotine transdermal delivery systems evaluated by both in vitro skin permeation (IVPT) and in vivo serum pharmacokinetics under the influence of transient heat application.

    Science.gov (United States)

    Shin, Soo Hyeon; Thomas, Sherin; Raney, Sam G; Ghosh, Priyanka; Hammell, Dana C; El-Kamary, Samer S; Chen, Wilbur H; Billington, M Melissa; Hassan, Hazem E; Stinchcomb, Audra L

    2018-01-28

    The in vitro permeation test (IVPT) has been widely used to characterize the bioavailability (BA) of compounds applied on the skin. In this study, we performed IVPT studies using excised human skin (in vitro) and harmonized in vivo human serum pharmacokinetic (PK) studies to evaluate the potential in vitro-in vivo correlation (IVIVC) of nicotine BA from two, matrix-type, nicotine transdermal delivery systems (TDS). The study designs used for both in vitro and in vivo studies included 1h of transient heat (42±2°C) application during early or late time periods post-dosing. The goal was to evaluate whether any IVIVC observed would be evident even under conditions of heat exposure, in order to investigate further whether IVPT may have the potential to serve as a possible surrogate method to evaluate the in vivo effects of heat on the bioavailability of a drug delivered from a TDS. The study results have demonstrated that the BA of nicotine characterized by the IVPT studies correlated with and was predictive of the in vivo BA of nicotine from the respective TDS, evaluated under the matched study designs and conditions. The comparisons of single parameters such as steady-state concentration, heat-induced increase in partial AUCs and post-treatment residual content of nicotine in TDS from the in vitro and in vivo data sets showed no significant differences (p≥0.05). In addition, a good point-to-point IVIVC (Level A correlation) for the entire study duration was achieved by predicting in vivo concentrations of nicotine using two approaches: Approach I requiring only an in vitro data set and Approach II involving deconvolution and convolution steps. The results of our work suggest that a well designed IVPT study with adequate controls can be a useful tool to evaluate the relative effects of heat on the BA of nicotine from TDS with different formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Cefepime and continuous renal replacement therapy (CRRT): in vitro permeability of two CRRT membranes and pharmacokinetics in four critically ill patients.

    Science.gov (United States)

    Isla, Arantxazu; Gascón, Alicia Rodríguez; Maynar, Javier; Arzuaga, Alazne; Toral, Darío; Pedraz, José Luis

    2005-05-01

    Cefepime is a fourth-generation cephalosporin with a broad spectrum of antimicrobial activity against gram-positive and gram-negative micro-organisms. It is a useful option for treating infections in critically ill patients in intensive care due to its high degree of activity and its tolerability. The aim of this study was to characterize in vitro the permeability to cefepime of 2 membranes frequently used in continuous renal replacement therapies (CRRTs). An in vivo study was also carried out to determine the pharmacokinetics of cefepime in critically ill patients undergoing CRRT. In vitro procedures were conducted in 3 different fluids using polyacrylonitrile (AN69) or polysulfone (PS) membranes. Continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD) were simulated. Four male patients undergoing CVVH or continuous venovenous hemodiafiltration, who received 2000 mg of cefepime intravenously every 8 hours, entered the in vivo study. Prefilter and ultrafiltrate samples were collected, and concentrations of cefepime were measured using high-performance liquid chromatography. The sieving coefficient (Sc), defined as the fraction of drug eliminated across the membrane, and the saturation coefficient (Sa), defined as the fraction of drug diffused through the membrane to the dialysate fluid, were analyzed. Pharmacokinetic parameters were determined according to a noncompartmental analysis. The patients ranged in age from 18 to 75 years and weighed from 65 to 80 kg. By analyzing Sc and Sa values in the in vitro procedures, no differences were detected in the permeability of AN69 or PS membranes to cefepime in CVVH or CVVHD. Sc/Sa values were between 0.93 and 1.03 in Ringer's lactate and in bovine albumin-containing Ringer's lactate samples, but Sc/Sa values were lower in plasma samples (0.82-0.95). In the in vivo portion of the study, the patients' mean (SD) Sc/Sa value was 0.76 (0.21) and correlated well with the fraction unbound to

  19. Pharmacokinetics of Chiral Dendrimer-Triamine-Coordinated Gd-MRI Contrast Agents Evaluated by in Vivo MRI and Estimated by in Vitro QCM

    Directory of Open Access Journals (Sweden)

    Yuka Miyake

    2015-12-01

    Full Text Available Recently, we developed novel chiral dendrimer-triamine-coordinated Gd-MRI contrast agents (Gd-MRI CAs, which showed longitudinal relaxivity (r1 values about four times higher than that of clinically used Gd-DTPA (Magnevist®, Bayer. In our continuing study of pharmacokinetic differences derived from both the chirality and generation of Gd-MRI CAs, we found that the ability of chiral dendrimer Gd-MRI CAs to circulate within the body can be directly evaluated by in vitro MRI (7 T. In this study, the association constants (Ka of chiral dendrimer Gd-MRI CAs to bovine serum albumin (BSA, measured and calculated with a quartz crystal microbalance (QCM in vitro, were found to be an extremely easy means for evaluating the body-circulation ability of chiral dendrimer Gd-MRI CAs. The Ka values of S-isomeric dendrimer Gd-MRI CAs were generally greater than those of R-isomeric dendrimer Gd-MRI CAs, which is consistent with the results of our previous MRI study in vivo.

  20. Genetic stability of in vitro conserved germplasm of Humulus lupulus L.

    Directory of Open Access Journals (Sweden)

    E.L. PEREDO

    2008-12-01

    Full Text Available The genetic and epigenetic stability of hop accessions cryopreserved for one year or cold stored for three years was evaluated using several molecular markers (RAPD, AFLP, and MSAP. Clear, repetitive patterns were obtained among accessions and between control and treated samples. Although no genetic changes were detected among the control plants grown in the greenhouse and in vitro plants regenerated from slow-cooling cryopreserved shoot tips or cold stored in vitro shoots, MSAP analysis detected methylation changes in 36% of the loci. Nevertheless, only 2.6 to 9.8% of the detected changes could be ascribed to the conservation procedure and most of them seemed to be generated as a result of the in vitro introduction. Due to the number of accessions analysed (51 we can cautiously deduce that the genetic behaviour described in this work after cryopreservation or cold-storage protocols is common to most hop genotypes and these storage procedures are suitable for standard use. However, it is important to keep in mind the epigenetic changes produced, particularly during any in vitro processes.;

  1. Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation.

    Science.gov (United States)

    Ye, Qiuping; Jiang, Min; Huang, Wotang T; Ling, Yun; Olson, Steven H; Sun, Daqing; Xu, Guifen; Yan, Xuelei; Wong, Bradley K; Jin, Lixia

    2015-01-01

    1. AMG 232 is a novel inhibitor of the p53-MDM2 protein-protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data. 2. AMG 232 exhibited low clearance (42%), but high clearance (0.74 × Qh) and low oral exposure in dogs (18%). 3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered (14)C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species. 4. The in vitro-in vivo correlation of AMG 232 clearance was within 2-fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials.

  2. Genotypic and serotypic stability of Campylobacter jejuni strains during in vitro and in vivo passage

    DEFF Research Database (Denmark)

    Nielsen, Eva M.; Engberg, J.; Fussing, V.

    2001-01-01

    The stability of four typing methods and the sero- and genotypic stability of three Campylobacter jejuni strains were evaluated after subculturing 50 times in triplicate and after colonising mice for up to 26 days. The employed methods were Penner heat-stable serotyping; automated ribotyping (Ribo...... these strains after the in vitro and in vivo passages. However, one isolate became untypeable with RAPD after passage in one of the mice. In addition, eleven other C. jejuni strains of four different serotypes were subcultured ten times to screen for instability. Neither of these showed instability using PFGE...... and serotyping. Furthermore, three of four strains previously identified as unstable, showed to consist of mixed cultures, which explains the reported profile changes. The results indicate that the applied typing methods are reliable and applicable for typing of Campylobacter isolates from different sources over...

  3. Oil-in-water emulsions stabilised by cellulose ethers: stability, structure and in vitro digestion.

    Science.gov (United States)

    Borreani, Jennifer; Espert, María; Salvador, Ana; Sanz, Teresa; Quiles, Amparo; Hernando, Isabel

    2017-04-19

    The effect of cellulose ethers in oil-in-water emulsions on stability during storage and on texture, microstructure and lipid digestibility during in vitro gastrointestinal digestion was investigated. All the cellulose ether emulsions showed good physical and oxidative stability during storage. In particular, the methylcellulose with high methoxyl substituents (HMC) made it possible to obtain emulsions with high consistency which remained almost unchanged during gastric digestion, and thus could enhance fullness and satiety perceptions at gastric level. Moreover, the HMC emulsion slowed down lipid digestion to a greater extent than a conventional protein emulsion or the emulsions stabilised by the other cellulose ethers. Therefore, HMC emulsions could be used in weight management to increase satiation capacity and decrease lipid digestion.

  4. A Workflow to Investigate Exposure and Pharmacokinetic Influences on High-Throughput in Vitro Chemical Screening Based on Adverse Outcome Pathways.

    Science.gov (United States)

    Phillips, Martin B; Leonard, Jeremy A; Grulke, Christopher M; Chang, Daniel T; Edwards, Stephen W; Brooks, Raina; Goldsmith, Michael-Rock; El-Masri, Hisham; Tan, Yu-Mei

    2016-01-01

    Adverse outcome pathways (AOPs) link adverse effects in individuals or populations to a molecular initiating event (MIE) that can be quantified using in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires incorporation of knowledge on exposure, along with absorption, distribution, metabolism, and excretion (ADME) properties of chemicals. We developed a conceptual workflow to examine exposure and ADME properties in relation to an MIE. The utility of this workflow was evaluated using a previously established AOP, acetylcholinesterase (AChE) inhibition. Thirty chemicals found to inhibit human AChE in the ToxCast™ assay were examined with respect to their exposure, absorption potential, and ability to cross the blood-brain barrier (BBB). Structures of active chemicals were compared against structures of 1,029 inactive chemicals to detect possible parent compounds that might have active metabolites. Application of the workflow screened 10 "low-priority" chemicals of 30 active chemicals. Fifty-two of the 1,029 inactive chemicals exhibited a similarity threshold of ≥ 75% with their nearest active neighbors. Of these 52 compounds, 30 were excluded due to poor absorption or distribution. The remaining 22 compounds may inhibit AChE in vivo either directly or as a result of metabolic activation. The incorporation of exposure and ADME properties into the conceptual workflow eliminated 10 "low-priority" chemicals that may otherwise have undergone additional, resource-consuming analyses. Our workflow also increased confidence in interpretation of in vitro results by identifying possible "false negatives." Phillips MB, Leonard JA, Grulke CM, Chang DT, Edwards SW, Brooks R, Goldsmith MR, El-Masri H, Tan YM. 2016. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways. Environ Health Perspect 124:53-60; http://dx.doi.org/10.1289/ehp.1409450.

  5. Toward in vitro-to-in vivo translation of monoclonal antibody pharmacokinetics: Application of a neonatal Fc receptor-mediated transcytosis assay to understand the interplaying clearance mechanisms.

    Science.gov (United States)

    Jaramillo, Claudia A Castro; Belli, Sara; Cascais, Anne-Christine; Dudal, Sherri; Edelmann, Martin R; Haak, Markus; Brun, Marie-Elise; Otteneder, Michael B; Ullah, Mohammed; Funk, Christoph; Schuler, Franz; Simon, Silke

    2017-07-01

    Monoclonal antibodies (mAbs) are a rapidly growing drug class for which great efforts have been made to optimize certain molecular features to achieve the desired pharmacokinetic (PK) properties. One approach is to engineer the interactions of the mAb with the neonatal Fc receptor (FcRn) by introducing specific amino acid sequence mutations, and to assess their effect on the PK profile with in vivo studies. Indeed, FcRn protects mAbs from intracellular degradation, thereby prolongs antibody circulation time in plasma and modulates its systemic clearance. To allow more efficient and focused mAb optimization, in vitro input that helps to identify and quantitatively predict the contribution of different processes driving non-target mediated mAb clearance in vivo and supporting translational PK modeling activities is essential. With this aim, we evaluated the applicability and in vivo-relevance of an in vitro cellular FcRn-mediated transcytosis assay to explain the PK behavior of 25 mAbs in rat or monkey. The assay was able to capture species-specific differences in IgG-FcRn interactions and overall correctly ranked Fc mutants according to their in vivo clearance. However, it could not explain the PK behavior of all tested IgGs, indicating that mAb disposition in vivo is a complex interplay of additional processes besides the FcRn interaction. Overall, the transcytosis assay was considered suitable to rank mAb candidates for their FcRn-mediated clearance component before extensive in vivo testing, and represents a first step toward a multi-factorial in vivo clearance prediction approach based on in vitro data.

  6. In vitro and in vivo pharmacokinetics and toxicity evaluation of curcumin incorporated titanium dioxide nanoparticles for biomedical applications.

    Science.gov (United States)

    Sherin, Sainulabdeen; Sheeja, Sathyabhama; Sudha Devi, Rukhmini; Balachandran, Sreedharan; Soumya, Rema Sreenivasan; Abraham, Annie

    2017-09-25

    The present study deals with the preparation of stable Curcumin incorporated Titaniumdioxide Nanoparticles (CTNPs) by coprecipitation method for improving the bioavailability of curcumin and site specific drug delivery. The prepared nanoparticles were characterized by UV visible spectroscopy, FTIR, XRD, DLS, SEM and EDX. The characterization studies showed the interaction of curcumin to titanium dioxide nanoparticles. The average size of the prepared CTNPs was found to be ∼29 nm with zetapotential of-53.790 mV. In vivo and in vitro toxicological evaluations were carried out to determine the biological effect of CTNPs. In vitro parameters like cell viability, Lactate dehydrogenase (LDH) Assay, Neutral red uptake (NRU) assay and uptake of curcumin from CTNPs by the cells had been investigated. In vitro toxicity studies in THP1 and H9c2 cell lines showed that CTNPs are safe even at a dose of 200 ng. The in vivo part of the study was carried out with different doses of Curcumin (1 mg-20 mg/kg body weight), Titaniumdioxide Nanoparticles (TNPs) (1 mg-5 mg/kg Body weight) and CTNPs (5 mg-10 mg/kg Body weight) in Sprague dawley rat models to determine the pharmacokinetics and genotoxicity of the nanoparticle. This was done by analysing the parameters like SGPT, SGOT, LDH, hematological parameters and biodistribution of the nanomaterial at different organ sites. Genotoxicity of samples were done by comet assay on blood cells. No significant toxicity was observed in the parameters in samples treated group compared to controls. The overall results indicated that the CTNPs are nontoxic and is highly stable with improved site specific application compared to native curcumin and are suitable for biomedical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Validation of an in vitro method to determine infectivity of cryopreserved sporozoites in stabilates of Theileria spp.

    Science.gov (United States)

    Wilkie, G M; Kirvar, E; Brown, C G D

    2002-03-20

    The infectivity of 15 cryopreserved Theileria spp. sporozoite stabilates was assessed semi-quantitatively by titration using naive peripheral blood mononuclear cells (PBM) in vitro in multi-well plates. Using the method described, the effective dilution, which would result in 50% of replicate wells infected (ED50), was calculated. The ED50 for 11 Theileria annulata stabilates in bovine PBM ranged from 10(-2.6) to 10(-4.2) dilutions of 1 tick equivalent (t.e.) ml(-1), one stabilate of Theileria parva 10(-2.2)t.e.ml(-1); and three Theileria lestoquardi stabilates in ovine PBM, from 10(-1.5) to 10(-1.8)t.e.ml(-1). Two of the T. annulata stabilates had been used individually to infect groups of calves: stabilate 52 produced more severe disease responses than stabilate 67, as measured by prepatent period, parasitosis, parasitaemia and death or recovery. This corresponded with the sixfold difference found in vitro between the ED50's of these two stabilates. This method is useful not only to measure the infection potential of the sporozoite stabilates but also as an in vitro model for chemotherapeutic and immunological studies of the early stages of theileriosis.

  8. Antifungal activity of amphotericin B and voriconazole against the biofilms and biofilm-dispersed cells of Candida albicans employing a newly developed in vitro pharmacokinetic model.

    Science.gov (United States)

    El-Azizi, Mohamed; Farag, Noha; Khardori, Nancy

    2015-04-03

    Candida albicans is a common cause of a variety of superficial and invasive disseminated infections the majority of which are associated with biofilm growth on implanted devices. The aim of the study is to evaluate the activity of amphotericin B and voriconazole against the biofilm and the biofilm-dispersed cells of Candida albicans using a newly developed in vitro pharmacokinetic model which simulates the clinical situation when the antifungal agents are administered intermittently. RPMI medium containing 1-5 X 10(6) CFU/ml of C. albicans was continuously delivered to the device at 30 ml/h for 2 hours. The planktonic cells were removed and biofilms on the catheter were kept under continuous flow of RPMI medium at 10 ml/h. Five doses of amphotericin B or voriconazole were delivered to 2, 5 and 10 day-old biofilms at initial concentrations (2 and 3 μg/ml respectively) that were exponentially diluted. Dispersed cells in effluents from the device were counted and the adherent cells on the catheter were evaluated after 48 h of the last dose. The minimum inhibitory concentration of voriconazole and amphotericin B against the tested isolate was 0.0325 and 0.25 μg/ml respectively. Amphotericin B significantly reduced the dispersion of C. albicans cells from the biofilm. The log10 reduction in the dispersed cells was 2.54-3.54, 2.30-3.55, and 1.94-2.50 following addition of 5 doses of amphotericin B to 2-, 5- and 10-day old biofilms respectively. The number of the viable cells within the biofilm was reduced by 18 (±7.63), 5 and 4% following addition of the 5 doses of amphotericin B to the biofilms respectively. Voriconazole showed no significant effect on the viability of C. albicans within the biofilm. Both antifungal agents failed to eradicate C. albicans biofilm or stop cell dispersion from them and the resistance progressed with maturation of the biofilm. These findings go along with the need for removal of devices in spite of antifungal therapy in patients

  9. Stability of esomeprazole capsule contents after in vitro suspension in common soft foods and beverages.

    Science.gov (United States)

    Johnson, David A; Roach, Albert C; Carlsson, Anders S; Karlsson, Anders A S; Behr, Dan E

    2003-06-01

    To determine the in vitro stability of esomeprazole pellets from an opened capsule after suspension in various common soft foods and beverages. In vitro study. Pharmaceutical company research laboratory. Pellets from opened esomeprazole 20-mg capsules were suspended in 100 ml of tap water, milk (1.5% fat), orange juice, apple juice, yogurt, or cultured milk for 30 minutes, then added to 500 ml of hydrochloric acid to simulate gastric acid exposure. After a 2-hour incubation, the mixture was filtered through a sieve, and the collected pellets were dissolved in an alkaline solution. Esomeprazole concentrations were measured using reverse-phase liquid chromatography The stability of the esomeprazole pellets exceeded 98% in all beverages and soft foods except milk. Administration of the pellets from an opened esomeprazole capsule shortly after suspending them in tap water, yogurt, cultured milk, orange juice, or apple juice may be a practical alternative for patients who cannot swallow an intact capsule. Bioavailability studies comparing esomeprazole administered as an intact capsule to that of the pellets from an opened capsule suspended in these beverages or soft foods are recommended to confirm these findings.

  10. Development and validation of UPLC/ESI-Q-TOF-MS for carteolol in aqueous humour: Stability, stress degradation and application in pharmacokinetics of nanoformulation

    Directory of Open Access Journals (Sweden)

    Ameeduzzafar

    2017-05-01

    Full Text Available Carteolol (CRT is currently under development as a potential therapeutic agent for the treatment of open angle glaucoma. The purpose of the present work is to develop and validate a stability indicating assay method and its application to estimate CRT in aqueous humour and study the pharmacokinetic parameters. An ultra performance liquid chromatographic tandem mass spectroscopy (UPLC–MS/MS method was developed and validated for the quantitative determination of CRT in rabbit aqueous humour, using propranolol as the internal standard (I.S.. Aqueous humour samples were prepared by a simple liquid–liquid extraction technique (LLE. The analyte and internal standard were separated by an Acquity UPLC BEH C18 (100.0 × 2.1 mm; 1.7 μm column with a mobile phase of acetonitrile – 2 mM (milli mole ammonium acetate (90/10, v/v over 3 min of retention time. Detection was based on the multiple reactions monitoring with the precursor-to-product ion transitions m/z 293.2 → 237.12 for CRT and m/z 260.09 → 183.04 for I.S. The method was validated according to FDA guidelines on the bio-analytical method validation. The method developed was linear (r2 = 0.999 over the concentration range of 1–1000 ng/mL. The selectivity, sensitivity, linearity, accuracy, precision, extraction recovery, and stability were within the acceptable ranges. Forced degradation studies were performed on bulk sample of CRT as per ICH prescribed stress conditions, such as acid, base, oxidative and photolytic to show the forced of the method. Significant degradation was observed during basic stress condition. The pharmacokinetic study of CRT solution and nanoparticles in aqueous humour of rabbit eye was performed and results showed that CRT nanoparticles enhance the ocular bioavailability by 5.61-fold as compared to CRT-solution.

  11. Pharmacokinetic and pharmacodynamic models of the antistaphylococcal effects of meropenem and cloxacillin in vitro and in experimental infection.

    Science.gov (United States)

    Mattie, H; Zhang, L C; van Strijen, E; Sekh, B R; Douwes-Idema, A E

    1997-01-01

    The efficacies of meropenem (MPM) and cloxacillin (CLC) against two Staphylococcus aureus strains were established in vitro. A pharmacodynamic model equation, based on the concept that the killing rate depends on concentration and time, was fitted to the numbers of CFU. The parameters of the equation are maximum killing rate, time point of maximum killing, and 50% effective concentration (EC50). The EC50s for the two strains were 0.047 and 0.040 mg/liter, respectively, for MPM and 0.105 and 0.121 mg/liter, respectively, for CLC. Calculated values of the parameters were used to predict the numbers of CFU at exponentially decreasing concentrations in vitro as well as in an experimental infection model. The prediction for in vitro conditions gave a satisfactory fit (R2, between 0.862 and 0.894). In vivo the numbers were predicted with the assumption that killing rate in vivo is proportional to that in vitro (R2, between 0.731 and 0.973). The proportionality factor ranged between 0.23 and 0.42; this variation was due mainly to covariation with growth rates in control animals, without other significant differences between antibiotics or strains. PMID:9333029

  12. Evaluation of Stability and In Vitro Security of Nanoemulsions Containing Eucalyptus globulus Oil

    Directory of Open Access Journals (Sweden)

    Samantha Nunes de Godoi

    2017-01-01

    Full Text Available Essential oil of Eucalyptus globulus presents several pharmacological properties. However, their therapeutic efficacy may be affected by limitations due to several conditions, rendering it difficult to obtain stable and effective pharmaceutical formulations. The use of nanotechnology is an alternative to improve their characteristics aiming to ensure their stability and effectiveness. Furthermore, studies about the possible toxic effects of nanostructures are necessary to evaluate safety when the formulation comes into contact with human cells. Hence, in this paper, we evaluate for the first time the stability and in vitro cytogenotoxicity of nanoemulsions containing Eucalyptus globulus in peripheral blood mononuclear cells. As a result, the stability study found that the best condition for storage up to 90 days was refrigeration (4°C; it was the condition that best preserved the nanometric features. The content of the major compounds of oil was maintained after nanoencapsulation and preserved over time. In tests to evaluate the safety of this formulation, we can conclude that, at a low concentration (approximately 0.1%, Eucalyptus globulus nanoemulsion did not cause toxicity in peripheral blood mononuclear cells and also showed a protective effect in cells against possible damage when compared to oil in free form.

  13. Primary stability of custom and anatomical uncemented femoral stems: a method for three-dimensional in vitro measurement of implant stability.

    Science.gov (United States)

    Østbyhaug, Per Olav; Klaksvik, Jomar; Romundstad, Pål; Aamodt, Arild

    2010-05-01

    Lack of primary stability of cementless hip stems prevents bone ingrowth and may lead to loosening of the stem. Direct measures of the implant stability require drilled holes in the bone at the measuring site. These holes weaken the cortical bone, limit the number of possible measuring points and inhibit other biomechanical measurements. This in vitro study aimed to develop a method for indirect measurement of primary stability of femoral stems, leaving the specimen intact. The method was used to compare the primary stability of two uncemented femoral stems with different proximal fit and fill and different stem length. An in vitro method for indirect full three-dimensional measurement of implant-bone interface motion was developed. Uncemented customized (n=10) and anatomical stems (n=10) were inserted in human cadaver femora and the primary stability during one leg stance and stair climbing was measured. The method had high precision, and the errors due to necessary assumption of rigid body components were minimal. The customized stem with optimal proximal fit and fill provided the best initial stability for rotation in retroversion. The anatomical stem with longer stem length was more resistant to permanent rotation in varus. During stem design development the primary stability can be measured at all wanted measuring sites with the presented method, leaving the specimen intact for further analyses. Copyright 2010 Elsevier Ltd. All rights reserved.

  14. The combination of colistin and fosfomycin is synergistic against NDM-1-producing Enterobacteriaceae in in vitro pharmacokinetic/pharmacodynamic model experiments.

    Science.gov (United States)

    Albur, Mahableshwar S; Noel, Alan; Bowker, Karen; MacGowan, Alasdair

    2015-11-01

    The chemotherapeutic options against NDM-1-producing Enterobacteriaceae infections are limited and therefore combination therapy is gaining momentum to counter the secondary resistance and potential suboptimal efficacy of monotherapy. Colistin and fosfomycin are two separate classes of antimicrobial agents that act on bacterial cells by different mechanisms. Hence, there is a potential for both synergy and antagonism. In this study, the antibacterial effects (ABEs) of colistin and fosfomycin were systematically investigated by time-kill curve studies over 48 h as well as in an in vitro pharmacokinetic model over 96 h against six well characterised strains of NDM-1-producing Enterobacteriaceae (three isolates resistant and three susceptible to fosfomycin) at a standard inoculum of 10(6)CFU/mL. Clinically achievable free serum concentrations of colistin sulphate and fosfomycin were used. In a single-chamber in vitro model, peak/trough concentrations (C(max)/C(min)) and the half-life (t(1/2)) for fosfomycin (250/40 mg/L and 2.7 h, respectively) and colistin sulphate (3.0/0.75 mg/L and 4 h, respectively) were used, along with a growth control. ABEs were measured by the decrease in viable bacterial counts (log kill), area under the bacterial kill curve (AUBKC) and population analysis profile (PAP). The combination of colistin and fosfomycin compared with either agent alone achieved increased bacterial killing and decreased the chance of emergence of resistance. Also, the ABEs of the combination were sustained for a longer duration and were evident both against fosfomycin-sensitive and -resistant strains. This study provides important information and support for the role of combination therapy against multidrug-resistant Gram-negative bacteria with limited therapeutic options. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  15. Pharmacokinetic-pharmacodynamic target attainment analyses to evaluate in vitro susceptibility test interpretive criteria for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae.

    Science.gov (United States)

    Van Wart, Scott A; Ambrose, Paul G; Rubino, Christopher M; Khariton, Tatiana; Riccobene, Todd A; Friedland, H David; Critchley, Ian A; Bhavnani, Sujata M

    2014-01-01

    To provide support for in vitro susceptibility test interpretive criteria decisions for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae, as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC (f%T>MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achieving f %T>MIC targets for S. aureus and S. pneumoniae based on murine infection models were calculated by MIC. At MICs of 2 mg/liter for S. aureus and 1 mg/liter for S. pneumoniae, the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achieving f %T>MIC targets (≥26 for S. aureus and ≥44 for S. pneumoniae) exceeded 90%. The results of these analyses, which suggested that in vitro susceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline against S. aureus and S. pneumoniae, respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also

  16. Pharmacokinetics and Pharmacodynamics of Fluconazole for Cryptococcal Meningoencephalitis: Implications for Antifungal Therapy and In Vitro Susceptibility Breakpoints

    Science.gov (United States)

    Sudan, Ajay; Livermore, Joanne; Howard, Susan J.; Al-Nakeeb, Zaid; Sharp, Andrew; Goodwin, Joanne; Gregson, Lea; Warn, Peter A.; Felton, Tim W.; Perfect, John R.; Harrison, Thomas S.

    2013-01-01

    Fluconazole is frequently the only antifungal agent that is available for induction therapy for cryptococcal meningitis. There is relatively little understanding of the pharmacokinetics and pharmacodynamics (PK-PD) of fluconazole in this setting. PK-PD relationships were estimated with 4 clinical isolates of Cryptococcus neoformans. MICs were determined using Clinical and Laboratory Standards Institute (CLSI) methodology. A nonimmunosuppressed murine model of cryptococcal meningitis was used. Mice received two different doses of fluconazole (125 mg/kg of body weight/day and 250 mg/kg of body weight/day) orally for 9 days; a control group of mice was not given fluconazole. Fluconazole concentrations in plasma and in the cerebrum were determined using high-performance liquid chromatography (HPLC). The cryptococcal density in the brain was estimated using quantitative cultures. A mathematical model was fitted to the PK-PD data. The experimental results were extrapolated to humans (bridging study). The PK were linear. A dose-dependent decline in fungal burden was observed, with near-maximal activity evident with dosages of 250 mg/kg/day. The MIC was important for understanding the exposure-response relationships. The mean AUC/MIC ratio associated with stasis was 389. The results of the bridging study suggested that only 66.7% of patients receiving 1,200 mg/kg would achieve or exceed an AUC/MIC ratio of 389. The potential breakpoints for fluconazole against Cryptococcus neoformans follow: susceptible, ≤2 mg/liter; resistant, >2 mg/liter. Fluconazole may be an inferior agent for induction therapy because many patients cannot achieve the pharmacodynamic target. Clinical breakpoints are likely to be significantly lower than epidemiological cutoff values. The MIC may guide the appropriate use of fluconazole. If fluconazole is the only option for induction therapy, then the highest possible dose should be used. PMID:23571544

  17. Nanohydroxyapatite Silicate-Based Cement Improves the Primary Stability of Dental Implants: An In Vitro Study

    Directory of Open Access Journals (Sweden)

    Hooman Khorshidi

    2017-01-01

    Full Text Available Objectives. Insufficient cortical bone volume when placing implants can lead to lack of primary stability. The use of cement as a bone fill material in bone defects around dental implant could result in better clinical outcome. HA has shown excellent biological properties in implant dentistry. The purpose of this study was to evaluate the effect of nanohydroxyapatite powder (Nano-HA in combination with accelerated Portland cement (APC on implant primary stability in surgically created circumferential bone defects in a bovine rib in vitro model. Materials and Methods. Sixteen bovine rib bones and thirty-six implants of same type and size (4 mm × 10 mm were used. Implants were divided into six groups: no circumferential bone defect, defect and no grafting, bone chips grafting, Nano-HA grafting, APC grafting, and Nano-HA mixed to APC grafting (Nano-HA-APC. Circumferential defects around the implants were prepared. The implant stability quotient (ISQ values were measured before and after the grafting. Results. APC exhibited the highest ISQ values. A significant increase of ISQ values following the grafting of Nano-HA-APC (18.08±5.82 and APC alone (9.50±4.12 was achieved. Increase of ISQ values after 72 hours was 24.16±5.01 and 17.58±4.89, respectively. Nano-HA grafting alone exhibited the least rise in ISQ values. Conclusions. Nanohydroxyapatite silicate-based cement could improve the primary stability of dental implants in circumferential bone defect around implants.

  18. Candesartan cilexetil microemulsions for transdermal delivery: formulation, in-vitro skin permeation and stability assessment.

    Science.gov (United States)

    Malakar, Jadupati; Basu, Aalok; Nayak, Amit Kumar

    2014-01-01

    The work investigates the formulation and evaluation of microemulsions containing olive oil, Tween 80 and isopropyl alcohol for transdermal candesartan cilexetil delivery. The pseudoternary phase diagram was constructed to determine composition of microemulsions. These formulated microemulsions were evaluated for in vitro skin permeation and stability. The microemulsion containing 72 % olive oil, 8 % water, 15 % Tween 80, and 5 % isopropylalcohol showed maximum viscosity of 29.54±0.32 mPas, average small droplet size of 180.90 nm, smaller polydispersity index of 0.37, zeta potential of -12.20 and maximum candesartan cilexetil permeation flux of 0.49±0.05 μg/cm2/h through excised porcine skin. The degradation of candesartan cilexetil microemulsions after 3 months storage was found low and its shelf-life was calculated as 3.92 years at room temperature.

  19. In vitro erythrocyte membrane stabilization properties of Carica papaya L. leaf extracts.

    Science.gov (United States)

    Ranasinghe, Priyanga; Ranasinghe, Pathmasiri; Abeysekera, W P Kaushalya M; Premakumara, G A Sirimal; Perera, Yashasvi S; Gurugama, Padmalal; Gunatilake, Saman B

    2012-10-01

    Carica papaya L. fruit juice and leaf extracts are known to have many beneficial medical properties. Recent reports have claimed possible beneficial effects of C. papaya L. leaf juice in treating patients with dengue viral infections. This study aims to evaluate the membrane stabilization potential of C. papaya L. leaf extracts using an in vitro hemolytic assay. The study was conducted in between June and August 2010. Two milliliters of blood from healthy volunteers and patients with serologically confirmed current dengue infection were freshly collected and used in the assays. Fresh papaya leaves at three different maturity stages (immature, partly matured, and matured) were cleaned with distilled water, crushed, and the juice was extracted with 10 ml of cold distilled water. Freshly prepared cold water extracts of papaya leaves (1 ml containing 30 μl of papaya leaf extracts, 20 μl from 40% erythrocytes suspension, and 950 μl of phosphate buffered saline) were used in the heat-induced and hypotonic-induced hemolytic assays. In dose response experiments, six different concentrations (9.375, 18.75, 37.5, 75, 150, and 300 μg/ml) of freeze dried extracts of the partly matured leaves were used. Membrane stabilization properties were investigated with heat-induced and hypotonicity-induced hemolysis assays. Extracts of papaya leaves of all three maturity levels showed a significant reduction in heat-induced hemolysis compared to controls (P Papaya leaf extracts of all three maturity levels showed more than 25% inhibition at a concentration of 37.5 μg/ml. The highest inhibition of heat-induced hemolysis was observed at 37.5 μg/ml. Inhibition activity of different maturity levels was not significantly (P papaya L. leaf extracts showed a significant inhibition of hemolysis in vitro and could have a potential therapeutic effect on disease processes causing destabilization of biological membranes.

  20. Assessment of membrane stabilizing activity from honey. An in-vitro approach.

    Science.gov (United States)

    Manukumar, Honnayakanahalli Marichenne Gowda; Umesha, Sharanaiah

    2015-01-01

    esent study was conducted to evaluate Manoflora (MF), Polyflora (PF), Polyflora forest (PFf), and Processed (Pro) honey varieties to compare the in-vitro anti-inflammatory effects of aqueous honey samples in dose dependent manner. In-vitro anti-inflammatory activity was evaluated using membrane stabilization assay of RBCs at different aqueous honey concentrations. Material and method. The present investigation carried out for selected varieties of honey against erythrocytes exposed to both heat and hypotonic lyses and inhibition of membrane damage was compared to the standard drug acetylsalicylic acid. Results. Membrane damage was inhibited in both the model hemolysis of erythrocytes in vitro in a concentration dependent manner. Hypotonic solution inducing damage was inhibited by aqueous honey sample in ascending order ranged from 8.25% to 97.76% at 10 to 50 mg/ml and standard drug acetylsalicylic acid showing hemolysis protection 96.09% at 100 μg/ml concentration. In heat induced hemolysis model aqueous honey sample exhibited its protecting property during external stress condition in all samples ranged from 0.44% to 21.23% at 10 to 50 mg/ml and acetylsalicylic acid showed 39.38% at 100 μg/ml concentration. Among the variety PFf showed highest protecting nature for hypotonic solution induced lyses (97.76%) and heat induced hemolysis (21.23%) at 50 mg/ml respectively. Conclusion. With these investigations data conclude that the model exhibits marked anti-inflammatory effect. Future research is to be carried out to identify the molecules responsible in honey and its mechanism. present study was conducted to evaluate Manoflora (MF), Polyflora (PF), Polyflora forest (PFf), and Processed (Pro) honey varieties to compare the in-vitro anti-inflammatory effects of aqueous honey samples in dose dependent manner. In-vitro anti-inflammatory activity was evaluated using membrane stabilization assay of RBCs at different aqueous honey concentrations. Material and method. The

  1. In vitro hematological and in vivo immunotoxicity assessment of dextran stabilized iron oxide nanoparticles.

    Science.gov (United States)

    Easo, Sheeja Liza; Mohanan, P V

    2015-10-01

    Iron oxide nanoparticles have attracted enormous interest as potential therapeutic agents. The purpose of this study was to examine the in vitro hematological toxicity and in vivo immune response toward previously synthesized and characterized dextran stabilized iron oxide nanoparticles (DIONPs) developed for hyperthermia application. Peripheral whole blood from human volunteers was used to investigate hemolysis, platelet aggregation, lymphocyte proliferation and cytokine mRNA expression induced by DIONPs in vitro. In the concentration range of 0.008-1 mg/ml, DIONPs did not induce relevant levels of hemolysis or platelet aggregation. Assessment of lymphocyte function showed significant suppression of the proliferation activity of T-lymphocytes in cultures stimulated with the mitogen phytohemagglutinin (PHA). In addition, inhibition of PHA-induced cytokine mRNA expressions was also seen. However, systemic administration of DIONPs resulted in enhanced proliferation of mitogen-stimulated spleen derived lymphocytes and secretion of IL-1β at day 7 post exposure. In conclusion, our results demonstrate that immune response is influenced variably by nanoparticles and its degradation milieu. Further investigation of the observed immunosuppressive effects of DIONPs in immune stimulated animal models is required to assess the functional impact of such a response. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Stability of polyphenols and carotenoids in strawberry and peach yoghurt throughout in vitro gastrointestinal digestion.

    Science.gov (United States)

    Oliveira, Ana; Pintado, Manuela

    2015-05-01

    The aim of this research was to evaluate the influence of in vitro gastrointestinal digestion on the stability and bio-accessibility of phenolic compounds and carotenoids, as well as on the antioxidant activity in strawberry and peach enriched yoghurt. The radical scavenging capacity of strawberry and peach yoghurt was 480 and 550% higher, respectively, at the level of the intestine than in fruit yoghurt not subjected to digestion. In strawberry the amount of bio-accessible anthocyanins increased during gastric digestion and the transition to the intestinal compartment produced a decrease in all the analyzed classes of polyphenols, being more pronounced in pelargonidin-3-glucoside (65%) and pelargonidin-3-rutinoside (58%). In peach the (+)-catechin content strongly decreased (80%), and neochlorogenic, chlorogenic acid, rutin and the carotenoid zeaxanthin decreased at lower levels, between 32-45%, while β-carotene was rather stable under gastric conditions (increased by 12%) during intestinal digestion. Despite the decrease in the concentration of these bioactive compounds after being subjected to in vitro gastrointestinal digestion, results suggest that fruit yoghurt is an important source of bio-accessible polyphenols and carotenoids and that despite some losses induced by digestion conditions, it still releases relevant amounts at the level of the intestine to be absorbed and to promote health benefits.

  3. Wired/Classic and Wireless/Periotest "M" instruments: an in vitro assessment of repeatability of stability measurements.

    Science.gov (United States)

    Crum, Patricia M; Morris, Harold Frederick; Winkler, Sheldon; DesRosiers, Deborah; Yoshino, Douglas

    2014-02-01

    This in vitro study evaluated agreement among 10 trained evaluators when assessing implant stability with the Wired/Classic and Wireless/Periotest "M." A difference of 1 Periotest value (PTV) between the wired (-7) and wireless (-8) instruments was observed for the pretest calibration ring. No significant differences were found between the instruments and for all evaluators for all tests (analysis of variance, P < .05). Each instrument can provide meaningful and reproducible recordings of stability measurements.

  4. In vitro pharmacokinetic/pharmacodynamic activity of NXL103 versus clindamycin and linezolid against clinical Staphylococcus aureus and Streptococcus pyogenes isolates.

    Science.gov (United States)

    Vidaillac, Celine; Parra-Ruiz, Jorge; Winterfield, Patricia; Rybak, Michael J

    2011-10-01

    NXL103 (linopristin/flopristin, 30/70) is a novel oral streptogramin combination with activity against a large variety of multidrug-resistant Gram-positive pathogens. The objective of this study was to evaluate the in vitro activity of NXL103 in comparison with oral comparators (clindamycin and linezolid). Six clinical isolates [four meticillin-resistant Staphylococcus aureus (MRSA) and two Streptococcus pyogenes] were exposed for 48 h in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model at a starting inoculum of ca. 10(6) colony-forming units (CFU)/mL. Antimicrobial simulations included NXL103 500 mg every 12 h, linezolid 600 mg every 12 h and clindamycin 450 mg every 6 h. Bactericidal and static effects were defined as ≥3log(10) and <3log(10) CFU/mL kill from the starting inoculum, respectively. Experiments were performed in duplicate to ensure reproducibility, and differences between regimens were evaluated by analysis of variance (ANOVA) with Tukey's post-hoc test. NXL103 exhibited lower minimum inhibitory concentrations than comparators, with values ≤0.06 mg/L for S. pyogenes and 0.125-0.25 mg/L for MRSA isolates. In the PK/PD model, NXL103 demonstrated significantly better activity than linezolid and clindamycin (P<0.05), achieving sustained bactericidal activity within <2 h against S. pyogenes strains and between 7.3-32 h against MRSA isolates. In contrast, linezolid only exhibited a static effect, whereas clindamycin achieved 3log(10) kill at 6h against the unique clindamycin-susceptible S. pyogenes strain evaluated. In conclusion, at therapeutic concentrations NXL103 exhibits promising activity against both MRSA and S. pyogenes strains, including clindamycin-resistant organisms. Further in vitro and in vivo experiments are warranted to explore the therapeutic benefit of NXL103 for the treatment of Gram-positive skin and soft-tissue infections. Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  5. In vitro color stability of double-layer veneers after accelerated aging.

    Science.gov (United States)

    Heydecke, G; Zhang, F; Razzoog, M E

    2001-06-01

    Porcelain laminates made from thin alumina shells veneered with feldspathic porcelain could be a promising alternative to conventional veneers. Long-term shade stability is critical for esthetics. This study compared changes in CIE L*a*b* color coordinates of simulated veneers made from aluminum oxide core material veneered with feldspathic porcelain after 300 hours of accelerated photothermal aging (weathering). Fifteen aluminum oxide disks (Procera) were divided into 3 groups. Each of the 5 disks was veneered with All-Ceram porcelain of the Vita shades A1 and B4, respectively. Five disks remained unfinished as controls. The disks were bonded to composite substrates simulating stained teeth. The color of the specimens was measured with a colorimeter. All specimens were subjected to 300 hours of accelerated aging under light exposure and thermocycling. Color measurements were repeated, and the data were statistically evaluated with multiple paired t tests. Color changes in the test groups involved an increase in lightness and a decrease in chroma. The calculated total color differences were not statistically significant compared with a level of 3 DeltaE units. This simulation of double-layer veneers appears to demonstrate acceptable color stability for this type of restoration. Clinical research is necessary to substantiate these in vitro findings.

  6. In Vitro Assembly and Stabilization of Dengue and Zika Virus Envelope Protein Homo-Dimers.

    Science.gov (United States)

    Metz, Stefan W; Gallichotte, Emily N; Brackbill, Alex; Premkumar, Lakshmanane; Miley, Michael J; Baric, Ralph; de Silva, Aravinda M

    2017-07-03

    Zika virus (ZIKV) and the 4 dengue virus (DENV) serotypes are mosquito-borne Flaviviruses that are associated with severe neuronal and hemorrhagic syndromes. The mature flavivirus infectious virion has 90 envelope (E) protein homo-dimers that pack tightly to form a smooth protein coat with icosahedral symmetry. Human antibodies that strongly neutralize ZIKV and DENVs recognize complex quaternary structure epitopes displayed on E-homo-dimers and higher order structures. The ZIKV and DENV E protein expressed as a soluble protein is mainly a monomer that does not display quaternary epitopes, which may explain the modest success with soluble recombinant E (sRecE) as a vaccine and diagnostic antigen. New strategies are needed to design recombinant immunogens that display these critical immune targets. Here we present two novel methods for building or stabilizing in vitro E-protein homo-dimers that display quaternary epitopes. In the first approach we immobilize sRecE to enable subsequent dimer generation. As an alternate method, we describe the use of human mAbs to stabilize homo-dimers in solution. The ability to produce recombinant E protein dimers displaying quaternary structure epitopes is an important advance with applications in flavivirus diagnostics and vaccine development.

  7. Mechanism of Action and Capsid-Stabilizing Properties of VHHs with an In Vitro Antipolioviral Activity

    Science.gov (United States)

    Schotte, Lise; Strauss, Mike; Thys, Bert; Halewyck, Hadewych; Filman, David J.; Bostina, Mihnea; Rombaut, Bart

    2014-01-01

    ABSTRACT Previously, we reported on the in vitro antiviral activity of single-domain antibody fragments (VHHs) directed against poliovirus type 1. Five VHHs were found to neutralize poliovirus type 1 in an in vitro setting and showed 50% effective concentrations (EC50s) in the nanomolar range. In the present study, we further investigated the mechanism of action of these VHHs. All five VHHs interfere at multiple levels of the viral replication cycle, as they interfere both with attachment of the virus to cells and with viral uncoating. The latter effect is consistent with their ability to stabilize the poliovirus capsid, as observed in a ThermoFluor thermal shift assay, in which the virus is gradually heated and the temperature causing 50% of the RNA to be released from the capsid is determined, either in the presence or in the absence of the VHHs. The VHH-capsid interactions were also seen to induce aggregation of the virus-VHH complexes. However, this observation cannot yet be linked to their mechanism of action. Cryo-electron microscopy (cryo-EM) reconstructions of two VHHs in complex with poliovirus type 1 show no conformational changes of the capsid to explain this aggregation. On the other hand, these reconstructions do show that the binding sites of VHHs PVSP6A and PVSP29F overlap the binding site for the poliovirus receptor (CD155/PVR) and span interfaces that are altered during receptor-induced conformational changes associated with cell entry. This may explain the interference at the level of cell attachment of the virus as well as their effect on uncoating. IMPORTANCE The study describes the mechanism of neutralization and the capsid-stabilizing activity of five single-domain antibody fragments (VHHs) that have an in vitro neutralizing activity against poliovirus type 1. The results show that the VHHs interfere at multiple levels of the viral replication cycle (cell attachment and viral uncoating). These mechanisms are possibly shared by some

  8. Biodegradable Injectable In Situ Implants and Microparticles for Sustained Release of Montelukast: In Vitro Release, Pharmacokinetics, and Stability

    OpenAIRE

    Ahmed, Tarek A.; Ibrahim, Hany M.; Ahmed M Samy; Kaseem, Alaa; Nutan, Mohammad T. H.; Hussain, Muhammad Delwar

    2014-01-01

    The objective of this study was to investigate the sustained release of a hydrophilic drug, montelukast (MK), from two biodegradable polymeric drug delivery systems, in situ implant (ISI) and in situ microparticles (ISM). N-Methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), triacetin, and ethyl acetate were selected as solvents. The release of 10% (w/v) MK from both systems containing poly-lactic-co-glycolic acid (PLGA) as the biodegradable polymer was compared. Upon contact with the aqueou...

  9. Understanding How the Stability of the Thiol-Maleimide Linkage Impacts the Pharmacokinetics of Lysine-Linked Antibody-Maytansinoid Conjugates.

    Science.gov (United States)

    Ponte, Jose F; Sun, Xiuxia; Yoder, Nicholas C; Fishkin, Nathan; Laleau, Rassol; Coccia, Jennifer; Lanieri, Leanne; Bogalhas, Megan; Wang, Lintao; Wilhelm, Sharon; Widdison, Wayne; Pinkas, Jan; Keating, Thomas A; Chari, Ravi; Erickson, Hans K; Lambert, John M

    2016-07-20

    Antibody-drug conjugates (ADCs) have become a widely investigated modality for cancer therapy, in part due to the clinical findings with ado-trastuzumab emtansine (Kadcyla). Ado-trastuzumab emtansine utilizes the Ab-SMCC-DM1 format, in which the thiol-functionalized maytansinoid cytotoxic agent, DM1, is linked to the antibody (Ab) via the maleimide moiety of the heterobifunctional SMCC linker. The pharmacokinetic (PK) data for ado-trastuzumab emtansine point to a faster clearance for the ADC than for total antibody. Cytotoxic agent release in plasma has been reported with nonmaytansinoid, cysteine-linked ADCs via thiol-maleimide exchange, for example, brentuximab vedotin. For Ab-SMCC-DM1 ADCs, however, the main catabolite reported is lysine-SMCC-DM1, the expected product of intracellular antibody proteolysis. To understand these observations better, we conducted a series of studies to examine the stability of the thiol-maleimide linkage, utilizing the EGFR-targeting conjugate, J2898A-SMCC-DM1, and comparing it with a control ADC made with a noncleavable linker that lacked a thiol-maleimide adduct (J2898A-(CH2)3-DM). We employed radiolabeled ADCs to directly measure both the antibody and the ADC components in plasma. The PK properties of the conjugated antibody moiety of the two conjugates, J2898A-SMCC-DM1 and J2898A-(CH2)3-DM (each with an average of 3.0 to 3.4 maytansinoid molecules per antibody), appear to be similar to that of the unconjugated antibody. Clearance values of the intact conjugates were slightly faster than those of the Ab components. Furthermore, J2898A-SMCC-DM1 clears slightly faster than J2898A-(CH2)3-DM, suggesting that there is a fraction of maytansinoid loss from the SMCC-DM1 ADC, possibly through a thiol-maleimide dependent mechanism. Experiments on ex vivo stability confirm that some loss of maytansinoid from Ab-SMCC-DM1 conjugates can occur via thiol elimination, but at a slower rate than the corresponding rate of loss reported for thiol

  10. The influence of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics of thioridazine and its metabolites: in vivo and in vitro studies.

    Science.gov (United States)

    Daniel, W A; Syrek, M; Haduch, A; Wójcikowski, J

    1999-07-01

    Due to its psychotropic profile, thioridazine is a neuroleptic suitable for a combination with antidepressants in a number of complex psychiatric illnesses. However, because of its serious side-effects, such a combination with selective serotonin reuptake inhibitors (SSRIs) which inhibit cytochrome P-450 may be dangerous. The aim of the present study was to investigate a possible impact of SSRIs on the pharmacokinetics and metabolism of thioridazine in a steady state in rats. Thioridazine (10 mg/kg) was injected intraperitoneally, twice a day, for two weeks, alone or jointly with one of the antidepressants (fluoxetine, fluvoxamine or sertraline). Concentrations of thioridazine and its main metabolites (2-sulfoxide = mesoridazine; 2-sulfone = sulforidazine; 5-sulfoxide = ring sulfoxide and N-desmethylthiorid-azine) were assessed in the blood plasma and brain at 30 min, 6 and 12 h after the last dose of the drugs using an HPLC method. Fluoxetine potently increased (up to 13 times!) the concentrations of thioridazine and its metabolites in the plasma, especially after 6 and 12 h. Moreover, an increase in the sum of concentrations of tioridazine + metabolites and thioridazine/metabolite ratios was observed. In vitro studies with control liver microsomes, as well as with microsomes of rats treated chronically with fluoxetine show that the changes in the thioridazine pharmacokinetics may be attributed to the competitive (N-demethylation, Ki = 23 microM) and mixed inhibition (2- and 5-sulfoxidation, Ki = 60 microM and 34 microM, respectively) of thioridazine metabolism by fluoxetine, and to the adaptive changes produced by chronic administration of fluoxetine, as reflected by inhibition of N-demethylation and formation of sulforidazine. Sertraline seemed to have a tendency to decrease thioridazine concentration in vivo, though in vitro studies showed that - like fluoxetine - it competitively or via mixed mechanism inhibited the three metabolic pathways of thioridazine (Ki

  11. Lipid digestion of protein stabilized emulsions investigated in a dynamic in vitro gastro-intestinal model system

    NARCIS (Netherlands)

    Helbig, A.; Silletti, E.; Aken, G.A. van; Oosterveld, A.; Minekus, M.; Hamer, R.J.; Gruppen, H.

    2013-01-01

    This study investigated the effect of gastric passage of protein stabilized emulsions, i.e., whey protein isolate (WPI) and lysozyme, under dynamic in vitro conditions on both the gastric and intestinal lipolysis. Emulsions were prepared at neutral pH to enable an opposite surface charge.

  12. Lipid Digestion of Protein Stabilized Emulsions Investigated in a Dynamic In Vitro Gastro-Intestinal Model System

    NARCIS (Netherlands)

    Helbig, A.; Silletti, E.; Aken, van G.A.; Oosterveld, A.; Minekus, M.; Hamer, R.J.; Gruppen, H.

    2013-01-01

    This study investigated the effect of gastric passage of protein stabilized emulsions, i.e., whey protein isolate (WPI) and lysozyme, under dynamic in vitro conditions on both the gastric and intestinal lipolysis. Emulsions were prepared at neutral pH to enable an opposite surface charge.

  13. Release, partitioning and stability of isoflavones from enriched custards during mouth, stomach and intestine in vitro simulations

    NARCIS (Netherlands)

    Sanz, T.; Luyten, J.M.J.G.

    2006-01-01

    Custard desserts were enriched with a soy germ extract as source of isoflavones and the influence of the thickening agent (starch or carboxymethylcellulose (CMC)) and the presence of fat on the release, partitioning and stability of the isoflavones after mouth, stomach and small intestine in vitro

  14. The Combination of Colistin and Doripenem Is Synergistic against Klebsiella pneumoniae at Multiple Inocula and Suppresses Colistin Resistance in an In Vitro Pharmacokinetic/Pharmacodynamic Model

    Science.gov (United States)

    Deris, Zakuan Z.; Yu, Heidi H.; Davis, Kathryn; Soon, Rachel L.; Jacob, Jovan; Ku, Caron K.; Poudyal, Anima; Bergen, Phillip J.; Tsuji, Brian T.; Bulitta, Jurgen B.; Forrest, Alan; Paterson, David L.; Velkov, Tony; Li, Jian

    2012-01-01

    Multidrug-resistant (MDR) Klebsiella pneumoniae may require combination therapy. We systematically investigated bacterial killing with colistin and doripenem mono- and combination therapy against MDR K. pneumoniae and emergence of colistin resistance. A one-compartment in vitro pharmacokinetic/pharmacodynamic model was employed over a 72-h period with two inocula (∼106 and ∼108 CFU/ml); a colistin-heteroresistant reference strain (ATCC 13883) and three clinical isolates (colistin-susceptible FADDI-KP032 [doripenem resistant], colistin-heteroresistant FADDI-KP033, and colistin-resistant FADDI-KP035) were included. Four combinations utilizing clinically achievable concentrations were investigated. Microbiological responses were examined by determining log changes and population analysis profiles (for emergence of colistin resistance) over 72 h. Against colistin-susceptible and -heteroresistant isolates, combinations of colistin (constant concentration regimens of 0.5 or 2 mg/liter) plus doripenem (steady-state peak concentration [Cmax] of 2.5 or 25 mg/liter over 8 h; half-life, 1.5 h) generally resulted in substantial improvements in bacterial killing at both inocula. Combinations were additive or synergistic against ATCC 13883, FADDI-KP032, and FADDI-KP033 in 9, 9, and 14 of 16 cases (4 combinations at 6, 24, 48, and 72 h) at the 106-CFU/ml inoculum and 14, 11, and 12 of 16 cases at the 108-CFU/ml inoculum, respectively. Combinations at the highest dosage regimens resulted in undetectable bacterial counts at 72 h in 5 of 8 cases (4 isolates at 2 inocula). Emergence of colistin-resistant subpopulations in colistin-susceptible and -heteroresistant isolates was virtually eliminated with combination therapy. Against the colistin-resistant isolate, colistin at 2 mg/liter plus doripenem (Cmax, 25 mg/liter) at the low inoculum improved bacterial killing. This investigation provides important information for optimization of colistin-doripenem combinations. PMID:22802247

  15. Synergistic Activity of Colistin and Rifampin Combination against Multidrug-Resistant Acinetobacter baumannii in an In Vitro Pharmacokinetic/Pharmacodynamic Model

    Science.gov (United States)

    Lee, Hee Ji; Bergen, Phillip J.; Bulitta, Jurgen B.; Tsuji, Brian; Forrest, Alan; Li, Jian

    2013-01-01

    Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of colistin resistance with colistin and rifampin combinations against MDR A. baumannii. Studies were conducted over 72 h in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼106 and ∼108 CFU/ml using two MDR clinical isolates of A. baumannii, FADDI-AB030 (colistin susceptible) and FADDI-AB156 (colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [Cmax] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 106-CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter colistin regimens at the 108-CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log10 CFU/ml greater at the low inoculum (all colistin concentrations) and high inoculum (2 and 5 mg/liter colistin), respectively. Emergence of colistin-resistant subpopulations was completely suppressed in the colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing colistin-rifampin combinations against colistin-susceptible and -resistant MDR A. baumannii. PMID:23716052

  16. The transcriptomic response of Acinetobacter baumannii to colistin and doripenem alone and in combination in an in vitro pharmacokinetics/pharmacodynamics model

    Science.gov (United States)

    Henry, Rebekah; Crane, Bethany; Powell, David; Deveson Lucas, Deanna; Li, Zhifeng; Aranda, Jesús; Harrison, Paul; Nation, Roger L.; Adler, Ben; Harper, Marina; Boyce, John D.; Li, Jian

    2015-01-01

    Objectives Colistin remains a last-line treatment for MDR Acinetobacter baumannii and combined use of colistin and carbapenems has shown synergistic effects against MDR strains. In order to understand the bacterial responses to these antibiotics, we analysed the transcriptome of A. baumannii following exposure to each. Methods RNA sequencing was employed to determine changes in the transcriptome following treatment with colistin and doripenem, both alone and in combination, using an in vitro pharmacokinetics (PK)/pharmacodynamics model to mimic the PK of both antibiotics in patients. Results After treatment with colistin (continuous infusion at 2 mg/L), >400 differentially regulated genes were identified, including many associated with outer membrane biogenesis, fatty acid metabolism and phospholipid trafficking. No genes were differentially expressed following treatment with doripenem (Cmax 25 mg/L, t1/2 1.5 h) for 15 min, but 45 genes were identified as differentially expressed after 1 h of growth under this condition. Treatment of A. baumannii with both colistin and doripenem together for 1 h resulted in >450 genes being identified as differentially expressed. More than 70% of these gene expression changes were also observed following colistin treatment alone. Conclusions These data suggest that colistin causes gross damage to the outer membrane, facilitates lipid exchange between the inner and outer membrane and alters the normal asymmetric outer membrane composition. The transcriptional response to colistin was highly similar to that observed for an LPS-deficient strain, indicating that many of the observed changes are responses to outer membrane instability resulting from LPS loss. PMID:25587995

  17. Synergistic Killing of Multidrug-Resistant Pseudomonas aeruginosa at Multiple Inocula by Colistin Combined with Doripenem in an In Vitro Pharmacokinetic/Pharmacodynamic Model ▿

    Science.gov (United States)

    Bergen, Phillip J.; Tsuji, Brian T.; Bulitta, Jurgen B.; Forrest, Alan; Jacob, Jovan; Sidjabat, Hanna E.; Paterson, David L.; Nation, Roger L.; Li, Jian

    2011-01-01

    Combination therapy may be required for multidrug-resistant (MDR) Pseudomonas aeruginosa. The aim of this study was to systematically investigate bacterial killing and emergence of colistin resistance with colistin and doripenem combinations against MDR P. aeruginosa. Studies were conducted in a one-compartment in vitro pharmacokinetic/pharmacodynamic model for 96 h at two inocula (∼106 and ∼108 CFU/ml) against a colistin-heteroresistant reference strain (ATCC 27853) and a colistin-resistant MDR clinical isolate (19147 n/m). Four combinations utilizing clinically achievable concentrations were investigated. Microbiological response was examined by log changes and population analysis profiles. Colistin (constant concentrations of 0.5 or 2 mg/liter) plus doripenem (peaks of 2.5 or 25 mg/liter every 8 h; half-life, 1.5 h) substantially increased bacterial killing against both strains at the low inoculum, while combinations containing colistin at 2 mg/liter increased activity against ATCC 27853 at the high inoculum; only colistin at 0.5 mg/liter plus doripenem at 2.5 mg/liter failed to improve activity against 19147 n/m at the high inoculum. Combinations were additive or synergistic against ATCC 27853 in 16 and 11 of 20 cases (4 combinations across 5 sample points) at the 106- and 108-CFU/ml inocula, respectively; the corresponding values for 19147 n/m were 16 and 9. Combinations containing doripenem at 25 mg/liter resulted in eradication of 19147 n/m at the low inoculum and substantial reductions in regrowth (including to below the limit of detection at ∼50 h) at the high inoculum. Emergence of colistin-resistant subpopulations of ATCC 27853 was substantially reduced and delayed with combination therapy. This investigation provides important information for optimization of colistin-doripenem combinations. PMID:21911563

  18. New antimalarial hits from Dacryodes edulis (Burseraceae)--part I: isolation, in vitro activity, in silico "drug-likeness" and pharmacokinetic profiles.

    Science.gov (United States)

    Zofou, Denis; Tematio, Esther Laure; Ntie-Kang, Fidele; Tene, Mathieu; Ngemenya, Moses N; Tane, Pierre; Titanji, Vincent P K

    2013-01-01

    The aims of the present study were to identify the compounds responsible for the anti-malarial activity of Dacryoedes edulis (Burseraceae) and to investigate their suitability as leads for the treatment of drug resistant malaria. Five compounds were isolated from ethyl acetate and hexane extracts of D. edulis stem bark and tested against 3D7 (chloroquine-susceptible) and Dd2 (multidrug-resistant) strains of Plasmodium falciparum, using the parasite lactate dehydrogenase method. Cytotoxicity studies were carried out on LLC-MK2 monkey kidney epithelial cell-line. In silico analysis was conducted by calculating molecular descriptors using the MOE software running on a Linux workstation. The "drug-likeness" of the isolated compounds was assessed using Lipinski criteria, from computed molecular properties of the geometry optimized structures. Computed descriptors often used to predict absorption, distribution, metabolism, elimination and toxicity (ADMET) were used to assess the pharmacokinetic profiles of the isolated compounds. Antiplasmodial activity was demonstrated for the first time in five major natural products previously identified in D. edulis, but not tested against malaria parasites. The most active compound identified was termed DES4. It had IC50 values of 0.37 and 0.55 µg/mL, against 3D7 and Dd2 respectively. In addition, this compound was shown to act in synergy with quinine, satisfied all criteria of "Drug-likeness" and showed considerable probability of providing an antimalarial lead. The remaining four compounds also showed antiplasmodial activity, but were less effective than DES4. None of the tested compounds was cytotoxicity against LLC-MK2 cells, suggesting their selective activities on malaria parasites. Based on the high in vitro activity, low toxicity and predicted "Drug-likeness" DES4 merits further investigation as a possible drug lead for the treatment of malaria.

  19. New antimalarial hits from Dacryodes edulis (Burseraceae--part I: isolation, in vitro activity, in silico "drug-likeness" and pharmacokinetic profiles.

    Directory of Open Access Journals (Sweden)

    Denis Zofou

    Full Text Available The aims of the present study were to identify the compounds responsible for the anti-malarial activity of Dacryoedes edulis (Burseraceae and to investigate their suitability as leads for the treatment of drug resistant malaria. Five compounds were isolated from ethyl acetate and hexane extracts of D. edulis stem bark and tested against 3D7 (chloroquine-susceptible and Dd2 (multidrug-resistant strains of Plasmodium falciparum, using the parasite lactate dehydrogenase method. Cytotoxicity studies were carried out on LLC-MK2 monkey kidney epithelial cell-line. In silico analysis was conducted by calculating molecular descriptors using the MOE software running on a Linux workstation. The "drug-likeness" of the isolated compounds was assessed using Lipinski criteria, from computed molecular properties of the geometry optimized structures. Computed descriptors often used to predict absorption, distribution, metabolism, elimination and toxicity (ADMET were used to assess the pharmacokinetic profiles of the isolated compounds. Antiplasmodial activity was demonstrated for the first time in five major natural products previously identified in D. edulis, but not tested against malaria parasites. The most active compound identified was termed DES4. It had IC50 values of 0.37 and 0.55 µg/mL, against 3D7 and Dd2 respectively. In addition, this compound was shown to act in synergy with quinine, satisfied all criteria of "Drug-likeness" and showed considerable probability of providing an antimalarial lead. The remaining four compounds also showed antiplasmodial activity, but were less effective than DES4. None of the tested compounds was cytotoxicity against LLC-MK2 cells, suggesting their selective activities on malaria parasites. Based on the high in vitro activity, low toxicity and predicted "Drug-likeness" DES4 merits further investigation as a possible drug lead for the treatment of malaria.

  20. Torsemide Fast Dissolving Tablets: Development, Optimization Using Box-Bhenken Design and Response Surface Methodology, In Vitro Characterization, and Pharmacokinetic Assessment.

    Science.gov (United States)

    El-Shenawy, Ahmed A; Ahmed, Mahmoud M; Mansour, Heba F; Abd El Rasoul, Saleh

    2017-08-01

    The present study planed to develop new fast dissolving tablets (FDTs) of torsemide. Solid dispersions (SDs) of torsemide and sorbitol (3:1) or polyvinylpyrrolidone (PVP) k25 were prepared. The prepared SDs were evaluated for in-vitro dissolution. Fourier transform infrared spectroscopy and differential scanning calorimetry for SDs revealed no drug/excipient interactions and transformation of torsemide to the amorphous form. Torsemide/sorbitol SD was selected for formulation of torsemide FDTs by direct compression method. Box-Bhenken factorial design was employed to design 15 formulations using croscarmellose sodium and crospovidone at different concentrations. The response surface methodology was used to analyze the effect of changing these concentrations (independent variables) on disintegration time (Y 1 ), percentage friability (Y 2 ), and amount torsemide released at 10 min. The physical mixtures of torsemide and the used excipients were evaluated for angle of repose, Hausner's ratio, and Carr's index. The prepared FDTs tablets were evaluated for wetting and disintegration time, weight variation, drug content, percentage friability, thickness, hardness, and in vitro release. Based on the in-vitro results and factorial design characterization, F10 and F7 were selected for bioavailability studies following administration to Albino New Zealand rabbits. They showed significantly higher C max and (AUC 0-12 ) and shorter T max than those obtained after administration of the corresponding ordinary commercial Torseretic ® tablets. Stability study was conducted for F10 that showed good stability upon storage at 30°C/75% RH and 40°C/75% RH for 3 months.

  1. Solubilization of beclomethasone dipropionate in sterically stabilized phospholipid nanomicelles (SSMs: physicochemical and in vitro evaluations

    Directory of Open Access Journals (Sweden)

    Peh KK

    2012-02-01

    Full Text Available Mohanad Naji Sahib, Shaymaa Abdalwahed Abdulameer, Yusrida Darwis, Kok Khiang Peh, Yvonne Tze Fung TanSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, MalaysiaBackground: The local treatment of lung disorders such as asthma and chronic obstructive pulmonary disease via pulmonary drug delivery offers many advantages over oral or intravenous routes of administration. This is because direct deposition of a drug at the diseased site increases local drug concentrations, which improves the pulmonary receptor occupancy and reduces the overall dose required, therefore reducing the side effects that result from high drug doses. From a clinical point of view, although jet nebulizers have been used for aerosol delivery of water-soluble compounds and micronized suspensions, their use with hydrophobic drugs has been inadequate.Aim: To evaluate the feasibility of sterically stabilized phospholipid nanomicelles (SSMs loaded with beclomethasone dipropionate (BDP as a carrier for pulmonary delivery.Methods: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 5000 polymeric micelles containing BDP (BDP-SSMs were prepared by the coprecipitation and reconstitution method, and the physicochemical and in vitro characteristics of BDP-SSMs were investigated.Results: BDP-SSMs were successfully prepared with a content uniformity and reproducibility suitable for pulmonary administration. The maximum solubility of BDP in SSMs was approximately 1300 times its actual solubility. The particle size and zeta potential of BDP-SSMs were 19.89 ± 0.67 nm and -28.03 ± 2.05 mV, respectively. The SSMs system slowed down the release of BDP and all of the aerodynamic values of the aerosolized rehydrated BDP-SSMs were not only acceptable but indicated a significant level of deposition in the lungs.Conclusion: The SSM system might be an effective way of improving the therapeutic index of nebulized, poorly soluble corticosteroids

  2. In vitro Dynamic Pharmacokinetic/Pharmacodynamic (PK/PD) study and COPD of Marbofloxacin against Haemophilus parasuis.

    Science.gov (United States)

    Sun, Jian; Xiao, Xia; Huang, Rui-Juan; Yang, Tao; Chen, Yi; Fang, Xi; Huang, Ting; Zhou, Yu-Feng; Liu, Ya-Hong

    2015-12-01

    Haemophilus parasuis (H. parasuis) can invade the body and cause systemic infection under stress conditions. Marbofloxacin has been recommended for the treatment of swine infections. However, few studies have investigated the PK/PD characteristics and PK/PD cutoff (COPD) of this drug against H. parasuis. MICs of marbofloxacin against 198 H. parasuis isolates were determined. The MIC50 and MIC90 were 2 and 8 mg/L, respectively. An in vitro dynamic PK/PD model was established to study the PK/PD relationship of marbofloxacin against H. parasuis. The PK/PD surrogate markers Cmax/MIC, Cmax/MPC (the maximum concentration divided by MIC or mutant prevention concentration (MPC)) and AUC 24h/MIC, AUC 24h/MPC (the area under the curve during the first 24 h divided by MIC or MPC) simulated the antimicrobial effect of marbofloxacin successfully with the R(2) of 0.9928 and 0.9911, respectively. The target values of 3-log10-unit and 4-log10-unit reduction for AUC 24h/MPC were 33 and 42, while the same efficacy for AUC 24h/MIC were 88 and 110. The COPD deduced from Monte Carlo simulation (MCS) for marbofloxacin against H. parasuis was 0.5 mg/L. The recommended dose of marbofloxacin against H. parasuis with MIC ≤ 2 mg/L was 16 mg/kg body weight (BW). The PK/PD surrogate markers AUC 24h/MIC, Cmax/MIC and AUC 24h/MPC, Cmax/MPC properly described the effects of marbofloxacin. Marbofloxacin can achieve the best efficacy at dosage of 16 mg/kg BW for strains with MIC values ≤ 2 mg/L, therefore, it is obligatory to know the sensitivity of the pathogen and to treat animals as early as possible. The very first COPD provide fundamental data for marbofloxacin breakpoint determination.

  3. Analysis of colour stability of selected provisional prosthetic materials: an in vitro study.

    Science.gov (United States)

    Koczorowski, Ryszard; Linkowska-Swidzińska, Kamila; Gedrange, Tomasz; Swidziński, Teodor

    2009-08-01

    Prosthetic restorative materials (that are) used for temporary fixed dentures tend to exhibit variable discolouration over several weeks of use. The aim of this study was to perform a spectrophotometric analysis of the influence of selected discolouring factors on the colour stability of provisional prosthetic materials in vitro. In the study, the following prosthetic materials for short-term use in the oral cavity were evaluated: Luxatemp, Structur 2S.C., Protemp II, Zhermacryl STC and Dentalon Plus. Samples of these materials were immersed in coffee, tea and dark fruit juice for 60 h at different pH values. Colour was evaluated by determining the monochromatic coefficients of light reflected by the samples, using a spectrophotometric method. Results received in artificial light (illuminant A) were compared with those obtained in daylight (illuminant D65). Changes in colour and its parameters according to the CIE L*a*b* system were analysed. The analysis (of the colour and colour parameters) of the tested materials in two types of light showed that Structur displayed the greatest tendency to discolouration and that the least tendency to discolouration was exhibited by Dentalon Plus. The fact that colour parameters obtained in two types of light were not identical suggests that changes in the colour of the same material may be perceived differently, depending on the illuminant. Provisional prosthetic materials show variable colour stability under different conditions in the oral cavity. The colour of prosthetic materials may be perceived differently, depending on the illuminant and the effect of the environment in which they are used.

  4. Sulfanilamide in solution and liposome vesicles; in vitro release and UV-stability studies

    Directory of Open Access Journals (Sweden)

    Sanja Petrović

    2017-12-01

    Full Text Available The main goal of this study was to develop a liposome formulation with sulfanilamide and to investigate the liposomes impact on its release and stability to the UV-A/UV-B and UV-C irradiation. Liposome dispersions with incorporated sulfanilamide were prepared by thin-film hydration method and liposomes role to the sulfanilamide release was investigated by using a dialysis method. Comparatively, sulfanilamide in phosphate buffer solution was subject to release study as well to the UV irradiation providing for the possibilities of kinetics analysis. In vitro drug release study demonstrated that 20% of sulfanilamide was released from liposomes within 1 h that is approximately twice as slower as in the case of dissolved sulfanilamide in phosphate buffer solution. The kinetic release process can be described by Korsmeyer–Peppas model and according to the value of diffusion release exponent it can be concluded that drug release mechanism is based on the phenomenon of diffusion. The sulfanilamide degradation in phosphate buffer solution and liposomes is related to the formation of UV-induced degradation products that are identified by UHPLC/MS analysis as: sulfanilic acid, aniline and benzidine. The UV-induced sulfanilamide degradation in the phosphate buffer solution and liposome vesicles fits the first- order kinetic model. The degradation rate constants are dependent on the involved UV photons energy input as well as sulfanilamide microenvironment. Liposome microenvironment provides better irradiation sulfanilamide stability. The obtained results suggest that liposomes might be promising carriers for delayed sulfanilamide delivery and may serve as a basis for further research.

  5. In vitro hyperthermia with improved colloidal stability and enhanced SAR of magnetic core/shell nanostructures.

    Science.gov (United States)

    Patil, R M; Thorat, N D; Shete, P B; Otari, S V; Tiwale, B M; Pawar, S H

    2016-02-01

    Magnetic core/shell nanostructures of Fe3O4 nanoparticles coated with oleic acid and betaine-HCl were studied for their possible use in magnetic fluid hyperthermia (MFH). Their colloidal stability and heat induction ability were studied in different media viz. phosphate buffer solution (PBS), saline solution and glucose solution with different physiological conditions and in human serum. The results showed enhanced colloidal stability in these media owing to their high zeta potential values. Heat induction studies showed that specific absorption rates (SAR) of core/shells were 82-94W/g at different pH of PBS and concentrations of NaCl and glucose. Interestingly, core/shells showed 78.45±3.90W/g SAR in human serum. The cytotoxicity of core/shells done on L929 and HeLa cell lines using 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide and trypan blue dye exclusion assays showed >89% and >80% cell viability for 24 and 48h respectively. Core/shell structures were also found to be very efficient for in vitro MFH on cancer cell line. About 95% cell death was occurred in 90min after hyperthermia treatment. The mechanism of cell death was found to be elevated ROS generation in cells after exposure to core/shells in external magnetic field. This study showed that these core/shells have a great potential to be used in in vivo MFH. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Comparison of the color stability of ten new-generation composites: an in vitro study.

    Science.gov (United States)

    Dietschi, D; Campanile, G; Holz, J; Meyer, J M

    1994-11-01

    The aim of this in vitro study was to evaluate the color stability of modern light-cured composites when subjected to various physico-chemical and staining conditions. Ten brands were evaluated including hybrids, microfine hybrids and microfilled composites. Some universal shade samples underwent only staining tests, while others were subjected to one of the following experimental conditions: thermocycling, postcuring, polishing or a 1 wk immersion in saline, prior to staining. The coloring solutions used for the staining tests were: coffee, E 110 food dye, vinegar and erythrosin. A colorimetric evaluation according to the CIE L*a*b* system was performed after experimental periods of 1 and 3 wk. Erythrosin caused the greatest color change for the composites tested. A reduced susceptibility to staining was observed where surfaces had been polished. Low water sorption, a high filler-resin ratio, reduced particle size and hardness, and an optimal filler-matrix coupling system were related to improved composite resistance to discoloration. Resistance of modern composites to discolorations still depends on their structure and manipulation.

  7. Brain temperature measurement: A study of in vitro accuracy and stability of smart catheter temperature sensors.

    Science.gov (United States)

    Li, Chunyan; Wu, Pei-Ming; Wu, Zhizhen; Ahn, Chong H; LeDoux, David; Shutter, Lori A; Hartings, Jed A; Narayan, Raj K

    2012-02-01

    The injured brain is vulnerable to increases in temperature after severe head injury. Therefore, accurate and reliable measurement of brain temperature is important to optimize patient outcome. In this work, we have fabricated, optimized and characterized temperature sensors for use with a micromachined smart catheter for multimodal intracranial monitoring. Developed temperature sensors have resistance of 100.79 ± 1.19Ω and sensitivity of 67.95 mV/°C in the operating range from15-50°C, and time constant of 180 ms. Under the optimized excitation current of 500 μA, adequate signal-to-noise ratio was achieved without causing self-heating, and changes in immersion depth did not introduce clinically significant errors of measurements (temperature sensors in comparison to two types of commercial temperature probes (USB Reference Thermometer, NIST-traceable bulk probe with 0.05°C accuracy; and IT-21, type T type clinical microprobe with guaranteed 0.1°C accuracy) under controlled laboratory conditions. These in vitro experimental data showed that the temperature measurement performance of our sensors was accurate and reliable over the course of 5 days. The smart catheter temperature sensors provided accuracy and long-term stability comparable to those of commercial tissue-implantable microprobes, and therefore provide a means for temperature measurement in a microfabricated, multimodal cerebral monitoring device.

  8. Preparation and in vitro stability of (n,{gamma}) yttrium-90 hydroxyapatite

    Energy Technology Data Exchange (ETDEWEB)

    Khalid, M. [Isotope Production Division, Pakistan Institute of Nuclear Science and Technology, P.O. Nilore, Islamabad (Pakistan); Mushtaq, A. [Isotope Production Division, Pakistan Institute of Nuclear Science and Technology, P.O. Nilore, Islamabad (Pakistan)]. E-mail: mushtaqa@pinstech.org.pk

    2005-04-01

    Yttrium-90, produced by irradiating Y{sub 2}O{sub 3} (15 mg) in the Pakistan Research Reactor (PARR-I) at a flux of {approx}1.5x10{sup 14} neutrons/cm{sup 2}/s, was used to prepare yttrium-90 hydroxyapatite particles for radiosynovectomy applications. The irradiated material was dissolved in concentrated hydrochloric acid, evaporated and taken up in distilled water. The 120 h irradiation resulted in the production of {approx}12 GBq (324 mCi) of {sup 90}Y at the end of irradiation (EOI) and the corresponding specific activity was {approx}1017 GBq/g of yttrium. Hydroxyapatite (HA) particles were synthesized by an already reported method. Labeling of HA particles with {sup 90}Y was studied without a transchelating agent. Labeling yields of {approx}100% could be achieved with 40 mg of HA and 0.4 mg of {sup 90}Y. In vitro studies showed <2% loss of {sup 90}Y activity in normal saline and 1% human serum albumin solution over a period of 8 days. The high labeling yield, good stability and ease of preparation of the {sup 90}Y-HA particles indicate that these particles may find wide application in radiation synovectomy.

  9. Initial Bacterial Adhesion on Different Yttria-Stabilized Tetragonal Zirconia Implant Surfaces in Vitro

    Directory of Open Access Journals (Sweden)

    Lamprini Karygianni

    2013-12-01

    Full Text Available Bacterial adhesion to implant biomaterials constitutes a virulence factor leading to biofilm formation, infection and treatment failure. The aim of this study was to examine the initial bacterial adhesion on different implant materials in vitro. Four implant biomaterials were incubated with Enterococcus faecalis, Staphylococcus aureus and Candida albicans for 2 h: 3 mol % yttria-stabilized tetragonal zirconia polycrystal surface (B1a, B1a with zirconium oxide (ZrO2 coating (B2a, B1a with zirconia-based composite coating (B1b and B1a with zirconia-based composite and ZrO2 coatings (B2b. Bovine enamel slabs (BES served as control. The adherent microorganisms were quantified and visualized using scanning electron microscopy (SEM; DAPI and live/dead staining. The lowest bacterial count of E. faecalis was detected on BES and the highest on B1a. The fewest vital C. albicans strains (42.22% were detected on B2a surfaces, while most E. faecalis and S. aureus strains (approximately 80% were vital overall. Compared to BES; coated and uncoated zirconia substrata exhibited no anti-adhesive properties. Further improvement of the material surface characteristics is essential.

  10. [Study of a lysis medium stabilizing microfilaments and microtubules in vitro and in vivo].

    Science.gov (United States)

    Foucault, G; Raymond, M N; Coffe, G; Pudles, J

    1984-01-01

    Determination of experimental conditions which allow the evaluation of the variations in the ratio of non polymerized and polymerized forms of actin and tubulin during the reorganization of the cytoskeletal cell system is of most valuable importance. In order to prepare cell homogenates which would reflect the in vivo situation, we tested in vitro a lysis medium which stabilized both microfilaments and microtubules, which were determined by DNase inhibition assays and colchicine binding assays respectively. This lysis medium containing 10 mM potassium phosphate, 1mM magnesium chloride, 5 mM EGTA, 1 M hexylene glycol, 1% Triton X-100, pH 6.4, used at 4 degrees C a) diffused rapidly into the cells; b) did not denature actin and tubulin; c) did not displace the equilibrium between non polymerized and polymerized forms of actin and tubulin, allowing biochemical assays on cell homogenates; d) blocked the evolution of the cytoskeletal system and permitted structural studies; e) and allowed the decoration of microfilaments by heavy meromyosin.

  11. Pharmacokinetics & Neurophysiology

    Science.gov (United States)

    Davis, Andrew S.; Salpekar, Jay A.

    2009-01-01

    Medications administered in clinical practice obtain their therapeutic effect only to the extent that the drug is present in the appropriate concentration at the desired site. To achieve this goal, the prescribing clinician must be aware of how a drug may interact with the physiology of the patient. Pharmacokinetics is the study of this process…

  12. Stability of Rosmarinic Acid in Aqueous Extracts from Different Lamiaceae Species after in vitro Digestion with Human Gastrointestinal Enzymes

    Directory of Open Access Journals (Sweden)

    Zoran Zorić

    2016-01-01

    Full Text Available The present study compares the gastrointestinal stability of rosmarinic acid in aqueous extracts of thyme, winter savory and lemon balm with the stability of pure rosmarinic acid. The stability of rosmarinic acid was detected after two-phase in vitro digestion process (gastric and duodenal with human gastrointestinal enzymes. The concentration of rosmarinic acid in undigested and digested samples was detected using HPLC-DAD. Results showed that gastrointestinal stability of pure rosmarinic acid was significantly higher than that of rosmarinic acid from plant extracts after both gastric and intestinal phases of digestion. Among plant extracts, rosmarinic acid was the most stable in lemon balm after gastric (14.10 % and intestinal digestion phases (6.5 %. The temperature (37 °C and slightly alkaline medium (pH=7.5 did not aff ect the stability of rosmarinic acid, while acid medium (pH=2.5 significantly decreased its stability (≥50 %. In addition, the stability rate of rosmarinic acid is influenced by the concentration of human gastrointestinal juices.

  13. Stability of Rosmarinic Acid in Aqueous Extracts from Different Lamiaceae Species after in vitro Digestion with Human Gastrointestinal Enzymes.

    Science.gov (United States)

    Zorić, Zoran; Markić, Joško; Pedisić, Sandra; Bučević-Popović, Viljemka; Generalić-Mekinić, Ivana; Grebenar, Katarina; Kulišić-Bilušić, Tea

    2016-03-01

    The present study compares the gastrointestinal stability of rosmarinic acid in aqueous extracts of thyme, winter savory and lemon balm with the stability of pure rosmarinic acid. The stability of rosmarinic acid was detected after two-phase in vitro digestion process (gastric and duodenal) with human gastrointestinal enzymes. The concentration of rosmarinic acid in undigested and digested samples was detected using HPLC-DAD. Results showed that gastrointestinal stability of pure rosmarinic acid was significantly higher than that of rosmarinic acid from plant extracts after both gastric and intestinal phases of digestion. Among plant extracts, rosmarinic acid was the most stable in lemon balm after gastric (14.10%) and intestinal digestion phases (6.5%). The temperature (37 °C) and slightly alkaline medium (pH=7.5) did not affect the stability of rosmarinic acid, while acid medium (pH=2.5) significantly decreased its stability (≥50%). In addition, the stability rate of rosmarinic acid is influenced by the concentration of human gastrointestinal juices.

  14. In vitro stability of low-concentration ziconotide alone or in admixtures in intrathecal pumps.

    Science.gov (United States)

    Dupoiron, Denis; Richard, Hélène; Chabert-Desnot, Vincent; Devys, Catherine; Leynia, Pierre; Boisdron-Celle, Michèle

    2014-07-01

    Ziconotide is often administered in combination with other analgesics via an intrathecal pump. Studies have established that ziconotide is stable when delivered alone in high concentrations. No stability data are available, however, for ziconotide given in low concentrations and/or with other analgesics as usually occurs in clinical oncology practice. The objective of this study was to assess the in vitro stability of ziconotide alone and combined with other analgesics in intrathecal pumps at 37 °C, as well as in syringes at 5 °C, to evaluate conditions for storing and transporting preparations. Various ziconotide concentrations (0.1, 0.25, 0.5, and 0.75 μg/mL) were combined with an admixture of ropivacaine (7.5 mg/mL), morphine (7.5 mg/mL), and clonidine (15 μg/mL) in 20-mL intrathecal pumps at 37 °C and in syringes at 5 °C. Solutions of ziconotide alone in concentrations of 0.25, 0.5, 0.75, and 1 μg/mL were introduced into pumps at 37 °C and syringes at 5 °C. Assays were performed using ultra high pressure liquid chromatography. In admixtures, mean ziconotide concentrations decreased linearly to 53.4% (± 3.33%) of baseline after 35 days. When ziconotide was introduced alone in pumps at 37 °C, the residual concentration on day 31 was 35.54% (± 0.04%) with 0.25 μg/mL, 39.37% (± 0.15%) with 0.5 μg/mL, and 44.49% (± 0.18%) with 1 μg/mL. Ziconotide alone or combined with the other analgesics was stable in syringes stored at 5 °C. The preparations complied with the prescriptions, with a mean error of less than 10%, except with the lowest ziconotide concentration (0.1 μg/mL). At the low ziconotide concentrations studied, the degradation of ziconotide admixed with other drugs was linear and only weakly influenced by the baseline concentration. Linear regression with intrapolation to 30 days showed that the degradation of ziconotide admixed with other drugs was consistent with previously published data. © 2014 International Neuromodulation Society.

  15. Solubility, Stability, Physicochemical Characteristics and In Vitro Ocular Tissue Permeability of Hesperidin: a Natural Bioflavonoid

    Science.gov (United States)

    Majumdar, Soumyajit; Srirangam, Ramesh

    2008-01-01

    Purpose Hesperidin holds potential in treating age-related macular degeneration, cataract and diabetic retinopathy. The aim of this study, constituting the first step towards efficient ocular delivery of hesperidin, was to determine its physicochemical properties and in vitro ocular tissue permeability. Methods pH dependent aqueous solubility and stability were investigated following standard protocols. Permeability of hesperidin across excised rabbit cornea, sclera, and sclera plus retinal pigmented epithelium (RPE) was determined using a side-bi-side diffusion apparatus. Results Hesperidin demonstrated poor, pH independent, aqueous solubility. Solubility improved dramatically in the presence of 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) and the results supported 1:1 complex formation. Solutions were stable in the pH and temperature (25, 40°C) conditions tested, except for samples stored at pH 9. Transcorneal permeability in the apical-basal and basal-apical directions was 1.11±0.86×10−6 and 1.16±0.05×10−6 cm/s, respectively. The scleral tissue was more permeable (10.2±2.1×10−6cm/s). However, permeability across sclera/choroid/RPE in the sclera to retina and retina to sclera direction was 0.82±0.69×10−6, 1.52±0.78×10−6 cm/s, respectively, demonstrating the barrier properties of the RPE. Conclusion Our results suggest that stable ophthalmic solutions of hesperidin can be prepared and that hesperidin can efficiently permeate across the corneal tissue. Further investigation into its penetration into the back-of-the eye ocular tissues is warranted. PMID:18810327

  16. In vitro study of color stability of polycrystalline and monocrystalline ceramic brackets

    Directory of Open Access Journals (Sweden)

    Cibele Braga de Oliveira

    2014-08-01

    Full Text Available OBJECTIVE: The aim of this in vitro study was to analyze color stability of monocrystalline and polycrystalline ceramic brackets after immersion in dye solutions. METHODS: Seven ceramic brackets of four commercial brands were tested: Two monocrystalline and two polycrystalline. The brackets were immersed in four dye solutions (coffee, red wine, Coke and black tea and in artificial saliva for the following times: 24 hours, 7, 14 and 21 days, respectively. Color changes were measured by a spectrophotometer. Data were assessed by Multivariate Profile Analysis, Analysis of Variance (ANOVA and Multiple Comparison Tests of means. RESULTS: There was a perceptible change of color in all ceramic brackets immersed in coffee (ΔE* Allure = 7.61, Inspire Ice = 6.09, Radiance = 6.69, Transcend = 7.44, black tea (ΔE* Allure = 6.24, Inspire Ice = 5.21, Radiance = 6.51, Transcend = 6.14 and red wine (ΔE* Allure = 6.49, Inspire Ice = 4.76, Radiance = 5.19, Transcend = 5.64, but no change was noticed in Coke and artificial saliva (ΔE < 3.7. CONCLUSION: Ceramic brackets undergo color change when exposed to solutions of coffee, black tea and red wine. However, the same crystalline structure, either monocrystalline or polycrystalline, do not follow the same or a similar pattern in color change, varying according to the bracket fabrication, which shows a lack of standardization in the manufacturing process. Coffee dye produced the most marked color changes after 21 days of immersion for most ceramic brackets evaluated.

  17. Stabilization of Resveratrol in Blood Circulation by Conjugation to mPEG and mPEG-PLA Polymers: Investigation of Conjugate Linker and Polymer Composition on Stability, Metabolism, Antioxidant Activity and Pharmacokinetic Profile: e0118824

    National Research Council Canada - National Science Library

    Basavaraj Siddalingappa; Heather A E Benson; David H Brown; Kevin T Batty; Yan Chen

    2015-01-01

    .... But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol...

  18. Stabilization of resveratrol in blood circulation by conjugation to mPEG and mPEG-PLA polymers: investigation of conjugate linker and polymer composition on stability, metabolism, antioxidant activity and pharmacokinetic profile

    National Research Council Canada - National Science Library

    Siddalingappa, Basavaraj; Benson, Heather A E; Brown, David H; Batty, Kevin T; Chen, Yan

    2015-01-01

    .... But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol...

  19. Shortening of an anatomical stem, how short is short enough? An in vitro study of load transfer and primary stability.

    Science.gov (United States)

    Østbyhaug, Per Olav; Klaksvik, Jomar; Romundstad, Pål; Aamodt, Arild

    2013-05-01

    An anatomical stem should be short enough to avoid distal locking and distal load transfer but long enough to ensure adequate primary stability of the stem. In this in vitro study, the cortical strains in the femur and the primary stability of the stem were measured after insertion of Anatomic Benoist Girard-I anatomical stems with gradually reduced stem length in six human cadaver femurs in order to find the optimal stem length. A shortening of 40-50 mm, corresponding to a stem extending 30-40 mm below the lesser trochanter, did not affect stem stability but nearly normalized the load distribution in the lower metaphysis and upper diaphysis. The large strain shielding observed in the calcar region was not influenced by shortening of the stem.

  20. Assessment of genetic and epigenetic stability in long-term in vitro shoot culture of pea (Pisum sativum L.).

    Science.gov (United States)

    Smýkal, P; Valledor, L; Rodríguez, R; Griga, M

    2007-11-01

    In vitro clonal propagation of plants should generate identical copies of the selected genotype. However, associated stress might result in a breakdown of control mechanisms and consequent instability of the genome. We have used several molecular methods to assess the genetic stability of long-term propagated (24 years) multiple shoot in vitro culture of pea (Pisum sativum L.). We focused on assessing the stability of repetitive sequences, such as simple sequence repeats (SSR) and retrotransposons, both comprising a large part of genome. No differences were found when seedlings (Co-2004) or original seed (Co-1982) controls and long-term or newly established in vitro (one subculture cycle) samples were investigated by the SSR, inter-repeats (ISSR) or inter-retrotransposon amplified polymorphism (IRAP) method. However, the more global amplified fragment length polymorphism (AFLP) and particularly the methylation sensitive MSAP methods detected 11 and 18% polymorphism among samples, respectively. Interestingly, investigation of the global cytosine methylation status by HPCE measurement revealed no statistically significant differences. Some evidence of retrotransposon re-arrangement was observed by sequence-specific amplification polymorphism. This occurred mostly in the abundant Ty3-gypsy type Cyclop element and to a smaller extent in the Ogre element. Alternatively, no polymorphism was detected among the PDR-1 element of the Ty1-copia type retrotransposon. Based on these results, multiple shoot culture of pea maintained over a long period may be considered as a true to type multiplication method of the original genotype.

  1. Transit time affects the community stability of Lactobacillus and Bifidobacterium species in an in vitro model of human colonic microbiotia.

    Science.gov (United States)

    Rodes, Laetitia; Paul, Arghya; Coussa-Charley, Michael; Al-Salami, Hani; Tomaro-Duchesneau, Catherine; Fakhoury, Marc; Prakash, Satya

    2011-12-01

    Retention time, which is analogous to transit time, is an index for bacterial stability in the intestine. Its consideration is of particular importance to optimize the delivery of probiotic bacteria in order to improve treatment efficacy. This study aims to investigate the effect of retention time on Lactobacilli and Bifidobacteria stability using an established in vitro human colon model. Three retention times were used: 72, 96, and 144 h. The effect of retention time on cell viability of different bacterial populations was analyzed with bacterial plate counts and PCR. The proportions of intestinal Bifidobacteria, Lactobacilli, Enterococci, Staphylococci and Clostridia populations, analyzed by plate counts, were found to be the same as that in human colonic microbiota. Retention time in the human colon affected the stability of Lactobacilli and Bifidobacteria communities, with maximum stability observed at 144 h. Therefore, retention time is an important parameter that influences bacterial stability in the colonic microbiota. Future clinical studies on probiotic bacteria formulations should take into consideration gastrointestinal transit parameters to improve treatment efficacy.

  2. Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction.

    Science.gov (United States)

    Zhang, TianHong; Zhang, KeRong; Ma, Li; Li, Zheng; Wang, Juan; Zhang, YunXia; Lu, Chuang; Zhu, Mingshe; Zhuang, XiaoMei

    2017-12-14

    Icotinib is the first self-developed small molecule drug in China for targeted therapy of non-small cell lung cancer. To date, systematic studies on the pharmacokinetic drug-drug interaction of icotinib were limited. By identifying metabolite generated in human liver microsomes and revealing the contributions of major cytochromes P450 (CYPs) in the formation of major metabolites, the aim of the present work was to understand the mechanisms underlying pharmacokinetic and pharmacological variability in clinic. A liquid chromatography/UV/high-resolution mass spectrometer method was developed to characterize the icotinib metabolites. The formation of 6 major metabolites was studied in recombinant CYP isozymes and human liver microsomes with specific inhibitors to identify the CYPs responsible for icotinib metabolism. The metabolic pathways observed in vitro are consistent with those observed in human. Results demonstrated that the metabolites are predominantly catalyzed by CYP3A4 (77%∼87%), with a moderate contribution from CYP3A5 (5%∼15%) and CYP1A2 (3.7%∼7.5%). The contribution of CYP2C8, 2C9, 2C19, and 2D6 is insignificant. Based on our observations, to minimize drug-drug interaction risk in clinic, coprescription of icotinib with strong CYP3A inhibitors or inducers must be weighed. CYP1A2, a highly inducible enzyme in the smoking population, may also represent a determinant of pharmacokinetic and pharmacological variability of icotinib, especially in lung cancer patients with smoking history. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  3. Kinetic stability and membrane structure of liposomes during in vitro infant intestinal digestion: Effect of cholesterol and lactoferrin.

    Science.gov (United States)

    Liu, Weilin; Wei, Fuqiang; Ye, Aiqian; Tian, Mengmeng; Han, Jianzhong

    2017-09-01

    The effects of cholesterol and lactoferrin on the kinetic stability and membrane structural integrity of negatively charged liposomes under in vitro infant intestinal digestion conditions were elucidated using dynamic light scattering, pH-stat titration, Fourier transform infrared spectroscopy, and pyrene steady state fluorescence probes. The liposomes had a smaller particle diameter, a wider size distribution, and a greater negative charge after digestion. The incorporation of cholesterol into the phospholipid bilayers resulted in a more ordered conformation in the aliphatic tail region and reduced micropolarity, indicating that cholesterol can improve the structural stability of liposomal membranes against intestinal environmental stress. Lactoferrin coverage facilitated the release of free fatty acids and increased the microfluidity of the bilayers, reducing the structural integrity of the liposomes. This study provides useful information on the design of liposomes and other microcapsules with improved and controlled release properties during digestion for particular groups of people. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Bioaccessibility and digestive stability of carotenoids in cooked eggs studied using a dynamic in vitro gastrointestinal model.

    Science.gov (United States)

    Nimalaratne, Chamila; Savard, Patricia; Gauthier, Sylvie F; Schieber, Andreas; Wu, Jianping

    2015-03-25

    Among dietary carotenoids, lutein and zeaxanthin are known to protect against age-related macular degeneration, a leading cause of irreversible vision loss in the elderly. Egg yolk is rich in lutein and zeaxanthin, however, the effect of cooking and gastrointestinal digestion on yolk carotenoids is poorly understood. An in vitro dynamic gastrointestinal model (TIM-1) was used to investigate the digestive stability and bioaccessibility of carotenoids from boiled, fried, and scrambled eggs. Bioaccessibility but not digestive stability was significantly affected by the method of cooking. The main egg carotenoids, all-E-lutein and all-E-zeaxanthin, were stable during the digestion with average recoveries of 90 and 88%, respectively. No trans-cis isomerization of carotenoids was observed during digestion. Both all-E-lutein and all-E-zeaxanthin from scrambled eggs showed significantly lower bioaccessibility compared to boiled eggs. The results indicate that the bioaccessibility of egg carotenoids can be affected by different food preparation methods.

  5. In vitro/in vivo investigations to examine the gender differences in the pharmacokinetics of novel oral Janus kinase (JAK) inhibitor ASP015K and sulfate metabolite M2 in rats.

    Science.gov (United States)

    Oda, Kazuo; Nakada, Naoyuki; Nagasaka, Yasuhisa

    2015-01-01

    1. Although marked gender differences have been reported for the exposure level of the sulfate metabolite M2 of ASP015K in rats, no such differences have been reported for the unchanged drug. To clarify the cause of these pharmacokinetic gender differences, we investigated the in vitro hepatic sulfation, glucuronidation, and cytochrome P450 (CYP) metabolism of ASP015K in rat liver cytosols or rat liver microsomes. Further, in vivo excretion and metabolic profiles were investigated using rat urine, bile, and feces post-ASP015K administration. 2. In vitro metabolism study using liver cytosols clearly suggested that the gender differences in the M2 exposure were mainly attributed to the female-predominant ASP015K metabolism mediated by sulfotransferase (SULT). Metabolic profiles in urine and bile from male rats suggested that the major elimination pathway of ASP015K is glucuronidation in rats. No remarkable gender differences in the in vitro glucuronidation were observed. 3. The contribution of the sulfation pathway to the clearance of ASP015K was markedly lower than that of the glucuronidation pathway in both male and female rats. These results might explain why gender differences were not marked for ASP015K exposure but were for M2.

  6. Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA-14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction.

    Science.gov (United States)

    Liu, Fei; Zhuang, Xiaomei; Yang, Cuiping; Li, Zheng; Xiong, Shan; Zhang, Zhiwei; Li, Jin; Lu, Chuang; Zhang, Zhenqing

    2014-07-01

    YQA-14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA-14, then to simulate the clinical PK of YQA-14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA-14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA-14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA-14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA-14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic. Copyright © 2014 John Wiley & Sons, Ltd.

  7. Nanoemulsion for Solubilization, Stabilization, and In Vitro Release of Pterostilbene for Oral Delivery

    National Research Council Canada - National Science Library

    Zhang, Yue; Shang, Zhenhua; Gao, Chunhui; Du, Man; Xu, Shixia; Song, Haiwen; Liu, Tingting

    2014-01-01

    .... But the poor solubility and stability of pterostilbene strictly restrained its applications. As a good protection and oral delivery system, an optimal nanoemulsion for pterostilbene was developed by using low-energy emulsification method...

  8. Color Stability of Teeth Restored with Biodentine: A 6-month In Vitro Study.

    Science.gov (United States)

    Vallés, Marta; Roig, Miguel; Duran-Sindreu, Fernando; Martínez, Syani; Mercadé, Montserrat

    2015-07-01

    White mineral trioxide aggregate (WMTA) has been reported to cause dental discoloration. A previous study on the color stability of 5 calcium silicate-based materials investigated the color stability of Biodentine (Septodont, Saint-Maur-des-Fossés, France) in different experimental environments; however, no data are available on the color stability of teeth restored with Biodentine. In this study, we assessed the color stability under artificial light of ex vivo human teeth restored coronally with WMTA or Biodentine. Cavities were prepared on coronal tooth specimens and restored with WMTA + composite (n = 16), Biodentine + composite (n = 16), or composite alone (control, n = 3). Color was assessed spectrophotometrically at 6 time points (initial, 1 week, 2 weeks, 1 month, 3 months, and 6 months), and color difference values were calculated. Statistical analysis was performed using analysis of variance and the Fisher least significant difference test for which P Biodentine and control groups showed color stability and were not significantly different from one another. Teeth treated with WMTA exhibited discoloration, whereas those treated with Biodentine maintained color stability throughout the study. However, further in vivo studies are necessary to corroborate these results. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  9. Effects of in vitro digestion and in vitro colonic fermentation on stability and functional properties of yerba mate (Ilex paraguariensis A. St. Hil.) beverages.

    Science.gov (United States)

    Correa, Vanesa G; Gonçalves, Geferson A; de Sá-Nakanishi, Anacharis B; Ferreira, Isabel C F R; Barros, Lillian; Dias, Maria I; Koehnlein, Eloá A; de Souza, Cristina G M; Bracht, Adelar; Peralta, Rosane M

    2017-12-15

    Yerba mate (Ilex paraguariensis) is a plant that grows naturally in South America. From its leaves and thin stems different kinds of beverages are prepared (chimarrão, tererê and tea mate), all of them rich in bioactive substances. The aim of this study was to evaluate the influence of in vitro gastrointestinal digestion and colonic fermentation on the stability of the polyphenols and on the antioxidant, antimicrobial and antitumoral activities of the yerba mate beverages. The phenolic chromatographic profile revealed that both the in vitro digestion and the colonic fermentation caused a pronounced decrease in 3,5-O-dicaffeoylquinic acid and 5-O-caffeoylquinic acid in the preparations. However, 3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid and salvianolic acid I were only barely affected in all preparations. Despite the decrease in the phytochemicals content, yerba mate beverages maintain their functional properties such as antioxidant, antibacterial and antitumoral activities. Copyright © 2017. Published by Elsevier Ltd.

  10. Population pharmacokinetics. A regulatory perspective.

    Science.gov (United States)

    Sun, H; Fadiran, E O; Jones, C D; Lesko, L; Huang, S M; Higgins, K; Hu, C; Machado, S; Maldonado, S; Williams, R; Hossain, M; Ette, E I

    1999-07-01

    data analysis, model development and model validation (i.e. predictive performance). Documentation for regulatory purposes should include a complete inventory of key runs in the analyses undertaken (with flow diagrams if possible), accompanied by articulation of objectives, assumptions and hypotheses. Use of diagnostic analyses of goodness of fit as evidence of reliability of results is advised. Finally, the use of stability testing or model validation may be warranted to support label claims. The opinions expressed in this article were revised by incorporating comments from various sources and published by the FDA as 'Guidance for Industry: Population Pharmacokinetics' (see the FDA home page http:/(/)www.fda.gov for further information).

  11. In Vitro Mass Multiplication and Assessment of Genetic Stability of In Vitro Raised Artemisia absinthium L. Plants Using ISSR and SSAP Molecular Markers

    Directory of Open Access Journals (Sweden)

    B. Kour

    2014-01-01

    Full Text Available The present investigations were made attempting to develop a rapid, reliable, and reproducible in vitro regeneration protocol for Artemisia absinthium L., a medicinal plant of Kashmir Himalayas. Out of several auxin-cytokinin combinations tested, Murashige and Skoog’s (MS medium supplemented with 0.5 mgL−1 2,4-dichlorophenoxyacetic acid (2,4-D and 0.5 mgL−1 kinetin (Kn was found to be the best for the callus induction. On the other hand, 4.5 mgL−1 6-benzylaminopurine (BAP and 0.5 mgL−1 1-α-naphthaleneacetic acid (NAA in the medium resulted in maximum shoot induction from the callus. Similarly, BAP and NAA at a concentration of 1.5 mgL−1 and 0.5 mgL−1, respectively, proved to be the best for the multiple shoot induction from nodal explants. Numerous shoots were obtained from nodal explants after third subculture. In vitro rooting was maximum on medium containing indole-3-butyric acid (IBA at 0.5 mgL−1. The genetic stability of the in vitro raised plants of Artemisia absinthium was assessed using the intersimple sequence repeat (ISSR and sequence-specific amplification polymorphism (SSAP molecular markers. Both markers were able to detect the somaclonal variations in the callus regenerated plants, while no variation was detected in the plants regenerated from the nodal explants. SSAP has been found to be more useful in detection of variability as compared to ISSR molecular marker. The results of present study concluded that the direct regeneration protocol will be useful for the production of true to type plants of this medicinally important plant. This will go a long way in reducing the pressure on the natural populations for the secondary metabolite production, especially for extraction of essential oils.

  12. Preparation, physical characterization and pharmacokinetic study of paclitaxel nanocrystals.

    Science.gov (United States)

    Wei, Lisha; Ji, Yanxia; Gong, Wei; Kang, Zhenqiao; Meng, Meng; Zheng, Aiping; Zhang, Xiaoyan; Sun, Jianxu

    2015-01-01

    Paclitaxel (PTX) is a natural broad-spectrum anticancer drug with poor aqueous solubility. PTX nanocrystals were formulated to improve the water solubility, and PTX nanosuspensions were prepared using anti-solvent precipitation, and then organic solvent and surfactants were removed by filtering through a vacuum system. The physical characterization of PTX nanocrystals were measured by transmission electron microscope, X-ray diffraction and differential scanning calorimetry. In addition, saturation solubility, in vitro release, stability and pharmacokinetic characteristics were examined. The average particle size of PTX nanocrystals was ∼200 nm, and they had a stable potential and a uniform distribution. Paclitaxel nanocrystals can effectively improve drug solubility and in vitro release. PTX pharmacokinetic and tissue distribution studies were compared after intravenous administration of nanocrystals versus a commercial injection formulation. PTX nanocrystals were rapidly distributed with a longer elimination phase. Moreover, tissue distribution indicated that PTX nanocrystals are mainly absorbed by the liver and spleen and may offer reduced renal and cardiovascular toxicity which may reduce side effects.

  13. Stability of the elbow joint: relevant anatomy and clinical implications of in vitro biomechanical studies

    NARCIS (Netherlands)

    de Haan, J.; Schep, N. W. L.; Eygendaal, D.; Kleinrensink, G.-J.; Tuinebreijer, W. E.; den Hartog, D.

    2011-01-01

    The aim of this literature review is to describe the clinical anatomy of the elbow joint based on information from in vitro biomechanical studies. The clinical consequences of this literature review are described and recommendations are given for the treatment of elbow joint dislocation.The PubMed

  14. Optimization of amino acid-stabilized erythropoietin parenteral formulation: In vitro and in vivo assessment

    Directory of Open Access Journals (Sweden)

    Fayed Bahgat E.

    2016-03-01

    Full Text Available The aim of this study was to optimize the formulation of erythropoietin (EPO using amino acids instead of human serum albumin (HSA and to evaluate its in vivo stability in order to avoid the risk of viral contamination and antigenicity. Different EPO formulations were developed in such a way as to allow studying the effects of amino acids and surfactants on the EPO stability profile. The main techniques applied for EPO analysis were ELISA, Bradford method, and SDS gel electrophoresis. The in vivo stability was evaluated in a Balb-c mouse animal model. The results showed that the presence of surfactant was very useful in preventing the initial adsorption of EPO on the walls of vials and in minimizing protein aggregation. Amino acid combinations, glycine with glutamic acid, provided maximum stability. Formulation F4 (containing glycine, glutamic acid and Tween 20 showed minimum aggregation and degradation and in vivo activity equivalent to commercially available HSA-stabilized EPO (Eprex®.

  15. Stability of angiogenic agents, ginsenoside Rg1 and Re, isolated from Panax ginseng: in vitro and in vivo studies.

    Science.gov (United States)

    Yu, Lin-Chien; Chen, Sung-Ching; Chang, Wei-Chun; Huang, Ya-Chun; Lin, Kurt M; Lai, Po-Hong; Sung, Hsing-Wen

    2007-01-10

    The study was designed to investigate the stability of ginsenoside Rg(1) (Rg(1)) and Re (Re), two natural herbal compounds isolated from Panax ginseng, based on their activity to promote angiogenesis in vitro and in vivo. After being treated at different temperatures, pHs, and solvent species for distinct durations, the remaining activities of Rg(1) and Re on human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation were examined in vitro. Additionally, the remaining activity of each treated test agent, mixed in a growth factor-reduced Matrigel, in stimulating angiogenesis was evaluated subcutaneously in a mouse model. Basic fibroblast growth factor (bFGF) was used as a control. It was found in vitro that HUVEC proliferation, migration in a Transwell plate, and tube formation on Matrigel were all significantly enhanced in the presence of bFGF, Rg(1), or Re. However, after being treated at different temperatures, pHs, or solvent species, the remaining activity of bFGF on HUVEC behaviors reduced significantly. This observation was more significant with increasing the duration of treatment. In contrast, the activities of Rg(1) and Re remained unchanged throughout the entire course of the study. The in vivo results observed on day 7 after implantation showed that the blank control (Matrigel alone) was slightly vascularized. In contrast, the density of neo-vessels in the Matrigel plug mixed with bFGF, Rg(1), or Re was significantly enhanced. However, after being treated, the density of neo-vessels was significantly reduced in the Matrigel plug mixed with bFGF, while those of Rg(1) and Re remained unchanged. The aforementioned results suggested that Rg(1) and Re could be a novel group of nonpeptide angiogenic agents with a superior stability and may be used for the management of tissue regeneration.

  16. In Vitro Assessment of the In Vivo Stability of Cu-64 Radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Packard, Alan B

    2011-12-15

    Research Plans: The successful development of Cu-64 radiopharmaceuticals depends upon retention of the Cu-64 atom in the radiopharmaceutical. To date, the focus has been on the development of chelators that better retain Cu-64, but there has been no effort to develop an effective method by which improved retention may be measured. In the absence of a suitable analytical method, the stability of Cu-64 radiopharmaceuticals is estimated indirectly, with decreased liver uptake suggesting higher in vivo complex stability. But this approach is inadequate for radiopharmaceuticals, such as radiolabeled antibodies, that are expected to accumulate in the liver even when there is no free Cu-64 present. The absence of such a method has also hampered efforts to systematically evaluate the chemical factors that may give rise to improved retention. The objective of this project is to develop and validate such a method. Accomplishments: The two primary accomplishments of this project will be 1) the development and validation of a method to measure the stability of Cu-64 radiopharmaceuticals and 2) the determination of the chemical factors that define the in vivo stability of Cu 64 radiopharmaceuticals. Because Cu(II) is extremely labile, the in vivo stability of Cu-64 radiopharmaceuticals is not primarily determined by the amount of free Cu that is present at any given time or by the thermodynamic stability constants, but rather by the rate at which Cu is lost from the complex, the dissociation rate constant, kd. The dissociation rate constants of the Cu-64 complexes from a series of bifunctional chelators (BFCs) will be measured using Free Ion Selective Radiotracer Extraction (FISRE), a technique originally developed to measure bioavailable Cu in environmental samples. FISRE will also be applied to the determination of the kd's of a series of reference Cu-64 complexes to determine the chemical factors that define the in vivo stability of Cu-64 radiopharmaceuticals. Potential

  17. Semi-mechanistic physiologically-based pharmacokinetic modeling of clinical glibenclamide pharmacokinetics and drug-drug-interactions

    NARCIS (Netherlands)

    Greupink, R.; Schreurs, M.; Benne, M.S.; Huisman, M.T.; Russel, F.G.M.

    2013-01-01

    We studied if the clinical pharmacokinetics and drug-drug interactions (DDIs) of the sulfonylurea-derivative glibenclamide can be simulated via a physiologically-based pharmacokinetic modeling approach. To this end, a glibenclamide PBPK-model was build in Simcyp using in vitro physicochemical and

  18. Dextran stabilized iron oxide nanoparticles: synthesis, characterization and in vitro studies.

    Science.gov (United States)

    Easo, Sheeja Liza; Mohanan, P V

    2013-01-30

    Iron oxide nanoparticles are one of the most important genres of nanoparticles with promise. Dextran, a stable biocompatible coating agent was employed in the synthesis of iron oxide nanoparticles in the presence of urea. The morphology of nanoparticles was confirmed by dynamic light scattering and transmission electron microscopy. These particles were also assessed for cytotoxicity, cellular uptake and cell adhesion in vitro using murine fibroblast cell line. The synthesized nanoparticles were superparamagnetic, possessed spherical shape with narrow size distribution and were found to be biocompatible and non-toxic. This study serves as a background for using DIONPs in further in vitro and in vivo studies with a long term goal of using it in biological applications. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Differences in the stability of the plasmids of Yersinia pestis cultures in vitro: impact on virulence

    Directory of Open Access Journals (Sweden)

    TC Leal-Balbino

    2004-11-01

    Full Text Available Plasmid and chromosomal genes encode determinants of virulence for Yersinia pestis, the causative agent of plague. However, in vitro, Y. pestis genome is very plastic and several changes have been described. To evaluate the alterations in the plasmid content of the cultures in vitro and the impact of the alterations to their pathogenicity, three Y. pestis isolates were submitted to serial subculture, analysis of the plasmid content, and testing for the presence of characteristic genes in each plasmid of colonies selected after subculture. Different results were obtained with each strain. The plasmid content of one of them was shown to be stable; no apparent alteration was produced through 32 subcultures. In the other two strains, several alterations were observed. LD50 in mice of the parental strains and the derived cultures with different plasmid content were compared. No changes in the virulence plasmid content could be specifically correlated with changes in the LD50.

  20. Triphenylphosphonium Moiety Modulates Proteolytic Stability and Potentiates Neuroprotective Activity of Antioxidant Tetrapeptides in Vitro

    Directory of Open Access Journals (Sweden)

    Rezeda A. Akhmadishina

    2018-02-01

    Full Text Available Although delocalized lipophilic cations have been identified as effective cellular and mitochondrial carriers for a range of natural and synthetic drug molecules, little is known about their effects on pharmacological properties of peptides. The effect of triphenylphosphonium (TPP cation on bioactivity of antioxidant tetrapeptides based on the model opioid YRFK motif was studied. Two tetrapeptide variants with L-arginine (YRFK and D-arginine (YrFK were synthesized and coupled with carboxyethyl-TPP (TPP-3 and carboxypentyl-TPP (TPP-6 units. The TPP moiety noticeably promoted YRFK cleavage by trypsin, but effectively prevented digestion of more resistant YrFK attributed, respectively, to structure-organizing and shielding effects of the TPP cation on conformational variants of the tetrapeptide motif. The TPP moiety enhanced radical scavenging activity of the modified YRFK in a model Fenton-like reaction, whereas decreased reactivity was revealed for both YrFK and its TPP derivative. The starting motifs and modified oligopeptides, especially the TPP-6 derivatives, suppressed acute oxidative stress in neuronal PC-12 cells during a brief exposure similarly with glutathione. The effect of oligopeptides was compared upon culturing of PC-12 cells with CoCl2, L-glutamic acid, or menadione to mimic physiologically relevant oxidative states. The cytoprotective activity of oligopeptides significantly depended on the type of oxidative factor, order of treatment and peptide structure. Pronounced cell-protective effect was established for the TPP-modified oligopeptides, which surpassed that of the unmodified motifs. The protease-resistant TPP-modified YrFK showed the highest activity when administered 24 h prior to the cell damage. Our results suggest that the TPP cation can be used as a modifier for small therapeutic peptides to improve their pharmacokinetic and pharmacological properties.

  1. Stabilization of Resveratrol in Blood Circulation by Conjugation to mPEG and mPEG-PLA Polymers: Investigation of Conjugate Linker and Polymer Composition on Stability, Metabolism, Antioxidant Activity and Pharmacokinetic Profile

    OpenAIRE

    Basavaraj Siddalingappa; Benson, Heather A. E.; Brown, David H.; Batty, Kevin T.; Yan Chen

    2015-01-01

    Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (...

  2. Stabilization

    Directory of Open Access Journals (Sweden)

    Muhammad H. Al-Malack

    2016-07-01

    Full Text Available Fuel oil flyash (FFA produced in power and water desalination plants firing crude oils in the Kingdom of Saudi Arabia is being disposed in landfills, which increases the burden on the environment, therefore, FFA utilization must be encouraged. In the current research, the effect of adding FFA on the engineering properties of two indigenous soils, namely sand and marl, was investigated. FFA was added at concentrations of 5%, 10% and 15% to both soils with and without the addition of Portland cement. Mixtures of the stabilized soils were thoroughly evaluated using compaction, California Bearing Ratio (CBR, unconfined compressive strength (USC and durability tests. Results of these tests indicated that stabilized sand mixtures could not attain the ACI strength requirements. However, marl was found to satisfy the ACI strength requirement when only 5% of FFA was added together with 5% of cement. When the FFA was increased to 10% and 15%, the mixture’s strength was found to decrease to values below the ACI requirements. Results of the Toxicity Characteristics Leaching Procedure (TCLP, which was performed on samples that passed the ACI requirements, indicated that FFA must be cautiously used in soil stabilization.

  3. Pharmacokinetics of tildipirosin in porcine plasma, lung tissue, and bronchial fluid and effects of test conditions on in vitro activity against reference strains and field isolates of Actinobacillus pleuropneumoniae.

    Science.gov (United States)

    Rose, M; Menge, M; Bohland, C; Zschiesche, E; Wilhelm, C; Kilp, S; Metz, W; Allan, M; Röpke, R; Nürnberger, M

    2013-04-01

    The pharmacokinetics of tildipirosin (Zuprevo(®) 40 mg/mL solution for injection for pigs), a novel 16-membered-ring macrolide for the treatment for swine respiratory disease (SRD), was investigated in studies collecting blood plasma and postmortem samples of lung tissue and bronchial fluid (BF) from swine. In view of factors influencing the in vitro activity of macrolides, and for the interpretation of tildipirosin pharmacokinetics in relation to minimum inhibitory concentrations (MIC), additional experiments were conducted to study the effects of pH, carbon dioxide-enriched atmosphere, buffers, and serum on tildipirosin MICs for various reference strains and Actinobacillus (A.) pleuropneumoniae field isolates. After single intramuscular (i.m.) injection at 4 mg/kg body weight, maximum plasma concentration (Cmax) was 0.9 μg/mL observed within 23 min (Tmax ). Mean residence time from the time of dosing to the time of last measurable concentration (MRTlast) and terminal half-life (T1/2) both were about 4 days. A dose-response relationship with no significant sex effect is observed for area under the plasma concentration-time curve from time 0 to the last sampling time with a quantifiable drug concentration (AUClast) over the range of doses up to 6 mg/kg. However, linear dose proportionality could not be proven with statistical methods. The time-concentration profile of tildipirosin in BF and lung far exceeded that in blood plasma. In lung, tildipirosin concentrations reached 3.1 μg/g at 2 h, peaked at 4.3 μg/g at day 1, and slowly declined to 0.8 μg/g at day 17. In BF, tildipirosin levels were 14.3, 7.0, and 6.5 μg/g at days 5, 10, and 14. T1/2 in lung was ∼7 days. Tildipirosin is rapidly and extensively distributed to the respiratory tract followed by slow elimination. Culture media pH and carbon dioxide-enriched atmosphere (CO2 -EA) had a marked impact on in vitro activity of tildipirosin in reference strains of various rapidly growing aerobic and

  4. Genetic Stability of Parainfluenza Virus 5-Vectored Human Respiratory Syncytial Virus Vaccine Candidates after In Vitro and In Vivo Passage.

    Science.gov (United States)

    Phan, Shannon I; Adam, Carolyn M; Chen, Zhenhai; Citron, Michael; Liang, Xiaoping; Espeseth, Amy S; Wang, Dai; He, Biao

    2017-10-01

    Human respiratory syncytial virus (RSV) is the leading etiologic agent of lower respiratory tract infections in children, but no licensed vaccine exists. Previously, we developed two parainfluenza virus 5 (PIV5)-based RSV vaccine candidates that protect mice against RSV challenge. PIV5 was engineered to express either the RSV fusion protein (F) or the RSV major attachment glycoprotein (G) between the hemagglutinin-neuraminidase (HN) and RNA-dependent RNA polymerase (L) genes of the PIV5 genome [PIV5-RSV-F (HN-L) and PIV5-RSV-G (HN-L), respectively]. To investigate the stability of the vaccine candidates in vitro, they were passaged in Vero cells at high and low multiplicities of infection (MOIs) for 11 generations and the genome sequences, growth kinetics, and protein expression of the resulting viruses were compared with those of the parent viruses. Sporadic mutations were detected in the consensus sequences of the viruses after high-MOI passages, and mutation rates increased under low-MOI-passage conditions. None of the mutations abolished antigen expression. Increased numbers of mutations correlated with increased growth rates in vitro, indicating that the viruses evolved through the course of serial passages. We also examined the in vivo stability of the vaccine candidates after a single passage in African green monkeys. No mutations were detected in the consensus sequences of viruses collected from the bronchoalveolar lavage (BAL) fluid of the animals. In vivo, mutations in RSV G and PIV5 L were found in individual isolates of PIV5-RSV-G (HN-L), but plaque isolates of PIV5-RSV-F (HN-L) had no mutations. To improve upon the PIV5-RSV-F (HN-L) candidate, additional vaccine candidates were generated in which the gene for RSV F was inserted into earlier positions in the PIV5 genome. These insertions did not negatively impact the sequence stability of the vaccine candidates. The results suggest that the RSV F and G gene insertions are stable in the PIV5 genome

  5. HPMA copolymer conjugate with pirarubicin: In vitro and ex vivo stability and drug release study.

    Science.gov (United States)

    Islam, Waliul; Fang, Jun; Etrych, Tomas; Chytil, Petr; Ulbrich, Karel; Sakoguchi, Akihiro; Kusakabe, Katsuki; Maeda, Hiroshi

    2017-11-10

    We have developed a tumor environment-responsive polymeric anticancer prodrug containing pirarubicin (THP) conjugated to N-(2-hydroxypropyl) methacrylamide copolymer (PHPMA), [P-THP], through a spacer containing pH-sensitive hydrazone bond, that showed remarkable therapeutic effect against various tumor models and in a human pilot study. Toward clinical development, here we report THP release profile from its HPMA copolymer conjugate, the conjugate stability, protein and cell-binding and solubility of P-THP. Size exclusion chromatography of P-THP (molecular weight 38 kDa) showed similar hydrodynamic volume as bovine serum albumin (BSA) in aqueous solution, with no apparent interactions with BSA, nor aggregation by itself. pH-responsive release of free THP was reconfirmed at pHs 6.5 and lower. The drug release was significantly affected by a type of used buffer. Phosphate buffer seems to facilitate faster hydrazone bond cleavage at pH 7.4 whereas higher stability was achieved in L-arginine solution which yielded only little cleavage and THP release, approx. 15% within 2 weeks at the same pH at 25 °C. Furthermore, ex vivo study using sera of different animal species showed very high stability of P-THP. Incubation with blood showed high stability of P-THP during circulation, without binding to blood cells. These findings revealed that L-arginine solution provides appropriate media for formulation of P-THP infusion solution as tumor-targeted polymeric anticancer drug based on EPR effect. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Lectin Digestibility and Stability of Elderberry Antioxidants to Heat Treatment In Vitro.

    Science.gov (United States)

    Jiménez, Pilar; Cabrero, Patricia; Cordoba-Diaz, Damian; Cordoba-Diaz, Manuel; Garrosa, Manuel; Girbés, Tomás

    2017-01-06

    Elderberry contains healthy low molecular weight nutraceuticals and lectins which are sequence-related to the elderberry allergen Sam n1. Some of these lectins are type II ribosome-inactivating proteins. The sensitivity of native lectins present in elderberry fruits and bark to the proteolysis triggered by in vitro simulated gastric and duodenal fluids has been investigated. It was found that these lectins are refractory to proteolysis. Nonetheless, incubation for 5-10 min in a boiling water bath completely sensitized them to the hydrolytic enzymes in vitro. Under these conditions neither total Folin-Ciocalteau's reagent reactive compounds, total anthocyanins and the mixture of cyanidin-3-glucoside plus cyanidin-3-sambubioside, nor antioxidant and free-radical scavenging activities were affected by more than 10% for incubations of up to 20 min. Therefore, short-time heat treatment reduces potential allergy-related risks deriving from elderberry consumption without seriously affecting its properties as an antioxidant and free-radical scavenging food.

  7. Lectin Digestibility and Stability of Elderberry Antioxidants to Heat Treatment In Vitro

    Directory of Open Access Journals (Sweden)

    Pilar Jiménez

    2017-01-01

    Full Text Available Elderberry contains healthy low molecular weight nutraceuticals and lectins which are sequence-related to the elderberry allergen Sam n1. Some of these lectins are type II ribosome-inactivating proteins. The sensitivity of native lectins present in elderberry fruits and bark to the proteolysis triggered by in vitro simulated gastric and duodenal fluids has been investigated. It was found that these lectins are refractory to proteolysis. Nonetheless, incubation for 5–10 min in a boiling water bath completely sensitized them to the hydrolytic enzymes in vitro. Under these conditions neither total Folin-Ciocalteau’s reagent reactive compounds, total anthocyanins and the mixture of cyanidin-3-glucoside plus cyanidin-3-sambubioside, nor antioxidant and free-radical scavenging activities were affected by more than 10% for incubations of up to 20 min. Therefore, short-time heat treatment reduces potential allergy-related risks deriving from elderberry consumption without seriously affecting its properties as an antioxidant and free-radical scavenging food.

  8. Colour improvement and stability of white spot lesions following infiltration, micro-abrasion, or fluoride treatments in vitro.

    Science.gov (United States)

    Yetkiner, Enver; Wegehaupt, Florian; Wiegand, Annette; Attin, Rengin; Attin, Thomas

    2014-10-01

    White spot lesions (WSLs) are unwelcome side effects of fixed appliances that compromise the treatment outcome. Recently, infiltration of WSLs has been introduced as a viable treatment alternative. The objective was to evaluate the colour improvement of WSLs and their stability against discolouration following infiltration, fluoride, or micro-abrasion treatments in vitro. Artificial WSLs were created in bovine enamel (N = 96) using acidic buffer solution (pH 5, 10 days) and were randomly allocated to four groups. Specimens were treated with infiltration (Icon, DMG), fluoride (Elmex Caries Protection, GABA), and micro-abrasion (Opalustre, Ultradent) or remained untreated (control). Groups were discoloured for 24 hours in tea or tea + citric acid. Colour components and visible colour change (L*, a*, b*, ΔE) were measured spectrophotometrically on following time points: baseline, after WSL formation, after treatment, and during discolouration (8, 16, and 24 hours). Data were analysed using Kruskal-Wallis and Mann-Whitney tests. WSL formation increased (L*) in all groups. Only infiltration reduced this effect to baseline. Highest ΔE improvement was obtained by infiltration and micro-abrasion followed by fluoride. This improvement was stable only for infiltration during discolouration. L*, a*, and b* changed significantly during discolouration in all groups except infiltration. Within the same treatment group, discolouration solutions did not differ significantly. In vitro testing cannot replicate the actual mode of colour improvement or stability but can be used for ranking materials and techniques. Infiltration and micro-abrasion treatments were capable of diminishing the whitish appearance of WSLs. Only infiltrated WSLs were stable following discolouration challenge. © The Author 2014. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  9. Development, stability and in vitro delivery profile of new loratadine-loaded nanoparticles

    Directory of Open Access Journals (Sweden)

    Jesus Rafael Rodriguez Amado

    2017-12-01

    Full Text Available Purpose: Loratadine is used as antihistaminic without side effects in nervous systems. This drug is a weak base and it is absorbed from the intestine. The nitrogen of the pyridine ring is protonated in the stomach affecting the oral bioavailability. The aim of this paper was obtaining, characterize and evaluate the release profiles and the stability of a gastroresistant loratadine nanosuspension. Methods: The nanosuspension was prepared by the solvent displacement evaporation method, using three different polymers (Eudragit® L 100 55, Kollicoat® MAE 100P and PEG 4000 and Polysorbate 80. Dynamic Light Scattering was used for evaluating the particle size (PS, zeta potential, and conductivity of the nanosuspension. Loratadine release profiles were evaluated in simulated gastrointestinal fluids. The shelf and accelerated stability were assessed during three months. Results: Nanosuspension particle size was 45.94 ± 0.50 nm, with a low polydispersion index (PdI, 0.300. Kollicoat® MAE 100P produced a hard and flexible coating layer. In simulated intestinal fluids, the 100 percent of loratadine was released in 40 min, while in simulated stomach fluids the release was lesser than 5%. Nanosuspension presented a good physicochemical stability showing a reduction in PS and PdI after three months (43.29 ± 0.16 and 0.250; respectively. Conclusions: A promissory loratadine nanosuspension for loratadine intestinal delivery was obtained, by using a low energy method, which is an advantage for a possible scale up for practical purpose.

  10. In vitro stability of free and glucuronidated cannabinoids in urine following controlled smoked cannabis.

    Science.gov (United States)

    Desrosiers, Nathalie A; Lee, Dayong; Scheidweiler, Karl B; Concheiro-Guisan, Marta; Gorelick, David A; Huestis, Marilyn A

    2014-01-01

    Analyte stability is an important factor in urine test interpretation, yet cannabinoid stability data are limited. A comprehensive study of Δ(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol, cannabinol, THC-glucuronide, and THCCOOH-glucuronide stabilities in authentic urine was completed. Urine samples after ad libitum cannabis smoking were pooled to prepare low and high pools for each study participant; baseline concentrations were measured within 24 h at room temperature (RT), 4 °C and -20 °C. Stability at RT, 4 °C and -20 °C was evaluated by Friedman tests for up to 1 year. THCCOOH, THC-glucuronide, and THCCOOH-glucuronide were quantified in baseline pools. RT THCCOOH baseline concentrations were significantly higher than -20 °C, but not 4 °C baseline concentrations. After 1 week at RT, THCCOOH increased, THCCOOH-glucuronide decreased, but THC-glucuronide was unchanged. In RT low pool, total THCCOOH (THCCOOH + THCCOOH-glucuronide) was significantly lower after 1 week. At 4 °C, THCCOOH was stable 2 weeks, THCCOOH-glucuronide 1 month and THC-glucuronide for at least 6 months. THCCOOH was stable frozen for 1 year, but 6 months high pool results were significantly higher than baseline; THC-glucuronide and THCCOOH-glucuronide were stable for 6 months. Total THCCOOH was stable 6 months at 4 °C, and frozen 6 months (low) and 1 year (high). THC, cannabidiol and cannabinol were never detected in urine; although not detected initially, 11-OH-THC was detected in 2 low and 3 high pools after 1 week at RT. Substantial THCCOOH-glucuronide deconjugation was observed at RT and 4 °C. Analysis should be conducted within 3 months if non-hydrolyzed THCCOOH or THCCOOH-glucuronide quantification is required.

  11. Color Stability of Silicone or Acrylic Denture Liners: An in Vitro Investigation

    OpenAIRE

    Ergun, Gulfem; Nagas, Isil Cekic

    2007-01-01

    Objectives The aim of this study was to compare the color stability of three acrylic based hard liners (Ufi gel hard, Dura-Liner II, Tokuso Rebase) and two silicone based soft liners (Ufi gel permanent, Molloplast B) by using the colorimeter. Methods Sixty disc-shaped samples, with uniform size of 10 mm diameter and 2 mm in thickness were fabricated for each material. Thirty samples were made as control group in distilled water and the remaining thirty samples were weathered in accelerated ag...

  12. In vitro stability of cemented and cementless femoral stems with compaction.

    Science.gov (United States)

    Chareancholvanich, Keerati; Bourgeault, Craig A; Schmidt, Andrew H; Gustilo, Ramon B; Lew, William D

    2002-01-01

    Rigidity of initial fixation is a key factor contributing to the longevity of cemented and cementless femoral components in total hip arthroplasty. The objective of this study was to measure the initial stability of primary cemented and cementless femoral components under load when 15 pairs of cadaveric femurs were prepared by outward compaction of femoral cancellous bone in situ or by conventional extraction broaching. Three-dimensional micromotion was measured at proximal and distal locations on the femoral components using a device with spherical targets and linear variable differential transformers. External loads simulating the stance phases of level walking and stair ascent were applied to the femoral components by a materials test machine. Bone preparation method significantly affected each of the translation and rotation components of micromotion with cemented and cementless fixation. Micromotion with broaching was consistently greater than with compaction. Compared with compaction, the magnitude of the micromotion translation vector for broaching was an average of 3.9 (standard deviation, 3.1) times greater with cemented fixation, and an average of 2.3 (standard deviation, 1.4) times greater with cementless fixation. The results of this study showed the effectiveness of compaction of femoral cancellous bone in improving the initial stability of cemented and cementless femoral components in primary total hip arthroplasty.

  13. [Handling G-protein-coupled receptors: expression, purification and in vitro stabilization].

    Science.gov (United States)

    Banères, Jean-Louis; Mouillac, Bernard

    2012-10-01

    Among the different classes of integral membrane proteins, G protein-coupled receptors (GPCR) constitute the largest family. They are involved in most essential physiological functions and particularly play a key role in cell-to-cell communication and sensory signal transduction. They represent targets for approximately 30% of currently marketed drugs. In order to better understand their functioning, define their tridimensional structure and develop novel selective and efficient therapeutic compounds, it is crucial to purify these proteins for a full characterization. However, this biochemical step is not trivial since GPCR are present in membranes at very low levels and they require detergents to be extracted from their natural lipid environment and be handled as functional proteins. No universal strategy for GPCR production, purification and stabilization is currently available; each single GPCR possesses a unique set of physicochemical characteristics, preference for some detergents upon solubilization and specific conditions for purification. During the last decade, major breakthroughs regarding overexpression, purification and above all GPCR stabilization, thanks to amphipols and nanodiscs, opened very exciting perspectives for structural and dynamic investigations of these membrane proteins. The aim of this chapter is to provide an overview of the different aspects of GPCR handling. © 2012 médecine/sciences – Inserm / SRMS.

  14. Color stability of esthetic restorative materials used in pediatric dentistry: An in vitro study.

    Science.gov (United States)

    Adusumilli, Hanisha; Avula, Jogendra Sai Sankar; Kakarla, Pranitha; Bandi, Sujatha; Mallela, George Manoj Kumar; Vallabhaneni, Krishna

    2016-01-01

    Children consume foods that are colorful which contain food additives that stain not only the tooth structure but also the restorations. As esthetics is of prime concern for both parents and children nowadays, long-term color stability of restorative materials is of utmost importance. To evaluate the color stability of two tooth-colored restorative materials (conventional glass ionomer cement [GIC] and giomer) when immersed in various consumable drinks and food (aerated beverage, ice candy, and health drink) at different immersion periods (low, moderate, and high). A total of 100 specimens were made with each restorative material. Ten were used as a control and remaining (n = 90) as experimental. The experimental specimens were divided into three groups based on media of immersion (n = 30 each) and were further divided into three subgroups based on immersion time (n = 10 each). The color changes (ΔE values) were measured using spectrophotometer. Both the tested materials showed color change; however, conventional GIC showed greater ΔE values when compared to giomer and the samples exposed to aerated beverage resulted in highest color change. It is also noticed that greater the exposure time, higher are the ΔE values. Giomer showed more resistance to color change than conventional GIC with all the tested media and immersion regimes.

  15. Color stability of esthetic restorative materials used in pediatric dentistry: An in vitro study

    Directory of Open Access Journals (Sweden)

    Hanisha Adusumilli

    2016-01-01

    Full Text Available Background: Children consume foods that are colorful which contain food additives that stain not only the tooth structure but also the restorations. As esthetics is of prime concern for both parents and children nowadays, long-term color stability of restorative materials is of utmost importance. Aim: To evaluate the color stability of two tooth-colored restorative materials (conventional glass ionomer cement [GIC] and giomer when immersed in various consumable drinks and food (aerated beverage, ice candy, and health drink at different immersion periods (low, moderate, and high. Materials and Methods: A total of 100 specimens were made with each restorative material. Ten were used as a control and remaining (n = 90 as experimental. The experimental specimens were divided into three groups based on media of immersion (n = 30 each and were further divided into three subgroups based on immersion time (n = 10 each. The color changes (ΔE values were measured using spectrophotometer. Results: Both the tested materials showed color change; however, conventional GIC showed greater ΔE values when compared to giomer and the samples exposed to aerated beverage resulted in highest color change. It is also noticed that greater the exposure time, higher are the ΔE values. Conclusion: Giomer showed more resistance to color change than conventional GIC with all the tested media and immersion regimes.

  16. Pharmacokinetic Analysis and in Vivo Antitumor Efficacy of Taccalonolides AF and AJ.

    Science.gov (United States)

    Risinger, April L; Li, Jing; Du, Lin; Benavides, Raymond; Robles, Andrew J; Cichewicz, Robert H; Kuhn, John G; Mooberry, Susan L

    2017-02-24

    The taccalonolides are microtubule stabilizers that covalently bind tubulin and circumvent clinically relevant forms of resistance to other drugs of this class. Efforts are under way to identify a taccalonolide with optimal properties for clinical development. The structurally similar taccalonolides AF and AJ have comparable microtubule-stabilizing activities in vitro, but taccalonolide AF has excellent in vivo antitumor efficacy when administered systemically, while taccalonolide AJ does not elicit this activity even at maximum tolerated dose. The hypothesis that pharmacokinetic differences underlie the differential efficacies of taccalonolides AF and AJ was tested. The effects of serum on their in vivo potency, metabolism by human liver microsomes and in vivo pharmacokinetic properties were evaluated. Taccalonolides AF and AJ were found to have elimination half-lives of 44 and 8.1 min, respectively. Furthermore, taccalonolide AJ was found to have excellent and highly persistent antitumor efficacy when administered directly to the tumor, suggesting that the lack of antitumor efficacy seen with systemic administration of AJ is likely due to its short half-life in vivo. These results help define why some, but not all, taccalonolides inhibit the growth of tumors at systemically tolerable doses and prompt studies to further improve their pharmacokinetic profile and antitumor efficacy.

  17. In vitro toxicity evaluation of Ti(4+)-stabilized γ-Bi2O3 sillenites.

    Science.gov (United States)

    Popescu, T; Lupu, A R; Feder, M; Tarabasanu-Mihaila, D; Teodorescu, V S; Vlaicu, A M; Diamandescu, L

    2014-12-01

    We report results regarding the in vitro toxicology of γ-Bi2O3 represented by its isomorphous phase Bi12TiO20 (γ-BTO). The γ-BTO microparticles were synthesized by two methods: coprecipitation from a bismuth nitrate-tetrabutyl titanate solution and solid state reaction of Bi2O3 and TiO2 oxides. The structural and morphological characteristics of the obtained materials were determined using X-ray diffraction (XRD), selected area electron diffraction (SAED), transmission (TEM) and scanning (SEM) electron microscopy. The elemental composition was investigated using energy dispersive spectrometry (EDS). The cytotoxicity and oxidative/nitrosative stress (intracellular reactive oxygen species (ROS) and nitric oxide (NO) release) induced by the studied microparticles in HepG2, SH-SY5Y and 3T3-L1 cell cultures were determined using the MTT, DCF-DA (2',7'-dichlorfluorescein-diacetate) and Griess methods respectively. Depending on the cell type and γ-BTO concentration, results showed only weak cytotoxic effects after 24h of γ-BTO exposure and cell proliferation effects for longer treatment times. Only reduced NO release increases (corresponding to high γ-BTO concentrations) were detected in case of SH-SY5Y and 3T3-L1 cells. The intracellular ROS production (higher for HepG2 cells) appeared inversely proportional to the γ-BTO concentration. The obtained results indicated a promising in vitro biocompatibility of γ-BTO and encourage further studies regarding its potential for biomedical applications. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. In vitro digestion of Pickering emulsions stabilized by soft whey protein microgel particles: influence of thermal treatment.

    Science.gov (United States)

    Sarkar, Anwesha; Murray, Brent; Holmes, Melvin; Ettelaie, Rammile; Abdalla, Azad; Yang, Xinyi

    2016-04-21

    Emulsions stabilized by soft whey protein microgel particles have gained research interest due to their combined advantages of biocompatibility and a high degree of resistance to coalescence. We designed Pickering oil-in-water emulsions using whey protein microgels by a facile route of heat-set gel formation followed by mechanical shear and studied the influence of heat treatment on emulsions stabilized by these particles. The aim of this study was to compare the barrier properties of the microgel particles and heat-treated fused microgel particles at the oil-water interface in delaying the digestion of the emulsified lipids using an in vitro digestion model. A combination of transmission electron microscopy and surface coverage measurements revealed an increased coverage of heat-treated microgel particles at the interface. The heat-induced microgel particle aggregation and, therefore, a fused network at the oil-water interface were more beneficial to delay the rate of digestion in the presence of pure lipase and bile salts compared to intact whey protein microgel particles, as shown by the measurements of zeta potential and free fatty acid release, plus theoretical calculations. However, simulated gastric digestion with pepsin impacted significantly on such barrier effects, due to the proteolysis of the particle network at the interface irrespective of the heat treatment, as visualized using sodium dodecyl sulfate polyacryl amide gel electrophoresis measurements.

  19. The rib cage stabilizes the human thoracic spine: An in vitro study using stepwise reduction of rib cage structures.

    Science.gov (United States)

    Liebsch, Christian; Graf, Nicolas; Appelt, Konrad; Wilke, Hans-Joachim

    2017-01-01

    The stabilizing effect of the rib cage on the human thoracic spine is still not sufficiently analyzed. For a better understanding of this effect as well as the calibration and validation of numerical models of the thoracic spine, experimental biomechanics data is required. This study aimed to determine (1) the stabilizing effect of the single rib cage structures on the human thoracic spine as well as the effect of the rib cage on (2) the flexibility of the single motion segments and (3) coupled motion behavior of the thoracic spine. Six human thoracic spine specimens including the entire rib cage were loaded quasi-statically with pure moments of ± 2 Nm in flexion/extension (FE), lateral bending (LB), and axial rotation (AR) using a custom-built spine tester. Motion analysis was performed using an optical motion tracking system during load application to determine range of motion (ROM) and neutral zone (NZ). Specimens were tested (1) in intact condition, (2) after removal of the intercostal muscles, (3) after median sternotomy, after removal of (4) the anterior rib cage up to the rib stumps, (5) the right sixth to eighth rib head, and (6) all rib heads. Significant (p spine rigidity, especially in axial rotation by a factor of more than two, and should therefore be considered in clinical scenarios, in vitro, and in silico.

  20. Analysis of ankle-hindfoot stability in multiple planes: an in vitro study.

    Science.gov (United States)

    Fujii, Tadashi; Kitaoka, Harold B; Luo, Zong-Ping; Kura, Hideji; An, Kai-Nan

    2005-08-01

    It is necessary to have an understanding of ankle and hindfoot motion and stability to accurately diagnosis and treat ankle-hindfoot disorders. We devised an ankle ligament testing apparatus to more critically determine ankle stability in all planes with a constant rotational force applied (inversion, eversion, internal rotation, external rotation) throughout the range of sagittal plane motion in 13 cadaver specimens. Three-dimensional kinematics were determined with a magnetic tracking device. With inversion force applied, calcaneal-tibial inversion was greatest in maximal plantarflexion (mean 22.1 +/- 6.0 degrees) and gradually decreased with dorsiflexion, which indicated that the ankle had the most inversion instability in plantarflexion. With eversion force applied, calcaneal-tibial eversion gradually increased with increasing dorsiflexion to 12.7 +/- 7.4 degrees indicating that the most eversion instability was in dorsiflexion. With internal rotation force applied, calcaneal-tibial internal rotation from plantarflexion to neutral ankle position increased. With external rotation force application, external rotation from neutral to maximal dorsiflexion increased. Ankle laxity was not constant but varied depending on the plantarflexion-dorsiflexion position and the direction of the applied force. The degree of ankle laxity was greater with inversion and internal rotation torque. Variation in laxity between specimens was observed, consistent with previous reports. These data indicate that the ankle is less stable in plantarflexion when inversion and internal rotation forces are applied. This may explain why the lateral ankle ligaments are most prone to injury in this position. The ankle was less stable in dorsiflexion when eversion and external rotation forces were applied. This is consistent with the observation that deltoid ligament injuries occur in the neutral to dorsiflexion position. The study demonstrates the importance of examining patients with suspected

  1. A robust LC-MS/MS method for the determination of pidotimod in different biological matrixes and its application to in vivo and in vitro pharmacokinetic studies.

    Science.gov (United States)

    Wang, Guangji; Wang, Qian; Rao, Tai; Shen, Boyu; Kang, Dian; Shao, Yuhao; Xiao, Jingcheng; Chen, Huimin; Liang, Yan

    2016-06-15

    Pidotimod, (R)-3-[(S)-(5-oxo-2-pyrrolidinyl) carbonyl]-thiazolidine-4-carboxylic acid, was frequently used to treat children with recurrent respiratory infections. Preclinical pharmacokinetics of pidotimod was still rarely reported to date. Herein, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine pidotimod in rat plasma, tissue homogenate and Caco-2 cells. In this process, phenacetin was chosen as the internal standard due to its similarity in chromatographic and mass spectrographic characteristics with pidotimod. The plasma calibration curves were established within the concentration range of 0.01-10.00μg/mL, and similar linear curves were built using tissue homogenate and Caco-2 cells. The calibration curves for all biological samples showed good linearity (r>0.99) over the concentration ranges tested. The intra- and inter-day precision (RSD, %) values were below 15% and accuracy (RE, %) was ranged from -15% to 15% at all quality control levels. For plasma, tissue homogenate and Caco-2 cells, no obvious matrix effect was found, and the average recoveries were all above 75%. Thus, the method demonstrated excellent accuracy, precision and robustness for high throughput applications, and was then successfully applied to the studies of absorption in rat plasma, distribution in rat tissues and intracellular uptake characteristics in Caco-2 cells for pidotimod. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Species Extrapolation of Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Models to Investigate the Developmental Toxicology of Ethanol Using In vitro to In vivo (IVIVE) Methods

    Science.gov (United States)

    To provide useful alternatives to in vivo animal studies, in vitro assays for dose-response assessments of xenobiotic chemicals must use concentrations in media and target tissues that are within biologically-plausible limits. Determining these concentrations is a complex matter,...

  3. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways, OpenTox USA 2015 Poster

    Science.gov (United States)

    Adverse outcome pathways (AOP) link known population outcomes to a molecular initiating event (MIE) that can be quantified using high-throughput in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires consideration of exposure and absorption,...

  4. In Vitro Evaluation of Dimensional Stability of Alginate Impressions after Disinfection by Spray and Immersion Methods

    Directory of Open Access Journals (Sweden)

    Fahimeh Hamedi Rad

    2010-12-01

    Full Text Available Background and aims. The most common method for alginate impression disinfection is spraying it with disinfecting agents, but some studies have shown that these impressions can be immersed, too. The aim of this study was to evaluate the dimensional stability of alginate impressions following disinfecting by spray and immersion methods. Materials and methods. Four common disinfecting agents (Sodium Hypochlorite, Micro 10, Glutaraldehyde and Deconex were selected and the impressions (n=108 were divided into four groups (n=24 and eight subgroups (n=12 for disinfecting by any of the four above-mentioned agents by spray or immersion methods. The control group (n=12 was not disinfected. Then the impressions were poured by type III Dental Stone Plaster in a standard method. The results were analyzed by descriptive methods (mean and standard deviation, t-test, two-way analysis of variance (ANOVA and Duncan test, using SPSS 14.0 software for windows. Results. The mean changes of length and height were significant between the various groups and disinfecting methods. Regarding the length, the greatest and the least amounts were related to Deconex and Micro 10 in the immersion method, respectively. Regarding height, the greatest and the least amounts were related to Glutaraldehyde and Deconex in the immersion method, respectively. Conclusion. Disinfecting alginate impressions by Sodium Hypochlorite, Deconex and Glutaraldehyde by immersion method is not recommended and it is better to disinfect alginate impressions by spraying of Micro 10, Sodium Hypochlorite, Glutaraldehyde and immersion in Micro 10.

  5. Color stability of silicone or acrylic denture liners: an in vitro investigation.

    Science.gov (United States)

    Ergun, Gulfem; Nagas, Isil Cekic

    2007-07-01

    The aim of this study was to compare the color stability of three acrylic based hard liners (Ufi gel hard, Dura-Liner II, Tokuso Rebase) and two silicone based soft liners (Ufi gel permanent, Molloplast B) by using the colorimeter. Sixty disc-shaped samples, with uniform size of 10 mm diameter and 2 mm in thickness were fabricated for each material. Thirty samples were made as control group in distilled water and the remaining thirty samples were weathered in accelerated aging chamber. Color measurements were made before and after distilled water and aging. Data were statistically analyzed using nonparametric Kruskal-Wallis and Mann-Whitney U tests. Data showed that there are significant differences among materials in both after distilled water and aging treatments (PDura Liner II after aging (DeltaE*=16.30) and the least discolored material was Ufi gel permanent after distilled water (DeltaE*=0.41). Based on the results of this study, silicone based liner materials are considered to be more color stable than acrylic based liner materials.

  6. Direct radiolabeling of monoclonal antibodies with rhenium-188 for radioimmunotherapy of solid tumors -- a review of radiolabeling characteristics, quality control and in vitro stability studies

    Energy Technology Data Exchange (ETDEWEB)

    Iznaga-Escobar, Normando E-mail: normando@ict.cim.sld.cu

    2001-03-01

    {sup 188}Re is one of the radioisotopes expected to emerge as useful for therapy. Development of new radiopharmaceuticals based on {sup 188}Re depends on the radiolabeling methods used, which would give stable complexes having predefined radiochemical properties and in vitro and in vivo stability. This paper has attempted to provide a perspective of {sup 188}Re-labeled monoclonal antibodies, their radiolabeling characteristics, methods for quality control of radioimmunoconjugates and in vitro stability for radioimmunotherapy of solid tumors. The direct method of {sup 188}Re radiolabeling of antibodies by reductive attachment of {sup 188}Re in which free sulfhydryl groups have been generated by reduction of the intramolecular S-S disulfide bonds has been shown to be a promising approach in particular. Moreover, excellent methods have been developed to test the radionuclide, radiochemical purity and stability of {sup 188}Re-radioimmunoconjugates using high performance liquid chromatography (HPLC) and paper chromatography.

  7. Direct radiolabeling of monoclonal antibodies with rhenium-188 for radioimmunotherapy of solid tumors--a review of radiolabeling characteristics, quality control and in vitro stability studies.

    Science.gov (United States)

    Iznaga-Escobar, N

    2001-03-01

    188Re is one of the radioisotopes expected to emerge as useful for therapy. Development of new radiopharmaceuticals based on 188Re depends on the radiolabeling methods used, which would give stable complexes having predefined radiochemical properties and in vitro and in vivo stability. This paper has attempted to provide a perspective of 188Re-labeled monoclonal antibodies, their radiolabeling characteristics, methods for quality control of radioimmunoconjugates and in vitro stability for radioimmunotherapy of solid tumors. The direct method of 188Re radiolabeling of antibodies by reductive attachment of 188Re in which free sulfhydryl groups have been generated by reduction of the intramolecular S-S disulfide bonds has been shown to be a promising approach in particular. Moreover, excellent methods have been developed to test the radionuclide, radiochemical purity and stability of 188Re-radioimmunoconjugates using high performance liquid chromatography (HPLC) and paper chromatography.

  8. Dose optimization of voriconazole/anidulafungin combination against Aspergillus fumigatus using an in vitro pharmacokinetic/pharmacodynamic model and response surface analysis: clinical implications for azole-resistant aspergillosis.

    Science.gov (United States)

    Siopi, Maria; Siafakas, Nikolaos; Vourli, Sophia; Mouton, Johan W; Zerva, Loukia; Meletiadis, Joseph

    2016-11-01

    Combination therapy of voriconazole with an echinocandin is often employed in order to increase the efficacy of voriconazole monotherapy. Four clinical Aspergillus fumigatus isolates with different in vitro susceptibilities to voriconazole (MIC 0.125-2 mg/L) and anidulafungin (MEC 0.008-0.016 mg/L) were tested in an in vitro pharmacokinetic/pharmacodynamic model simulating human serum concentrations of standard dosages of voriconazole and anidulafungin. Fungal growth was assessed using galactomannan production and quantitative PCR. Drug concentrations were determined with bioassays. Pharmacodynamic interactions were assessed using Bliss independence analysis (BI) and Loewe additivity-based canonical mixture response-surface non-linear regression analysis (LA). Probability of target attainment (PTA) was estimated with Monte Carlo analysis for different doses of anidulafungin (25, 50 and 100 mg) and azole resistance rates (5%-25%). Synergy [BI 51% (8%-80%), LA 0.63 (0.38-0.79)] was found at low anidulafungin (fC max /MEC voriconazole (fAUC/MIC voriconazole MIC distributions with high (>10%) resistance rates. PTAs for isolates with voriconazole MICs of 1, 2 and 4 mg/L was 78%, 12% and 0% with voriconazole monotherapy and 96%-100%, 68%-82% and 9%-20% with combination therapy, respectively. Optimal activity was associated with a voriconazole tC min /MIC ratio of 1.5 for monotherapy and 0.75 for combination therapy. The present study indicated that the combination of voriconazole with low-dose anidulafungin may increase the efficacy and reduce the cost and potential toxicity of antifungal therapy, particularly against azole-resistant A. fumigatus isolates and in patients with subtherapeutic serum levels. This hypothesis warrants further in vivo verification. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  9. Development of a discriminative biphasic in vitro dissolution test and correlation with in vivo pharmacokinetic studies for differently formulated racecadotril granules.

    Science.gov (United States)

    Deng, Jia; Staufenbiel, Sven; Hao, Shilei; Wang, Bochu; Dashevskiy, Andriy; Bodmeier, Roland

    2017-06-10

    The purpose of this study was to discriminate the release behavior from three differently formulated racecadotril (BCS II) granules and to establish an in vitro-in vivo correlation. Three granule formulations of the lipophilic drug were prepared with equivalent composition but prepared with different manufacturing processes (dry granulation, wet granulation with or without binder). In vitro release of the three granules was investigated using a biphasic dissolution system (phosphate buffer pH6.8 and octanol) and compared to the conventional single phase USP II dissolution test performed under sink and non-sink conditions. In vivo studies with each granule formulation were performed in rats. Interestingly, the granule formulations exhibited pronouncedly different behavior in the different dissolution systems depending on different wetting and dissolution conditions. Single phase USP II dissolution tests lacked discrimination. In contrast, remarkable discrimination between the granule formulations was observed in the octanol phase of biphasic dissolution system with a rank order of release from granules prepared by wet granulation with binder>wet granulation without binder>dry granulation. This release order correlated well with the wettability of these granules. An excellent correlation was also established between in vitro release in the octanol phase of the biphasic test and in vivo data (R(2)=0.999). Compared to conventional dissolution methods, the biphasic method provides great potential to discriminate between only minor formulation and process changes within the same dosage form for poorly soluble drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. In vitro ageing and wear behaviour of ceria stabilized zirconia toughened alumina (CSZ-TA) bio-ceramic

    Energy Technology Data Exchange (ETDEWEB)

    Pandey, Ajoy Kumar; Jena, Usha Rani; Biswas, Koushik, E-mail: k_biswas@metal.iitkgp.ernet.in

    2014-08-01

    15–25 wt% zirconia (stabilized with 14 mol% ceria) toughened alumina was synthesized by co-precipitation technique. The synthesized powders were calcined at different temperatures, compacted and conventionally sintered following two steps sintering process. Uniformly distributed submicron sized grains with Vickers' hardness value up to 1730±6HV20 were achieved after conventional sintering. In order to assess the ageing behaviour, samples were hydrothermally treated (in vitro) at 134 °C under 0.2 MPa in presence of simulated body fluid. Rietveld refinement of the X-ray diffraction patterns was carried out to estimate the phase content after calcination, sintering and after different stages of hydrothermal treatment. No significant phase change (only ∼3%) was observed even after 100 h of hydrothermal treatment. Very few bulged grains (resulted from the tetragonal to monoclinic phase transformation) on the surface and slight decrease in hardness value were observed after hydrothermal treatment. Fretting wear in dry condition was carried out taking ball on flat geometry for 10{sup 5} cycles at different loads before and after hydrothermal treatment. Wear volumes were directly estimated from the surface scanning of the wear scar using profilometer. Transition of wear and its related mechanisms at different loads along with the effect of ageing on wear were discussed. - Highlights: • Ceria stabilized zirconia toughened alumina was developed. • Ageing behaviour of developed materials was studied through hydrothermal treatment. • Phase transformation during ageing was characterized through Rietveld refinement. • Only 3% phase transformation was observed even after 100 h hydrothermal treatment. • Fretting wear volume before band after hydrothermal treatment were estimated.

  11. In vitro permeability and metabolic stability of bile pigments and the effects of hydrophilic and lipophilic modification of biliverdin.

    Science.gov (United States)

    Bulmer, Andrew C; Blanchfield, Joanne T; Coombes, Jeff S; Toth, Istvan

    2008-04-01

    Bile pigments, including bilirubin and biliverdin are tetrapyrrolic, dicarboxylic acids capable of forming conjugates at their propionic acid groups via ester or amide bonds. They possess substantial antioxidant and anti-mutagenic activities and therefore their intestinal absorption might influence the development of cardiovascular disease and cancer. The aim of this study was to investigate whether altering the physico-chemical properties of bile pigments would improve their permeability in an in vitro assay of absorption. Native and synthetically modified bile pigments were tested for gastrointestinal permeability and metabolic stability using the Caco-2 cell line. In addition, a gross measure of their toxic effects was tested in a red blood cell co-incubation assay. The apparent permeability of unconjugated bilirubin (1), bilirubin ditaurate (2) and biliverdin (3) through Caco-2 cell monolayers was determined to be 10.4+/-1.2x10(-7), 35.2+/-3.4x10(-7) and 37.0+/-1.6x10(-7) cm/s (mean+/-SD), respectively, while biliverdin diglucosamine (4), and biliverdin dioctylamine (5) were impermeable. Unconjugated bilirubin, biliverdin, bilirubin ditaurate and biliverdin diglucosamine did not decompose when incubated in Caco-2 cell homogenates, whereas biliverdin dioctylamine decomposed over time. Only unconjugated bilirubin showed toxicity towards red blood cells (> or = 1000 microM), an effect that was abolished by the addition of 40 g/L serum albumin. The data presented here suggest that bile pigments are absorbed across the Caco-2 cell monolayer and that conjugation of biliverdin to hydrophilic or lipophilic moieties decreases their absorption and can reduce their metabolic stability. In summary, exogenous bilirubin and biliverdin supplements could be absorbed across the intestinal epithelium in vivo and potentially increase circulating concentrations of these antioxidant compounds.

  12. Clinical pharmacokinetic profile of modafinil.

    Science.gov (United States)

    Robertson, Philmore; Hellriegel, Edward T

    2003-01-01

    Modafinil is a unique wake-promoting agent for oral administration. Its pharmacological properties are distinct from those of other CNS agents, and it selectively targets neuronal pathways in the sleep/wake centres of the brain. After single or multiple oral doses, modafinil is readily absorbed, reaching maximum plasma concentrations at 2-4 hours after administration and pharmacokinetic steady state within 2-4 days. Its pharmacokinetics are dose-independent between 200 and 600 mg/day. The elimination half-life is approximately 12-15 hours, which is largely reflective of the pharmacokinetics of the longer-lived l-enantiomer. Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine. Less than 10% of the dose is excreted as unchanged drug. Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways. In patients who are renally or hepatically compromised, the elimination processes can be slowed, and in a similar manner (although to a lesser extent), elimination in the elderly may be reduced due to normal effects of aging. Because modafinil is administered concomitantly with other medications, the potential for metabolic drug-drug interactions has been examined both in vitro and in vivo. In vitro, modafinil was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small, but concentration-dependent, induction of CYP1A2, CYP2B6 and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes. Clinical studies have been conducted to examine the potential for interactions with methylphenidate, dexamfetamine, warfarin, ethinylestradiol and triazolam. The only substantive interactions observed were with ethinylestradiol and triazolam, apparently through induction of CYP3A4, primarily in the gastrointestinal system. Overall, the results of the interaction studies suggest that

  13. Length of encapsidated cargo impacts stability and structure of in vitro assembled alphavirus core-like particles

    Science.gov (United States)

    Rayaprolu, Vamseedhar; Moore, Alan; Che-Yen Wang, Joseph; Goh, Boon Chong; Perilla, Juan R.; Zlotnick, Adam; Mukhopadhyay, Suchetana

    2017-12-01

    In vitro assembly of alphavirus nucleocapsid cores, called core-like particles (CLPs), requires a polyanionic cargo. There are no sequence or structure requirements to encapsidate single-stranded nucleic acid cargo. In this work, we wanted to determine how the length of the cargo impacts the stability and structure of the assembled CLPs. We hypothesized that cargo neutralizes the basic region of the alphavirus capsid protein and if the cargo is long enough, it will also act to scaffold the CP monomers together. Experimentally we found that CLPs encapsidating short 27mer oligonucleotides were less stable than CLPs encapsidating 48mer or 90mer oligonucleotides under different chemical and thermal conditions. Furthermore, cryo-EM studies showed there were structural differences between CLPs assembled with 27mer and 48mer cargo. To mimic the role of the cargo in CLP assembly we made a mutant (4D) where we substituted a cluster of four Lys residues in the CP with four Asp residues. We found that these few amino acid substitutions were enough to initiate CLP assembly in the absence of cargo. The cargo-free 4D CLPs show higher resistance to ionic strength and increased temperature compared to wild-type cargo containing CLPs suggesting their CLP assembly mechanism might also be different.

  14. Formation and stability of oil-in-water nanoemulsions containing rice bran oil: in vitro and in vivo assessments

    Directory of Open Access Journals (Sweden)

    Rocha-Filho Pedro A

    2011-09-01

    Full Text Available Abstract Background Nanoemulsions have practical application in a multitude of commercial areas, such as the chemical, pharmaceutical and cosmetic industries. Cosmetic industries use rice bran oil in sunscreen formulations, anti ageing products and in treatments for skin diseases. The aim of this study was to create rice bran oil nanoemulsions using low energy emulsification methods and to evaluate their physical stability, irritation potential and moisturising activity on volunteers with normal and diseased skin types. Results The nanoemulsion developed by this phase diagram method was composed of 10% rice bran oil, 10% surfactants sorbitan oleate/PEG-30 castor oil, 0.05% antioxidant and 0.50% preservatives formulated in distilled water. The nanoemulsion was stable over the time course of this study. In vitro assays showed that this formulation has a low irritation potential, and when applied to human skin during in vivo studies, the nanoemulsion improved the skin's moisture and maintained normal skin pH values. Conclusion The results of irritation potential studies and in vivo assessments indicate that this nanoemulsion has potential to be a useful tool to treat skin diseases, such as atopic dermatitis and psoriasis.

  15. Development, stability and in vitro permeation studies of gels containing mometasone furoate for the treatment of dermatitis of the scalp

    Directory of Open Access Journals (Sweden)

    Ana Cristina Gomes Barros Salgado

    2010-03-01

    Full Text Available Dermatological inflammatory diseases such as atopic dermatitis, psoriasis and seborrhoeic dermatitis often affect the scalp and the eyebrows. Although there are many dosage forms available, these are particularly critical anatomic regions for application of topical formulations because of the presence of hair. Lotions are therefore the recommended type of drug delivery system for these areas. The presence of hair may limit the application and thus the acceptability of the formulation and its compliance. Because of its low apparent viscosity, lotion application is unpleasant. Gels, given their consistency and adhesiveness, are a suitable alternative to lotions in this situation. The aim of this study was to formulate a stable gel containing mometasone furoate, which is an anti-inflammatory and anti-pruritic corticosteroid, in order to improve topical treatment of scalp dermatitis. In this study, pharmaceutical development, physical-chemical characterization, stability and in vitro permeation studies were performed. In terms of the pH, viscosity, assay and macroscopic and microbiological properties, the gel was stable over the period of study. The in vitro permeation studies allowed the characterization of the mometasone furoate permeation profile for the gel through different membranes. Mometasone furoate presented a slow permeation through the skin. This gel appears safe for topical application.Afecções dermatológicas do tipo inflamatório como a dermatite atópica, psoríase e dermatite seborreica, afetam freqüentemente o couro cabeludo e sobrancelhas. Apesar de existirem várias formas farmacêuticas para o seu tratamento, apenas as loções são indicadas para estas zonas, mas devido à baixa viscosidade, a aplicação de loções torna-se desagradável. Os geles, pela maior consistência e capacidade de adesão, apresentam-se como alternativa nesta situação. Neste trabalho procedeu-se ao desenvolvimento galênico de um gel com furoato

  16. Intra-articular administration of lidocaine plus adrenaline in dogs: Pharmacokinetic profile and evaluation of toxicity in vivo and in vitro.

    Science.gov (United States)

    Di Salvo, A; Chiaradia, E; della Rocca, G; Mancini, F; Galarini, R; Giusepponi, D; De Monte, V; Cagnardi, P; Marenzoni, M L; Bufalari, A

    2016-02-01

    The aim of this study was to evaluate the safety of intra-articular (IA) lidocaine plus adrenaline for improving peri-operative analgesia in anaesthetized dogs undergoing arthroscopy of the elbow. A solution of lidocaine (L) 1.98% plus adrenaline 1:100.000 was administered via the IA route and its safety evaluated in terms of cardio-, neuro-, and chondro-toxicity. No bradycardia or hypotension was recorded from induction to the last observational time point. Signs of toxicity of the nervous system could have been masked by the general anaesthesia but lidocaine concentrations detected in the blood were lower than those thought to be capable of producing toxicity. The assessment of in vitro chondrotoxicity showed a dose- and time-dependent effect of lidocaine on the viability of articular cells. Adrenaline appeared to reduce the chondrotoxicity of 1% lidocaine, following an exposure of up to 30 min. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. In vitro effects of proteases in human pancreatic juice on stability of liquid and carrier-bound fibrin sealants.

    Science.gov (United States)

    Adelmeijer, J; Porte, R J; Lisman, T

    2013-10-01

    Fibrin sealants are used in pancreatic surgery to prevent leakage of pancreatic fluid and reduce associated complications. The efficacy of this approach is unclear. Fibrin clots were generated in vitro from two commercially available liquid fibrin sealants (Tissucol Duo® and Evicel®) and the carrier-bound fibrin sealant Tachosil®, and exposed to normal saline or human pancreatic fluid. Stability of the sealants was assessed by release of the fibrin and collagen degradation products, D-dimer and hydroxyproline. The effect of protease inhibitors on sealant breakdown was assessed. Clots generated from liquid fibrin sealants degraded rapidly in pancreatic fluid, but not in normal saline. D-dimer release from fibrin clots by pancreatic fluid was approximately 1700 µg/ml after 24 h and less than 20 µg/ml by saline. Pancreatic fluid, but not normal saline, degraded both the fibrin and collagen component of Tachosil®. After 6 h, mean(s.e.m.) D-dimer levels in pancreatic fluid exposed to Tachosil® were 850(183) ng/ml, compared with 60(6) ng/ml in normal saline. The mean(s.e.m.) hydroxyproline concentration in pancreatic fluid was 497(17) µg/ml after a 24-h exposure to Tachosil®, compared with 26(12) µg/ml in normal saline. Protease inhibitors significantly inhibited breakdown of liquid sealants (D-dimer levels less than 50 µg/ml after 24 h) and Tachosil® (D-dimer release 179(12) ng/ml at 6 h; hydroxyproline release 181(29) µg/ml at 24 h). Proteases in pancreatic juice effectively degrade both liquid and carrier-bound fibrin sealants in vitro. The use of these products in pancreatic surgery with the aim of preventing leakage of pancreatic fluid is not supported by this experimental study. © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd.

  18. In vitro and in vivo investigation on genomic stability of Salmonella enterica Typhimurium DT41 obtained from broiler breeders in Denmark

    DEFF Research Database (Denmark)

    Barua, Himel; Lindblom, Ina Lucilia; Bisgaard, Magne

    2013-01-01

    Salmonella enterica serovar Typhimurium phage type DT41 has previously been identified from salmonella-positive broiler breeder flocks in Denmark and isolates obtained from different flocks have demonstrated major diversity by multiple-locus variable-number tandem-repeats analysis (MLVA) typing...... and human origin, respectively. The in vitro experiment demonstrated that DT41 survived more than 6 months in feed-pellets at 20 °C whereas the survival in dust was less than 4 weeks. Infection pattern and excretion varied for the poultry and human strain and birds of different age groups as revealed...... by the in vivo experiment. Genetic stability of cultures obtained from the in vitro and in vivo survival/passage was investigated by plasmid profiling, pulsed-field gel electrophoresis (PFGE) and MLVA. The results of plasmid profiling and PFGE demonstrated genomic stability of all but one strain kept in dust...

  19. Effect of alcoholic and non-alcoholic beverages on color stability and surface roughness of resin composites: An in vitro study

    OpenAIRE

    Kshitij Bansal; Shashi Rashmi Acharya; Vidya Saraswathi

    2012-01-01

    Background: Consumption of certain beverages may affect the esthetic and physical properties of the resin composite, thereby undermining the quality of restorations. Aim: To analyze the effect of three beverages (Whiskey, Coca-Cola, and Nimbooz) on color stability and surface roughness of two different types of resin composites at various time intervals in vitro. Materials and Methods: A methacrylate-based nanofilled composite and a silorane-based microhybrid composite were used. Each...

  20. Immunochemical faecal occult blood tests have superior stability and analytical performance characteristics over guaiac-based tests in a controlled in vitro study.

    LENUS (Irish Health Repository)

    Lee, Chun Seng

    2011-06-01

    The aims of this study were (1) to determine the measurement accuracy of a widely used guaiac faecal occult blood test (gFOBT) compared with an immunochemical faecal occult blood test (iFOBT) during in vitro studies, including their analytical stability over time at ambient temperature and at 4°C; and (2) to compare analytical imprecision and other characteristics between two commercially available iFOBT methods.

  1. Interspecies Variation of In Vitro Stability and Metabolic Diversity of YZG-331, a Promising Sedative-Hypnotic Compound

    Directory of Open Access Journals (Sweden)

    Zhihao Liu

    2017-08-01

    Full Text Available YZG-331, a synthetic adenosine derivative, express the sedative and hypnotic effects via binding to the adenosine receptor. The current study was taken to investigate the metabolic pathway of YZG-331 as well as species-specific differences in vitro. YZG-331 was reduced by 14, 11, 6, 46, and 11% within 120 min incubation in human, monkey, dog, rat, and mouse liver microsomes (LMs, respectively. However, YZG-331 was stable in human, monkey, dog, rat, and mouse liver cytoplasm. In addition, YZG-331 was unstable in rat or mouse gut microbiota with more than 50% of prototype drug degraded within 120 min incubation. Interestingly, the systemic exposure of M2 and M3 in rats and mice treated with antibiotics were significantly decreased in the pseudo germ-free group. YZG-331 could be metabolized in rat and human liver under the catalysis of CYP enzymes, and the metabolism showed species variation. In addition, 3 phase I metabolites were identified via hydroxyl (M1, hydrolysis (M2, or hydrolysis/ hydroxyl (M3 pathway. Flavin-containing monooxygenase 1 (FMO1 and FMO3 participated in the conversion of YZG-331 in rat LMs. Nevertheless, YZG-331 expressed stability with recombinant human FMOs, which further confirmed the species variation in the metabolism. Overall, these studies suggested that YZG-331 is not stable in LMs and gut microbiota. CYP450 enzymes and FMOs mediated the metabolism of YZG-331, and the metabolic pathway showed species difference. Special attention must be paid when extrapolating data from other species to humans.

  2. Methylglyoxal modification enhances the stability of hemoglobin and lowers its iron-mediated oxidation reactions: An in vitro study.

    Science.gov (United States)

    Banerjee, Sauradipta; Chakraborti, Abhay Sankar

    2017-02-01

    Post-translational modification of proteins by Maillard reaction, known as glycation, is thought to be the root cause of different complications, particularly in diabetes mellitus and age-related disorders. Methylglyoxal (MG), a reactive α-oxoaldehyde, increases in diabetic condition and reacts with proteins to form advanced glycation end products (AGEs) following Maillard-like reaction. In the present study, we have investigated the in vitro effect of methylglyoxal (200, 300μm) on the heme protein hemoglobin (HbA0) (100μm) after incubation for one week at 25°C. Compared to HbA0, MG-treated HbA0 exhibited decreased absorbance around 280nm, reduced intrinsic fluorescence and lower surface hydrophobicity. MG treatment was not found to significantly affect the secondary structure of HbA0. The stability of MG-treated HbA0 was found to be higher compared to HbA0. Moreover, H2O2-mediated iron release and subsequent iron-mediated oxidation (Fenton) reactions were found to be lower in presence of MG-treated HbA0 compared to HbA0. As shown by mass spectrometric studies, MG modified Arg-92α, Arg-104β, Arg-31α and Arg-40β of HbA0 to hydroimidazolone adducts. The modifications thus appear to be associated with the observed structural alterations of the heme protein. Considering the increased level of MG in diabetes mellitus as well as its high reactivity, AGEs might be associated with structural and functional modifications of the protein including physiological significance. Published by Elsevier B.V.

  3. In vitro propagation and assessment of genetic stability of acclimated plantlets of Cornus alba L. using RAPD and ISSR markers.

    Science.gov (United States)

    Ilczuk, Agnieszka; Jacygrad, Ewelina

    2016-01-01

    Cornus alba L. (white dogwood) is an important ornamental shrub having a wide range of applications such as reforestation programs and soil retention systems. The vegetative propagation of dogwood by cuttings may be slow, difficult, and cultivar dependent; therefore, an improved micropropagation method was developed. Nodal stem segments of C. alba cultivars 'Aurea' and 'Elegantissima' were cultured on media enriched with six different sources of macronutrients. Media were supplemented with either N6-benzyladenine (BA) or thidiazuron (TDZ) in combination with 1-naphthaleneacetic acid (NAA). Regardless of the cultivar, the best shoot proliferation was observed on Lloyd and McCown medium (woody plant medium (WPM)) at pH 6.2, containing 1.0 mg L-1 BA, 0.1 mg L-1 NAA, and 20-30 g L-1 sucrose. Rooting of regenerated shoots was achieved by an in vitro method when different concentrations of NAA or indole-3-butyric acid (IBA) were tested. Microcuttings were rooted for 8 wk on medium enriched with 0.25 mg L-1 NAA and potted into P9 containers in the greenhouse. The final survival rate of the plants after 20 wk was 80% for 'Aurea' and 90% for 'Elegantissima'. Genetic stability of the micropropagated plants was confirmed by using two DNA-based molecular marker techniques. A total of 30 random amplified polymorphic DNA (RAPD) and 20 inter-simple sequence repeat (ISSR) primers resulted in 197-199 and 184-187 distinct and reproducible band classes, respectively, in 'Aurea' and 'Elegantissima' plantlets. All of the RAPD and ISSR profiles were monomorphic and comparable with the mother plant.

  4. Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs.

    Science.gov (United States)

    Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kloft, Charlotte

    2015-07-01

    During the last decades, the importance of modeling and simulation in clinical drug development, with the goal to qualitatively and quantitatively assess and understand mechanisms of pharmacokinetic processes, has strongly increased. However, this increase could not equally be observed for orally inhaled drugs. The objectives of this review are to understand the reasons for this gap and to demonstrate the opportunities that mathematical modeling of pharmacokinetics of orally inhaled drugs offers. To achieve these objectives, this review (i) discusses pulmonary physiological processes and their impact on the pharmacokinetics after drug inhalation, (ii) provides a comprehensive overview of published pharmacokinetic models, (iii) categorizes these models into physiologically based pharmacokinetic (PBPK) and (clinical data-derived) empirical models, (iv) explores both their (mechanistic) plausibility, and (v) addresses critical aspects of different pharmacometric approaches pertinent for drug inhalation. In summary, pulmonary deposition, dissolution, and absorption are highly complex processes and may represent the major challenge for modeling and simulation of PK after oral drug inhalation. Challenges in relating systemic pharmacokinetics with pulmonary efficacy may be another factor contributing to the limited number of existing pharmacokinetic models for orally inhaled drugs. Investigations comprising in vitro experiments, clinical studies, and more sophisticated mathematical approaches are considered to be necessary for elucidating these highly complex pulmonary processes. With this additional knowledge, the PBPK approach might gain additional attractiveness. Currently, (semi-)mechanistic modeling offers an alternative to generate and investigate hypotheses and to more mechanistically understand the pulmonary and systemic pharmacokinetics after oral drug inhalation including the impact of pulmonary diseases.

  5. Iron availability and complex stability of iron hydroxyethyl starch and iron dextran a comparative in vitro study with liver cells and macrophages.

    Science.gov (United States)

    Ternes, Nina; Scheiber-Mojdehkar, Barbara; Landgraf, Grit; Goldenberg, Hans; Sturm, Brigitte

    2007-10-01

    Intravenous iron (IVI) therapy is required in patients with end-stage renal disease (ESRD) under chronic haemodialysis (HD). In this in vitro study we investigated the availability and stability of iron hydroxyethyl starch (iron-Hes) compounds in THP-1 cells (macrophage phenotype) and liver cells (HepG2 cells) and compared it with the well-known iron dextran. The uptake and release of these iron formulations by THP-1 cells (macrophage phenotype) and HepG2 cells were investigated with atomic absorption spectrometry (AAS). Ferritin was measured by ELISA. HepG2 cells were used to investigate effects of IVI on the intracellular labile iron pool (LIP), which was measured by using the fluorescent calcein assay. The amount of redox-active iron within the iron formulations was assayed using dichlorofluorescein as fluorescent probe. All iron preparations were taken up, stored in ferritin and released again by macrophages and HepG2-cells. This study shows that the availability and stability of iron-HES formulations in vitro are comparable with the well-known iron dextran compounds. Our results indicate that these new iron formulations have a good stability and availability in vitro and are comparable with the well-known iron dextran complexes.

  6. Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability

    DEFF Research Database (Denmark)

    Petersen, Asger Bjørn; Andersen, Nikolaj Sten; Konotop, Gleb

    2017-01-01

    potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve...... the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation...... studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low μM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral...

  7. In-vitro release pharmacokinetics of amikacin, teicoplanin and polyhexanide in a platelet rich fibrin-layer (PRF-a laboratory evaluation of a modern, autologous wound treatment.

    Directory of Open Access Journals (Sweden)

    Daniela Knafl

    Full Text Available Platelet rich fibrin (PRF is an autologous fibrin glue, produced from patients' blood, which, besides intraoperative use, has applications in the treatment of infected wounds. The combination with antimicrobial agents results in a prolonged antibacterial effect allowing for wound dressing change intervals of seven days even in infected wounds. The aim of this study was to evaluate release kinetics of amikacin, teicoplanin or polyhexanide from a PRF-layer.PRF mixed with teicoplanin, amikacin or polyhexanide was sprayed on a silicon gauze patch and put on a colombia agar with bacteria with known minimal inhibitory concentration (MIC and incubated for 24 hours and afterwards transferred to another agar with the same bacterial strain. Inhibition zones were measured every 24 hours. This was repeated on 7 consecutive days. Antibiotic concentrations were calculated by interpolation.More than 1000 mg/L teicoplanin were released within the first 24 hours and 28.22 mg/L after 168 hours. Amikacin release was above 10,000 mg/L within the first 24 hours and still 120.8 mg/L after 120 hours. A release of polyhexanide could be verified for the first 24 hours only. Consequently teicoplanin and amikacin released from PRF showed antimicrobial in-vitro effects for almost a week, whereas an antimicrobial effect of polyhexanide could only be verified for the first 24 hours.Our Results show that a weekly dressing regimen may be justified in wounds treated with PRF plus amikacin or teicoplanin, since bacteria will be eradicated over a considerable period of time after a single application of PRF.

  8. In-vitro release pharmacokinetics of amikacin, teicoplanin and polyhexanide in a platelet rich fibrin-layer (PRF)-a laboratory evaluation of a modern, autologous wound treatment.

    Science.gov (United States)

    Knafl, Daniela; Thalhammer, Florian; Vossen, Matthias G

    2017-01-01

    Platelet rich fibrin (PRF) is an autologous fibrin glue, produced from patients' blood, which, besides intraoperative use, has applications in the treatment of infected wounds. The combination with antimicrobial agents results in a prolonged antibacterial effect allowing for wound dressing change intervals of seven days even in infected wounds. The aim of this study was to evaluate release kinetics of amikacin, teicoplanin or polyhexanide from a PRF-layer. PRF mixed with teicoplanin, amikacin or polyhexanide was sprayed on a silicon gauze patch and put on a colombia agar with bacteria with known minimal inhibitory concentration (MIC) and incubated for 24 hours and afterwards transferred to another agar with the same bacterial strain. Inhibition zones were measured every 24 hours. This was repeated on 7 consecutive days. Antibiotic concentrations were calculated by interpolation. More than 1000 mg/L teicoplanin were released within the first 24 hours and 28.22 mg/L after 168 hours. Amikacin release was above 10,000 mg/L within the first 24 hours and still 120.8 mg/L after 120 hours. A release of polyhexanide could be verified for the first 24 hours only. Consequently teicoplanin and amikacin released from PRF showed antimicrobial in-vitro effects for almost a week, whereas an antimicrobial effect of polyhexanide could only be verified for the first 24 hours. Our Results show that a weekly dressing regimen may be justified in wounds treated with PRF plus amikacin or teicoplanin, since bacteria will be eradicated over a considerable period of time after a single application of PRF.

  9. Gelatin Particle-Stabilized High-Internal Phase Emulsions for Use in Oral Delivery Systems: Protection Effect and in Vitro Digestion Study.

    Science.gov (United States)

    Tan, Huan; Zhao, Lifeng; Tian, Sisi; Wen, Hui; Gou, Xiaojun; Ngai, To

    2017-02-01

    The potential application of Pickering high-internal phase emulsions (HIPEs) in the food and pharmaceutical industries has yet to be fully developed. Herein, we synthesized fairly monodisperse, nontoxic, autofluorescent gelatin particles for use as sole stabilizers for fabricating oil-in-water (O/W) HIPEs in an effort to improve the protection and bioaccessibility of entrapped β-carotene. Our results showed that the concentration of gelatin particles determined the formation, microstructure, droplet size distribution, and digestion profile of the HIPEs. For storage stability, the retention of β-carotene in HIPEs was significantly higher than in dispersion in bulk oil, even after storage for 27 days. In addition, in vitro digestion experiments indicated that the bioaccessibility of β-carotene was improved 5-fold in HIPEs. This study will help establish a correlation between the physicochemical properties of gelatin particle-stabilized HIPEs with their applications in the oral delivery of bioactive nutraceuticals.

  10. Stability of prototype two-piece zirconia and titanium implants after artificial aging: an in vitro pilot study.

    Science.gov (United States)

    Kohal, Ralf-Joachim; Finke, Hans Christian; Klaus, Gerold

    2009-12-01

    Zirconia oral implants are a new topic in implant dentistry. So far, no data are available on the biomechanical behavior of two-piece zirconia implants. Therefore, the purpose of this pilot investigation was to test in vitro the fracture strength of two-piece cylindrical zirconia implants after aging in a chewing simulator. This laboratory in vitro investigation comprised three different treatment groups. Each group consisted of 16 specimens. In group 1, two-piece zirconia implants were restored with zirconia crowns (zirconia copings veneered with Triceram; Esprident, Ispringen, Germany), and in group 2 zirconia implants received Empress 2 single crowns (Ivoclar Vivadent AG, Schaan, Liechtenstein). The implants, including the abutments, in the two zirconia groups were identical. In group 3, similar titanium implants were reconstructed with porcelain-fused-to-metal crowns. Eight samples of each group were submitted to artificial aging with a long-term load test in the artificial mouth (chewing simulator). Subsequently, all not artificially aged samples and all artificially aged samples that survived the long-term loading of each group were submitted to a fracture strength test in a universal testing machine. For the pairwise comparisons in the different test groups with or without artificial loading and between the different groups at a given artificial loading condition, the Wilcoxon rank-sum test for independent samples was used. The significance level was set at 5%. One sample of group 1 (veneer fracture), none of group 2, and six samples of group 3 (implant abutment screw fractures) failed while exposed to the artificial mouth. The values for the fracture strength after artificial loading with 1.2 million cycles for group 1 were between 45 and 377 N (mean: 275.7 N), in group 2 between 240 and 314 N (mean: 280.7 N), and in the titanium group between 45 and 582 N (mean: 165.7 N). The fracture strength results without artificial load for group 1 amounted to between

  11. Lisdexamfetamine: A pharmacokinetic review.

    Science.gov (United States)

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Genome stability of bovine in vivo-conceived cleavage-stage embryos is higher compared to in vitro-produced embryos.

    Science.gov (United States)

    Tšuiko, Olga; Catteeuw, Maaike; Zamani Esteki, Masoud; Destouni, Aspasia; Bogado Pascottini, Osvaldo; Besenfelder, Urban; Havlicek, Vitezslav; Smits, Katrien; Kurg, Ants; Salumets, Andres; D'Hooghe, Thomas; Voet, Thierry; Van Soom, Ann; Robert Vermeesch, Joris

    2017-11-01

    Is the rate and nature of chromosome instability (CIN) similar between bovine in vivo-derived and in vitro-cultured cleavage-stage embryos? There is a major difference regarding chromosome stability of in vivo-derived and in vitro-cultured embryos, as CIN is significantly lower in in vivo-derived cleavage-stage embryos compared to in vitro-cultured embryos. CIN is common during in vitro embryogenesis and is associated with early embryonic loss in humans, but the stability of in vivo-conceived cleavage-stage embryos remains largely unknown. Because human in vivo preimplantation embryos are not accessible, bovine (Bos taurus) embryos were used to study CIN in vivo. Five young, healthy, cycling Holstein Friesian heifers were used to analyze single blastomeres of in vivo embryos, in vitro embryos produced by ovum pick up with ovarian stimulation (OPU-IVF), and in vitro embryos produced from in vitro matured oocytes retrieved without ovarian stimulation (IVM-IVF). Single blastomeres were isolated from embryos, whole-genome amplified and hybridized on Illumina BovineHD BeadChip arrays together with the bulk DNA from the donor cows (mothers) and the bull (father). DNA was also obtained from the parents of the bull and from the parents of the cows (paternal and maternal grandparents, respectively). Subsequently, genome-wide haplotyping and copy-number profiling was applied to investigate the genomic architecture of 171 single bovine blastomeres of 16 in vivo, 13 OPU-IVF and 13 IVM-IVF embryos. The genomic stability of single blastomeres in both of the in vitro-cultured embryo cohorts was severely compromised (P vitro than in embryos derived in vivo. Only 18.8% of in vivo-derived embryos contained at least one blastomere with chromosomal anomalies, compared to 69.2% of OPU-IVF embryos (P vitro procedures exacerbate chromosomal abnormalities during early embryo development. Hence, the present study highlights that IVF treatment compromises embryo viability and should be

  13. Pharmacokinetics of Abamectin/Levamisole Combination in a Medium Chain Mono and Diglyceride-Based Vehicle and an In Vitro Release and In Vitro In Vivo Correlation Study for Levamisole.

    Science.gov (United States)

    Sari, Peyami; Sun, Jianguo; Razzak, Majid; Tucker, Ian G

    2017-05-01

    A combination of lipophilic and hydrophilic drugs in a single solution is a challenge due to their different physicochemical properties. In vitro and in vivo release studies are useful to optimize this solution. The in vitro (Franz diffusion cell) release rate of levamisole phosphate from an isotropic vehicle of medium chain mono and diglycerides (MCMDG) was significantly slower than the release from water. The injectable solution of the isotropic MCMDG-based system was prepared with 13.65% of levamisole phosphate and 0.5% of abamectin. Two milliliters/50 kg (0.04 ml/kg) was injected subcutaneously into five healthy adult sheep. None of the animals showed the signs of inflammation at injection site. Both drugs were assayed using validated HPLC methods. The absorption rates for levamisole (0.71 ± 0.32 h -1 ) and abamectin (0.24 ± 0.08 day -1 ) from the MCMDG-based formulation were considerably slower than those of other studies conducted on the commercial products. The t max was delayed for levamisole (2.20 ± 0.45 h) and abamectin (4.20 ± 1.64 days) compared with those in published studies. Longer MRT values for levamisole (6.14 ± 1.14 h) and abamectin (8.80 ± 1.39 days) were found in this study compared to those reported. A correlation was observed between in vivo fraction absorbed and in vitro fraction released for levamisole phosphate in the MCMDG-based formulation. The injection vehicle of isotropic MCMDG-based system delayed the subcutaneous absorption of levamisole phosphate and abamectin compared to the commercial subcutaneous injection products for levamisole and abamectin. Notably, this isotropic MCMDG-based vehicle system is prepared with a combination of two drugs with different physicochemical properties.

  14. Effect of inclusion complexation of meloxicam with β-cyclodextrin- and β-cyclodextrin-based nanosponges on solubility, in vitro release and stability studies.

    Science.gov (United States)

    Shende, Pravin K; Gaud, R S; Bakal, Ravindra; Patil, Dipmala

    2015-12-01

    The objective of the present work was to develop inclusion complexes of meloxicam with β-cyclodextrin- and β-cyclodextrin-based nanosponges to enhance their solubility and stability and to prolong release using different methods that included physical mixing, kneading and sonication. Particle size, zeta potential, encapsulation efficiency, stability study results, in vitro and in vivo drug release study results, FTIR, DSC and XRPD were used as characterization parameters. SEM (Scanning Electron Microscope) studies revealed that the particle sizes of the inclusion complexes of meloxicam were within the range of 350 ± 5.69-765 ± 13.29 nm. The zeta potentials were sufficiently high to obtain stable formulations. In vitro and in vivo release studies revealed the controlled release of meloxicam from the nanosponges for 24h. The interaction of the meloxicam with the nanosponges was confirmed by FTIR and DSC. A XRPD study revealed that the crystalline nature of meloxicam was changed to an amorphous form due to the complexation with the nanosponges. A stability study revealed that the meloxicam nanosponges were stable. Therefore, β-cyclodextrin-based nanosponges represent a novel approach for the controlled release of meloxicam for anti-inflammatory and analgesic effects. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. In vitro microrhizomes induction and genetic stability of a medicinal plant Acorus calamus L. towards germplasm conservation through synthetic seed production

    Directory of Open Access Journals (Sweden)

    Satyajit KANUNGO

    2012-11-01

    Full Text Available Germplasm conservation through in vitro multiplication is one of the important mass cloning method to protect endangered medicinal plants. Synthetic seed technology offers potential advantages by increased efficiency for in vitro propagation in terms of space, labour, time and overall experimental costs. In vitro shoot formation (3.1±0.34 shoots per in vitro raised explants with shoot length of 2.9±0.11 cm of Acorus calamus (Bach was achieved after 4 weeks of culture in Murashige & Skoog (MS media supplemented with 4 mg l-1 BAP and 1 mg l-1 IAA with 30g sucrose l-1. Highest number of shoot multiplication per explant was recorded in 8 mg l-1 BAP and 2mg l-1 IAA and successful profuse rooting was observed in 1 mg l-1 IBA (3.6±0.2 roots per explant with an average root length of 4.7±0.6 cm. Synthetic seeds of in vitro raised microrhizomes were produced in a artificial matrix containing 3% (w/v sodium alginate prepared in MS basal medium for 20 min and dropped in to 3% (w/v calcium chloride solution for 30 min for polymerization. The encapsulated microrhizomes were stored at cold (10ºC in dark condition with different storage intervals of 3 and 6 months to evaluate the effect of storage duration and germination of zygotic embryos in A. calamus. From the RAPD analysis of both in vivo and in vitro regenerated plants it was observed that there were no significant variation of DNA profiles, thus ensuring the genetic stability of the plants and regeneration of true to type plants.

  16. The Role of Extracellular Binding Proteins in the Cellular Uptake of Drugs: Impact on Quantitative In Vitro-to-In Vivo Extrapolations of Toxicity and Efficacy in Physiologically Based Pharmacokinetic-Pharmacodynamic Research.

    Science.gov (United States)

    Poulin, Patrick; Burczynski, Frank J; Haddad, Sami

    2016-02-01

    A critical component in the development of physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) models for estimating target organ dosimetry in pharmacology and toxicology studies is the understanding of the uptake kinetics and accumulation of drugs and chemicals at the cellular level. Therefore, predicting free drug concentrations in intracellular fluid will contribute to our understanding of concentrations at the site of action in cells in PBPK/PD research. Some investigators believe that uptake of drugs in cells is solely driven by the unbound fraction; conversely, others argue that the protein-bound fraction contributes a significant portion of the total amount delivered to cells. Accordingly, the current literature suggests the existence of a so-called albumin-mediated uptake mechanism(s) for the protein-bound fraction (i.e., extracellular protein-facilitated uptake mechanisms) at least in hepatocytes and cardiac myocytes; however, such mechanism(s) and cells from other organs deserve further exploration. Therefore, the main objective of this present study was to discuss further the implication of potential protein-facilitated uptake mechanism(s) on drug distribution in cells under in vivo conditions. The interplay between the protein-facilitated uptake mechanism(s) and the effects of a pH gradient, metabolism, transport, and permeation limitation potentially occurring in cells was also discussed, as this should violate the basic assumption on similar free drug concentration in cells and plasma. This was made because the published equations used to calculate drug concentrations in cells in a PBPK/PD model did not consider potential protein-facilitated uptake mechanism(s). Consequently, we corrected some published equations for calculating the free drug concentrations in cells compared with plasma in PBPK/PD modeling studies, and we proposed a refined strategy for potentially performing more accurate quantitative in vitro-to-in vivo extrapolations

  17. Detailed Characterization of the In Vitro Pharmacological and Pharmacokinetic Properties ofN-(2-Hydroxybenzyl)-2,5-Dimethoxy-4-Cyanophenylethylamine (25CN-NBOH), a Highly Selective and Brain-Penetrant 5-HT2AReceptor Agonist.

    Science.gov (United States)

    Jensen, Anders A; McCorvy, John D; Leth-Petersen, Sebastian; Bundgaard, Christoffer; Liebscher, Gudrun; Kenakin, Terry P; Bräuner-Osborne, Hans; Kehler, Jan; Kristensen, Jesper Langgaard

    2017-06-01

    Therapeutic interest in augmentation of 5-hydroxytryptamine 2A (5-HT 2A ) receptor signaling has been renewed by the effectiveness of psychedelic drugs in the treatment of various psychiatric conditions. In this study, we have further characterized the pharmacological properties of the recently developed 5-HT 2 receptor agonist N -2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine (25CN-NBOH) and three structural analogs at recombinant 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors and investigated the pharmacokinetic properties of the compound. 25CN-NBOH displayed robust 5-HT 2A selectivity in [ 3 H]ketanserin/[ 3 H]mesulergine, [ 3 H]lysergic acid diethylamide and [ 3 H]Cimbi-36 binding assays ( K i 2C / K i 2A ratio range of 52-81; K i 2B / K i 2A ratio of 37). Moreover, in inositol phosphate and intracellular Ca 2+ mobilization assays 25CN-NBOH exhibited 30- to 180-fold 5-HT 2A /5-HT 2C selectivities and 54-fold 5-HT 2A /5-HT 2B selectivity as measured by Δlog( R max /EC 50 ) values. In an off-target screening 25CN-NBOH (10 μ M) displayed either substantially weaker activity or inactivity at a plethora of other receptors, transporters, and kinases. In a toxicological screening, 25CN-NBOH (100 μ M) displayed a benign acute cellular toxicological profile. 25CN-NBOH displayed high in vitro permeability (P app = 29 × 10 -6 cm/s) and low P-glycoprotein-mediated efflux in a conventional model of cellular transport barriers. In vivo, administration of 25CN-NBOH (3 mg/kg, s.c.) in C57BL/6 mice mice produced plasma and brain concentrations of the free (unbound) compound of ∼200 nM within 15 minutes, further supporting that 25CN-NBOH rapidly penetrates the blood-brain barrier and is not subjected to significant efflux. In conclusion, 25CN-NBOH appears to be a superior selective and brain-penetrant 5-HT 2A receptor agonist compared with (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), and thus we propose that the compound could be a valuable tool for future investigations

  18. A Review on Pharmacokinetic Modeling and the Effects of Environmental Stressors on Pharmacokinetics for Operational Medicine: Operational Pharmacokinetics

    Science.gov (United States)

    2009-09-01

    buproprion & pharmacokinetic* 0 Stress* & citalopram & pharmacokinetic* 10 2 Stress* & venlfaxine & pharmacokinetic* 5 1 motion sickness...Pharmacokinetic model* & venlafaxine ISI 15 5 Pharmacokinetic model* citalopram Scopus 84 Pharmacokinetic model* & buproprion Scopus 17 10...3 3 Malarone & exercise* 0 Pyridostigmine & exercise* 55 Buproprion & exercise* 2 0 Venlafaxine & exercise* 17 0 Citalopram & exercise

  19. Improved pharmacokinetics and reduced toxicity of brucine after encapsulation into stealth liposomes: role of phosphatidylcholine.

    Science.gov (United States)

    Chen, Jun; Yan, Guo-jun; Hu, Rong-rong; Gu, Qian-wen; Chen, Ming-lei; Gu, Wei; Chen, Zhi-peng; Cai, Bao-chang

    2012-01-01

    Brucine was encapsulated into stealth liposomes using the ammonium sulfate gradient method to improve therapeutic index. Four brucine stealth liposomal formulations were prepared, which were made from different phosphatidylcholines (PCs) with different phase transition temperatures (T(m)). The PCs used were soy phosphatidylcholine (SPC), dipalmitoyl phosphatidylcholine (DPPC), hydrogenated soy phosphatidylcholine (HSPC), and distearoyl phosphatidylcholine (DSPC). The stabilities, pharmacokinetics, and toxicities of these liposomal formulations were evaluated and compared. Size, zeta potential, and entrapment efficiency of brucine-loaded stealth liposomes (BSL) were not influenced by PC composition. In vitro release studies revealed that drug release rate increased with decreased T(m) of PCs, especially with the presence of rat plasma. After intravenous administration, the area under the curve (AUC) values of BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC in plasma were 7.71, 9.24, 53.83, and 56.83-fold as large as that of free brucine, respectively. The LD(50) values of brucine solution, BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC following intravenous injection were 13.17, 37.30, 37.69, 51.18, and 52.86 mg/kg, respectively. It was found in calcein retention experiments that the order of calcein retention in rat plasma was SPC < DPPC < HSPC < DSPC stealth liposomes. PC composition could exert significant influence on the stabilities, pharmacokinetics, and toxicities of brucine-loaded stealth liposomes. DSPC or HSPC with T(m) above 50°C should be used to prepare the stealth liposomal formulation for the intravenous delivery of brucine. However, it was found in the present paper that the pharmacokinetics and toxicity of BSL were not influenced by the PC composition when the T(m) of the PC was in the range of -20°C to 41°C.

  20. Prediction of overall in vitro microsomal stability of drug candidates based on molecular modeling and support vector machines. Case study of novel arylpiperazines derivatives.

    Directory of Open Access Journals (Sweden)

    Szymon Ulenberg

    Full Text Available Other than efficacy of interaction with the molecular target, metabolic stability is the primary factor responsible for the failure or success of a compound in the drug development pipeline. The ideal drug candidate should be stable enough to reach its therapeutic site of action. Despite many recent excellent achievements in the field of computational methods supporting drug metabolism studies, a well-recognized procedure to model and predict metabolic stability quantitatively is still lacking. This study proposes a workflow for developing quantitative metabolic stability-structure relationships, taking a set of 30 arylpiperazine derivatives as an example. The metabolic stability of the compounds was assessed in in vitro incubations in the presence of human liver microsomes and NADPH and subsequently quantified by liquid chromatography-mass spectrometry (LC-MS. Density functional theory (DFT calculations were used to obtain 30 models of the molecules, and Dragon software served as a source of structure-based molecular descriptors. For modeling structure-metabolic stability relationships, Support Vector Machines (SVM, a non-linear machine learning technique, were found to be more effective than a regression technique, based on the validation parameters obtained. Moreover, for the first time, general sites of metabolism for arylpiperazines bearing the 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione system were defined by analysis of Q-TOF-MS/MS spectra. The results indicated that the application of one of the most advanced chemometric techniques combined with a simple and quick in vitro procedure and LC-MS analysis provides a novel and valuable tool for predicting metabolic half-life values. Given the reduced time and simplicity of analysis, together with the accuracy of the predictions obtained, this is a valid approach for predicting metabolic stability using structural data. The approach presented provides a novel, comprehensive and reliable tool

  1. Human adipose stromal cells (ASC for the regeneration of injured cartilage display genetic stability after in vitro culture expansion.

    Directory of Open Access Journals (Sweden)

    Simona Neri

    Full Text Available Mesenchymal stromal cells are emerging as an extremely promising therapeutic agent for tissue regeneration due to their multi-potency, immune-modulation and secretome activities, but safety remains one of the main concerns, particularly when in vitro manipulation, such as cell expansion, is performed before clinical application. Indeed, it is well documented that in vitro expansion reduces replicative potential and some multi-potency and promotes cell senescence. Furthermore, during in vitro aging there is a decrease in DNA synthesis and repair efficiency thus leading to DNA damage accumulation and possibly inducing genomic instability. The European Research Project ADIPOA aims at validating an innovative cell-based therapy where autologous adipose stromal cells (ASCs are injected in the diseased articulation to activate regeneration of the cartilage. The primary objective of this paper was to assess the safety of cultured ASCs. The maintenance of genetic integrity was evaluated during in vitro culture by karyotype and microsatellite instability analysis. In addition, RT-PCR array-based evaluation of the expression of genes related to DNA damage signaling pathways was performed. Finally, the senescence and replicative potential of cultured cells was evaluated by telomere length and telomerase activity assessment, whereas anchorage-independent clone development was tested in vitro by soft agar growth. We found that cultured ASCs do not show genetic alterations and replicative senescence during the period of observation, nor anchorage-independent growth, supporting an argument for the safety of ASCs for clinical use.

  2. In vitro digestion of Pickering emulsions stabilized by soft whey protein microgel particles: influence of thermal treatment

    OpenAIRE

    Sarkar, A.; Murray, B.; Holmes, M.; Ettelaie, R; Abdalla, A; X. Yang

    2016-01-01

    Emulsions stabilized by soft whey protein microgel particles have gained research interest due to their combined advantages of biocompatibility and a high degree of resistance to coalescence. We designed Pickering oil-in-water emulsions using whey protein microgels by a facile route of heat-set gel formation followed by mechanical shear and studied the influence of heat treatment on emulsions stabilized by these particles. The aim of this study was to compare the barrier properties of the mic...

  3. Design strategies to address the effect of hydrophobic epitope on stability and in vitro assembly of modular virus-like particle.

    Science.gov (United States)

    Tekewe, Alemu; Connors, Natalie K; Middelberg, Anton P J; Lua, Linda H L

    2016-08-01

    Virus-like particles (VLPs) and capsomere subunits have shown promising potential as safe and effective vaccine candidates. They can serve as platforms for the display of foreign epitopes on their surfaces in a modular architecture. Depending on the physicochemical properties of the antigenic modules, modularization may affect the expression, solubility and stability of capsomeres, and VLP assembly. In this study, three module designs of a rotavirus hydrophobic peptide (RV10) were synthesized using synthetic biology. Among the three synthetic modules, modularization of the murine polyomavirus VP1 with a single copy of RV10 flanked by long linkers and charged residues resulted in the expression of stable modular capsomeres. Further employing the approach of module titration of RV10 modules on each capsomere via Escherichia coli co-expression of unmodified VP1 and modular VP1-RV10 successfully translated purified modular capomeres into modular VLPs when assembled in vitro. Our results demonstrate that tailoring the physicochemical properties of modules to enhance modular capsomeres stability is achievable through synthetic biology designs. Combined with module titration strategy to avoid steric hindrance to intercapsomere interactions, this allows bioprocessing of bacterially produced in vitro assembled modular VLPs. © 2016 The Protein Society.

  4. MEGen: A Physiologically Based Pharmacokinetic Model Generator

    Directory of Open Access Journals (Sweden)

    George D Loizou

    2011-11-01

    Full Text Available Physiologically based pharmacokinetic models are being used in an increasing number of different areas. These not only include the human safety assessment of pharmaceuticals, pesticides, biocides and environmental chemicals but also for food animal, wild mammal and avian risk assessment. The value of PBPK models is that they are tools for estimating tissue dosimetry by integrating in vitro and in vivo mechanistic, pharmacokinetic and toxicological information through their explicit mathematical description of important anatomical, physiological and biochemical determinants of chemical uptake, disposition and elimination. However, PBPK models are perceived as complex, data hungry, resource intensive and time consuming. In addition, model validation and verification are hindered by the relative complexity of the equations. To begin to address these issues a freely available web application for the rapid construction and documentation of bespoke PBPK models is under development. Here we present an overview of the current capabilities of MEGen, a model equation generator and parameter database and discuss future developments.

  5. Stability of Pycnogenol® as an ingredient in fruit juices subjected to in vitro gastrointestinal digestion.

    Science.gov (United States)

    Frontela, Carmen; Ros, Gaspar; Martínez, Carmen; Sánchez-Siles, Luis M; Canali, Raffaella; Virgili, Fabio

    2011-01-30

    The enrichment of fruit juices with concentrated polyphenolic extracts is an expedient strategy to compensate possible phenolic loss through gastrointestinal processing. Pycnogenol, a standardised procyanidin-rich extract from pine bark, has been proposed as a potential candidate for polyphenol enrichment of foods. In this study the effects of in vitro digestion on the phenolic profile of fruit juices enriched with Pycnogenol were investigated. After in vitro digestion the level of detectable total phenolic compounds (expressed as gallic acid equivalent) was higher in both pineapple and red fruit juices enriched with Pycnogenol than in non-enriched commercial juices. Five phenolic monomeric compounds were identified by high-performance liquid chromatography, namely chlorogenic acid, caffeic acid, ferulic acid, gallic acid and taxifolin, the last two being predominant. In vitro digestion of both Pycnogenol-enriched pineapple and red fruit juices led to a significant (P Pycnogenol after in vitro gastrointestinal digestion makes it a good choice for phenolic enrichment of fruit juices. 2010 Society of Chemical Industry.

  6. Pharmacokinetics of fexofenadine

    DEFF Research Database (Denmark)

    Lappin, Graham; Shishikura, Yoko; Jochemsen, Roeline

    2010-01-01

    with an oral unlabelled therapeutic dose (120mg). Plasma was collected from all 3 periods and analysed for both total (14)C content and parent drug by accelerator mass spectrometry (AMS). For period 3, plasma samples were also analysed using HPLC-fluorescence to determine total drug concentration. Urine......A human pharmacokinetic study was performed to assess the ability of a microdose to predict the pharmacokinetics of a therapeutic dose of fexofenadine and to determine its absolute oral bioavailability. Fexofenadine was chosen to represent an unmetabolized transporter substrate (P-gP and OATP...

  7. Effect of Grape Seed Proanthocyanidin-Gelatin Colloidal Complexes on Stability and in Vitro Digestion of Fish Oil Emulsions.

    Science.gov (United States)

    Su, Yu-Ru; Tsai, Yi-Chin; Hsu, Chun-Hua; Chao, An-Chong; Lin, Cheng-Wei; Tsai, Min-Lang; Mi, Fwu-Long

    2015-11-25

    The colloidal complexes composed of grape seed proanthocyanidin (GSP) and gelatin (GLT), as natural antioxidants to improve stability and inhibit lipid oxidation in menhaden fish oil emulsions, were evaluated. The interactions between GSP and GLT, and the chemical structures of GSP/GLT self-assembled colloidal complexes, were characterized by isothermal titration calorimetry (ITC), circular dichroism (CD), and Fourier transform infrared spectroscopic (FTIR) studies. Fish oil was emulsified with GLT to obtain an oil-in-water (o/w) emulsion. After formation of the emulsion, GLT was fixed by GSP to obtain the GSP/GLT colloidal complexes stabilized fish oil emulsion. Menhaden oil emulsified by GSP/GLT(0.4 wt %) colloidal complexes yielded an emulsion with smaller particles and higher emulsion stability as compared to its GLT emulsified counterpart. The GSP/GLT colloidal complexes inhibited the lipid oxidation in fish oil emulsions more effectively than free GLT because the emulsified fish oil was surrounded by the antioxidant GSP/GLT colloidal complexes. The digestion rate of the fish oil emulsified with the GSP/GLT colloidal complexes was reduced as compared to that emulsified with free GLT. The extent of free fatty acids released from the GSP/GLT complexes stabilized fish oil emulsions was 63.3% under simulated digestion condition, indicating that the fish oil emulsion was considerably hydrolyzed with lipase.

  8. The role of the medial ligaments in lateral stabilization of the ankle joint: an in vitro study.

    Science.gov (United States)

    Ziai, Pejman; Benca, Emir; Skrbensky, Gobert V; Wenzel, Florian; Auffarth, Alexander; Krpo, Selma; Windhager, Reinhard; Buchhorn, Tomas

    2015-07-01

    The deltoid ligament complex is known as medial stabilizer in the ankle against pronation/eversion. Lateral dual-ligament laxity often results in chronic ankle instability with recurring ankle sprain trauma. The goal of this study is to examine the lateral stabilizing role of the deltoid ligament complex against supination/inversion in case of existing lateral ligament instability. A torsion simulation was performed on 12 fresh human lower leg cadaver specimens in a loading frame and a specially designed mounting platform. The preset torsion between tibia and calcaneus was primarily set at 30° of internal rotation on specimen in plantar flexion and hindfoot inversion. The measured variable was the resisting torque recorded around mechanical tibial axis, which ensures stability in ankle sprain trauma. The first series of measurements were performed on healthy specimens and the following after transecting structures in following order: anterior talofibular ligament (ATFL) in combination with calcaneofibular ligament (CFL), followed by anterior tibiotalar ligament and posterior tibiotalar ligament and finally tibiocalcaneal ligament (TCL). The combined lateral ATFL and CFL instability showed a decrease in the resisting torque, which ensures stability in ankle sprain trauma. Only a transection of TCL (superficial layer of deltoid ligament complex) with existing lateral dual-ligament instability results in a significant decrease in torque (pankle joint in case of repetitive sprain trauma at a present lateral ligament lesion. Diagnostics of and treatment for lateral ligament instability need to consider the deltoid ligament complex,especially TCL in clinical routine.

  9. An in situ synthesis of mesoporous SBA-16/hydroxyapatite for ciprofloxacin release: in vitro stability and cytocompatibility studies.

    Science.gov (United States)

    Andrade, Gracielle Ferreira; Gomide, Viviane Silva; da Silva Júnior, Armando Cunha; Goes, Alfredo Miranda; de Sousa, Edésia Martins Barros

    2014-11-01

    The present work developed a biomaterial (HA/SBA-16) based on the growth of calcium phosphate (HA) particles within an organized silica structure (SBA-16) to evaluate its application as a drug delivery system. The samples were charged with ciprofloxacin as a model drug and in vitro release assays were carried out. The samples were characterized by elemental analysis (CHN), Fourier transform infrared spectroscopy, nitrogen adsorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), small angle X-ray scattering (SAXS) and X-ray diffraction. The results obtained by TEM, SEM and SAXS reveal a well-defined cubic arrangement of a uniform spherical mesoporous structure, an intrinsic characteristic of these materials, which indicated that SBA-16 and HA/SBA-16 could potentially encapsulate bioactive molecules by means of ordered mesopores. It was found that both surface interaction and pore volume affect the rate and amount of ciprofloxacin released from the mesoporous materials. In vitro assays were performed to evaluate the adhesion, viability, and growth behavior of human adipose tissue-derived stem cells (hADSC) on SBA-16 and HA/SBA-16 nanocomposites to verify their potential as a scaffold for application in bone-tissue engineering using MTT assay and alkaline phosphatase activity tests. The results showed that the materials are promising systems for bone repair, providing a good environment for the adhesion and proliferation of rat mesenchymal stem cells and hADSC in vitro.

  10. Pharmacokinetic profile of zafirlukast.

    NARCIS (Netherlands)

    Dekhuijzen, P.N.R.; Koopmans, P.P.

    2002-01-01

    Zafirlukast is a cysteinyl leukotriene type 1 receptor antagonist that causes bronchodilation and has anti-inflammatory properties. Clinical efficacy has been demonstrated when using oral doses of 20 to 40 mg twice daily. The pharmacokinetics of zafirlukast are best described by a two-compartment

  11. Clinical pharmacokinetics of melatonin

    DEFF Research Database (Denmark)

    Harpsøe, Nathja Groth; Andersen, Lars Peter Holst; Gögenur, Ismail

    2015-01-01

    PURPOSE: The aim of the review was to provide an overview of studies investigating the pharmacokinetics of exogenous melatonin in humans and if possible, to provide recommendations for clinical use. METHODS: The review was conducted in accordance to PRISMA guidelines. A systematic literature search...

  12. Stability of major allergen tropomyosin and other food proteins of mud crab (Scylla serrata) by in vitro gastrointestinal digestion.

    Science.gov (United States)

    Huang, Yuan-Yuan; Liu, Guang-Ming; Cai, Qiu-Feng; Weng, Wu-Yin; Maleki, Soheila J; Su, Wen-Jin; Cao, Min-Jie

    2010-05-01

    Stability in simulated gastric fluid is regarded as an important parameter for the estimation of food allergenicity. In this study, the digestive stability of allergenic protein tropomyosin (TM) and other food proteins from mud crab in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) digestion assay system was investigated and compared by SDS-PAGE and Western blot. In SGF system, proteins such as actin and the original band of myosin heavy chain (MHC) were rapidly degraded within a short period of time, while TM was relatively resistant to pepsin digestion. In SIF system, MHC was easily decomposed, while TM and actin were similarly resistant to digestion. Further study by IgE-immunoblotting and inhibition ELISA using sera from crab-allergic patients indicated that allergenicity of TM was partially decreased, suggesting proteinase digestion is effective in reducing the allergenicity of crab TM. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  13. Influence of implant length and bone defect situation on primary stability after distal femoral replacement in vitro.

    Science.gov (United States)

    Nadorf, Jan; Klein, Simon B; Gantz, Simone; Jakubowitz, Eike; Kretzer, Jan Philippe; Bischel, Oliver E

    2017-10-01

    Aseptic loosening is the major reason for failure of distal femoral replacement using current modular megaprostheses. Although the same stems are used for proximal and distal replacement, survival rates in clinical studies with distal reconstruction were lower within the same system compared to proximal reconstruction. We analyzed whether primary stability as presupposition for long-term fixation can be achieved with a current tapered stem design. Additionally, we hypothesized that stem length affects primary stability depending on bone defect situations. A modular tumor system (Megasystem-C®, Link GmbH, Hamburg, Germany) with two different tapered stems (100 and 160mm) was implanted in eight Sawbones® in two consecutively created defect situations (10 and 20cm proximal to knee joint level). Primary rotational stability was investigated by measuring relative micromotions between implant and bone to identify the main fixation areas and to characterize the fixation pattern. The fixation differed between the two stem lengths and with respect to both defect situations; however in each case the main fixation area was located at or close to the femoral isthmus. Highest relative micromotions were measured with the 160-mm stem at the distal end within small bone defects and at the proximal end when defects were increased. The analyzed design seemed to create sufficient primary stability along the main fixation areas of the implant. Based on these results and with respect to oncologic or potential revision situations, we suggest the use of the shorter stem to be more favorable in case of primary implant fixation. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Overview of the in vitro stability of commonly measured vitamins and carotenoids in whole blood.

    Science.gov (United States)

    Cuerq, Charlotte; Peretti, Noël; Chikh, Karim; Mialon, Anne; Guillaumont, Marc; Drai, Jocelyne; Blond, Emilie

    2015-03-01

    The pre-analytical stabilities of vitamins A, E, K, B1, B2, B6, B12, C, carotenoids and folates in whole blood were studied. The aim of this work was to provide clear and workable pre-analytical procedures specifying optimal delay before freezing for laboratories which perform themselves such analyses or which receive and transfer such specimens to referral laboratories. The stability of vitamins was studied in whole blood at room temperature after light exposure up to 24 h (vitamin C), 48 h (vitamins A, E, B1, B2, B6 and carotenoids) and 72 h (vitamins K, B12, red blood cell (RBC) and serum folates). Vitamin C stability after baseline acidification was analysed up to 48 h. Changes observed were compared to a clinical cut-off defined as total change limit based on a combination of analytical performance and within-subject variation. Clinically and statistically significant changes occurred only in vitamins C (-22.5%), B6 (+9.9%) and serum folates (-16.8%) concentrations after 6, 24 and 48 h, respectively. Vitamins A, E, K, B1, B2, B12, RBC folates and carotenoids showed good stability up to 48 or 72 h. Vitamin C in acidified serum conserved at room temperature appeared unstable. The optimal condition for acidified vitamin C conservation was at less than -20℃. The majority of vitamins remain stable for up to 48 h. Vitamin C quantification requires serum acidification followed by freezing as soon as possible. Freezing, respectively, within 12 h and 24 h for determination of plasma vitamin B6 and serum folates concentrations is recommended. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  15. An in vitro and in vivo toxicologic evaluation of a stabilized aloe vera gel supplement drink in mice.

    Science.gov (United States)

    Sehgal, Inder; Winters, Wallace D; Scott, Michael; Kousoulas, Konstantine

    2013-05-01

    Aloe vera gel is increasingly consumed as a beverage dietary supplement. The purpose of this study was to determine potential toxicity of a stabilized aloe vera gel derived from the inner gel fillet and marketed as a drink. The gel juice was assessed through assays of genotoxicity in vivo and acute and subchronic toxicity in B6C3F1 mice. Aloe vera did not increase the SOS DNA repair response in Escherichia coli and at 1× and 0.25× it did not increase mutagenesis of Salmonella TA100 resulting in histidine biosynthesis. At 3 and 14days following acute exposure, male and female mice gavaged with the stabilized aloe gel had daily appearances, total body weight gain, selected organ weights, necropsy and hematology tests similar to control mice gavaged with water. After a 13-week aloe gel feed study, male and female mice evaluated by the same criteria as the acute study plus feed consumption and serum chemistry tests were found to be equivalent to control groups. These data indicate that a commercial stabilized aloe gel consumed as a beverage was not genotoxic or toxic in vivo. These results contrast with those obtained using preparations containing aloe latex phenolic compounds such as anthraquinones. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Factorial design studies of antiretroviral drug-loaded stealth liposomal injectable: PEGylation, lyophilization and pharmacokinetic studies

    Science.gov (United States)

    Sudhakar, Beeravelli; Krishna, Mylangam Chaitanya; Murthy, Kolapalli Venkata Ramana

    2016-01-01

    The aim of the present study was to formulate and evaluate the ritonavir-loaded stealth liposomes by using 32 factorial design and intended to delivered by parenteral delivery. Liposomes were prepared by ethanol injection method using 32 factorial designs and characterized for various physicochemical parameters such as drug content, size, zeta potential, entrapment efficiency and in vitro drug release. The optimization process was carried out using desirability and overlay plots. The selected formulation was subjected to PEGylation using 10 % PEG-10000 solution. Stealth liposomes were characterized for the above-mentioned parameters along with surface morphology, Fourier transform infrared spectrophotometer, differential scanning calorimeter, stability and in vivo pharmacokinetic studies in rats. Stealth liposomes showed better result compared to conventional liposomes due to effect of PEG-10000. The in vivo studies revealed that stealth liposomes showed better residence time compared to conventional liposomes and pure drug solution. The conventional liposomes and pure drug showed dose-dependent pharmacokinetics, whereas stealth liposomes showed long circulation half-life compared to conventional liposomes and pure ritonavir solution. The results of statistical analysis showed significance difference as the p value is (<0.05) by one-way ANOVA. The result of the present study revealed that stealth liposomes are promising tool in antiretroviral therapy.

  17. [Comparison of various topical sun protection formulations, based on cosmetic vs medical device status, using in vitro methods to assess their efficacy, photo-stability and water resistance].

    Science.gov (United States)

    Couteau, C; Paparis, E; Coiffard, L-J-M

    2016-02-01

    Within the European Union, sun protection products have long been considered cosmetics whereas in other parts of the world, such as the United States, they are considered as medicinal products. In France, sun protection products with medical device status have recently appeared. Our aim was to compare medical and cosmetic sun protection products. We subjected 4 sun protection products to in vitro testing in order to determine their efficacy in the UVB and UVA ranges, as well as their photo-stability and water resistance. We tested two cosmetic products (Dépiwhite S Soin photoprotecteur(®) SPF 50+ and Urgo cicatrices(®) SPF 30) and two class I medical devices (MD) (Actinica lotion(®) and Kelocote UV(®) Gel for scars). The main in vitro method used involved measuring the transmittance of a sample of each product applied to a dish containing poly(methyl methacrylate) using a spectrophotometer with integrating spheres. This method enabled us to determine the SPF of the various products as well as their photo-stability and degree of water resistance. Regarding efficacy, three of the four test products met the European recommendations governing sun protection products, i.e. a ratio between UVB and UVA protection of 3 or less, and a critical wavelength (λc) of 370 nm or higher. Actinica lotion(®) was the more effective of the two medical devices tested, and was also the most photo-stable, at least within the UVB range. All four products tested were water-resistant. The products tested, while having different status and different claims, exhibited equivalent filtration properties under the study conditions. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  18. Size-dependent studies of macromolecular crowding on the thermodynamic stability, structure and functional activity of proteins: in vitro and in silico approaches.

    Science.gov (United States)

    Shahid, Sumra; Hassan, Md Imtaiyaz; Islam, Asimul; Ahmad, Faizan

    2017-02-01

    The environment inside cells in which proteins fold and function are quite different from that of the dilute buffer solutions often used during in vitro experiments. The presence of large amounts of macromolecules of varying shapes, sizes and compositions makes the intracellular milieu extremely crowded. The overall concentration of macromolecules ranges from 50 to 400gl-1, and they occupy 10-40% of the total cellular volume. These differences in solvent conditions and the level of crowdedness resulting in excluded volume effects can have significant consequences on proteins' biophysical properties. A question that arises is: how important is it to examine the roles of shape, size and composition of macromolecular crowders in altering the biological properties of proteins? This review article aims at focusing, gathering and summarizing all of the research investigations done by means of in vitro and in silico approaches taking into account the size-dependent influence of the crowders on proteins' properties. Altogether, the internal architecture of macromolecular crowding environment including size, shape and concentration of crowders, appears to be playing an extremely important role in causing changes in the biological processes. Most often the small sized crowders have been found more effective crowding agents. However, thermodynamic stability, structure and functional activity of proteins have been governed by volume exclusion as well as soft (chemical) interactions. The article provides an understanding of importance of internal architecture of the cellular environment in altering the biophysical properties of proteins. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Modulation of Cytokine Production by Drugs with Antiepileptic or Mood Stabilizer Properties in Anti-CD3- and Anti-CD40-Stimulated Blood In Vitro

    Directory of Open Access Journals (Sweden)

    Hubertus Himmerich

    2014-01-01

    Full Text Available Increased cytokine production possibly due to oxidative stress has repeatedly been shown to play a pivotal role in the pathophysiology of epilepsy and bipolar disorder. Recent in vitro and animal studies of valproic acid (VPA report antioxidative and anti-inflammatory properties, and suppression of interleukin (IL-6 and tumor necrosis factor (TNF-α. We tested the effect of drugs with antiepileptic or mood stabilizer properties, namely, primidone (PRM, carbamazepine (CBZ, levetiracetam (LEV, lamotrigine (LTG, VPA, oxcarbazepine (OXC, topiramate (TPM, phenobarbital (PB, and lithium on the production of the following cytokines in vitro: interleukin (IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22, and TNF-α. We performed a whole blood assay with stimulated blood of 14 healthy female subjects. Anti-human CD3 monoclonal antibody OKT3, combined with 5C3 antibody against CD40, was used as stimulant. We found a significant reduction of IL-1 and IL-2 levels with all tested drugs other than lithium in the CD3/5C3-stimulated blood; VPA led to a decrease in IL-1β, IL-2, IL-4, IL-6, IL-17, and TNF-α production, which substantiates and adds knowledge to current hypotheses on VPA’s anti-inflammatory properties.

  20. Exploring the antioxidant potentiality of two food by-products into a topical cream: stability, in vitro and in vivo evaluation.

    Science.gov (United States)

    Rodrigues, F; Sarmento, B; Amaral, M Helena; Oliveira, M Beatriz P P

    2016-01-01

    Coffee silverskin (CS), a food by-product of the coffee roasting industry, has been studied as an active ingredient for skin care products due to its high potential of antioxidant activity and low cytotoxicity. Another food waste used as ingredient with promising characteristics is obtained from Medicago sativa (MS), which antioxidants and isoflavones content is high. The aim of this study is to evaluate and characterize a new body formulation containing two food by-products extracts. Different parameters (such as pH, rheological behavior, color, antioxidant content and microbiological analysis) of a body cream formulation containing by-products (CSMS) and a formulation without extracts (F) were evaluated under a stability study during 180 days at different temperatures. Moreover, the in vitro cell toxicity and the in vivo skin safety and protective effects were also assessed. Formulation showed stable physical properties and antioxidant activity during 180 days of storage. In vitro toxicity was screened in two skin cell lines (fibroblasts and keratinocytes) and any toxicity was reported. The in vivo test carried out showed that, with respect to irritant effects, CSMS formulation can be regarded as safe for topical application and the skin hydratation improved after 30 days of its use. Also, considering the consumer acceptance, more than 90% of volunteers classified it as very pleasant. CSMS formulation is stable and safe for topical use as no adverse and/or side effects were observed during the application period of testing, improving skin protective properties.

  1. Stability of genotyping target sequences of Mycobacterium avium subsp. paratuberculosis upon cultivation on different media, in vitro- and in vivo passage, and natural infection.

    Science.gov (United States)

    Kasnitz, Nadine; Köhler, Heike; Weigoldt, Mathias; Gerlach, Gerald F; Möbius, Petra

    2013-12-27

    Mycobacterium (M.) avium subsp. paratuberculosis - the causative agent of paratuberculosis (Johne's disease) - affects domestic and wild ruminants worldwide. Recently, different typing techniques have been combined to provide sufficient discriminatory power for the differentiation of isolates and for epidemiological studies. In order to challenge the reliability of this approach the stability of different M. avium subsp. paratuberculosis genotypes determined after primary isolation was investigated after sub-cultivation on six different media (A), twelve in vitro passages (B), or a singular in vivo passage (C). In addition, different isolates from a single animal or herd were investigated (D). Sub-cultures of type- and reference strains, re-isolated inoculation strain after in vivo passage, and 23 field isolates were genotyped by mycobacterial interspersed repetitive unit-variable-number of tandem-repeat (MIRU-VNTR)-, short-sequence-repeat (SSR)-, and IS900-based restriction-fragment length-polymorphism (IS900-RFLP)-analyses and compared with initial genotypes. MIRU-VNTR-alleles (at loci 292, X3, 25, 47, 7, and 32) were stable after in vitro cultivations and after animal passage. Results of SSR analysis at Locus 1 with 7G nucleotides and at Loci 8 and 9 (tri-nucleotides) were also stable. At Locus 2 9G repeats changed into 10G after goat passage. After in vitro subculture (A+B) but not after animal passage (C) IS900-RFLP-typing revealed changes of BstEII-patterns for 3 of 23 strains (including ATCC 19698). Multiple isolates from individual animals or from a single cattle herd with natural infection (D) which exhibited identical IS900-RFLP- and MIRU-VNTR- genotypes, showed different G repeat numbers at SSR locus 2. This implies strand slippage events during chromosomal duplication of bacteria in the course of bacterial spreading within hosts and herds. Consequently, SSR-Locus 2 is not suitable as genome marker for epidemiological studies. Copyright © 2013 Elsevier

  2. In vitro selection of oligonucleotides that bind double-stranded DNA in the presence of triplex-stabilizing agents.

    Science.gov (United States)

    Ayel, Elodie; Escudé, Christophe

    2010-03-01

    A SELEX approach has been developed in order to select oligonucleotides that bind double-stranded DNA in the presence of a triplex-stabilizing agent, and was applied to a target sequence containing an oligopurine-oligopyrimidine stretch. After only seven rounds of selection, the process led to the identification of oligonucleotides that were able to form triple helices within the antiparallel motif. Inspection of the selected sequences revealed that, contrary to GC base pair which were always recognized by guanines, recognition of AT base pair could be achieved by either adenine or thymine, depending on the sequence context. While thymines are strongly preferred for several positions, some others can accommodate the presence of adenines. These results contribute to set the rules for designing oligonucleotides that form stable triple helices in the presence of triplex-stabilizing agents at physiological pH. They set the basis for further experiments regarding extension of potential target sequences for triple-helix formation or recognition of ligand-DNA complexes.

  3. [Analysis on microdialysis probe recovery of baicalin in vitro and in vivo based on LC-MS/MS].

    Science.gov (United States)

    Chen, Teng-Fei; Liu, Jian-Xun; Zhang, Ying; Lin, Li; Song, Wen-Ting; Yao, Ming-Jiang

    2017-06-01

    To further study the brain behavior and the pharmacokinetics of baicalin in intercellular fluid of brain, and study the recovery rate and stability of brain and blood microdialysis probe of baicalin in vitro and in vivo. The concentration of baicalin in brain and blood microdialysates was determined by LC-MS/MS and the probe recovery for baicalin was calculated. The effects of different flow rates (0.50, 1.0, 1.5, 2.0,3.0 μL•min⁻¹) on recovery in vitro were determined by incremental method and decrement method. The effects of different drug concentrations (50.00, 200.0, 500.0, 1 000 μg•L⁻¹) and using times (0, 1, 2) on recovery in vitro were determined by incremental method. The probe recovery stability and effect of flow rate on recovery in vivo were determined by decrement method, and its results were compared with those in in vitro trial. The in vitro recovery of brain and blood probe of baicalin was decreased with the increase of flow rate under the same concentration; and at the same flow rate, different concentrations of baicalin had little influence on the recovery. The probe which had been used for 2 times showed no obvious change in probe recovery by syringe with 2% heparin sodium and ultrapure water successively. In vitro recovery rates obtained by incremental method and decrement method were approximately equal under the same condition, and the in vivo recovery determined by decrement method was similar with the in vitro results and they were showed a good stability within 10 h. The results showed that decrement method can be used for pharmacokinetic study of baicalin, and can be used to study probe recovery in vivo at the same time. Copyright© by the Chinese Pharmaceutical Association.

  4. Physical chemistry evaluation of stability, spreadability, in vitro antioxidant, and photo-protective capacities of topical formulations containing Calendula officinalis L. leaf extract

    Directory of Open Access Journals (Sweden)

    Viviane Cecília Kessler Nunes Deuschle

    2015-03-01

    Full Text Available Calendula is used widely in cosmetic formulations that present phenolic compounds in their chemical constitution. The objective of our research was to develop and evaluate the stability of topical formulations containing 5% hydro-ethanolic extract of calendula leaves, including spreadability, and in vitro photo-protective, and antioxidant capacity. To evaluate the stability, we used organoleptic characteristics, pH, and viscosity parameters. Antioxidant capacity was measured by the DPPH (2,2-diphenyl-1-picrylhydrazyl method, and the photo-protective capacity by SPF spectrophotometric measure. All formulations were stable. The calendula extract formulations in gel and cream showed no significant variations in pH, and the cream formulations presented lower viscosity variations than gel formulations. The spreadability of the gel formulations was superior to those in cream. The formulations also presented good antioxidant capacities and an FPS of around 1.75. In accordance with the results, the formulations can be used as antioxidants, but considering the low SPF obtained, calendula cannot be considered as a stand-alone sunscreen, yet may well be tested in future studies towards verifying enhancement of synthetic sunscreens.

  5. Amsacrine analog-loaded solid lipid nanoparticle to resolve insolubility for injection delivery: characterization and pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Fang YP

    2016-03-01

    Full Text Available Yi-Ping Fang,1 Chih-Hung Chuang,2 Pao-Chu Wu,1 Yaw-Bin Huang,1 Cherng-Chyi Tzeng,3 Yeh-Long Chen,3 Ya-Ting Liu,1 Yi-Hung Tsai,1 Ming-Jun Tsai4–6 1School of Pharmacy, College of Pharmacy, 2Department of Biomedical and Environment Biology, College of Life Science, 3School of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung, 4Department of Neurology, China Medical University Hospital, 5School of Medicine, Medical College, China Medical University, Taichung, 6Department of Neurology, China Medical University An-Nan Hospital, Tainan, Taiwan Abstract: Amsacrine analog is a novel chemotherapeutic agent that provides potentially broad antitumor activity when compared to traditional amsacrine. However, the major limitation of amsacrine analog is that it is highly lipophilic, making it nonconductive to intravenous administration. The aim of this study was to utilize solid lipid nanoparticles (SLN to resolve the delivery problem and to investigate the biodistribution of amsacrine analog-loaded SLN. Physicochemical characterizations of SLN, including particle size, zeta potential, entrapment efficiency, and stability, were evaluated. In vitro release behavior was also measured by the dialysis method. In vivo pharmacokinetics and biodistribution behavior of amsacrine analog were investigated and incorporated with a non invasion in vivo imaging system to confirm the localization of SLN. The results showed that amsacrine analog-loaded SLN was 36.7 nm in particle size, 0.37 in polydispersity index, and 34.5±0.047 mV in zeta potential. More than 99% of amsacrine analog was successfully entrapped in the SLN. There were no significant differences in the physicochemical properties after storage at room temperature (25°C for 1 month. Amsacrine analog-loaded SLN maintained good stability. An in vitro release study showed that amsacrine analog-loaded SLN sustained a release pattern and followed the zero equation. An

  6. Stability-Diversity Tradeoffs Impose Fundamental Constraints on Selection of Synthetic Human VH/VLSingle-Domain Antibodies fromIn VitroDisplay Libraries.

    Science.gov (United States)

    Henry, Kevin A; Kim, Dae Young; Kandalaft, Hiba; Lowden, Michael J; Yang, Qingling; Schrag, Joseph D; Hussack, Greg; MacKenzie, C Roger; Tanha, Jamshid

    2017-01-01

    Human autonomous V H /V L single-domain antibodies (sdAbs) are attractive therapeutic molecules, but often suffer from suboptimal stability, solubility and affinity for cognate antigens. Most commonly, human sdAbs have been isolated from in vitro display libraries constructed via synthetic randomization of rearranged V H /V L domains. Here, we describe the design and characterization of three novel human V H /V L sdAb libraries through a process of: (i) exhaustive biophysical characterization of 20 potential V H /V L sdAb library scaffolds, including assessment of expression yield, aggregation resistance, thermostability and tolerance to complementarity-determining region (CDR) substitutions; (ii) in vitro randomization of the CDRs of three V H /V L sdAb scaffolds, with tailored amino acid representation designed to promote solubility and expressibility; and (iii) systematic benchmarking of the three V H /V L libraries by panning against five model antigens. We isolated ≥1 antigen-specific human sdAb against four of five targets (13 V H s and 7 V L s in total); these were predominantly monomeric, had antigen-binding affinities ranging from 5 nM to 12 µM (average: 2-3 µM), but had highly variable expression yields (range: 0.1-19 mg/L). Despite our efforts to identify the most stable V H /V L scaffolds, selection of antigen-specific binders from these libraries was unpredictable (overall success rate for all library-target screens: ~53%) with a high attrition rate of sdAbs exhibiting false positive binding by ELISA. By analyzing V H /V L sdAb library sequence composition following selection for monomeric antibody expression (binding to protein A/L followed by amplification in bacterial cells), we found that some V H /V L sdAbs had marked growth advantages over others, and that the amino acid composition of the CDRs of this set of sdAbs was dramatically restricted (bias toward Asp and His and away from aromatic and hydrophobic residues). Thus, CDR sequence

  7. Radio frequency induced hyperthermia mediated by dextran stabilized LSMO nanoparticles: in vitro evaluation of heat shock protein response

    Science.gov (United States)

    Bhayani, K. R.; Rajwade, J. M.; Paknikar, K. M.

    2013-01-01

    Dextran stabilized La0.7Sr0.3MnO3 (Dex-LSMO) is an alternative cancer hyperthermia agent holding considerable promise. Here, we have carried out a comparative study on radio frequency (˜264 kHz) induced Dex-LSMO mediated heating and extraneous heating (mimicking generalized hyperthermia) in terms of changes in the morphology, proliferation pattern and induction of heat shock proteins in a human melanoma cell line (A375). Our results clearly show that the cellular effects seen with extraneous heating (60 min at 43 °C) could be reproduced by just six minutes of radio frequency induced Dex-LSMO mediated heating. More importantly, the observed enhanced levels of HSP 70 and 90 (molecular markers of heat shock that trigger favorable immunological reactions) seen with Dex-LSMO mediated heating were comparable to extraneous heating. These results suggest the possible utility of Dex-LSMO as a cancer hyperthermia agent.

  8. Clinical pharmacokinetics of ropinirole.

    Science.gov (United States)

    Kaye, C M; Nicholls, B

    2000-10-01

    Ropinirole is a selective non-ergoline dopamine D2 receptor agonist indicated for use in treating Parkinson's disease. When taken as oral tablets, ropinirole is rapidly and almost completely absorbed, and it is extensively distributed from the vascular compartment. The bioavailability is approximately 50%. Ropinirole shows low plasma protein binding. The drug is inactivated by metabolism in the liver, and none of the major circulating metabolites have pharmacological activity. The principal metabolic enzyme is the cytochrome P450 (CYP) isoenzyme CYP1A2. Ropinirole shows approximately linear pharmacokinetics when given as single or repeated doses, and is eliminated with a half-life of approximately 6 hours. Population pharmacokinetics have demonstrated that gender, mild or moderate renal impairment, Parkinson's disease stage and concomitant illnesses or the use of several common concomitant medications have no effect on the pharmacokinetics of ropinirole. Clearance is slower for patients older than 65 years compared with those who are younger, and in women taking hormone replacement therapy compared with those who are not. The CYP1A2 inhibitor ciprofloxacin produced increases in the plasma concentrations of ropinirole when these 2 drugs were coadministered, but no interaction was seen with theophylline which, like ropinirole, is also a substrate for CYP1A2. There is no obvious plasma concentration-effect relationship for ropinirole.

  9. Mechanism of crosslinking of proteins by glutaraldehyde. IV: In vitro and in vivo stability of a crosslinked collagen matrix.

    Science.gov (United States)

    Cheung, D T; Tong, D; Perelman, N; Ertl, D; Nimni, M E

    1990-01-01

    The use of native or reconstituted collagen as a bioprothesis for tissue augmentation requires the introduction of exogenous synthetic crosslinks. The degree of crosslinking determines the rate of resorption or replacement of the implanted materials by the host. Since biophysical and chemical methods to quantify these crosslinks have in general been difficult to evaluate, we have developed in vitro enzymatic approaches which enable us to correlate the degree of crosslinking with the rates of enzymatic degradation. When the number of stable crosslinks formed is large it is essential to partially unfold the collagen fibrils by heating or by exposure to denaturing agents to enhance their susceptibility to hydrolysis. In the present study we demonstrate that increasing the number of reactive amino groups on collagen by coupling 1,6-diaminohexane to carboxyl groups using a water soluble carbodiimide can significantly enhance the number of crosslinks introduced by glutaraldehyde. We also show that the enzymatic method developed correlates well with the biodegradation of radiolabeled crosslinked collagenous tissues implanted subcutaneously in rats.

  10. In Vitro and In Vivo Behaviour of I111n Complexes of TTHA, TTHA-Bis(Butylamide) and TTHA-Bis(Glucamide) : Stability, Biodistribution and Excretion Studied by Gamma Imaging

    NARCIS (Netherlands)

    Prata, M.I.M.; Ribeiro, M.J.; Santos, A.C.; Peters, J.A.; Nepveu, F.; Geraldes, C.F.G.C.; De Lima, J.J.P.

    1998-01-01

    Aiming at radiopharmaceutical application, I111n3+ complexes of the polyaminocarboxylates TTHA, TTHA-bis(butylamide) and TTHA-bis(glucamide) were investigated. The in vitro stability of I111n(TTHA)3- and I111n(TTHA-bis(butylamide)- was evaluated by measuring the exchange of I111n3+ from the

  11. In Vitro and In Vivo Evaluation of Niosomal Formulation for Controlled Delivery of Clarithromycin

    Directory of Open Access Journals (Sweden)

    Gyati Shilakari Asthana

    2016-01-01

    Full Text Available The present study was focused on formulating and evaluating clarithromycin (CLR containing niosomal formulation for in vitro and in vivo pharmacokinetic behavior. Niosomal formulations (empty and drug loaded were prepared by using different ratio of surfactant (various Span grades 20, 40, 60, and 80 and cholesterol by thin film hydration method and were evaluated for in vitro characteristics, stability studies, and in vivo study. Dicetyl phosphate (DCP was added to the niosomal formulation. Various pharmacokinetic parameters were determined from plasma of male SD rats. Span 60 containing niosomal formulation NC2 (cholesterol to surfactant ratio 1 : 1 displayed highest entrapment efficiency with desired particle size of 4.67 μm. TEM analyses showed that niosomal formulation was spherical in shape. Niosomes containing Span 60 displayed higher percentage of drug release after 24 h as compared to other formulations. NC2 formulation was found to be stable at the end of the study on storage condition. Various pharmacokinetic parameters, namely, AUC, AUMC, and MRT of niosomal formulation, were found to be 1.5-fold, 4-fold, and 3-fold plain drug, respectively. The present study suggested that niosomal formulations provide sustained and prolonged delivery of drug with enhance bioavailability.

  12. Facile reduction and stabilization of ginsenoside-functionalized gold nanoparticles: optimization, characterization, and in vitro cytotoxicity studies

    Science.gov (United States)

    Hurh, Joon; Markus, Josua; Kim, Yeon-Ju; Ahn, Sungeun; Castro-Aceituno, Veronica; Mathiyalagan, Ramya; Kim, Yu Jin; Yang, Deok Chun

    2017-09-01

    Gold nanoparticles (GNPs) are forecasted to provide an attractive platform in biomedicine and catalysis with their potentials of combining a variety of biophysicochemical properties into an integrated nanodevice with great therapeutic and optical functions. There are several reports of crude plant extracts mediating the conversion of metal ions into nanoparticles. However, we aimed to investigate the capability of single bioactive compounds, namely ginsenosides compound K (C-K) and Rh2, to accommodate a synergistic chemical reduction of gold salts by one-pot green chemistry. Ginsenosides C-K and Rh2 are unique triterpenoid saponins present in Panax ginseng Meyer, a perennial plant traditionally used as an oriental medicinal herbal with long history. C-K and Rh2 have demonstrated diverse pharmacological properties such as anticancer, anti-inflammation, anti-aging, and neuroprotective properties. The reduction of gold ions by these ginsenosides led to the production of nontoxic GNPs as tested in mouse macrophage (J774A.1) and human kidney epithelial (HEK-293) in vitro. The kinetics of the bioreduction and the influence of pH were examined by an ultraviolet-visible (UV-Vis) spectrophotometer. GNPs were characterized by field emission transmission electron microscopy (FE-TEM), X-ray diffraction (XRD), dynamic light scattering (DLS), and Fourier transform infrared (FTIR) spectroscopy. Ginsenoside loading efficiency of C-K-GNPs and Rh2-GNPs was determined to be approximately 62.83% and 54.91%, respectively, by thermogravimetric analysis (TGA). These results suggest that one-pot synthesis by ginsenosides C-K and Rh2 may be useful for producing ginsenoside-loaded gold nanocarriers. [Figure not available: see fulltext.

  13. In vitro biocompatibility and electrical stability of thick-film platinum/gold alloy electrodes printed on alumina

    Science.gov (United States)

    Carnicer-Lombarte, Alejandro; Lancashire, Henry T.; Vanhoestenberghe, Anne

    2017-06-01

    Objective. High-density electrode arrays are a powerful tool in both clinical neuroscience and basic research. However, current manufacturing techniques require the use of specialised techniques and equipment, which are available to few labs. We have developed a high-density electrode array with customisable design, manufactured using simple printing techniques and with commercially available materials. Approach. Electrode arrays were manufactured by thick-film printing a platinum-gold alloy (Pt/Au) and an insulating dielectric on 96% alumina ceramic plates. Arrays were conditioned in serum and serum-free conditions, with and without 1 kHz, 200 µA, charge balanced stimulation for up to 21 d. Array biocompatibility was assessed using an extract assay and a PC-12 cell contact assay. Electrode impedance, charge storage capacity and charge injection capacity were before and after array conditioning. Main results. The manufactured Pt/Au electrodes have a highly porous surface and exhibit electrical properties comparable to arrays manufactured using alternative techniques. Materials used in array manufacture were found to be non-toxic to L929 fibroblasts by extract assay, and neuronal-like PC-12 cells adhered and extended neurites on the array surfaces. Arrays remained functional after long-term delivery of electrical pulses while exposed to protein-rich environments. Charge storage capacities and charge injection capacities increased following stimulation accounted for by an increase in surface index (real surface area) observed by vertical scanning interferometry. Further, we observed accumulation of proteins at the electrode sites following conditioning in the presence of serum. Significance. This study demonstrates the in vitro biocompatibility of commercially available thick-film printing materials. The printing technique is both simple and versatile, with layouts readily modified to produce customized electrode arrays. Thick-film electrode arrays are an

  14. The effect of bleaching agents on the color stability of ceromer and porcelain restorative materials in vitro.

    Science.gov (United States)

    Kara, H B; Aykent, F; Ozturk, B

    2013-01-01

    The aim of this in vitro study was to determine the color changes of five different restorative materials after exposing these materials to two different home bleaching agents. This study applied bleaching agents to an ultralow-fusing porcelain, a low-fusing porcelain, two types of heat-pressed glass ceramics, and a ceromer. A total of 24 disc-shaped specimens were fabricated (with a diameter of 10 mm and a thickness of 2 mm) from each material (n=12). The initial color measurements were taken with a spectrophotometer. The first set of specimens were bleached with 10% hydrogen peroxide (HP) for one hour daily for 10 days. The other set of specimens were bleached with 10% carbamide peroxide (CP) bleaching gel for eight hours daily for 14 days. Data were analyzed with the one-way analysis of variance and Kruskal-Wallis statistical test. The difference in the prebleaching and postbleaching color of each material was considered to be statistically significant at p < 0.05. The study found a statistically significant difference among the color changes of the test groups after exposing them to both bleaching agents (p<0.05). Appreciable color change was observed in the Estenia (ΔE=3.99) specimens that were bleached with the HP, and noticeable color changes were observed in the Estenia (ΔE=1.89) and IPS Empress 2 (ΔE=1.66) groups when they were treated with the CP. Restorations (especially polymer-containing restorative materials) should be protected before any bleaching procedure due to the high risk of color change.

  15. The Pharmacokinetics of Raloxifene and Its Interaction with Apigenin in Rat

    OpenAIRE

    Ming Hu; Yan Chen; Xiaobin Jia; Jinyan Wang; Jian Chen

    2010-01-01

    Purpose: Raloxifene is a selective estrogen receptor modulator which is structurally similar to tamoxifen. As flavonoids can interact with raloxifene in vitro, we evaluated the in vivo pharmacokinetics of raloxifene in rats when co-administered with apigenin. Methods: The pharmacokinetics of raloxifene in the absence or presence of apigenin was investigated in rats after different dosage regimens. The plasma concentrations before and after enzymatic hydrolysis were analyzed by HPLC, and the p...

  16. Towards long lasting zirconia-based composites for dental implants. Part I: innovative synthesis, microstructural characterization and in vitro stability.

    Science.gov (United States)

    Palmero, Paola; Fornabaio, Marta; Montanaro, Laura; Reveron, Helen; Esnouf, Claude; Chevalier, Jérôme

    2015-05-01

    In order to fulfill the clinical requirements for strong, tough and stable ceramics used in dental applications, we designed and developed innovative zirconia-based composites, in which equiaxial α-Al2O3 and elongated SrAl12O19 phases are dispersed in a ceria-stabilized zirconia matrix. The composite powders were prepared by an innovative surface coating route, in which commercial zirconia powders were coated by inorganic precursors of the second phases, which crystallize on the zirconia particles surface under proper thermal treatment. Samples containing four different ceria contents (in the range 10.0-11.5 mol%) were prepared by carefully tailoring the amount of the cerium precursor during the elaboration process. Slip cast green bodies were sintered at 1450 °C for 1 h, leading to fully dense materials. Characterization of composites by SEM and TEM analyses showed highly homogeneous microstructures with an even distribution of both equiaxial and elongated-shape grains inside a very fine zirconia matrix. Ce content plays a major role on aging kinetics, and should be carefully controlled: sample with 10 mol% of ceria were transformable, whereas above 10.5 mol% there is negligible or no transformation during autoclave treatment. Thus, in this paper we show the potential of the innovative surface coating route, which allows a perfect tailoring of the microstructural, morphological and compositional features of the composites; moreover, its processing costs and environmental impacts are limited, which is beneficial for further scale-up and real use in the biomedical field. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Genetic stability and phytochemical analysis of the in vitro regenerated plants of Dendrobium nobile Lindl., an endangered medicinal orchid

    Science.gov (United States)

    Bhattacharyya, Paromik; Kumaria, Suman; Diengdoh, Reemavareen; Tandon, Pramod

    2014-01-01

    An efficient genetically stable regeneration protocol with increased phytochemical production has been established for Dendrobium nobile, a highly prized orchid for its economic and medicinal importance. Protocorm like bodies (PLBs) were induced from the pseudostem segments using thidiazuron (TDZ; 1.5 mg/l), by-passing the conventional auxin–cytokinin complement approach for plant regeneration. Although, PLB induction was observed at higher concentrations of TDZ, plantlet regeneration from those PLBs was affected adversely. The best rooting (5.41 roots/shoot) was achieved in MS medium with 1.5 mg/l TDZ and 0.25% activated charcoal. Plantlets were successfully transferred to a greenhouse with a survival rate of 84.3%, exhibiting normal development. Genetic stability of the regenerated plants was investigated using randomly amplified polymorphic DNA (RAPD) and start codon targeted (SCoT) polymorphism markers which detected 97% of genetic fidelity among the regenerants. The PIC values of RAPD and SCoT primers were recorded to be 0.92 and 0.76 and their Rp values ranged between 3.66 and 10, and 4 and 12 respectively. The amplification products of the regenerated plants showed similar banding patterns to that of the mother plant thus demonstrating the homogeneity of the micropropagated plants. A comparative phytochemical analysis among the mother and the micropropagated plants showed a higher yield of secondary metabolites. The regeneration protocol developed in this study provides a basis for ex-situ germplasm conservation and also harnesses the various secondary metabolite compounds of medicinal importance present in D. nobile. PMID:25606433

  18. A comparative evaluation of dimensional stability of three types of interocclusal recording materials-an in-vitro multi-centre study.

    Science.gov (United States)

    Tejo, Sampath Kumar; Kumar, Anil G; Kattimani, Vivekanand S; Desai, Priti D; Nalla, Sandeep; Chaitanya K, Krishna

    2012-10-05

    The introduction of different interocclusal recording materials has put clinicians in dilemma that which material should be used in routine clinical practice for precise recording and transferring of accurate existing occlusal records for articulation of patient's diagnostic or working casts in the fabrication of good satisfactory prosthesis. In the era of developing world of dentistry the different materials are introduced for interocclusal record with different brand names because of this; the utility of the material is confusing for successful delivery of prosthesis with lack of in vitro or in vivo studies which will predict the property of the material with utility recommendations. The aim of this multicenter research is to evaluate the time dependent linear dimensional stability of three types of interocclusal recording materials; which gives very clear idea to clinicians in regard to its usage in routine practice and recommendations for usage of the different materials. Also to find out ideal time for articulation of three types of interocclusal recording materials with accuracy. Commercially available and ADA approved Polyether bite registration paste (Ramitec), Poly vinyl siloxane bite registration paste (Jetbite) and Zinc oxide eugenol (ZOE) bite registration paste (Super bite) were used in the study.A stainless steel die was made according to modified American dental Associations (ADA) specification no. 19. Each one of the tested materials were manipulated according to manufacturers' instructions. The materials separated from die, 3-mins after their respective setting time, resulted in disks of standard diameter. Two parallel lines and three perpendicular lines reproduced on the surface. The distance between two parallel lines was measured at different time intervals i.e. 1 hour, 24, 48 and 72 hours by using travelling microscope (magnus) and compared with standard die measurements made according to ADA specification no.19 to find out the dimensional

  19. Color Stability Assessment of Two Different Composite Resins with Variable Immersion Time Using Various Beverages: An In vitro Study.

    Science.gov (United States)

    Kumar, M Senthil; Ajay, R; Miskeen Sahib, S A; Chittrarasu, M; Navarasu, M; Ragavendran, N; Burhanuddin Mohammed, Omar Farooq

    2017-11-01

    The aim of the study was to evaluate the difference in the color of microhybrid (MH) and nanofilled (NF) composite resins after 24 and 48 h in beverages such as red wine (RW), Coca-Cola, and distilled water. The specific objective of this study was to investigate the cumulative effect of the colorant solutions on the dental composites. MH and NF composite resins (A2 shade) were used in this current study. Sixty disk-shaped material specimens (10 mm in diameter × 2 mm in thickness) were prepared using a fiber mold (ring), with the desired dimensions. The specimen surfaces were polished using super-snap polishing system. Sixty specimens were divided into two groups of 30 each (Group I: MH resin composite; Group II: NF resin composite). Both the groups divided into six subgroups (Subgroup I: RW for 24 h [RW-24]; Subgroup II: RW for 48 h; Subgroup III: Coca-Cola for 24 h [CC-24]; Subgroup IV: Coca-Cola for 48 h [CC-48]; Subgroup V: Distilled water for 24 h [DW-24]; Subgroup VI: Distilled water for 48 h [DW-48]). All the samples were immersed in respective drinks for a period of 24 h, and color differences were measured using ultraviolet spectrophotometer. Once again, all the samples were immersed for another 24 h in the same drinks. After 48 h, the color change of the samples was measured. Measurements were made according to the CIE L × a × b × color space relative to the CIE standard illuminant D65. The color changes of the specimens were evaluated using the following formula: Statistical analysis was performed. The data were analyzed using the one-way ANOVA and t-test at a significance level of 0.05. Color stability of MH composite resin was found to be inferior than the NF resin composite irrespective of immersion medium and time. In RW, the color change observed was maximum for both composite resins followed by Coca-Cola. Immersing the resin composites in distilled water for 24 and 48 h had negligible color change. A 48-h immersion of both composite resins in

  20. Color stability assessment of two different composite resins with variable immersion time using various beverages: An In vitro study

    Directory of Open Access Journals (Sweden)

    M Senthil Kumar

    2017-01-01

    Full Text Available Purpose of the Study: The aim of the study was to evaluate the difference in the color of microhybrid (MH and nanofilled (NF composite resins after 24 and 48 h in beverages such as red wine (RW, Coca-Cola, and distilled water. The specific objective of this study was to investigate the cumulative effect of the colorant solutions on the dental composites. Materials and Methods: MH and NF composite resins (A2 shade were used in this current study. Sixty disk-shaped material specimens (10 mm in diameter × 2 mm in thickness were prepared using a fiber mold (ring, with the desired dimensions. The specimen surfaces were polished using super-snap polishing system. Sixty specimens were divided into two groups of 30 each (Group I: MH resin composite; Group II: NF resin composite. Both the groups divided into six subgroups (Subgroup I: RW for 24 h [RW-24]; Subgroup II: RW for 48 h; Subgroup III: Coca-Cola for 24 h [CC-24]; Subgroup IV: Coca-Cola for 48 h [CC-48]; Subgroup V: Distilled water for 24 h [DW-24]; Subgroup VI: Distilled water for 48 h [DW-48]. All the samples were immersed in respective drinks for a period of 24 h, and color differences were measured using ultraviolet spectrophotometer. Once again, all the samples were immersed for another 24 h in the same drinks. After 48 h, the color change of the samples was measured. Measurements were made according to the CIE L × a × b × color space relative to the CIE standard illuminant D65. The color changes of the specimens were evaluated using the following formula: [INSIDE:1]Statistical analysis was performed. The data were analyzed using the one-way ANOVA and t-test at a significance level of 0.05. Conclusion: Color stability of MH composite resin was found to be inferior than the NF resin composite irrespective of immersion medium and time. In RW, the color change observed was maximum for both composite resins followed by Coca-Cola. Immersing the resin composites in distilled water for 24 and

  1. Gold nanostar-polymer hybrids for siRNA delivery: Polymer design towards colloidal stability and in vitro studies on breast cancer cells.

    Science.gov (United States)

    Sardo, Carla; Bassi, Barbara; Craparo, Emanuela F; Scialabba, Cinzia; Cabrini, Elisa; Dacarro, Giacomo; D'Agostino, Agnese; Taglietti, Angelo; Giammona, Gaetano; Pallavicini, Piersandro; Cavallaro, Gennara

    2017-03-15

    To overcome the low bioavailability of siRNA (small interfering RNA) and to improve their transfection efficiency, the use of non-viral delivery carriers is today a feasible approach to transform the discovery of these incredibly potent and versatile drugs into clinical practice. Polymer-modified gold nanoconstructs (AuNCs) are currently viewed as efficient and safe intracellular delivery carriers for siRNA, as they have the possibility to conjugate the ability to stably entrap and deliver siRNAs inside cells with the advantages of gold nanoparticles, which can act as theranostic agents and radiotherapy enhancers through laser-induced hyperthermia. In this study, AuNCs were prepared by coating Gold Nano Stars (GNS) with suitable functionalised polymers, to give new insight on the choice of the coating in order to obtain colloidal stability, satisfying in vitro transfection behaviour and reliability in terms of homogeneous results upon GNS type changing. For this goal, GNS synthesized with three different sizes and shapes were coated with two different polymers: i) α-mercapto-ω-amino polyethylene glycol 3000Da (SH-PEG 3000 -NH 2 ), a hydrophilic linear polymer; ii) PHEA-PEG 2000 -EDA-LA (PPE-LA), an amphiphilic hydroxyethylaspartamide copolymer containing a PEG moiety. Both polymers contain SH or SS groups for anchoring on gold surface and NH 2 groups, which can be protonated in order to obtain a positive surface for successive siRNA layering. The effect of the features of the coating polymers on siRNA layering, and the extent of intracellular uptake and luciferase gene silencing effect were evaluated for each of the obtained coated GNS. The results highlight that amphiphilic biocompatible polymers with multi-grafting function are more suitable for ensuring the colloidal stability and the effectiveness of these colloidal systems, compared to the coating with linear PEG. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. A Comparative Study of Sodium Houttuyfonate and 2-Undecanone for Their in Vitro and in Vivo Anti-Inflammatory Activities and Stabilities

    Directory of Open Access Journals (Sweden)

    Jing Chen

    2014-12-01

    Full Text Available Houttuynia cordata Thunb. (H. cordata is an anti-inflammatory herbal drug that is clinically used in Asia. The essential oil obtained from H. cordata is known to contain 2-undecanone (2-methyl nonyl ketone. In addition, sodium houttuyfonate is a compound that can be derived from H. cordata and has important clinical uses as an anti-inflammatory agent. Sodium houttuyfonate can be converted to decanoyl acetaldehyde (houttuynin and then to 2-undecanone. Therefore, the experiments described here explore the comparative anti-inflammatory activities of these compounds. Sodium houttuyfonate showed more potent anti-inflammatory activities than that of 2-undecanone at the same dosage, both in vitro and in vivo, although both compounds significantly inhibited the production of tumor necrosis factor-α (TNF-α, interleukin-1β (IL-1β and the expression of toll-like receptor 4 (TLR4, but increased the secretion of interleukin-10 (IL-10 in lipopolysaccharide (LPS-stimulated RAW264.7 cells. In addition, both compounds showed dose-dependent inhibitory effects on xylene-induced mouse ear edema. In a previous study, we found sodium houttuyfonate to be transformed to 2-undecanone during steam distillation (SD. Optimum therapeutic effects are related to the stability and pharmacological activity of the drugs. Consequently, we studied the stability of sodium houttuyfonate under a simulated gastrointestinal environment with the main influencing factors being solvent, temperature and pH effects. For the first time, sodium houttuyfonate and 2-undecanone were detected simultaneously in the mouse serum and the gastrointestinal tissue after oral administration. Sodium houttuyfonate is detected within a short period of time in the systemic circulation and tissues without conversion to 2-undecanone.

  3. Pharmacokinetics of Melatonin

    DEFF Research Database (Denmark)

    Andersen, Lars Peter Holst; Gögenur, Ismail; Rosenberg, Jacob

    2016-01-01

    Despite widespread clinical application of melatonin, several unanswered questions remain regarding the pharmacokinetics of this drug. This lack of knowledge may contribute to the inconsistency of results in previous clinical studies. Currently, a t max value of 30-45 min and a t ½elimination of 45...... min are well established. Several questions relate to what constitutes a clinically effective plasma concentration, the choice of ideal administration route, and the optimal method of analysis. Furthermore, investigations of melatonin metabolites in humans are urgently needed in order to characterize...

  4. PEGylation of {sup 99m}Tc-labeled bombesin analogues improves their pharmacokinetic properties

    Energy Technology Data Exchange (ETDEWEB)

    Daepp, Simone; Garayoa, Elisa Garcia [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, CH-5232 Villigen-PSI (Switzerland); Maes, Veronique; Brans, Luc; Tourwe, Dirk A. [Department of Organic Chemistry, Vrije Universiteit Brussel, 1050 Brussels (Belgium); Mueller, Cristina [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, CH-5232 Villigen-PSI (Switzerland); Schibli, Roger, E-mail: roger.schibli@psi.ch [Paul Scherrer Institute, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, CH-5232 Villigen-PSI (Switzerland); Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich (Switzerland)

    2011-10-15

    Introduction: Radiolabeled bombesin (BN) conjugates are promising radiotracers for imaging and therapy of breast and prostate tumors in which BN{sub 2}/gastrin-releasing peptide (GRP) receptors are overexpressed. However, the low in vivo stability of BN conjugates may limit their clinical application. In an attempt to improve their pharmacokinetics and counteract their rapid enzymatic degradation, we prepared a series of polyethylene glycol (PEG)-ylated BN(7-14) analogues for radiolabeling with {sup 99m}Tc(CO){sub 3} and evaluated them in vitro and in vivo. Methods: Derivatization of a stabilized (N{sup {alpha}H}is)Ac-BN(7-14)[Cha{sup 13},Nle{sup 14}] analogue with linear PEG molecules of various sizes [5 kDa (PEG{sub 5}), 10 kDa (PEG{sub 10}) and 20 kDa (PEG{sub 20})] was performed by PEGylation of the {epsilon}-amino group of a {beta}{sup 3}hLys-{beta}Ala-{beta}Ala spacer between the stabilized BN sequence and the (N{sup {alpha}H}is)Ac chelator. The analogues were then radiolabeled by employing the {sup 99m}Tc-tricarbonyl technique. Binding affinity and internalization/externalization studies were performed in vitro in human prostate carcinoma PC-3 cells. Stability was investigated in vitro in human plasma and in vivo in Balb/c mice. Finally, single photon emission computed tomography (SPECT)/X-ray computed tomography studies were performed in nude mice bearing PC-3 tumor xenografts. Results: PEGylation did not affect the binding affinity of BN analogues, as the binding affinity for BN{sub 2}/GRP receptors remained high (K{sub d}<0.9 nM). However, in vitro binding kinetics of the PEGylated analogues were slower. Steady-state condition was reached after 4 h, and the total cell binding was 10 times lower than that for the non-PEGylated counterpart. Besides, PEGylation improved the stability of BN conjugates in vitro and in vivo. The BN derivative conjugated with a PEG{sub 5} molecule showed the best pharmacokinetics in vivo, i.e., faster blood clearance and

  5. A comparative evaluation of dimensional stability of three types of interocclusal recording materials-an in-vitro multi-centre study

    Directory of Open Access Journals (Sweden)

    Tejo Sampath

    2012-10-01

    Full Text Available Abstract Background The introduction of different interocclusal recording materials has put clinicians in dilemma that which material should be used in routine clinical practice for precise recording and transferring of accurate existing occlusal records for articulation of patient’s diagnostic or working casts in the fabrication of good satisfactory prosthesis. In the era of developing world of dentistry the different materials are introduced for interocclusal record with different brand names because of this; the utility of the material is confusing for successful delivery of prosthesis with lack of in vitro or in vivo studies which will predict the property of the material with utility recommendations. Purpose of the study The aim of this multicenter research is to evaluate the time dependent linear dimensional stability of three types of interocclusal recording materials; which gives very clear idea to clinicians in regard to its usage in routine practice and recommendations for usage of the different materials. Also to find out ideal time for articulation of three types of interocclusal recording materials with accuracy. Materials and method Commercially available and ADA approved Polyether bite registration paste (Ramitec, Poly vinyl siloxane bite registration paste (Jetbite and Zinc oxide eugenol (ZOE bite registration paste (Super bite were used in the study. A stainless steel die was made according to modified American dental Associations (ADA specification no. 19. Each one of the tested materials were manipulated according to manufacturers’ instructions. The materials separated from die, 3-mins after their respective setting time, resulted in disks of standard diameter. Two parallel lines and three perpendicular lines reproduced on the surface. The distance between two parallel lines was measured at different time intervals i.e. 1 hour, 24, 48 and 72 hours by using travelling microscope (magnus and compared with standard die

  6. Physiologically Based Pharmacokinetic Modeling of Palbociclib.

    Science.gov (United States)

    Yu, Yanke; Loi, Cho-Ming; Hoffman, Justin; Wang, Diane

    2017-02-01

    Palbociclib is an orally available CDK4/6 inhibitor. In humans, palbociclib undergoes metabolism mediated primarily by CYP3A and SULT2A1, and it is also a weak time-dependent CYP3A inhibitor. The objectives of the current study are to (1) develop a physiologically based pharmacokinetic (PBPK) model of palbociclib based on the in silico, in vitro, and in vivo pharmacokinetic data of palbociclib, (2) verify the PBPK model with clinical drug-drug interaction (DDI) results of palbociclib with strong CYP3A inhibitor (itraconazole), inducer (rifampin), and a sensitive CYP3A substrate (midazolam), and (3) predict the DDI risk of palbociclib with moderate/weak CYP3A inhibitors. The developed PBPK model adequately described the observed pharmacokinetics of palbociclib after administration of a single oral or intravenous dose of palbociclib. The model-predicted DDIs of palbociclib with itraconazole, rifampin, and midazolam were consistent with the observed DDIs, with the discrepancies of the predicted vs observed AUCR and Cmax R within 20%, except for the AUC ratio of palbociclib with coadministration of rifampin. Using this final PBPK model, it was predicted that weak CYP3A inhibitors (fluoxetine and fluvoxamine) are anticipated to have negligible DDI risk with palbociclib, whereas moderate CYP3A inhibitors (diltiazem and verapamil) may increase plasma palbociclib AUC by ∼40%. A moderate CYP3A inducer (efavirenz) may decrease plasma palbociclib AUC by ∼40%. The established model is considered sufficiently robust for other applications in support of the continued development for palbociclib. © 2016, The American College of Clinical Pharmacology.

  7. Synthesis and formulation studies of griseofulvin analogues with improved solubility and metabolic stability.

    Science.gov (United States)

    Petersen, Asger B; Andersen, Nikolaj S; Konotop, Gleb; Hanafiah, Nur Hafzan Md; Raab, Marc S; Krämer, Alwin; Clausen, Mads H

    2017-04-21

    Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low μM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. Effects of applying molasses, lactic acid bacteria and propionic acid on fermentation quality, aerobic stability and in vitro gas production of total mixed ration silage prepared with oat-common vetch intercrop on the Tibetan Plateau.

    Science.gov (United States)

    Chen, Lei; Guo, Gang; Yuan, Xianjun; Zhang, Jie; Li, Junfeng; Shao, Tao

    2016-03-30

    The objective of this study was to investigate the effect of molasses, lactic acid bacteria and propionic acid on the fermentation quality, aerobic stability and in vitro gas production of total mixed ration (TMR) silage prepared with oat-common vetch intercrop on the Tibetan plateau. TMR (436 g kg(-1) dry matter (DM)) was ensiled with six experimental treatments: (1) no additives (control); (2) molasses (M); (3) an inoculant (Lactobacillus plantarum) (L); (4) propionic acid (P); (5) molasses + propionic acid (MP); (6) inoculant + propionic acid (LP). All silages were well preserved with low pH (digestibility (IVDMD) as compared with the control. L treatment decreased (P oat-common vetch intercrop can be well preserved. Although propionic acid is compatible with lactic acid bacteria, and when used together, they had minor effects on fermentation, aerobic stability and in vitro digestibility of TMR silage prepared with oat-common vetch intercrop. © 2015 Society of Chemical Industry.

  9. Insulin aspart pharmacokinetics

    DEFF Research Database (Denmark)

    Rasmussen, Christian Hove; Roge, Rikke Meldgaard; Ma, Zhulin

    2014-01-01

    Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between...... to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for human insulin are used to understand and quantify the systemic...... distribution and elimination (Porksen et al., 1997; Sjostrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b...

  10. Impact of C4'-O-Alkyl Linker on in Vivo Pharmacokinetics of Near-Infrared Cyanine/Monoclonal Antibody Conjugates.

    Science.gov (United States)

    Sato, Kazuhide; Nagaya, Tadanobu; Nakamura, Yuko; Harada, Toshiko; Nani, Roger R; Shaum, James B; Gorka, Alexander P; Kim, Insook; Paik, Chang H; Choyke, Peter L; Schnermann, Martin J; Kobayashi, Hisataka

    2015-09-08

    Near-infrared (NIR) fluorophores have several advantages over visible-light fluorophores, including superior tissue penetration and lower autofluorescence. We recently accessed a new class of readily synthesized NIR cyanines containing a novel C4'-O-alkyl linker, which provides both high chemical stability and excellent optical properties. In this study, we provide the first in vivo analysis of this new class of compounds, represented by the tetrasulfonate FNIR-774 (Frederick NIR 774). Monoclonal antibody (mAb) conjugates of FNIR-774 were compared to conjugates of the commercially available dye (IRDye800CW (IR800)), one of the most widely used NIR fluorophores for clinical translation. Both dyes were conjugated to panitumumab (pan) or cetuximab (cet) with ratios of 1:2 or 1:5. Conjugates of both dyes demonstrated similar quenching capacity, stability, and brightness in target cells in vitro. In contrast, in vivo imaging in mice showed different pharmacokinetics between pan-FNIR-774 (1:5) and pan-IR800 (1:5), or cet-FNIR-774 (1:5) and cet-IR800 (1:5). Particularly at the higher labeling density, mAb-FNIR-774 conjugates showed superior specific accumulation in tumors compared with mAb-IR800 conjugates. Thus, FNIR-774 conjugates showed superior in vivo pharmacokinetics compared with IR800 conjugates, independent of the mAb. These results suggest that FNIR-774 is a promising fluorescent probe for NIR optical imaging.

  11. Pharmacokinetics of Cannabinoids

    Directory of Open Access Journals (Sweden)

    Iain J McGilveray

    2005-01-01

    Full Text Available Delta-9-tetrahydrocannabinol (Δ-9-THC is the main psychoactive ingredient of cannabis (marijuana. The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC and nabilone. The variability of THC in plant material (0.3% to 30% leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152±86.3 ng/mL occured approximately 10 min after inhalation. Oral THC, on the other hand, is only 4% to 12% bioavailable and absorption is highly variable. THC is eliminated from plasma in a multiphasic manner, with low amounts detectable for over one week after dosing. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20% and 100% of parent, respectively. THC is widely distributed, particularly to fatty tissues, but less than 1% of an administered dose reaches the brain, while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes occurs via the feces and urine. Metabolites persist in the urine and feces for severalweeks. Nabilone is well absorbed and the pharmacokinetics, although variable, appear to be linear from oral doses of 1 mg to 4 mg (these doses show a plasma elimination half-life of approximately 2 h. As with THC, there is a high first-pass effect, and the feces to urine ratio of excretion is similar to other cannabinoids. Pharmacokineticpharmacodynamic modelling with plasma THC versus cardiac and psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials have found that nabilone produces less tachycardia and less euphoria than THC for a similar antiemetic response.

  12. In vitro effects of anthocyanin extracts from Justicia secunda Vahl on the solubility of haemoglobin S and membrane stability of sickle erythrocytes.

    Science.gov (United States)

    Mpiana, Pius T; Ngbolua, KotoTe Niwa N; Bokota, Matthieu T; Kasonga, Teddy K; Atibu, Emmanuel K; Tshibangu, Damien S T; Mudogo, Virima

    2010-10-01

    Sickle cell disease or drepanocytosis is caused by the polymerisation of abnormal haemoglobin S when oxygen tension decreases. This lead to the changes in the shape of red blood cells and anaemia. It has also been postulated that the red cells of patients with sickle cell disease contain a higher than normal concentration of calcium ions. These ions are bound to membrane proteins resulting in dehydration and loss of red blood cell deformability and cell-to-cell adherence. Anthocyanins extracted from some Congolese plants used in traditional medicine against sickle cell disease have recently been shown to have anti-sickling activity in vitro. Justicia secunda is a plant used in Congo by Jehovah's Witnesses, well known for their refusal of blood transfusions, against anaemia. Emmel, Itano and osmotic fragility tests were used to test the effect of anthocyanin extracts from Justicia secunda leaves on haemoglobin S solubility and sickle cell membrane stability. Anthocyanins from Justicia secunda were found to possess anti-sickling activity. Treated SS red blood cells recovered a normal, classical biconcave form with a radius of 3.3±0.3 μm, similar to that of normal erythrocytes. The solubility of deoxyhaemoglobin S increased and the osmotic fragility of drepanocytes decreased upon treatment with anthocyanin extracts. These findings suggest that anthocyanin extracts play a role in both stabilising the red blood cell membrane and inhibiting polymerisation of haemoglobin S. This provides a possible molecular basis for earlier reports on the anti-sickling properties of anthocyanins from some Congolese plants and their use in the management of sickle cell disease by Congolese traditional healers.

  13. Pharmacokinetics of clomipramine during pregnancy

    NARCIS (Netherlands)

    Ter Horst, P G J; Proost, J H; Smit, J P; Vries, M T; de Jong-van den Berg, Lolkje; Wilffert, B

    2015-01-01

    Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their

  14. Clinical Pharmacokinetics of Paclitaxel Monotherapy

    DEFF Research Database (Denmark)

    Stage, Tore B; Bergmann, Troels K; Kroetz, Deanna L

    2017-01-01

    Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic efficacy of paclitaxel, we reviewed the literature on paclitaxel pharmacokinetics. Systematic data mining was performed to extract...... the maximum concentration (C max), clearance (CL), and time of paclitaxel plasma concentration above 0.05 µmol/L (T > 0.05 µmol/L) following monotherapy of both the widely used cremophor-diluted paclitaxel and nanoparticle albumin-bound (nab-)paclitaxel. We identified a total of 53 studies yielding 121...... aggregated pharmacokinetic profiles for paclitaxel monotherapy and extracted reported mean and median estimates of pharmacokinetic parameters. Paclitaxel has been studied formally at doses of 15-825 mg/m(2) and infused over 0.5-96 h; included studies examined both weekly and every 3-weeks dosing cycles...

  15. The Pharmacokinetics and Pharmacodynamics of Iron Preparations

    Directory of Open Access Journals (Sweden)

    Susanna Burckhardt

    2011-01-01

    Full Text Available Standard approaches are not appropriate when assessing pharmacokinetics of iron supplements due to the ubiquity of endogenous iron, its compartmentalized sites of action, and the complexity of the iron metabolism. The primary site of action of iron is the erythrocyte, and, in contrast to conventional drugs, no drug-receptor interaction takes place. Notably, the process of erythropoiesis, i.e., formation of new erythrocytes, takes 3−4 weeks. Accordingly, serum iron concentration and area under the curve (AUC are clinically irrelevant for assessing iron utilization. Iron can be administered intravenously in the form of polynuclear iron(III-hydroxide complexes with carbohydrate ligands or orally as iron(II (ferrous salts or iron(III (ferric complexes. Several approaches have been employed to study the pharmacodynamics of iron after oral administration. Quantification of iron uptake from radiolabeled preparations by the whole body or the erythrocytes is optimal, but alternatively total iron transfer can be calculated based on known elimination rates and the intrinsic reactivity of individual preparations. Degradation kinetics, and thus the safety, of parenteral iron preparations are directly related to the molecular weight and the stability of the complex. High oral iron doses or rapid release of iron from intravenous iron preparations can saturate the iron transport system, resulting in oxidative stress with adverse clinical and subclinical consequences. Appropriate pharmacokinetics and pharmacodynamics analyses will greatly assist our understanding of the likely contribution of novel preparations to the management of anemia.

  16. Novel self-assembled nano-tubular mixed micelles of Pluronics P123, Pluronic F127 and phosphatidylcholine for oral delivery of nimodipine: In vitro characterization, ex vivo transport and in vivo pharmacokinetic studies.

    Science.gov (United States)

    Basalious, Emad B; Shamma, Rehab N

    2015-09-30

    Subarachnoid hemorrhage (SAH) is a major cause of death in patients suffering from stroke. Nimodipine (NM) is the only FDA-approved drug for treating SAH-induced vasospasm. However, NM suffers from poor oral bioavailability (5-13%) due to its low aqueous solubility, extensive first pass metabolism and short elimination half-life (1-2h). The objective of this study was to develop NM-loaded Pluronic/phosphatidylcholine/polysorbate 80 mixed micelles (PPPMM) that can solubilize NM in aqueous media even after dilution, prolong its circulation time, improve its bioavailability and eventually help in targeting it to the brain tissue. PPPMM formulations were prepared using the thin film hydration technique, and evaluated for drug payload, solubilization efficiency (SE), micellar size, zeta potential, transmission electron microscopy (TEM) and ex vivo transport through rat intestine. The selected NM-loaded PPPMM, containing PC to Pluronics(®) molar ratio of 75:25, showed a drug payload, SE, micellar size and zeta potential of 1.06 ± 0.03 mg/mL, 99.2 ± 2.01%, 571.5 ± 11.87 nm and -31.2 ± 0.06 mv, respectively. The selected formulation had a much larger hydrophobic core volume for solubilization of NM and exhibited the highest NM transport. TEM micrographs illustrated the formation of highly flexible nano-tubular mixed micelles (NTMM). The in vivo pharmacokinetic study showed greater bioavailability of NM in plasma (232%) and brain (208%) of rats from NM-loaded PPPMM compared to that of the drug solution due to the efficiency of flexible NTMM to enhance absorption of NM from the intestinal mucosa. The significant increase in drug solubility, enhanced drug absorption and the long circulation time of the NTMM could be promising to improve oral and parenteral delivery of NM. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Evaluation of vancomycin and daptomycin against methicillin-resistant Staphylococcus aureus and heterogeneously vancomycin-intermediate S. aureus in an in vitro pharmacokinetic/pharmacodynamic model with simulated endocardial vegetations.

    Science.gov (United States)

    Leonard, Steven N; Rybak, Michael J

    2009-01-01

    Glycopeptides have historically been the drugs of choice for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). However, the continued selective pressure has led to the emergence of non-susceptible strains including heterogeneously vancomycin-intermediate S. aureus (hVISA). Infections with hVISA have been associated with poor outcomes including vancomycin treatment failures. The objective of this study was to evaluate vancomycin and daptomycin against vancomycin-susceptible MRSA and hVISA in a pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations. Six clinical isolates obtained from patients at the Detroit Medical Center were used: MRSA 494, MRSA 67, hVISA R1720, hVISS R2295, hVISA R3640 and hVISA R1629. All heteroresistant strains were confirmed by a population analysis profile ratio, with Mu3 as a control strain. Vancomycin regimens of 1 g every 12 h and 2 g every 12 h and daptomycin regimens of 6, 10 and 12 mg/kg daily were utilized in a PK/PD model over 72 h. Against MRSA isolates, vancomycin displayed minimal activity and minimal-to-no activity against hVISA. In general, the use of high dose vancomycin over standard dose vancomycin did not improve activity except against one of six isolates (MRSA 494). Daptomycin was bactericidal against both MRSA and hVISA isolates, although the rate of kill was slower against hVISA. Overall, daptomycin achieved rapid and effective kill against both MRSA and hVISA while vancomycin displayed slow and minimal kill against MRSA and minimal-to-no activity against hVISA, regardless of high dose exposure.

  18. Optimization (Central Composite Design and Validation of HPLC Method for Investigation of Emtricitabine Loaded Poly(lactic-co-glycolic acid Nanoparticles: In Vitro Drug Release and In Vivo Pharmacokinetic Studies

    Directory of Open Access Journals (Sweden)

    Gurinder Singh

    2014-01-01

    Full Text Available The objective of the current study is to develop nanoparticles (NPs drug delivery system of emtricitabine solely using poly(lactic-co-glycolic acid (PLGA and evaluate its in vitro and in vivo release performance by systematically optimized HPLC method using Formulation by Design (FbD. NPs were evaluated for in vitro release and in vivo absorption study. The desired chromatographic separation was achieved on a Phenomenex C18 (250 mm × 4.6 mm I.D., 5 μm column, under isocratic conditions using UV detection at 280 nm. The optimized mobile phase consisted of a mixture of 40 mM phosphate dihydrogen phosphate buffer (pH 6.8, methanol, and 2% acetonitrile in a ratio of (83 : 15 : 2, v/v/v at a flow rate of 1 mL/min. The linear regression analysis for the calibration curves showed a good linear correlation over the concentration range 0.040–2.0 μg/mL, with retention time of 4.39 min. An average encapsulation efficiency of 74.34% was obtained for NPs. In vitro studies showed zero-order release and about 95% drug being released within 15 days in PBS (pH 7.4. In conclusion, the proposed optimized method was successfully applied for the determination of in vitro and in vivo release studies of emtricitabine NPs.

  19. The pharmacokinetics of intravenous fenoldopam in healthy, awake cats.

    Science.gov (United States)

    O'Neill, K E; Labato, M A; Court, M H

    2016-04-01

    Fenoldopam is a selective dopamine-1 receptor agonist that improves diuresis by increasing renal blood flow and perfusion and causing peripheral vasodilation. Fenoldopam has been shown to induce diuresis and be well-tolerated in healthy cats. It is used clinically in cats with oliguric kidney injury at doses extrapolated from human medicine and canine studies. The pharmacokinetics in healthy beagle dogs has been reported; however, pharmacokinetic data in cats are lacking. The goal of this study was to determine pharmacokinetic data for healthy, awake cats receiving an infusion of fenoldopam. Six healthy, awake, client-owned cats aged 2-6 years old received a 120-min constant rate infusion of fenoldopam at 0.8 μg/kg/min followed by a 20-min washout period. Ascorbate stabilized plasma samples were collected during and after the infusion for the measurement of fenoldopam concentration by HPLC with mass spectrometry detection. This study showed that the geometric mean of the volume of distribution, clearance, and half-life (198 mL/kg, 46 mL/kg/min, and 3.0 mins) is similar to pharmacokinetic parameters for humans. No adverse events were noted. Fenoldopam at a constant rate infusion of 0.8 μg/kg per min was well tolerated in healthy cats. Based on the results, further evaluation of fenoldopam in cats with kidney disease is recommended. © 2016 John Wiley & Sons Ltd.

  20. An on-chip small intestine-liver model for pharmacokinetic studies.

    Science.gov (United States)

    Kimura, Hiroshi; Ikeda, Takashi; Nakayama, Hidenari; Sakai, Yasuyuki; Fujii, Teruo

    2015-06-01

    Testing of drug effects and cytotoxicity by using cultured cells has been widely performed as an alternative to animal testing. However, the estimation of pharmacokinetics by conventional cell-based assay methods is difficult because of the inability to evaluate multiorgan effects. An important challenge in the field is to mimic the organ-to-organ network in the human body by using a microfluidic network connecting small-scale tissues based on recently emerging MicroTAS (Micro Total Analysis Systems) technology for prediction of pharmacokinetics. Here, we describe an on-chip small intestine-liver coupled model for pharmacokinetic studies. To construct an in vitro pharmacokinetic model that appropriately models in vivo conditions, physiological parameters such as the structure of internal circulation, volume ratios of each organ, and blood flow ratio of the portal vein to the hepatic artery were mimicked using microfluidic networks. To demonstrate interactions between organs in vitro in pharmacokinetic studies, Caco-2, HepG2, and A549 cell cultures were used as organ models of the small intestine, liver, and lung, respectively, and connected to each other through a microporous membrane and microchannels to prepare a simple model of a physiological organ-to-organ network. The on-chip organ model assay using three types of substrate-epirubicine (EPI), irinotecan (CPT-11), and cyclophosphamide (CPA)-were conducted to model the effects of orally administered or biologically active anticancer drugs. The result suggested that the device can replicate physiological phenomena such as activity of the anticancer drugs on the target cells. This microfluidic device can thus be used as an in vitro organ model to predict the pharmacokinetics of drugs in the human body and may thus provide not only an alternative to animal testing but also a method of obtaining parameters for in silico models of physiologically based pharmacokinetics. © 2014 Society for Laboratory Automation and

  1. Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP)

    DEFF Research Database (Denmark)

    Viby-Mogensen, J.; Østergaard, D.; Donati, F.

    2000-01-01

    Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design......Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design...

  2. Design, Characterization, and In Vivo Pharmacokinetics of Tacrolimus Proliposomes.

    Science.gov (United States)

    Nekkanti, Vijaykumar; Rueda, Javier; Wang, Zhijun; Betageri, Guru V

    2016-10-01

    The objective of this study was to develop proliposomal formulation for a poorly bioavailable drug, tacrolimus. Proliposomes were prepared by thin film hydration method using different lipids such as hydrogenated soy phosphatidylcholine (HEPC), soy phosphatidylcholine (SPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoylphosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. Proliposomes were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague-Dawley (SD) rats. Among the different formulations, proliposomes with drug/DSPC/cholesterol in the ratio of 1:2:0.5 demonstrated the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes compared to pure tacrolimus in purified water after 1 h. Tacrolimus permeability across PAMPA and everted rat intestinal perfusion models was significantly higher with proliposomes. The optimized formulation of proliposomes indicated a significant improvement in the rate and absorption of tacrolimus. Following a single oral administration, a relative bioavailability of 193.33% was achieved compared to pure tacrolimus suspension.

  3. Evaluation of feed value of a by-product of pickled radish for ruminants: analyses of nutrient composition, storage stability, and in vitro ruminal fermentation

    Directory of Open Access Journals (Sweden)

    Seoyoung Jeon

    2016-09-01

    Full Text Available Abstract Background By-products of pickled radish (BPR are considered food waste. Approximately 300 g/kg of the total mass of raw materials becomes BPR. Production of pickled radish has grown continuously and is presently about 40,000 metric tons annually in Korea. The objective of the present study was thus to explore the possibility of using BPR as a ruminant feed ingredient. Results BPR contained a large amount of moisture (more than 800 g/kg and ash, and comprised mostly sodium (103 g/kg DM and chloride (142 g/kg DM. On a dry matter basis, the crude protein (CP and ether extract (EE levels in BPR were 75 g/kg and 7 g/kg, respectively. The total digestible nutrient (TDN level was 527 g/kg and the major portion of digestible nutrients was carbohydrate; 88 % organic matter (OM was carbohydrate and 65 % of total carbohydrate was soluble or degradable fiber. The coefficient of variation (CV of nutrient contents among production batches ranged from 4.65 to 33.83 %. The smallest CV was observed in OM, and the largest, in EE. The variation in CP content was relatively small (10.11 %. The storage stability test revealed that storage of BPR at 20 °C (room temperature might not cause spoilage for 4 d, and possibly longer. If BPR is refrigerated, spoilage can be deferred for 21 d and longer. The in vitro ruminal fermentation study showed that substitution of annual ryegrass straw with BPR improved ruminal fermentation, as evidenced by an increase in VFA concentration, DM degradability, and total gas production. Conclusion The major portion of nutrients in BPR is soluble or degradable fiber that can be easily fermented in the rumen without adverse effects, to provide energy to ruminant animals. Although its high sodium chloride content needs to be considered when formulating a ration, BPR can be successfully used as a feed ingredient in a ruminant diet, particularly if it is one component of a total mixed ration.

  4. [Pharmacokinetic-pharmacodynamic models for inhaled anaesthetics

    NARCIS (Netherlands)

    Kreuer, S.; Bruhn, J.; Wilhelm, W.; Bouillon, T.

    2007-01-01

    Pharmacokinetic models can be differentiated into two groups: physiological-based models and empirical models. Traditionally the pharmacokinetics of volatile anaesthetics are described using physiological-based models together with the respective tissue-blood distribution coefficients. The

  5. Clinical pharmacokinetics of phenobarbital in neonates

    NARCIS (Netherlands)

    Touw, D J; Graafland, O; Cranendonk, A; Vermeulen, R J; van Weissenbruch, M M

    2000-01-01

    Demographic and clinical pharmacokinetic data collected from term and preterm neonates who were treated with intravenous phenobarbital have been analysed to evaluate the role of patient characteristics in pharmacokinetic parameters. Significant relationships between total body weight (TBW) or body

  6. Synthesis and pharmacokinetic property improvement of deuterated plinabulin 9

    Science.gov (United States)

    Zhao, Jianchun; Cheng, Hejuan; Sun, Tianwen; Wang, Shixiao; Ding, Zhongpeng; Dou, Guifang; Meng, Zhiyun; Guan, Huashi; Li, Wenbao

    2017-04-01

    Plinabulin, a potent microtubule-targeting agent, is derived from marine natural diketopiperazine `phenylahistin'. To develop novel plinabulin analogue that could display better pharmacokinetic properties and less side effects, deuterated plinabulin 9 was synthesized and evaluated in vitro and in vivo. In comparison with plinabulin, in vivo pharmacokinetic studies indicated that the deuterated derivative 9 could alter blood circulation behavior obviously, which was proved by increased area under the plasma concentration- time curve (AUC0-∞), reduced clearance (CL), and prolonged total body mean residence time (MRT). The derivative 9 also has higher inhibition rates against BxPC-3, Jurkat and A-431 tumor cell lines as compared with its prototype plinabulin. Therefore, the deuterated compound 9 might be developed as a potential agent for different cancer treatments.

  7. Pharmacokinetic and pharmacodynamic variability as possible causes for different drug responses in migraine. A comment

    DEFF Research Database (Denmark)

    Tfelt-Hansen, P; Edvinsson, L

    2007-01-01

    The pharmacokinetics of antimigraine drugs zolmitriptan and sumatriptan varied considerably with a fourfold to 10-fold variation in plasma levels. In addition, the pharmacodynamics of triptans as investigated in vitro also varied considerably. In theory, there should probably be a 10-fold variati...... in doses available, but in clinical practice a fourfold difference in doses will probably cover the needs of most patients....

  8. Pharmacokinetics and anti-HIV-1 efficacy of negatively charged human serum albumins in mice

    NARCIS (Netherlands)

    Kuipers, M E; Swart, P J; Schutten, Martin; Smit, C; Proost, J H; Osterhaus, A D; Meijer, D K

    Negatively charged albumins (NCAs, with the prototypes succinylated human serum albumin (Suc-HSA) and aconitylated human serum albumin (Aco-HSA)), modified proteins with a potent anti-human immunodeficiency virus type 1 (anti-HIV-1) activity in vitro, were studied for their pharmacokinetic behaviour

  9. Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion

    NARCIS (Netherlands)

    J.W. Mouton (Johan); A.A. Vinks; N.C. Punt

    1997-01-01

    textabstractWe developed and applied pharmacokinetic-pharmacodynamic (PK-PD) models to characterize in vitro bacterial rate of killing as a function of ceftazidime concentrations over time. For PK-PD modeling, data obtained during continuous and intermittent infusion of

  10. Antiretroviral Pharmacokinetics in Pregnant Women.

    Science.gov (United States)

    Gilbert, Elise M; Darin, Kristin M; Scarsi, Kimberly K; McLaughlin, Milena M

    2015-09-01

    For women infected with the human immunodeficiency virus (HIV) who become pregnant, the use of combination antiretroviral therapy (ART) significantly reduces transmission of HIV from mother to child. Selection of an appropriate ART regimen for use among pregnant women requires consideration of numerous factors including maternal and fetal safety, antiretroviral pharmacokinetics, and regimen efficacy. Optimization of antiretroviral pharmacokinetics during pregnancy requires special consideration because pregnancy-associated changes in drug absorption, distribution, metabolism, and excretion are known to occur throughout pregnancy and postpartum. Understanding antiretroviral placental transfer may offer additional insight into each drug's potential role in preventing HIV transmission in utero and may also have implications regarding viral resistance in cases where transmission does occur. In this review, we summarize key published data describing antiretroviral pharmacokinetics in pregnant women, providing suggestions for clinical application of these data where appropriate. © 2015 Pharmacotherapy Publications, Inc.

  11. Surface stabilized efavirenz nanoparticles for oral bioavailability enhancement.

    Science.gov (United States)

    Jain, Sanyog; Sharma, Jagadish M; Agrawal, Ashish K; Mahajan, Rahul R

    2013-11-01

    The aim of the present study was to prepare surface stabilized nanoparticles for oral bioavailability enhancement of efavirenz (EFZ). EFZ nanoparticles (EFZ-NPs) were prepared by combination of anti-solvent precipitation and high pressure homogenization technique, using hydroxy propyl methyl cellulose as stabilizer which resulted in formation of EFZ-NPs of average particle size -350 nm with excellent particles size distribution (distribution and drug content. EFZ-NPs demonstrated an increase in saturation solubility by 5.16 folds in comparison with free EFZ. In vitro dissolution studies established advantage of EFZ-NPs over free EFZ as more than 75% drug was dissolved within 5 min in case of EFZ-NPs while it was approx 20% in case of free EFZ. In vivo pharmacokinetic studies further confirmed the potential of EFZ-NPs as 2.02 folds increase in peak plasma concentration and 2.29 folds increase in AUC(0-infinity) were observed in comparison to free EFZ. The In vitro-In vivo relationship of the formulations further suggested higher correlation coefficient of 0.9995 for EFZ-NPs in Levys plot as compared to 0.8726 for free EFZ.

  12. Use of Physiologically Based Pharmacokinetic (PBPK) Models ...

    Science.gov (United States)

    EPA announced the availability of the final report, Use of Physiologically Based Pharmacokinetic (PBPK) Models to Quantify the Impact of Human Age and Interindividual Differences in Physiology and Biochemistry Pertinent to Risk Final Report for Cooperative Agreement. This report describes and demonstrates techniques necessary to extrapolate and incorporate in vitro derived metabolic rate constants in PBPK models. It also includes two case study examples designed to demonstrate the applicability of such data for health risk assessment and addresses the quantification, extrapolation and interpretation of advanced biochemical information on human interindividual variability of chemical metabolism for risk assessment application. It comprises five chapters; topics and results covered in the first four chapters have been published in the peer reviewed scientific literature. Topics covered include: Data Quality ObjectivesExperimental FrameworkRequired DataTwo example case studies that develop and incorporate in vitro metabolic rate constants in PBPK models designed to quantify human interindividual variability to better direct the choice of uncertainty factors for health risk assessment. This report is intended to serve as a reference document for risk assors to use when quantifying, extrapolating, and interpretating advanced biochemical information about human interindividual variability of chemical metabolism.

  13. Pharmacokinetics of mitragynine in man.

    Science.gov (United States)

    Trakulsrichai, Satariya; Sathirakul, Korbtham; Auparakkitanon, Saranya; Krongvorakul, Jatupon; Sueajai, Jetjamnong; Noumjad, Nantida; Sukasem, Chonlaphat; Wananukul, Winai

    2015-01-01

    Kratom, known botanically as Mitragyna speciosa (Korth.), is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users. Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method. Ten male subjects completed the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour), terminal half-life (23.24±16.07 hours), and the apparent volume of distribution (38.04±24.32 L/kg). The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half-life of about 1 day. The pharmacokinetic

  14. Perinatal pharmacokinetics of azithromycin for cesarean prophylaxis.

    Science.gov (United States)

    Sutton, Amelia L; Acosta, Edward P; Larson, Kajal B; Kerstner-Wood, Corenna D; Tita, Alan T; Biggio, Joseph R

    2015-06-01

    Postpartum infections are polymicrobial and typically include Ureaplasma, an intracellular microbe that is treated by macrolides such as azithromycin. The aim of this study was to evaluate the perinatal pharmacokinetics of azithromycin after a single preincision dose before cesarean delivery. Thirty women who underwent scheduled cesarean delivery were assigned randomly to receive 500 mg of intravenous azithromycin that was initiated 15, 30, or 60 minutes before incision and infused over 1 hour. Serial maternal plasma samples were drawn from the end of infusion up to 8 hours after the infusion. Samples of amniotic fluid, umbilical cord blood, placenta, myometrium, and adipose tissue were collected intraoperatively. Breast milk samples were collected 12-48 hours after the infusion in 8 women who were breastfeeding. Azithromycin was quantified with high performance liquid chromatography separation coupled with tandem mass spectrometry detection. Plasma pharmacokinetic parameters were estimated with the use of noncompartmental analysis and compartmental modeling and simulations. The maximum maternal plasma concentration was reached within 1 hour and exceeded the in vitro minimum inhibitory concentration (MIC50) of 250 ng/mL of Ureaplasma spp in all 30 patients. The concentrations were sustained with a half-life of 6.7 hours. The median concentration of azithromycin in adipose tissue was 102 ng/g, which was below the MIC50. The median concentration in myometrium was 402 ng/g, which exceeded the MIC50. Azithromycin was detectable in both the umbilical cord plasma and amniotic fluid after the single preoperative dose. Azithromycin concentrations in breast milk were high and were sustained up to 48 hours after the single dose. Simulations demonstrated accumulation in breast milk after multiple doses. A single dose of azithromycin achieves effective plasma and tissue concentrations and is transported rapidly across the placenta. The tissue concentrations that are achieved

  15. Prediction of pharmacokinetics and drug-drug interactions when hepatic transporters are involved.

    Science.gov (United States)

    Li, Rui; Barton, Hugh A; Varma, Manthena V

    2014-08-01

    Hepatobiliary transport mechanisms have been identified to play a significant role in determining the systemic clearance for a number of widely prescribed drugs and an increasing number of new molecular entities (NMEs). While determining the pharmacokinetics, drug transporters also regulate the target tissue exposure and play a key role in regulating the pharmacological and/or toxicological responses. Consequently, it is of great relevance in drug discovery and development to assess hepatic transporter activity in regard to pharmacokinetic and dose predictions and to evaluate pharmacokinetic variability associated with drug-drug interactions (DDIs) and genetic variants. Mechanistic predictions utilizing physiological-based pharmacokinetic modeling are increasingly used to evaluate transporter contribution and delineate the transporter-enzyme interplay on the basis of hypothesis-driven functional in vitro findings. Significant strides were made in the development of in vitro techniques to facilitate characterization of hepatobiliary transport. However, challenges exist in the quantitative in vitro-in vivo extrapolation of transporter kinetics due to the lack of information on absolute abundance of the transporter in both in vitro and in vivo situations, and/or differential function in the holistic in vitro reagents such as suspended and plated hepatocytes systems, and lack of complete mechanistic understanding of liver model structure. On the other hand, models to predict transporter-mediated DDIs range from basic models to mechanistic static and dynamic models. While basic models provide conservative estimates and are useful upfront in avoiding false negative predictions, mechanistic models integrate multiple victim and perpetrator drugs parameters and are expected to provide quantitative predictions. The aim of this paper is to review the current state of the model-based approaches to predict clinical pharmacokinetics and DDIs of drugs or NMEs that are substrates

  16. Interspecies pharmacokinetic scaling and the Dedrick plots.

    Science.gov (United States)

    Boxenbaum, H; Ronfeld, R

    1983-12-01

    Interspecies variations in pharmacokinetics are frequently the consequence of organisms living in different time domains. Whereas species' parameter values differ when referenced to chronological time, scaling of data with respect to active mass (ergosomes) and to ideal (mathematical) pharmacokinetic space time (mesochrons, kallynochrons, or apolysichrons) removes the astronomical time dependency. A theory of pharmacokinetic similarities is presented which states that both physiological and pharmacokinetic processes are biologically interrelated and governed by a master synchronization mechanism; consequently interspecies pharmacokinetic events frequently may be expressed as invariant values; e.g., hexobarbital disposition half-life is approximately the duration of 1,680 gut beats (time standard) regardless of mammalian species. The depletion theory hypothesis of aging that each mammalian organism of set mass is genetically endowed with a set total energy or metabolism (lebenszeitliche Kraft) is found to be adaptable at the microscopic pharmacokinetic level; thus it is hypothesized that each mammalian organism has a genetically determined and finite quantity of phase I hepatic pharmacokinetic stuff (activity) to expend during a lifetime and that this pharmacokinetic stuff (ml cleared X kg-1 X maximum life-span potential-1) is a constant. The rate at which this pharmacokinetic stuff is utilized (comparative pharmacokinetics) is presumed to be regulated by a pharmacokinetic clock, which may undergo either acute or chronic perturbations having either a genetic or environmental origin.

  17. Effect of the fermentation pH on the storage stability of Lactobacillus rhamnosus preparations and suitability of in vitro analyses of cell physiological functions to predict it.

    Science.gov (United States)

    Saarela, M H; Alakomi, H-L; Puhakka, A; Mättö, J

    2009-04-01

    To investigate how cell physiological functions can predict the stability of freeze-dried probiotics. In addition, the effect of the fermentation pH on the stability of probiotics was investigated. Fermenter-grown (pH 5.8 or 5.0) Lactobacillus rhamnosus cells were freeze-dried and their survival was evaluated during storage at 37 degrees C, in apple juice and during acid [hydrochloric acid (HCl) and malic acid] and bile exposure. Cells grown at pH 5.0 were generally coping better with acid-stress than cells grown at pH 5.8. Cells were more sensitive to malic acid compared with HCl. Short-term stability results of Lact. rhamnosus cells in malic acid correlated well with the long-term stability results in apple juice, whereas the results of cell membrane integrity studies were in accordance with bile exposure results. Malic acid exposure can prove useful in evaluating the long-term stability of probiotic preparations in apple juice. Fermentation at reduced pH may ensure a better performance of Lact. rhamnosus cells during the subsequent acid-stress. The beneficial effect of lowered fermentation pH to Lact. rhamnosus stability during storage in apple juice and the usefulness of malic acid test in predicting the stability were shown.

  18. Thalidomide pharmacokinetics in sheep.

    Science.gov (United States)

    Smith, S L; Singh, P; Harding, D; Lun, D; Chambers, J P

    2016-07-01

    To determine the half life (T1/2), time taken to reach maximum plasma concentration (Tmax) and maximum plasma concentration (Cmax) of thalidomide in sheep following I/V, oral and topical treatment with a single dose of thalidomide. Three groups of 4-6-month-old ram lambs were treated with thalidomide dissolved in dimethylsulphoxide (DMSO). The first group (n=10) was treated I/V with 100 mg thalidomide in 2 mL DMSO; the second group (n=8) received 400 mg thalidomide in 2 mL DMSO orally, and the third group (n=8) had 400 mg thalidomide in 4 mL DMSO applied topically. Plasma samples were collected up to 36 hours after treatment, snap-frozen at -80°C and analysed for concentrations of thalidomide using high performance liquid chromatography. Following I/V administration, T1/2 was 5.0 (SEM 0.4) hours, volume of distribution was 3,372.0 (SEM 244.3) mL/kg and clearance was 487.1 (SEM 46.1) mL/hour.kg. Topical application of 400 mg thalidomide did not increase plasma concentrations. Following oral administration, thalidomide bioavailability was 89%, with T1/2, Tmax, and Cmax being 7.2 (SEM 0.8) hours, 3.0 (SEM 0.4) hours and 1,767.3 (SEM 178.1) ng/mL, respectively. Topical administration using DMSO as a solvent did not increase concentrations of thalidomide in plasma. The mean pharmacokinetic parameters determined following oral treatment with 400 mg of thalidomide were similar to those reported in humans receiving a single 400 mg oral dose (T1/2 7.3 hours; Tmax 4.3 hours and Cmax 2,820 ng/mL). There is potential for thalidomide to be used as a model for the treatment of chronic inflammatory conditions in sheep, such as Johne's disease, where tumour necrosis factor alpha plays a pathogenic role.

  19. In-vitro release pharmacokinetics of amikacin, teicoplanin and polyhexanide in a platelet rich fibrin—layer (PRF)—a laboratory evaluation of a modern, autologous wound treatment

    Science.gov (United States)

    Thalhammer, Florian

    2017-01-01

    Objectives Platelet rich fibrin (PRF) is an autologous fibrin glue, produced from patients' blood, which, besides intraoperative use, has applications in the treatment of infected wounds. The combination with antimicrobial agents results in a prolonged antibacterial effect allowing for wound dressing change intervals of seven days even in infected wounds. The aim of this study was to evaluate release kinetics of amikacin, teicoplanin or polyhexanide from a PRF-layer. Methods PRF mixed with teicoplanin, amikacin or polyhexanide was sprayed on a silicon gauze patch and put on a colombia agar with bacteria with known minimal inhibitory concentration (MIC) and incubated for 24 hours and afterwards transferred to another agar with the same bacterial strain. Inhibition zones were measured every 24 hours. This was repeated on 7 consecutive days. Antibiotic concentrations were calculated by interpolation. Results More than 1000 mg/L teicoplanin were released within the first 24 hours and 28.22 mg/L after 168 hours. Amikacin release was above 10,000 mg/L within the first 24 hours and still 120.8 mg/L after 120 hours. A release of polyhexanide could be verified for the first 24 hours only. Consequently teicoplanin and amikacin released from PRF showed antimicrobial in-vitro effects for almost a week, whereas an antimicrobial effect of polyhexanide could only be verified for the first 24 hours. Conclusions Our Results show that a weekly dressing regimen may be justified in wounds treated with PRF plus amikacin or teicoplanin, since bacteria will be eradicated over a considerable period of time after a single application of PRF. PMID:28686663

  20. Preclinical Pharmacokinetics and Pharmacodynamic Target of SCY-078, a First-in-Class Orally Active Antifungal Glucan Synthesis Inhibitor, in Murine Models of Disseminated Candidiasis.

    Science.gov (United States)

    Wring, Stephen A; Randolph, Ryan; Park, SeongHee; Abruzzo, George; Chen, Qing; Flattery, Amy; Garrett, Graig; Peel, Michael; Outcalt, Russell; Powell, Kendall; Trucksis, Michelle; Angulo, David; Borroto-Esoda, Katyna

    2017-04-01

    SCY-078 (MK-3118) is a novel, semisynthetic derivative of enfumafungin and represents the first compound of the triterpene class of antifungals. SCY-078 exhibits potent inhibition of β-(1,3)-d-glucan synthesis, an essential cell wall component of many pathogenic fungi, including Candida spp. and Aspergillus spp. SCY-078 is currently in phase 2 clinical development for the treatment of invasive fungal diseases. In vitro disposition studies to assess solubility, intestinal permeability, and metabolic stability were predictive of good oral bioavailability. Preclinical pharmacokinetic studies were consistent with once-daily administration to humans. After intravenous delivery, plasma clearance in rodents and dogs was low, representing candidiasis, exceeded plasma by 20- to 25-fold for the area under the concentration-time curve from 0 h to infinity (AUC 0-∞ ) and C max SCY-078 achieved efficacy endpoints following oral delivery across multiple murine models of disseminated candidiasis. The pharmacokinetic/pharmacodynamic indices C max /MIC and AUC/MIC correlated with outcome. Target therapeutic exposure, expressed as the plasma AUC 0-24 , was comparable across models, with an upper value of 11.2 μg·h/ml (15.4 μM·h); the corresponding mean value for free drug AUC/MIC was ∼0.75. Overall, these results demonstrate that SCY-078 has the oral and intravenous (i.v.) pharmacokinetic properties and potency in murine infection models of disseminated candidiasis to support further investigation as a novel i.v. and oral treatment for invasive fungal diseases. Copyright © 2017 Wring et al.

  1. Two cholesterol derivative-based PEGylated liposomes as drug delivery system, study on pharmacokinetics and drug delivery to retina

    Science.gov (United States)

    Geng, Shengyong; Yang, Bin; Wang, Guowu; Qin, Geng; Wada, Satoshi; Wang, Jin-Ye

    2014-07-01

    In this study, two cholesterol derivatives, (4-cholesterocarbonyl-4‧-(N,N,N-triethylamine butyloxyl bromide) azobenzene (CAB) and 4-cholesterocarbonyl-4‧-(N,N-diethylamine butyloxyl) azobenzene (ACB), one of which is positively charged while the other is neutral, were synthesized and incorporated with phospholipids and cholesterol to form doxorubicin (DOX)-loaded liposomes. PEGylation was achieved by including 1,2-distearoyl-sn-glycero-3-phosphatiylethanol-amine-N-[methoxy-(polyethylene glycol)-2000 (DSPE-PEG2000). Our results showed that PEGylated liposomes displayed significantly improved stability and the drug leakage was decreased compared to the non-PEGylated ones in vitro. The in vivo study with rats also revealed that the pharmacokinetics and circulation half-life of DOX were significantly improved when liposomes were PEGylated (p derivative ACB played some role in improving liposomes’ stability in systemic circulation compared to the conventional PC liposome and the positively charged CAB liposome, with or without PEGylation. In addition, in the case of local drug delivery, the positively charged PEG-liposome not only delivered much more of the drug into the rats’ retinas (p < 0.001), but also maintained much longer drug retention time compared to the neutral PEGylated liposomes.

  2. In vitro model of infected stratum corneum for the efficacy evaluation of poloxamer 407-based formulations of ciclopirox olamine against Trichophyton rubrum as well as differential scanning calorimetry and stability studies.

    Science.gov (United States)

    Täuber, Anja; Müller-Goymann, Christel C

    2015-10-15

    Superficial fungal skin infections are a common disease and concern 20-25% of the world's population with the dermatophyte Trichophyton rubrum being the main trigger. Due to autoinoculation, fungal skin infections of the feet (tinea pedis) often occur simultaneously with fungal nail infections (onychomycosis). Therefore, the overall objective was the development and characterisation of poloxamer 407-based formulations with the antimycotic active ingredient ciclopirox olamine (CPX) for simultaneous antifungal therapy. The formulations consisted of poloxamer 407, water, isopropyl alcohol, propylene glycol and medium chain triglycerides in given ratios. The in vitro antifungal efficacy against T. rubrum was tested in a novel in vitro model of infected stratum corneum in comparison to a marketed semi-solid formulation containing 1% (w/w) ciclopirox olamine and a marketed nail lacquer containing 8% ciclopirox. Several liquid poloxamer 407-based formulations with only 1% CPX completely inhibited fungal growth after 6 days of incubation, whereas the marketed semi-solid formulation did not inhibit fungal growth. Differential scanning calorimetry studies revealing the interaction between the formulations and the SC showed that increasing isopropyl alcohol/propylene glycol concentrations as well as increasing CPX concentrations caused increasing endothermic transition shifts. Moreover, stability studies at 30 °C exhibited only a slight decrease of the CPX amount after 12 months of storage. Each formulation contained >90% of the initial CPX concentration after termination of the stability studies. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Pharmacokinetics of mitragynine in man

    Directory of Open Access Journals (Sweden)

    Trakulsrichai S

    2015-04-01

    Full Text Available Satariya Trakulsrichai,1,2 Korbtham Sathirakul,3,4 Saranya Auparakkitanon,5 Jatupon Krongvorakul,5 Jetjamnong Sueajai,5 Nantida Noumjad,5 Chonlaphat Sukasem,5 Winai Wananukul2,6 1Department of Emergency Medicine, Faculty of Medicine Ramathibodi Hospital, 2Ramathibodi Poison Center, Faculty of Medicine Ramathibodi Hospital, 3Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 4Center for Drug Research Discovery and Development, Thammasat Univerisity, Prathumthani, Thailand; 5Department of Pathology, Faculty of Medicine Ramathibodi Hospital, 6Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Background: Kratom, known botanically as Mitragyna speciosa (Korth., is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users.Methods: Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method. Results: Ten male subjects completed

  4. A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling

    Science.gov (United States)

    Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

    2016-01-01

    Background Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients’ compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. Methods The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box–Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Results and Discussion Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box–Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry

  5. A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling.

    Science.gov (United States)

    Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

    2016-01-01

    Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients' compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box-Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box-Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry® film to produce pulsatile tablet of

  6. Comparison of pharmacodynamics of azithromycin and erythromycin in vitro and in vivo

    NARCIS (Netherlands)

    J.G. den Hollander (Jan); J.D. Knudsen; J.W. Mouton (Johan); K. Fuursted; N. Frimodt-Moller; H.A. Verbrugh (Henri); F. Espersen

    1998-01-01

    textabstractIn this study, we determined the efficacy of various dosing regimens for erythromycin and azithromycin against four pneumococci with different susceptibilities to penicillin in an in vitro pharmacokinetic model and in a mouse peritonitis model. The MIC was

  7. Unravelling bisphenol A pharmacokinetics using physiologically based pharmacokinetic modeling

    Directory of Open Access Journals (Sweden)

    Xiaoxia eYang

    2015-01-01

    Full Text Available Physiologically based pharmacokinetic (PBPK models integrate both chemical- and system-specific information into a mathematical framework, offering a mechanistic approach to predict the internal dose metrics of a chemical and an ability to perform species and dose extrapolations. Bisphenol A (BPA, because of its ubiquitous presence in a variety of consumer products, has received a considerable amount of attention from the public and regulatory bodies. PBPK models using deuterated BPA were developed for immature and adult rats and non-human primates and for adult humans to understand better the dosimetry of BPA. The focus of the present paper is to provide a rationale for interpreting species- and age-related pharmacokinetics of BPA. Gastrointestinal tract metabolism was an important consideration to predict unconjugated BPA serum kinetic profiles in adult and immature rats and monkeys. Biliary excretion and enterohepatic recirculation of BPA conjugates accounted for the slowed systemic clearance of BPA conjugates in rats. For monkeys, renal reabsorption was proposed as a mechanism influencing systemic clearance of BPA conjugates. The quantitative understanding of the processes driving the pharmacokinetics of BPA across different species and life stages using a computational modeling approach provides more confidence in the interpretation of human biomonitoring data and the extrapolation of experimental animal findings to humans.

  8. Availability, Pharmaceutics, Security, Pharmacokinetics, and Pharmacological Activities of Patchouli Alcohol

    Directory of Open Access Journals (Sweden)

    Guanying Hu

    2017-01-01

    Full Text Available Patchouli alcohol (PA, a tricyclic sesquiterpene, is one of the critical bioactive ingredients and is mainly isolated from aerial part of Pogostemon cablin (known as guanghuoxiang in China belonging to Labiatae. So far, PA has been widely applied in perfume industries. This review was written with the use of reliable information published between 1974 and 2016 from libraries and electronic researches including NCKI, PubMed, Reaxys, ACS, ScienceDirect, Springer, and Wiley-Blackwell, aiming at presenting comprehensive outline of security, pharmacokinetics, and bioactivities of PA and at further providing a potential guide in exploring the PA and its use in various medical fields. We found that PA maybe was a low toxic drug that was acquired numerously through vegetable oil isolation and chemical synthesis and its stability and low water dissolution were improved in pharmaceutics. It also possessed specific pharmacokinetic characteristics, such as two-compartment open model, first-order kinetic elimination, and certain biometabolism and biotransformation process, and was shown to have multiple biological activities, that is, immunomodulatory, anti-inflammatory, antioxidative, antitumor, antimicrobial, insecticidal, antiatherogenic, antiemetic, whitening, and sedative activity. However, the systematic evaluations of preparation, pharmaceutics, toxicology, pharmacokinetics, and bioactivities underlying molecular mechanisms of action also required further investigation prior to practices of PA in clinic.

  9. Availability, Pharmaceutics, Security, Pharmacokinetics, and Pharmacological Activities of Patchouli Alcohol.

    Science.gov (United States)

    Hu, Guanying; Peng, Cheng; Xie, Xiaofang; Zhang, Sanyin; Cao, Xiaoyu

    2017-01-01

    Patchouli alcohol (PA), a tricyclic sesquiterpene, is one of the critical bioactive ingredients and is mainly isolated from aerial part of Pogostemon cablin (known as guanghuoxiang in China) belonging to Labiatae. So far, PA has been widely applied in perfume industries. This review was written with the use of reliable information published between 1974 and 2016 from libraries and electronic researches including NCKI, PubMed, Reaxys, ACS, ScienceDirect, Springer, and Wiley-Blackwell, aiming at presenting comprehensive outline of security, pharmacokinetics, and bioactivities of PA and at further providing a potential guide in exploring the PA and its use in various medical fields. We found that PA maybe was a low toxic drug that was acquired numerously through vegetable oil isolation and chemical synthesis and its stability and low water dissolution were improved in pharmaceutics. It also possessed specific pharmacokinetic characteristics, such as two-compartment open model, first-order kinetic elimination, and certain biometabolism and biotransformation process, and was shown to have multiple biological activities, that is, immunomodulatory, anti-inflammatory, antioxidative, antitumor, antimicrobial, insecticidal, antiatherogenic, antiemetic, whitening, and sedative activity. However, the systematic evaluations of preparation, pharmaceutics, toxicology, pharmacokinetics, and bioactivities underlying molecular mechanisms of action also required further investigation prior to practices of PA in clinic.

  10. A Physiologically Based Pharmacokinetic Model for Ganciclovir and Its Prodrug Valganciclovir in Adults and Children.

    Science.gov (United States)

    Lukacova, V; Goelzer, P; Reddy, M; Greig, G; Reigner, B; Parrott, N

    2016-11-01

    A physiologically based pharmacokinetic (PBPK) model has been developed for ganciclovir and its prodrug valganciclovir. Initial bottom-up modeling based on physicochemical drug properties and measured in vitro inputs was verified in preclinical animal species, and then, a clinical model was verified in a stepwise fashion with pharmacokinetic data in adult, children, and neonatal patients. The final model incorporated conversion of valganciclovir to ganciclovir through esterases and permeability-limited tissue distribution of both drugs with active transport processes added in gut, liver, and kidney. A PBPK model which accounted for known age-related tissue volumes, composition and blood flows, and renal filtration clearance was able to simulate well the measured plasma exposures in adults and pediatric patients. Overall, this work illustrates the stepwise development of PBPK models which could be used to predict pharmacokinetics in infants and neonates, thereby assisting drug development in a vulnerable patient population where clinical data are challenging to obtain.

  11. Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients

    NARCIS (Netherlands)

    Yu, H.; Erp, N. van; Bins, S.; Mathijssen, R.H.; Schellens, J.H.; Beijnen, J.H.; Steeghs, N.; Huitema, A.D.

    2017-01-01

    BACKGROUND AND OBJECTIVE: Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. METHODS: Pharmacokinetic data were available from 96

  12. Population Pharmacokinetics of Intranasal Scopolamine

    Science.gov (United States)

    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  13. Six-day stability of erythrocyte and reticulocyte parameters in-vitro: a comparison of blood samples from healthy, iron-deficient, and thalassemic individuals.

    Science.gov (United States)

    Sudmann-Day, Åshild A; Piehler, Armin; Klingenberg, Olav; Urdal, Petter

    2015-05-01

    Stability for up to 6 days' storage of erythrocyte and reticulocyte parameters in samples from iron-deficient and thalassemic individuals has not yet been reported. This lack of knowledge challenges evaluation of the full blood count in referral samples for hemoglobinopathy evaluation. We therefore hereby present such sample stability data. We included fresh (less than 4 hours old) blood samples from eight healthy, eight iron-deficient, and 11 thalassemic individuals. A full blood count, including reticulocyte parameters, was performed on a Sysmex XE-2100 once daily during a 6-day storage period at room temperature. For healthy individuals, we also studied stability of refrigerated samples and investigated analytical and biological variation. Hemoglobin concentration, erythrocyte count, and mean corpuscular hemoglobin were stable for 6 days in all diagnostic groups. Mean corpuscular volume increased less in samples from iron-deficient individuals while the number of reticulocytes increased more in samples from thalassemic, as compared to healthy individuals. Ret-He stability depended on its baseline value. Within-person biological variation in samples from healthy individuals was low both for erythrocyte parameters and for reticulocyte hemoglobin, while higher for reticulocyte counts. Results for hemoglobin concentration, erythrocyte count, and mean corpuscular hemoglobin are reliable in hemoglobinopathy investigation of referred samples for up to 6 days. Storage time-dependent changes of other erythrocyte and reticulocyte parameters in blood samples from iron-deficient and thalassemic individuals differ from those of healthy individuals.

  14. Comparison of two systems for rigidly connecting 2.0-mm bone screws to an implantable device : in vitro stability testing

    NARCIS (Netherlands)

    van Loon, JP; de Bont, LGM; Verkerke, GJ

    The stability of a screw-fixed implantable device can be improved by eliminating the freedom of movement between the screws and the device. Two systems have been developed for rigidly connecting 2.0-mm bone screws to an implantable device, and the aim of this study was to test and compare the

  15. Optimal design of pharmacokinetic studies.

    Science.gov (United States)

    Aarons, Leon; Ogungbenro, Kayode

    2010-03-01

    Experimental design is fundamental to successful scientific investigation. Poorly designed experiments lead to the loss of information, which is costly and potentially unethical. Experiments can be designed in an optimal fashion to maximize the amount of information they provide. Optimal design theory uses prior information about the model and parameter estimates to optimize a function of the Fisher information matrix to obtain the best combination of the design factors. In the case of population pharmacokinetic experiments, this involves the selection and a careful balance of a number of design factors, including the number and location of measurement times and the number of subjects to include in the study. It is expected that as the awareness about the benefits of this approach increases, more people will embrace it and ultimately will lead to more efficient population pharmacokinetic experiments and can also help to reduce both cost and time during drug development. This MiniReview provides an introduction to optimal design using examples taken from different pharmacokinetic experiments.

  16. Biochemical and pharmacokinetic evaluation of a novel pyrimidine nucleoside nitric oxide donor as a potential anticancer/antiviral agent.

    Science.gov (United States)

    Khalili, Panteha; Naimi, Ebrahim; Sun, Wei Yan; Knaus, Edward E; Wiebe, Leonard I

    2003-07-01

    The objective of this study was to determine the physiochemical, biochemical and pharmacokinetic properties of 5-iodo-3'-O-nitro-2'-deoxyuridine (INUdR), a novel prodrug releasing both nitric oxide (NO) and 5-iodo-2'-deoxyuridine. The INUdR partition coefficient (log P=1.12) was determined by both the shake-flask method and by calculation using Interactive Analysis Log P Program. In vitro binding of INUdR to bovine serum albumin (BSA) was estimated using an ultrafiltration method to be 65 to 77%, depending on the INUdR concentration. INUdR was stable in phosphate buffer (pH 7.4) and in water, at both ambient temperature and at 37 degrees C. INUdR was resistant to phosphorolysis when incubated with thymidine phosphorylase. Plasma, L-cysteine and glutathione catalyzed release of NO from INUdR, as determined using the Griess reaction. In all three systems, the release of NO by INUdR was equal to or greater than that of the reference drug isosorbide dinitrate. The pharmacokinetics of INUdR following single intravenous bolus and oral doses of INUdR (40 mg/kg) to male Sprague-Dawley rats were characterized by a short elimination half-life (T(1/2) 0.27 h), a large steady-state volume of distribution (V(ss) 0.89 l/kg) and high oral bioavailability (F=0.95). In conclusion, INUdR lipophilicity, shelf-stability, and resistance towards catabolic breakdown by thymidine phosphorylase, together with its non-spontaneous, yet considerable NO release, constitute favorable characteristics of a potential anticancer/antiviral agent.

  17. A Novel Approach to Flurbiprofen Pulsatile Colonic Release: Formulation and Pharmacokinetics of Double-Compression-Coated Mini-Tablets.

    Science.gov (United States)

    Vemula, Sateesh Kumar

    2015-12-01

    A significant plan is executed in the present study to study the effect of double-compression coating on flurbiprofen core mini-tablets to achieve the pulsatile colonic delivery to deliver the drug at a specific time as per the patho-physiological need of the disease that results in improved therapeutic efficacy. In this study, pulsatile double-compression-coated tablets were prepared based on time-controlled hydroxypropyl methylcellulose K100M inner compression coat and pH-sensitive Eudragit S100 outer compression coat. Then, the tablets were evaluated for both physical evaluation and drug-release studies, and to prove these results, in vivo pharmacokinetic studies in human volunteers were conducted. From the in vitro drug-release studies, F6 tablets were considered as the best formulation, which retarded the drug release in the stomach and small intestine (3.42 ± 0.12% in 5 h) and progressively released to the colon (99.78 ± 0.74% in 24 h). The release process followed zero-order release kinetics, and from the stability studies, similarity factor between dissolution data before and after storage was found to be 88.86. From the pharmacokinetic evaluation, core mini-tablets producing peak plasma concentration (C max) was 14,677.51 ± 12.16 ng/ml at 3 h T max and pulsatile colonic tablets showed C max = 12,374.67 ± 16.72 ng/ml at 12 h T max. The area under the curve for the mini and pulsatile tablets was 41,238.52 and 72,369.24 ng-h/ml, and the mean resident time was 3.43 and 10.61 h, respectively. In conclusion, development of double-compression-coated tablets is a promising way to achieve the pulsatile colonic release of flurbiprofen.

  18. [Pharmacokinetics of amodiaquine and prevention of Plasmodium falciparum malaria].

    Science.gov (United States)

    Pussard, E; Verdier, F; Faurisson, F; Blayo, M C

    1985-01-01

    Amodiaquine might appear as an alternative in prophylaxis of chloroquine-resistant P. falciparum malaria. In an attempt to explain the discrepancy between its in vivo-in vitro activity, a pharmacokinetic study was conducted in healthy subjects with HPLC assays. The results showed that: amodiaquine was no more detected in the blood, a main metabolite (monodesethyl derivative) appeared as the active form of the drug in vivo, metabolite's half-life had a mean value of 15.6 +/- 5.4 days. This study shows that monodesethylamodiaquine (and not amodiaquine) must be monitored in vitro. Furthermore the high individual variations of blood levels and half-life's values suggest that the weekly prophylactic schedule must be eventually re-evaluated.

  19. Preparation and pharmacokinetic study of fenofibrate cubic liquid crystalline

    Directory of Open Access Journals (Sweden)

    Shijie Wei

    2017-11-01

    Full Text Available An LCC delivery system for Fenofibrate (Fen was developed to improve its poorly oral bioavailability. Fen-LCC preparation methods were screened, and the prepared Fen-LCC was then characterized by a polarizing microscope and transmission electron microscopy (TEM. The spray drying technique was selected to dry and solidify particles into powder. The in vitro release of Fen-LCC was measured and in vivo pharmacokinetic experiments were carried out on rats after oral administration. Particles prepared through the high-temperature input method exhibited structural characteristics of LCC, and re-dissolved particles maintained the same features. The LCC delivery system can significantly improve in vitro release outcomes. After oral administration, AUCs of the suspension and LCC systems were measured at 131.6853 µg⋅h/ml and 1435.72893 µg⋅h/ml, respectively. The spray drying process presented here better maintains cubic structures, and the LCC system significantly improves bioavailability levels.

  20. Does pedicle screw fixation of the subaxial cervical spine provide adequate stabilization in a multilevel vertebral body fracture model? An in vitro biomechanical study.

    Science.gov (United States)

    Duff, John; Hussain, Mir M; Klocke, Noelle; Harris, Jonathan A; Yandamuri, Soumya S; Bobinski, Lukas; Daniel, Roy T; Bucklen, Brandon S

    2018-02-14

    Cervical vertebral body fractures generally are treated through an anterior-posterior approach. Cervical pedicle screws offer an alternative to circumferential fixation. This biomechanical study quantifies whether cervical pedicle screws alone can restore the stability of a three-column vertebral body fracture, making standard 360° reconstruction unnecessary. Range of motion (2.0 Nm) in flexion-extension, lateral bending, and axial rotation was tested on 10 cadaveric specimens (five/group) at C2-T1 with a spine kinematics simulator. Specimens were tested for flexibility of intact when a fatigue protocol with instrumentation was used to evaluate construct longevity. For a C4-6 fracture, spines were instrumented with 360° reconstruction (corpectomy spacer + plate + lateral mass screws) (Group 1) or cervical pedicle screw reconstruction (C3 and C7 only) (Group 2). Results are expressed as percentage of intact (100%). In Group 1, 360° reconstruction resulted in decreased motion during flexion-extension, lateral bending, and axial rotation, to 21.5%, 14.1%, and 48.6%, respectively, following 18,000 cycles of flexion-extension testing. In Group 2, cervical pedicle screw reconstruction led to reduced motion after cyclic flexion-extension testing, to 38.4%, 12.3%, and 51.1% during flexion-extension, lateral bending, and axial rotation, respectively. The 360° stabilization procedure provided the greatest initial stability. Cervical pedicle screw reconstruction resulted in less change in motion following cyclic loading with less variation from specimen to specimen, possibly caused by loosening of the shorter lateral mass screws. Cervical pedicle screw stabilization may be a viable alternative to 360° reconstruction for restoring multilevel vertebral body fracture. Copyright © 2018. Published by Elsevier Ltd.

  1. A comparative biomechanical study of a novel integrated plate spacer for stabilization of cervical spine: an in vitro human cadaveric model.

    Science.gov (United States)

    Majid, Kamran; Chinthakunta, Suresh; Muzumdar, Aditya; Khalil, Saif

    2012-07-01

    Integrated plate-spacer may provide adequate construct stability while potentially lowering operative time, decreasing complications, and providing less mechanical obstruction. The purpose of the current study was to compare the biomechanical stability of an anatomically profiled 2-screw integrated plate-spacer to a traditional spacer only and to a spacer and anterior cervical plate construct. In addition, the biomechanical stability of 2-screw integrated plate-spacer was compared to a commercially available 4-screw integrated plate-spacer. Two groups, each of nine cervical cadaver spines (C2-C7), were tested under pure moments of 1.5Nm. Range of motion was recorded at C5-C6 in all loading conditions (flexion, extension, lateral bending, and axial rotation) for the following constructs: 1) Intact; 2) 2-screw or 4-screw integrated plate-spacer; 3) spacer and anterior cervical plate; and 4) spacer only. All fusion constructs significantly reduced motion compared to the intact condition. Within the instrumented constructs, spacer and anterior cervical plate, 2-screw and 4-screw integrated plate-spacer resulted in reduced motion compared to the spacer only construct. No significant differences were found in motion between any of the instrumented conditions in any of the loading conditions. The application of integrated plate-spacer for anterior cervical discectomy and fusion is based on several factors including surgical ease-of-use, biomechanical characteristics, and surgeon preference. The study suggests that integrated plate-spacer provide biomechanical stability comparable to traditional spacer and plate constructs in the cervical spine. Clinical studies on integrated plate spacer devices are necessary to understand the performance of these devices in vivo. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. PEG-metronidazole conjugates: synthesis, in vitro and in vivo properties.

    Science.gov (United States)

    Bersani, Cinzia; Berna, Manuela; Pasut, Gianfranco; Veronese, Francesco Maria

    2005-09-01

    Metronidazole (MTZ), a drug used for the treatment of protozoal infections caused by protozoa and anaerobic microorganisms, was conjugated to linear or branched poly(ethylene glycol) of 5,000, 10,000 and 20,000 Da. An ester linkage between polymer and drug was used in the coupling to yield a polymeric prodrug. The modification allowed overcoming the known MTZ solubility problem leading us to obtain a bioconjugate more suitable for parental administration. The conjugates of various molecular weight polymers have been tested in vitro toward chemical degradation and digestive enzymes. It was found that molecular weight and shape of PEG is critical for the prodrugs stability. Good resistance in the stomach acidic media was found and a slow release of the drug in the large intestinal fluid may take place. In vivo studies carried out following i.v. or s.c. administration to mice revealed improved pharmacokinetics properties upon conjugation.

  3. [The pharmacokinetic of drugs in elderly patients].

    Science.gov (United States)

    Jabłecka, Anna; Korzeniowska, Katarzyna; Smolarek, Iwona

    2008-01-01

    The use of pharmacotherapy in the elderly requires caution because of increasing with age drug sensitivity and risk of dangerous adverse effects. The process of ageing induce alteration in pharmacokinetics of drugs. Modifications affect practically each pharmacokinetic phase. Processes of distribution and, first of all, drug elimination are the most essential for clinical practice.

  4. Drug Transport and Pharmacokinetics for Chemical Engineers

    Science.gov (United States)

    Simon, Laurent; Kanneganti, Kumud; Kim, Kwang Seok

    2010-01-01

    Experiments in continuous-stirred vessels were proposed to introduce methods in pharmacokinetics and drug transport to chemical engineering students. The activities can be incorporated into the curriculum to illustrate fundamentals learned in the classroom. An appreciation for the role of pharmacokinetics in drug discovery will also be gained…

  5. Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers

    NARCIS (Netherlands)

    Schöller-Gyüre, Monika; van den Brink, Wim; Kakuda, Thomas N.; Woodfall, Brian; de Smedt, Goedele; Vanaken, Hilde; Stevens, Tanja; Peeters, Monika; Vandermeulen, Kati; Hoetelmans, Richard M. W.

    2008-01-01

    TMC125 is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. TMC125 is an inducer of CYP3A and an inhibitor of CYP2C. This trial evaluated the effect of TMC125 on the pharmacokinetics and pharmacodynamics of methadone.

  6. Naringenin-loaded solid lipid nanoparticles: preparation, controlled delivery, cellular uptake, and pulmonary pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Ji P

    2016-03-01

    Full Text Available Peng Ji, Tong Yu, Ying Liu, Jie Jiang, Jie Xu, Ying Zhao, Yanna Hao, Yang Qiu, Wenming Zhao, Chao WuCollege of Pharmacy, Liaoning Medical University, Jinzhou, Liaoning Province, People’s Republic of ChinaAbstract: Naringenin (NRG, a flavonoid compound, had been reported to exhibit extensive pharmacological effects, but its water solubility and oral bioavailability are only ~46±6 µg/mL and 5.8%, respectively. The purpose of this study is to design and develop NRG-loaded solid lipid nanoparticles (NRG-SLNs to provide prolonged and sustained drug release, with improved stability, involving nontoxic nanocarriers, and increase the bioavailability by means of pulmonary administration. Initially, a group contribution method was used to screen the best solid lipid matrix for the preparation of SLNs. NRG-SLNs were prepared by an emulsification and low-temperature solidification method and optimized using an orthogonal experiment approach. The morphology was examined by transmission electron microscopy, and the particle size and zeta potential were determined by photon correlation spectroscopy. The total drug content of NRG-SLNs was measured by high-performance liquid chromatography, and the encapsulation efficiency (EE was determined by Sephadex gel-50 chromatography and high-performance liquid chromatography. The in vitro NRG release studies were carried out using a dialysis bag. The best cryoprotectant to prepare NRG-SLN lyophilized powder for future structural characterization was selected using differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy. The short-term stability, 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyl-tetrazolium bromide (MTT assay, cellular uptake, and pharmacokinetics in rats were studied after pulmonary administration of NRG-SLN lyophilized powder. Glycerol monostearate was selected to prepare SLNs, and the optimal formulation of NRG-SLNs was spherical in shape, with a particle

  7. Proximate composition, phenolic content and in vitro antioxidant activity of aqueous extracts of the seaweeds Ascophyllum nodosum, Bifurcaria bifurcata and Fucus vesiculosus. Effect of addition of the extracts on the oxidative stability of canola oil under accelerated storage conditions.

    Science.gov (United States)

    Agregán, Rubén; Munekata, Paulo E; Domínguez, Ruben; Carballo, Javier; Franco, Daniel; Lorenzo, José M

    2017-09-01

    Extracts from three macroalgae species (Ascophyllum nodosum (ANE), Bifurcaria bifurcata (BBE) and Fucus vesiculosus (FVE)) were tested for proximate composition (total solid, protein and total carbohydrate contents), total phenols content (TPC), and for their antioxidant activities in vitro in comparison to that of BHT compound by using four different assays (ABTS radical cation decolouration, DPPH free radical scavenging activity, ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC)). The inclusion of the extracts as oil stabilizers in canola oil in substitution of the synthetic antioxidant (BHT) was also evaluated by assessing lipid oxidation parameters (peroxide value (PV), p-anisidine value (AV), TBARS value, conjugated dienes (CD) and TOTOX index) under accelerated storage conditions (16days, 60°C). There was an inverse relationship between total solid content and total polyphenols content in the seaweed extracts. FVE showed an intermediate TPC (1.15g PGE/100g extract), but it presented the highest in vitro antioxidant activity when measured using the ABTS, DPPH and FRAP tests. BBE, that displayed the highest TPC (1.99g PGE/100g extract), only showed the highest in vitro antioxidant activity when measured using the ORAC test. ANE showed the lowest TPC and the lowest antioxidant activity in all the tests performed. The seaweed extracts added in a 500ppm concentration significantly reduced the oxidation during canola oil storage at 60°C, being this antioxidant effect significantly higher than that of BHT added at 50ppm. Results indicate that seaweed extracts can effectively inhibit the oxidation of canola oil and they can be a healthier alternative to the synthetic antioxidants in the oil industry. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Loratadine: multiple-dose pharmacokinetics.

    Science.gov (United States)

    Radwanski, E; Hilbert, J; Symchowicz, S; Zampaglione, N

    1987-07-01

    The steady-state pharmacokinetics of loratadine (L), a new long-acting antihistamine devoid of CNS activity, was investigated in 12 healthy male volunteers. Each volunteer received 40-mg L capsules q24h for ten days. Blood samples were collected at various times on day 1, 5, 7, and 10 and assayed for L by radioimmunoassay (RIA) and for descarboethoxyloratadine (DCL), a known active metabolite, by high-performance liquid chromatography (HPLC). The plasma L and DCL concentration-time data in the disposition phases were fitted to a biexponential equation for pharmacokinetic analysis. Steady-state plasma L Cmax concentrations were reached at 1.5 hour (Tmax) after each dose. DCL steady-state Cmax values ranged 26 to 29 ng/mL at a Tmax ranging from 1.8 to 3 hours. The AUC at steady state, AUC tau, was 80 to 96 and 349 to 421 h X ng/mL for L and DCL, respectively. The accumulation indexes (Ra) based on AUC tau ratios, did not change for either compound after day 5. Ra values for L and DCL after the fifth dose were 1.4 and 1.9, respectively, indicating that there is little accumulation of either L or DCL after a multiple (once-a-day) dosage regimen. The t1/2 beta at steady state were 14.4 and 18.7 hours for L and DCL, respectively, which were similar to those reported following a single-dose L administration. Observed plasma drug concentrations were in good agreement with predicted values derived for pharmacokinetic parameters.

  9. In vitro pharmacokinetics of anti-psoriatic fumaric acid esters

    NARCIS (Netherlands)

    N.H.R. Litjens (Nicolle); E. van Strijen (Elizabeth); C. van Gulpen (Co); H. Mattie (Herman); J.T. van Dissel (Jaap); H.B. Thio (Bing); P.H. Nibbering (Peter)

    2004-01-01

    textabstractBackground: Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main

  10. In vitro complementation of Tdp1 deficiency indicates a stabilized enzyme-DNA adduct from tyrosyl but not glycolate lesions as a consequence of the SCAN1 mutation.

    Science.gov (United States)

    Hawkins, Amy J; Subler, Mark A; Akopiants, Konstantin; Wiley, Jenny L; Taylor, Shirley M; Rice, Ann C; Windle, Jolene J; Valerie, Kristoffer; Povirk, Lawrence F

    2009-05-01

    A homozygous H493R mutation in the active site of tyrosyl-DNA phosphodiesterase (TDP1) has been implicated in hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1), an autosomal recessive neurodegenerative disease. However, it is uncertain how the H493R mutation elicits the specific pathologies of SCAN1. To address this question, and to further elucidate the role of TDP1 in repair of DNA end modifications and general physiology, we generated a Tdp1 knockout mouse and carried out detailed behavioral analyses as well as characterization of repair deficiencies in extracts of embryo fibroblasts from these animals. While Tdp1(-/-) mice appear phenotypically normal, extracts from Tdp1(-/-) fibroblasts exhibited deficiencies in processing 3'-phosphotyrosyl single-strand breaks and 3'-phosphoglycolate double-strand breaks (DSBs), but not 3'-phosphoglycolate single-strand breaks. Supplementing Tdp1(-/-) extracts with H493R TDP1 partially restored processing of 3'-phosphotyrosyl single-strand breaks, but with evidence of persistent covalent adducts between TDP1 and DNA, consistent with a proposed intermediate-stabilization effect of the SCAN1 mutation. However, H493R TDP1 supplementation had no effect on phosphoglycolate (PG) termini on 3' overhangs of double-strand breaks; these remained completely unprocessed. Altogether, these results suggest that for 3'-phosphoglycolate overhang lesions, the SCAN1 mutation confers loss of function, while for 3'-phosphotyrosyl lesions, the mutation uniquely stabilizes a reaction intermediate.

  11. An oral formulation of efavirenz-loaded lactoferrin nanoparticles with improved biodistribution and pharmacokinetic profile.

    Science.gov (United States)

    Kumar, P; Lakshmi, Y S; Kondapi, A K

    2017-08-01

    Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, is a drug that is frequently included in highly active antiretroviral therapy for treatment of HIV infection. Decreased bioavailability and increased toxicity limit its use. We report a formulation of efavirenz-loaded lactoferrin nanoparticles (lacto-EFV-nano) for oral delivery which exhibited significantly improved pharmacological properties coupled with reduced toxicity compared with its free form. Lacto-EFV-nano was prepared using the Sol-oil protocol and characterized using various sources of characterization. In vitro and in vivo studies were performed to test the stability, safety, efficacy, biodistribution and pharmacokinetics of lacto-EFV-nano. The nanoparticles prepared for the present study had an average size of 45-60 nm as revealed by field emission scanning electron microscope measurements. Further, dynamic light scattering data showed a hydrodynamic radius of 103 ± 5.3 nm, a zeta potential of -23 ± 1.2 mV and a polydispersity index of EFV-nano was found to be stable as assessed using differential scanning calorimetry and Fourier-transform infrared spectroscopy. Cell viability studies showed that lacto-EFV-nano was at least 2-fold less toxic to peripheral blood mononuclear cells, Jurkat T cell and B16-F10 cell lines than free EFV. Furthermore, lacto-EFV-nano [50% inhibitory concentration (IC50 ) 2-fold enhanced anti-HIV-1 activity compared with free EFV (IC50 = 2.56 nM). Lacto-EFV-nano exhibited improved oral bioavailability and an improved in vivo pharmacokinetic profile, with a > 3-4-fold increase in the area under the plasma concentration-time curve (AUC), a 6-7-fold increase in the area under the first moment curve (AUMC), a > 30% increase in the peak plasma concentration of the drug after oral administration (Cmax ) and a 2-fold increase in the time to reach Cmax (Tmax ) and the time required for the concentration of the drug to reach half of its original value (t1

  12. Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties.

    Science.gov (United States)

    Xu, Ruixue; Zhan, Miao; Peng, Lingling; Pang, Xuehai; Yang, Jun; Zhang, Tao; Jiang, Hongxia; Zhao, Lifeng; Chen, Yuanwei

    2015-06-15

    Nintedanib is a novel triple angiokinase inhibitor that inhibits three growth factors simultaneously. Deuterated derivatives of nintedanib at certain metabolically active sites were prepared and evaluated in vitro and in vivo. In particular, deuterated compound SKLB-C2202 had significantly improved pharmacokinetic properties compared with nintedanib. These efforts lay the foundation for further investigating the druggability of SKLB-C2202. Copyright © 2015 John Wiley & Sons, Ltd.

  13. Evaluation of Pharmacokinetics of Bioreducible Gene Delivery Vectors by Real-time PCR

    Science.gov (United States)

    Zhou, Qing-Hui; Wu, Chao; Manickam, Devika Soundara; Oupický, David

    2013-01-01

    Purpose To investigate pharmacokinetics of reversibly stabilized DNA nanoparticles (rSDN) using a single-step lysis RT-PCR. Methods rSDN were prepared by coating bioreducible polycation/DNA polyplexes with multivalent N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. Targeted polyplexes were formulated by linking cyclic RGD ligand (c(RGDyK)) to the HPMA surface layer of rSDN. The pharmacokinetic parameters in tumor-bearing mice were analyzed by PKAnalyst®. Results The pharmacokinetics of naked plasmid DNA, simple DNA polyplexes, rSDN, and RGD-targeted rSDN exhibited two-compartment model characteristics with area under the blood concentration–time curve (AUC) increasing from 1,102 ng·ml−1·min−1 for DNA to 3,501 ng·ml−1·min−1 for rSDN. Non-compartment model analysis revealed increase in mean retention time (MRT) from 4.5 min for naked DNA to 22.9 min for rSDN. Conclusions RT-PCR is a sensitive and convenient method suitable for analyzing pharmacokinetics and biodistribution of DNA polyplexes. Surface stabilization of DNA polyplexes can significantly extend their MRT and AUC compared to naked DNA. DNA degradation in rSDN in blood circulation, due to a combined effect of disulfide reduction and competitive reactions with charged molecules in the blood, contributes to DNA elimination. PMID:19240986

  14. Microencapsulation of Lactobacillus acidophilus NCIMB 701748 in matrices containing soluble fibre by spray drying: Technological characterization, storage stability and survival after in vitro digestion☆

    Science.gov (United States)

    Yonekura, Lina; Sun, Han; Soukoulis, Christos; Fisk, Ian

    2014-01-01

    We evaluated sodium alginate, chitosan and hydroxypropyl methylcellulose (HPMC) as co-encapsulants for spray dried Lactobacillus acidophilus NCIMB 701748 by assessing their impact on cell viability and physicochemical properties of the dried powders, viability over 35 days of storage at 25 °C and survival after simulated digestion. Fibres were added to a control carrier medium containing whey protein concentrate, d-glucose and maltodextrin. Sodium alginate and HPMC did not affect cell viability but chitosan reduced viable counts in spray dried powders, as compared to the control. Although chitosan caused large losses of viability during spray-drying, these losses were counteracted by the excellent storage stability compared to control, sodium alginate and HPMC, and the overall effect became positive after the 35-day storage. Chitosan also improved survival rates in simulated GI conditions, however no single fibre could improve L. acidophilus NCIMB 701748 viability in all steps from production through storage and digestion. PMID:24748900

  15. A comprehensive physiologically based pharmacokinetic ...

    Science.gov (United States)

    Published physiologically based pharmacokinetic (PBPK) models from peer-reviewed articles are often well-parameterized, thoroughly-vetted, and can be utilized as excellent resources for the construction of models pertaining to related chemicals. Specifically, chemical-specific parameters and in vivo pharmacokinetic data used to calibrate these published models can act as valuable starting points for model development of new chemicals with similar molecular structures. A knowledgebase for published PBPK-related articles was compiled to support PBPK model construction for new chemicals based on their close analogues within the knowledgebase, and a web-based interface was developed to allow users to query those close analogues. A list of 689 unique chemicals and their corresponding 1751 articles was created after analysis of 2,245 PBPK-related articles. For each model, the PMID, chemical name, major metabolites, species, gender, life stages and tissue compartments were extracted from the published articles. PaDEL-Descriptor, a Chemistry Development Kit based software, was used to calculate molecular fingerprints. Tanimoto index was implemented in the user interface as measurement of structural similarity. The utility of the PBPK knowledgebase and web-based user interface was demonstrated using two case studies with ethylbenzene and gefitinib. Our PBPK knowledgebase is a novel tool for ranking chemicals based on similarities to other chemicals associated with existi

  16. Effects of common beverage colorants on color stability of dental composite resins: the utility of a thermocycling stain challenge model in vitro.

    Science.gov (United States)

    Ren, Yan-Fang; Feng, Lin; Serban, Diana; Malmstrom, Hans S

    2012-07-01

    To study the color stability of dental composite resins using a thermocycling stain challenge model accounting for the complex effects of oral environment and tooth brushing. Composite resin discs were made from Filtek Supreme Ultra (FiltekSU), TPH3 and Renamel, and subjected to thermocycling challenges in warm coffee (55 °C/pH 5.2) and a cold tea and fruit juice mixtures (5 °C/pH 3.6) for a total of 1000 cycles with 30 seconds dwell time in each solution per cycle. Color was assessed in the CIELAB color space using a Crystaleye dental spectrophotometer before and after thermocycling, and after brushing vigorously for 3 min. The thermocycling stain challenge was repeated for a second 1000 cycles and the discs were brushed again. Color changes were compared among the 3 groups using Kruskal-Wallis test. All 3 groups showed statistically significant color changes after stain challenge, with ΔE* as 5.74 for FiltekSU, 3.21 for TPH3 and 2.52 for Renamel. Color change was more significant in FiltekSU than in TPH3 and Renamel (p<0.05). After brushing, color recovered mostly to its original CIELAB values in TPH3 and Renamel but less so in FiltekSU. The second round of thermocycling stain challenge resulted in color changes in FiltekSU that largely could not be removed by vigorous brushing. Color stability of FiltekSU is inferior to that of TPH3 and Renamel. The thermocycling stain challenge model can potentially differentiate surface staining that can be removed by brushing from true discoloration of the material that is refractory to oral hygiene procedures. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Effects of Laboratory Disinfecting Agents on Dimensional Stability of Three Commercially Available Heat-Cured Denture Acrylic Resins in India: An In-Vitro Study.

    Science.gov (United States)

    Basavanna, Jayaprakash Mugur; Jujare, Ravikanth Haridas; Varghese, Rana Kalappattil; Singh, Vishwa Deepak; Gaurav, Amit

    2016-03-01

    Dental professionals are exposed to a wide variety of microorganisms which calls for use of effective infection control procedures in the dental office and laboratories that can prevent cross-contamination that could extend to dentists, dental office staff, dental technicians as well as patients. This concern has led to a renewed interest in denture sterilization and disinfection. Heat polymerized dentures exhibit dimensional change during disinfection procedure. The purpose of this study was to determine the influence of different types of widely used laboratory disinfecting agents on the dimensional stability of heat-cured denture acrylic resins and to compare the dimensional stability of three commercially available heat-cured denture acrylic resins in India. Twelve specimens of uniform dimension each of three different brands namely Stellon, Trevalon and Acralyn-H were prepared using circular metal disc. Chemical disinfectants namely 2% alkaline glutaraldehyde, 1% povidone-iodine, 0.5% sodium hypochlorite and water as control group were used. Diameter of each specimen was measured before immersion and after immersion with time interval of 1 hour and 12 hours. The data was evaluated statistically using one way analysis of variance. All the specimens in three disinfectants and in water exhibited very small amount of linear expansion. Among three disinfectants, specimens in 2% alkaline glutaraldehyde exhibited least(0.005mm) and water showed highest (0.009mm) amount of dimensional change. Among resins, Trevalon showed least (0.067mm) and Acralyn-H exhibited highest (0.110mm) amount of dimensional change. Although, all the specimens of three different brands of heat-cured denture acrylic resins exhibited increase in linear dimensional change in all the disinfectants and water, they were found to be statistically insignificant.

  18. In vitro and in vivo evaluation of silybin nanosuspensions for oral and intravenous delivery

    Energy Technology Data Exchange (ETDEWEB)

    Wang Yancai; Zhang Dianrui; Liu Guangpu; Duan Cunxian; Jia Lejiao; Feng Feifei [Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012 (China); Liu Zhaoping; Zhang Xiaoyu; Shi Yanqiu [Center for New Drugs Evaluation, Shandong University, Jinan 250012 (China); Zhang Qiang, E-mail: zhang_dr2006@yahoo.com.cn [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083 (China)

    2010-04-16

    In this study, we evaluate the effect of particle sizes on the physicochemical properties of silybin and identify the influence of silybin nanosuspensions on its permeation across the Caco-2 cell monolayer. In vivo pharmacokinetic evaluation of silybin nanosuspensions was also carried out in beagle dogs. TEM, AFM and SEM analyses revealed the effect of homogenization pressure on particle size and morphology, and confirmed the existence of a surfactant-stabilizer film on the surface of nanoparticles. DSC and XRPD experiments manifested that the crystalline state was maintained as particle size was reduced and the enhanced dissolution property was due to the increased surface area. Nanosuspensions had a significant influence on drug transport across the Caco-2 cell monolayer and the enhanced dissolution velocity was responsible for the increased permeability. A pharmacokinetics study in beagle dogs further confirmed the in vitro results and demonstrated that oral administration of silybin nanosuspensions significantly increase its bioavailability compared to the coarse powder. Nanosuspensions of silybin with smaller particle size reveal a higher potential to increase their oral bioavailability; while for intravenous infusion the lower pressure produced silybin nanosuspensions appeared to maintain a more sustained drug release profile.

  19. Computational Analysis of Pharmacokinetic Behavior of Ampicillin

    Directory of Open Access Journals (Sweden)

    Mária Ďurišová

    2016-07-01

    Full Text Available orrespondence: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, 841 04 Bratislava, Slovak Republic. Phone + 42-1254775928; Fax +421254775928; E-mail: maria.durisova@savba.sk 84 RESEARCH ARTICLE The objective of this study was to perform a computational analysis of the pharmacokinetic behavior of ampicillin, using data from the literature. A method based on the theory of dynamic systems was used for modeling purposes. The method used has been introduced to pharmacokinetics with the aim to contribute to the knowledge base in pharmacokinetics by including the modeling method which enables researchers to develop mathematical models of various pharmacokinetic processes in an identical way, using identical model structures. A few examples of a successful use of the modeling method considered here in pharmacokinetics can be found in full texts articles available free of charge at the website of the author, and in the example given in the this study. The modeling method employed in this study can be used to develop a mathematical model of the pharmacokinetic behavior of any drug, under the condition that the pharmacokinetic behavior of the drug under study can be at least partially approximated using linear models.

  20. Evaluation of the Stability of the Total Antioxidant Capacity, Polyphenol Contents, and Starch Hydrolase Inhibitory Activities of Kombucha Teas Using an In Vitro Model of Digestion

    Directory of Open Access Journals (Sweden)

    Mindani I. Watawana

    2015-01-01

    Full Text Available The objective of this study was to evaluate and compare antioxidant and starch hydrolase inhibitory activity of three different types of Kombucha beverages prepared by three pellicles with different microbial compositions. The fermentation process was carried out for 7 days and the assessments of antioxidant and starch hydrolase inhibitory activities as well as tea phenolic compounds were carried out. These parameters were also evaluated after subjecting the final fermented samples to gastric and duodenal digestion in an in vitro digestion model. The pH had a statistically significant decrease during the period of fermentation. The total phenolics content and antioxidant activities had increased during the fermentation process as well as when subjected to digestion. The starch hydrolase inhibitory activities also increased in a similar manner during the different phases. The α-amylase and α-glucosidase inhibitory activities showed statistically significant increases (P<0.05 as the fermentation progressed, while an increase was observed after being subjected to pancreatic and duodenal digestion as well. All three types of tea showed a higher α-amylase inhibitory activity than α-glucosidase inhibitory activity.

  1. Influence of blinded wound closure on the volume stability of different GBR materials: an in vitro cone-beam computed tomographic examination.

    Science.gov (United States)

    Mir-Mari, Javier; Wui, Hu; Jung, Ronald E; Hämmerle, Christoph H F; Benic, Goran I

    2016-02-01

    To test whether the use of (i) particulated bone substitute + collagen membrane used for guided bone regeneration (GBR) of peri-implant bone defects renders different results from (ii) particulated bone substitute + collagen membrane + fixation pins and from (iii) block bone substitute + collagen membrane with respect to the volume stability of the augmented region during suturing of mucosal flaps. Twenty peri-implant box-shaped bone defects were created in 10 pig mandibles. Every bone defect was augmented once with each of the following GBR procedures: Granulate (particulated xenograft + collagen membrane), Granulate + Pins (particulated xenograft + collagen membrane + fixation pins), and Block (block xenograft + collagen membrane). Cone-beam computed tomography scans were obtained prior and after blinded wound closure. The horizontal thickness (HT) of the augmented region (bone substitute + membrane) was assessed at the implant shoulder (HT0 mm ) and at 1-5 mm apical to the implant shoulder (HT1 mm -HT5 mm ). The changes of HT during flap suturing were calculated as absolute (mm) and relative values (%). Repeated-measures ANOVA was used for statistical analysis. Wound closure induced a statistically significant change of HT0 mm and of HT1 mm in all the treatment groups (P ≤ 0.05). The change in HT0 mm measured -42.8 ± 17.9% (SD) for Granulate, -22.9 ± 21.2% (SD) for Granulate + Pins, and -20.2 ± 18.9% (SD) for Block. The reduction in HT0 mm, HT1 mm , HT2 mm, and HT3 mm for the Granulate procedure was significantly higher as compared to the Granulate + Pins and the Block procedures (P ≤ 0.05). There were no statistically significant differences in the change of HT between the Granulate + Pins and the Block procedures (P > 0.05). Wound closure induced displacement of the bone substitute resulting in a partial collapse of the collagen membrane in the coronal portion of the augmented site. The stability of the bone substitute and collagen membrane was enhanced

  2. The Use of Spreadsheets for Pharmacokinetic Simulations

    Directory of Open Access Journals (Sweden)

    Joseph Chamberlain

    2003-01-01

    Full Text Available The use of simple spreadsheets is described to create simulations of complex pharmacokinetic phenomena. The basics of spreadsheets are first described and are developed to demonstrate classical pharmacokinetics without the use of differential or integral calculus. Using standard spreadsheet commands, the technique is shown to be applicable to the full range of advanced pharmacokinetic simulations. Demonstrations of the effect of a variety of physiological eventualities are included to show the versatility of the technique. The technique is very simple to use and is always in the complete control of the modeller.

  3. Thiolated carboxymethyl dextran as a nanocarrier for colon delivery of hSET1 antisense: In vitro stability and efficiency study

    Energy Technology Data Exchange (ETDEWEB)

    Kiani, Melika, E-mail: Melika.kiani@gmail.com [Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran (Iran, Islamic Republic of); Mirzazadeh Tekie, Farnaz Sadat, E-mail: mirzazadehf@yahoo.com [Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran (Iran, Islamic Republic of); Dinarvand, Meshkat, E-mail: mdinarvand@hotmail.com [Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran (Iran, Islamic Republic of); Soleimani, Masoud, E-mail: soleim_m@modares.ac.ir [Stem Cell Technology Research Centre, P.O. Box 14155-3174, Tehran (Iran, Islamic Republic of); Department of Hematology, School of Medical Sciences, Tarbiat Modares University, P.O. Box: 14115-111, Tehran (Iran, Islamic Republic of); Dinarvand, Rassoul, E-mail: dinarvand@tums.ac.ir [Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran (Iran, Islamic Republic of); Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Atyabi, Fatemeh, E-mail: atyabifa@tums.ac.ir [Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran (Iran, Islamic Republic of); Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of)

    2016-05-01

    Gene therapy is an optimistic approach in cancer treatment. However, for efficient delivery of gene materials, designing an appropriate vector is necessary. Polyelectrolyte complexes (PECs) of chitosan and dextran could be considered a proper nanoparticulate carrier for sensitive biomaterials. In this study, PECs of chitosan and thiolated dextran were used as either an injectable or oral gene delivery system. hSET1 antisense was loaded into the PECs to suppress proliferation of colon cancer cell line. The prepared nanoparticles have ~ 115 nm diameter size and positive zeta potential with high mucoadhesion properties. They are able to protect antisense from degradation in serum and biorelevant fluids (FaSSIF and FaSSGF). Furthermore, prepared nanoparticles demonstrated superior cellular penetration and inhibitory effect on SW480 colon cancer cell proliferation. All nanoparticles significantly down regulated hSET1 in comparison with naked antisense. It can be concluded that thiolated PECs have potential use for injectable or oral delivery of nucleic acids such as antisense. - Highlights: • Formation of stable nanoparticle with dextran and chitosan derivatives for oral and intravenous gene delivery. • Satifactory cellular uptake of nanoparticles and approximately complete suppression of hSET1 expression in SW480 cell lines • Prolonged stability of nanoparticles against biorelevent media with desirable release rate.

  4. Effect of two fluoride varnishes on the color stability of three resin-based restorative materials: an in vitro study.

    Science.gov (United States)

    Tafaroji, Raha; Biria, Mina; Ameri, Farhad; Torabzadeh, Hassan; Qahari, Pasha; Akbarzadeh Baghban, Alireza

    2016-11-01

    The aim of the present study was to evaluate the effect of two fluoride varnishes on color stability of three resin-based restorative materials. Fifty-four discs (14.5 × 1.7 mm) were fabricated from A2 and A3 shades of a compomer (F2000), a flowable composite (Z350), and a hybrid composite (Z250), and incubated at 37°C for 48 h. Dura Shield (colored) and Fluor Protector (colorless) fluoride varnishes were applied onto the discs. The coating was cleaned using a low-speed handpiece and nylon bristle brush after 24 h of storage in distilled water. A second coating was then applied. A control group with no coating was immersed in distilled water and used. The CIE L*a*b* color scale was measured before the treatments and following each cleaning utilizing a spectrophotometer. The colored fluoride varnish exhibited the highest overall color change (∆E) after the first and the second cleaning procedures in all the materials. Among these, the greatest color change was observed in the A3 shade of F2000, followed by the A3 shade of Z-250. The ∆E was less than 3.3 in all groups, and was therefore clinically acceptable. Color changes following the application of fluoride varnishes were found to be clinically acceptable in all groups. © 2015 Wiley Publishing Asia Pty Ltd.

  5. Angle of insertion and confirmation of angles measured after in vitro implantation during laminar vertebral stabilization in vertebral columns obtained from canine cadavers.

    Science.gov (United States)

    Knell, Sebastian C; Kircher, Patrick; Dennler, Matthias; Montavon, Pierre M; Voss, Katja; Hurter, Karin

    2011-12-01

    To determine angles of insertion for laminar vertebral fixation of L1 and L2 by use of a locking plate in dogs and to confirm screw placement by use of computed tomography (CT). Vertebral specimens harvested from 8 canine cadavers. The point of insertion and minimum and maximum insertion angles for laminar and facet screws for laminar vertebral stabilization were determined by use of CT. A precontoured locking plate was then placed by use of 1 locking screw in the lamina of each lumbar vertebra and 1 nonlocking screw in the facet joint. The position and angle of the screws were examined by use of CT, and penetration into the vertebral canal was recorded. Mean ± SD insertion angles for L1 and L2 were 18 ± 4° and 21 ± 5° toward the vertebral canal and 11 ± 4.4° and 10 ± 3° in a dorsal direction, respectively. Insertion angles for the facet joint were between 24 ± 4° ventrally and 12 ± 2° dorsally. Insertion of the screw did not penetrate the vertebral canal for 23 of 24 (96%) screws. For 23 of 24 inserted screws, the previously determined angle was maintained and purchase of bone and cortices was satisfactory. Placement of laminar and facet screws in canine vertebrae was possible and can be performed safely if angles of insertion determined pre-operatively via CT are maintained.

  6. Effect of long-term physiological activity on the long-term stem stability of cemented hip arthroplasty: in vitro comparison of three commercial bone cements.

    Science.gov (United States)

    Bialoblocka-Juszczyk, E; Cristofolini, L; Erani, P; Viceconti, M

    2010-01-01

    Long-term endurance of the cement mantle is fundamental for the survival of cemented hip prostheses. Current protocols to characterize bone cements are unsuitable to predict the actual clinical outcome. The aim of this study was to assess if it is possible to rank cement types having diverse clinical outcome by using a simplified in vitro physiological test. Composite femurs were implanted with identical stems (Lubinus-SPII), using different commercial cement types: CMW1 to represent cement with poor clinical outcome; Simplex-P and Cemex-RX to represent cements with a positive clinical outcome. Implanted femurs were subjected to a validated protocol that simulated a demanding but physiological loading spectrum. Inducible micromotions and permanent migrations were recorded throughout the test. After test completion, the cement mantles were sectioned and inspected with dye penetrants to quantify the fatigue-induced cracks. Micromotions did not differ significantly between cement types (possibly because a successful prosthesis was chosen that is very stable in the host bone). Significant differences were observed in terms of cement cracks: CMW1 induced significantly more numerous and larger cracks than Simplex-P and Cemex-RX; no difference was observed between Simplex-P and Cemex-RX. This indicates that this protocol: (a) can discriminate between 'good' and 'bad' cements and (b) yields consistent results when comparable cements are tested. The proposed protocol overcomes the limitations of existing standardized material tests for bone cements. New cements can be assessed in comparison with other cements with known (positive/negative) clinical outcome, tested with the same protocol.

  7. Enantiomers of nifurtimox do not exhibit stereoselective anti-Trypanosoma cruzi activity, toxicity, or pharmacokinetic properties.

    Science.gov (United States)

    Moraes, Carolina B; White, Karen L; Braillard, Stéphanie; Perez, Catherine; Goo, Junghyun; Gaspar, Luis; Shackleford, David M; Cordeiro-da-Silva, Anabela; Thompson, R C Andrew; Freitas-Junior, Lucio; Charman, Susan A; Chatelain, Eric

    2015-01-01

    With the aim of improving the available drugs for the treatment of Chagas disease, individual enantiomers of nifurtimox were characterized. The results indicate that the enantiomers are equivalent in their in vitro activity against a panel of Trypanosoma cruzi strains; in vivo efficacy in a murine model of Chagas disease; in vitro toxicity and absorption, distribution, metabolism, and excretion characteristics; and in vivo pharmacokinetic properties. There is unlikely to be any therapeutic benefit of an individual nifurtimox enantiomer over the racemic mixture. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  8. Pharmacokinetics of drugs in spontaneously or secondary hypertensive rats.

    Science.gov (United States)

    Yang, Sihyung; Lee, Young Sun; Oh, Euichaul

    2014-01-01

    1. Spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats) have been developed as animal models for human essential (idiopathic or primary) and secondary hypertensions, respectively. 2. In order to identify pharmacokinetic changes (mainly non-renal clearance, CLNR) in 16-week-old SHRs due to hereditary characteristics and/or neither the hypertensive state itself, we reviewed the pharmacokinetics of drugs in 6- (blood pressure within a normotensive range) and 16-week-old SHRs and 16-week-old DOCA-salt rats compared with respective control rats. 3. We reviewed changes in CLNRs of drugs which are primarily metabolized via hepatic microsomal cytochrome P 450 enzymes (CYPs) based mainly on data from hypertensive rats, and present the data in terms of changes in in vitro hepatic intrinsic clearance (CLint), free fraction in plasma (fp) and hepatic blood flow rate (QH) depending on the hepatic excretion ratios of drugs. In general, changes in the CLNRs of drugs in this category were well-explained by the above-described factors. 4. We also reviewed and discussed the mechanism of urinary excretion of drugs (i.e. glomerular filtration and active renal secretion or reabsorption) in hypertensive rats.

  9. Comparison of disinfectants by immersion and spray atomization techniques on the linear dimensional stability of different interocclusal recording materials: An in vitro study.

    Science.gov (United States)

    Gounder, Revathy; Vikas, B V J

    2016-01-01

    To evaluate and compare the effect of 0.5% chlorhexidine gluconate, 1% sodium hypochlorite, and 2% glutaraldehyde by immersion and spray atomization technique on the linear dimensional stability of Jet bite, Aluwax and Ramitec interocclusal recording materials. Three representative materials: Jet bite (addition silicone), Aluwax and Ramitec (polyether) were mixed according to manufacturer's instructions and then specimens were prepared according to the specifications of ISO 4823. All the specimens except the control (distilled water) were treated with disinfectant solutions (0.5% chlorhexidine gluconate, 1% sodium hypochlorite, and 2% glutaraldehyde) for 30 and 60 min (n = 10) by spray and immersion technique. Once removed from the solutions, the test samples were washed in water for 15 s, dried and measured after 24 h 3 times using a measuring microscope with an accuracy of 0.0001 mm. Two-way ANOVA and Tukey's test with significance level of 5% were used to assess the statistical data (α = 0.05). All groups showed no significant difference statistically, in linear dimension when disinfected for 30 min by spray or immersion technique. Polyether had significantly higher dimensional variation when immersed in sodium hypochlorite for 60 min. Addition silicone showed the least dimensional change which ranged from 0.024% to 0.05%, followed by polyether from 0.004% to 0.171% and Aluwax from 0.146% to 0.228%. To preserve the dimensions and surface of the recording materials and effective microbial elimination, restrictions should be applied in the method of disinfection and time duration. However, using the disinfectants either by spray or immersion technique, the dimensional change was <0.5% which was not clinically significant according to the American Dental Association specification no. 19 criteria within the first 24 h.

  10. Pharmacokinetics of ceftibuten in children.

    Science.gov (United States)

    Barr, W H; Affrime, M; Lin, C C; Batra, V

    1995-07-01

    The bioavailability and pharmacokinetics of ceftibuten administered as an oral suspension were characterized by several studies in young healthy male adults (19 to 39 years old) and children ranging in age from 6 months to 17 years. Ceftibuten suspension was found to be bioequivalent and thus interchangeable with a standard 400-mg capsule. As with the capsule formulation, food slightly (Ceftibuten rapidly and extensively reaches the middle ear fluid in children with acute otitis media. Within 4 hours concentrations in middle ear fluid are similar to plasma concentrations and can be measured for 12 hours. The ratio of area under the concentration time curve for middle ear fluid relative to plasma was about 70%.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Data sharing for pharmacokinetic studies.

    Science.gov (United States)

    Anderson, Brian J; Merry, Alan F

    2009-10-01

    Pooling data from different pediatric studies can provide a single robust pharmacokinetic analysis that allows covariate analysis and hypothesis testing. Data sharing should be driven by the altruistic purpose of improving drug understanding to the clinical benefit of children. Electronic communications have rendered the sharing of data relatively easy, and data sharing within the wider scientific community has become commonplace. Data sharing allows verification of results, save costs and time, allows new interpretation of old data, and can fulfill teaching benefits. It may stimulate cooperative competition between researchers and allow individual researchers to concentrate on unique aspects of the scientific puzzle. However, there is occasionally a reluctance to share, in part because of fear of others stealing the hard work of a research group, which may not be recognized in subsequent publications that reuse data. Providing data may require additional effort for presentation in a suitable format. Data may be abused or used for purposes other than those for which they were collected. Propriety claims may limit access to industry-sponsored drug research. The question of who has ownership of data is contentious. Investigators often consider data they have collected to be their own property. Reputations and grants may be hinge on ownership of a data set. However, other team members, institutions, funding agencies, and the public also have a stake. The difficulties identified in the general scientific community also apply to data sharing for pediatric pharmacokinetic studies. There are few clearly established rules at present, and consideration of the issues hinges on ethical and philosophical arguments. The development of databases will depend on collaboration and cooperation and greater clarity and consensus over appropriate processes and procedures.

  12. Opioid pharmacokinetic drug-drug interactions.

    Science.gov (United States)

    Overholser, Brian R; Foster, David R

    2011-09-01

    Pharmacokinetic drug-drug interactions (DDIs) involving opioid analgesics can be problematic. Opioids are widely used, have a narrow therapeutic index, and can be associated with severe toxicity. The purpose of this review is to describe pharmacokinetic DDIs associated with opioids frequently encountered in managed care settings (morphine, codeine, oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, tramadol, and methadone). An introduction to the pharmacokinetic basis of DDIs is provided, and potential DDIs associated with opioids are reviewed. Opioids metabolized by the drug metabolizing enzymes of the cytochrome P450 (CYP450) system (codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone) are associated with numerous DDIs that can result in either a reduction in opioid effect or excess opioid effects. Conversely, opioids that are not metabolized by that system (morphine, oxymorphone, and hydromorphone) tend to be involved in fewer CYP450-associated pharmacokinetic DDIs.

  13. Pharmacokinetic aspects of the anti-epileptic drug substance vigabatrin

    DEFF Research Database (Denmark)

    Nøhr, Martha Kampp; Frølund, Sidsel; Holm, René

    2014-01-01

    are discussed in detail. Special focus is on the contribution of the proton-coupled amino acid transporter 1 (PAT1) for intestinal vigabatrin absorption. Furthermore, the review gives an overview of the pharmacokinetic parameters of vigabatrin across different species and drug-food and drug-drug interactions......Drug transporters in various tissues, such as intestine, kidney, liver and brain, are recognized as important mediators of absorption, distribution, metabolism and excretion of drug substances. This review gives a current status on the transporter(s) mediating the absorption, distribution......, metabolism and excretion properties of the anti-epileptic drug substance vigabatrin. For orally administered drugs, like vigabatrin, the absorption from the intestine is a prerequisite for the bioavailability. Therefore, transporter(s) involved in the intestinal absorption of vigabatrin in vitro and in vivo...

  14. Phase I population pharmacokinetics of irofulven.

    Science.gov (United States)

    Urien, S; Alexandre, J; Raymond, E; Brain, E; Smith, S; Shah, A; Cvitkovic, E; Lokiec, F

    2003-06-01

    Our aim was to develop a population pharmacokinetic model for irofulven and to assess covariates that might affect irofulven pharmacokinetics. Irofulven was administered by 5- or 30-min i.v. infusion to cancer patients during a phase I study. Blood samples were collected over 4 h. Plasma samples were analyzed to quantitate irofulven by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a non-linear mixed effects modeling program, MP2. Fifty-nine patients were available for pharmacokinetic analysis. Irofulven plasma concentration-time profiles were best described by a two-compartment pharmacokinetic model. Clearance and central volume of distribution were not significantly influenced by individual characteristics, i.e. body weight (BW), body surface area (BSA), age and gender. Final parameter estimates of clearance and central volume of distribution were 616 l/h and 37 l, respectively, resulting in a very short terminal half-life of less than 10 min. A relatively high level of variability was observed in irofulven pharmacokinetics, which was mainly due to a significant residual variability, 39%. For a 30-min irofulven infusion, the optimal sampling schedule for clearance estimation using the Bayesian method was the three time points 0.35-0.45, 0.80 and 1-1.2 h from the beginning of a 30-min infusion. We conclude that after i.v. infusion of irofulven, plasma clearance was high and not dependent upon patient age, gender, BSA or BW.

  15. Pharmacokinetics of oral amantadine in greyhound dogs.

    Science.gov (United States)

    Norkus, C; Rankin, D; Warner, M; KuKanich, B

    2015-06-01

    This study reports the pharmacokinetics of amantadine in greyhound dogs after oral administration. Five healthy greyhound dogs were used. A single oral dose of 100 mg amantadine hydrochloride (mean dose 2.8 mg/kg as amantadine hydrochloride) was administered to nonfasted subjects. Blood samples were collected at predetermined time points from 0 to 24 h after administration, and plasma concentrations of amantadine were measured by liquid chromatography with triple quadrupole mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Amantadine was well tolerated in all dogs with no adverse effects observed. The mean (range) amantadine CMAX was 275 ng/mL (225-351 ng/mL) at 2.6 h (1-4 h) with a terminal half-life of 4.96 h (4.11-6.59 h). The results of this study can be used to design dosages to assess multidose pharmacokinetics and dosages designed to achieve targeted concentrations in order to assess the clinical effects of amantadine in a variety of conditions including chronic pain. Further studies should also assess the pharmacokinetics of amantadine in other dog breeds or using population pharmacokinetics studies including multiple dog breeds to assess potential breed-specific differences in the pharmacokinetics of amantadine in dogs. © 2014 John Wiley & Sons Ltd.

  16. The pharmacokinetic interaction between levofloxacin and sunitinib.

    Science.gov (United States)

    Czyrski, Andrzej; Kondys, Katarzyna; Szałek, Edyta; Karbownik, Agnieszka; Grześkowiak, Edmund

    2015-06-01

    The aim of this study was to evaluate the impact of sunitinib on pharmacokinetics of levofloxacin. The previous study proved that levofloxacin co-administered with sunitib changes the following pharmacokinetic parameters i.e. Cmax and AUC for both sunitinib and SU012662 (sunitinib metabolite). We will also investigate if the limited sample strategy can be applied for levofloxacin. Rabbits were divided into two groups. In both groups there were six animals. In the control group levofloxacin was administered and in investigated group levofloxacin and sunitinib were co-administered. The dose of levofloxacin was 20mg/kg and the dose of sunitinib was 25mg. The concentration in plasma was determined by HPLC-FLD. The pharmacokinetic parameters were evaluated by WinNonLin software. The results were evaluated by the following statistical tests: Shapiro-Wilk, t-Student and Mann-Whitney test. Pharmacokinetics of levofloxacin obeys the two-compartment model. Sunitinib influences the following pharmacokinetic parameters of levofloxacin: half-life, elimination constant and volume of distribution. Statistical analysis proved that there is a correlation between AUC and the following five time-points: 0.25 h, 4h, 6h, 10h and 12h. The study proved that there is a potential pharmacokinetic interaction between sunitinib and levofloxacin. The statistical analysis proved that the limited sample strategy can be applied for levofloxacin. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  17. Pharmacokinetic, pharmacodynamic, efficacy, and safety data from two randomized, double-blind studies in patients with asthma and an in vitro study comparing two dry-powder inhalers delivering a combination of salmeterol 50 microg and fluticasone propionate 250 microg: implications for establishing bioequivalence of inhaled products.

    Science.gov (United States)

    Daley-Yates, Peter T; Parkins, David A; Thomas, Marian J; Gillett, Benjamin; House, Karen W; Ortega, Hector G

    2009-02-01

    The use of dry-powder inhalers (DPIs) to administer respiratory medicines is increasing, and new DPIs are likely to be developed because of expiring patents. However, there is considerable debate concerning the extent to which DPIs are interchangeable without altering disease control or the safety profile of the treatment. This study was designed to compare the pharmacokinetic (PK), pharmacodynamic (PD), efficacy, and safety data for 2 DPIs delivering a combination of salmeterol 50 microg plus fluticasone propionate (FP) 250 microg (SFC 50/250) to investigate assumptions of bioequivalence. Three studies compared SFC 50/250 delivery using a reservoir powder inhalation device (RPID) and a Diskus multiple-dose inhaler: an in vitro assessment of fine-particle-mass (FPM) profiles of the emitted doses; a PK/PD study of SFC 50/250 administered in two 14-day crossover treatment periods to 22 adults with moderate, persistent asthma to determine the equivalence of the RPID and Diskus inhaler in terms of drug delivery and systemic exposure; and a 12-week clinical efficacy and safety study of SFC 50/250 in 270 patients > or =12 years of age with moderate, persistent asthma to assess the equivalence of the RPID and Diskus inhaler based on peak expiratory flow (PEF) rates. FPM was summed from the quantity of active pharmaceutical ingredient deposited on stages 1 to 5 of a cascade impactor, representing an aerodynamic particle size range of 0.8 to 6.2 microm. Systemic exposure to SFC 50/250 was declared no greater with RPID than with the Diskus inhaler if the upper limit of the 90% CI for the ratio of FP AUC for the 2 devices was below the upper limit of the equivalence range (ie, <1.25). Adverse events, clinical laboratory test results, and vital signs were recorded throughout the 2 clinical studies. In vitro, mean FPM values for the RPID and Diskus inhaler, respectively, were 13.1 and 12.8 microg/dose for salmeterol (P = NS) and 66.8 and 66.2 microg/dose for FP (P = NS). The

  18. Pharmacokinetics and pharmacokinetic-dynamic modelling of rocuronium in infants and children

    NARCIS (Netherlands)

    Wierda, J.MKH; Meretoja, O.A; Taivainen, T; Proost, Hans

    We have determined the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of rocuronium in infants and children. We studied infants (n = 5, 0.1-0.8 yr) and children (n = 5, 2.3-8 yr), ASA II, in the ICU while undergoing artificial ventilation under i.v. anaesthesia with an arterial

  19. Clinical pharmacokinetics and pharmacodynamics of solifenacin.

    Science.gov (United States)

    Doroshyenko, Oxana; Fuhr, Uwe

    2009-01-01

    The succinate salt of solifenacin, a tertiary amine with anticholinergic properties, is used for symptomatic treatment of overactive bladder. Solifenacin peak plasma concentrations of 24.0 and 40.6 ng/mL are reached 3-8 hours after long-term oral administration of a 5 or 10 mg solifenacin dose, respectively. Studies in healthy adults have shown that the drug has high absolute bioavailability of about 90%, which does not decrease with concomitant food intake. Solifenacin has an apparent volume of distribution of 600 L, is 93-96% plasma protein bound, and probably crosses the blood-brain barrier. Solifenacin is eliminated mainly through hepatic metabolism via cytochrome P450 (CYP) 3A4, with about only 7% (3-13%) of the dose being excreted unchanged in the urine. Solifenacin metabolites are unlikely to contribute to clinical solifenacin effects. In healthy adults, total clearance of solifenacin amounts to 7-14 L/h. The terminal elimination half-life ranges from 33 to 85 hours, permitting once-daily administration. Urinary excretion plays a minor role in the elimination of solifenacin, resulting in renal clearance of 0.67-1.51 L/h. Solifenacin does not influence the activity of CYP1A1/2, 2C9, 2D6 and 3A4, and shows a weak inhibitory potential for CYP2C19 and P-glycoprotein in vitro; however, clinical drug-drug interactions with CYP2C19 and P-glycoprotein substrates are very unlikely. Exposure to solifenacin is increased about 1.2-fold in elderly subjects and about 2-fold in subjects with moderate hepatic and severe renal impairment, as well as by coadministration of the potent CYP3A4 inhibitor ketoconazole 200 mg/day. The full therapeutic effects of solifenacin occur after 2-4 weeks of treatment and are maintained upon long-term therapy. Although solifenacin pharmacokinetics display linearity at doses of 5-40 mg, no obvious dose dependency was observed in efficacy and tolerability studies. The efficacy of solifenacin (5 or 10 mg/day) is at least equal to that of

  20. The intravenous and oral pharmacokinetics of lotilaner in dogs

    Directory of Open Access Journals (Sweden)

    Céline E. Toutain

    2017-11-01

    Full Text Available Abstract Background Lotilaner is a new oral ectoparasiticide from the isoxazoline class developed for the treatment of flea and tick infestations in dogs. It is formulated as pure S-enantiomer in flavoured chewable tablets (Credelio™. The pharmacokinetics of lotilaner were thoroughly determined after intravenous and oral administration and under different feeding regimens in dogs. Methods Twenty-six adult beagle dogs were enrolled in a pharmacokinetic study evaluating either intravenous or oral administration of lotilaner. Following the oral administration of 20 mg/kg, under fed or fasted conditions, or intravenous administration of 3 mg/kg, blood samples were collected up to 35 days after treatment. The effects of timing of offering food and the amount of food consumed prior or after dosing on bioavailability were assessed in a separate study in 25 adult dogs. Lotilaner blood concentrations were measured using a validated liquid chromatography/tandem mass spectrometry (LC-MS/MS method. Pharmacokinetic parameters were calculated by non-compartmental analysis. In addition, in vivo enantiomer stability was evaluated in an analytical study. Results Following oral administration in fed animals, lotilaner was readily absorbed and peak blood concentrations reached within 2 hours. The terminal half-life was 30.7 days. Food enhanced the absorption, providing an oral bioavailability above 80% and reduced the inter-individual variability. Moreover, the time of feeding with respect to dosing (fed 30 min prior, fed at dosing or fed 30 min post-dosing or the reduction of the food ration to one-third of the normal daily ration did not impact bioavailability. Following intravenous administration, lotilaner had a low clearance of 0.18 l/kg/day, large volumes of distribution Vz and Vss of 6.35 and 6.45 l/kg, respectively and a terminal half-life of 24.6 days. In addition, there was no in vivo racemization of lotilaner. Conclusions The pharmacokinetic

  1. Promazine pharmacokinetics during concurrent treatment with tricyclic antidepressants.

    Science.gov (United States)

    Syrek, M; Wójcikowski, J; Daniel, W A

    1997-01-01

    The aim of the present study was to search for a possible effect of tricyclic antidepressants on the pharmacokinetics of promazine. Male Wistar rats received promazine and/or an antidepressant (amitriptyline, imipramine) at a dose of 10 mg/kg i.p. twice a day for two weeks. Amitriptyline increased the plasma concentrations of promazine and N-desmethylpromazine. The concentration of promazine sulfoxide was lowered after 30 min, but later it was raised after 6 and 12 h. The interaction was pronounced after 6 and 12 h when the concentration of promazine was 3 times as high, that of N-desmethylpromazine 25 times as high, and that of sulfoxide 22 times as high as those observed after administration of promazine alone. Similar results were obtained in the brain. Imipramine produced less distinct changes in promazine pharmacokinetics. It did not produce any significant changes in promazine concentration (a tendency to raise it after 30 min was observed) in plasma, but it significantly increased the concentration of N-desmethylpromazine and decreased that of promazine sulfoxide. Changes in the brain did not follow closely those in the plasma. In the brain, significant increases in the levels of promazine and its metabolites were observed after 6 and 12 h. In vitro studies with liver microsomes showed that chronic co-administration of the antidepressants did not significantly influence the rate of promazine demethylation and sulfoxidation. Instead, the Lineweaver-Burk's analysis showed that both amitriptyline and imipramine competitively inhibited the two metabolic pathways of the neuroleptic. The potency of imipramine to inhibit the promazine metabolism in vitro was lower than that of amitriptyline, which was in line with its weaker effect on the pharmacokinetics of promazine in vivo. The observed increase in the sum of concentrations of the measured compounds (promazine + metabolites) in the plasma suggests additional inhibition by amitriptyline of another, metabolic

  2. Sodium Dodecyl Sulfate-Modified Doxorubicin-Loaded Chitosan-Lipid Nanocarrier with Multi Polysaccharide-Lecithin Nanoarchitecture for Augmented Bioavailability and Stability of Oral Administration In Vitro and In Vivo.

    Science.gov (United States)

    Su, Chia-Wei; Chiang, Min-Yu; Lin, Yu-Ling; Tsai, Nu-Man; Chen, Yen-Po; Li, Wei-Ming; Hsu, Chin-Hao; Chen, San-Yuan

    2016-05-01

    For oral anti-cancer drug delivery, a new chitosan-lipid nanoparticle with sodium dodecyl sulfate modification was designed and synthesized using a double emulsification. TEM examination showed that the DOX-loaded nanoparticles, termed D-PL/TG NPs, exhibited a unique core-shell configuration composed of multiple amphiphilic chitosan-lecithin reverse micelles as the core and a triglyceride shell as a physical barrier to improve the encapsulation efficiency and reduce the drug leakage. In addition, the D-PL/TG NPs with sodium dodecyl sulfate modification on the surface have enhanced stability in the GI tract and increased oral bioavailability of doxorubicin. In vitro transport studies performed on Caco-2 monolayers indicated that the D-PL/TG NPs enhanced the permeability of DOX in the Caco-2 monolayers by altering the transport pathway from passive diffusion to transcytosis. The in vivo intestinal absorption assay suggested that the D-PL/TG NPs were preferentially absorbed through the specialized membranous epithelial cells (M cells) of the Peyer's patches, resulting in a significant improvement (8-fold) in oral bioavailability compared to that of free DOX. The experimental outcomes in this work demonstrate that the D-PL/TG NPs provide an exciting opportunity for advances in the oral administration of drugs with poor bioavailability that are usually used in treating tough and chronic diseases.

  3. Investigation of the metabolites of the HIF stabilizer FG-4592 (roxadustat) in five different in vitro models and in a human doping control sample using high resolution mass spectrometry.

    Science.gov (United States)

    Hansson, Annelie; Thevis, Mario; Cox, Holly; Miller, Geoff; Eichner, Daniel; Bondesson, Ulf; Hedeland, Mikael

    2017-02-05

    FG-4592 is a hypoxia-inducible factor (HIF) stabilizer, which can increase the number of red blood cells in the body. It has not been approved by regulatory authorities, but is available for purchase on the Internet. Due to its ability to improve the oxygen transportation mechanism in the body, FG-4592 is of interest for doping control laboratories, but prior to this study, little information about its metabolism was available. In this study, the metabolism of FG-4592 was investigated in a human doping control sample and in five in vitro models: human hepatocytes and liver microsomes, equine liver microsomes and S9 fraction and the fungus Cunninghamella elegans. By using liquid chromatography coupled to a Q-TOF mass spectrometer operated in MS(E) and MSMS modes, twelve different metabolites were observed for FG-4592. One monohydroxylated metabolite was detected in both the human and equine liver microsome incubations. For the fungus Cunninghamella elegans eleven different metabolites were observed of which the identical monohydroxylated metabolite had the highest response. This rich metabolic profile and the higher levels of metabolites produced by Cunninghamella elegans demonstrates its usefulness as a metabolite producing medium. In the doping control urine sample, one metabolite, which was the result of a direct glucuronidation, was observed. No metabolites were detected in neither the human hepatocyte nor in the equine liver S9 fraction incubates. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Pharmacotherapy for mood disorders in pregnancy: a review of pharmacokinetic changes and clinical recommendations for therapeutic drug monitoring.

    Science.gov (United States)

    Deligiannidis, Kristina M; Byatt, Nancy; Freeman, Marlene P

    2014-04-01

    Pharmacotherapy for mood disorders during pregnancy is often complicated by pregnancy-related pharmacokinetic changes and the need for dose adjustments. The objectives of this review are to summarize the evidence for change in perinatal pharmacokinetics of commonly used pharmacotherapies for mood disorders, discuss the implications for clinical and therapeutic drug monitoring (TDM), and make clinical recommendations. The English-language literature indexed on MEDLINE/PubMed was searched for original observational studies (controlled and uncontrolled, prospective and retrospective), case reports, and case series that evaluated or described pharmacokinetic changes or TDM during pregnancy or the postpartum period. Pregnancy-associated changes in absorption, distribution, metabolism, and elimination may result in lowered psychotropic drug levels and possible treatment effects, particularly in late pregnancy. Mechanisms include changes in both phase 1 hepatic cytochrome P450 and phase 2 uridine diphosphate glucuronosyltransferase enzyme activities, changes in hepatic and renal blood flow, and glomerular filtration rate. Therapeutic drug monitoring, in combination with clinical monitoring, is indicated for tricyclic antidepressants and mood stabilizers during the perinatal period. Substantial pharmacokinetic changes can occur during pregnancy in a number of commonly used antidepressants and mood stabilizers. Dose increases may be indicated for antidepressants including citalopram, clomipramine, imipramine, fluoxetine, fluvoxamine, nortriptyline, paroxetine, and sertraline, especially late in pregnancy. Antenatal dose increases may also be needed for lithium, lamotrigine, and valproic acid because of perinatal changes in metabolism. Close clinical monitoring of perinatal mood disorders and TDM of tricyclic antidepressants and mood stabilizers are recommended.

  5. Pharmacokinetics of Tacrolimus during Pregnancy

    Science.gov (United States)

    Zheng, Songmao; Easterling, Thomas R.; Umans, Jason G.; Miodovnik, Menachem; Calamia, Justina C.; Thummel, Kenneth E.; Shen, Danny D.; Davis, Connie L.; Hebert, Mary F.

    2012-01-01

    Background Information on the pharmacokinetics of tacrolimus during pregnancy is limited to case reports despite the increasing number of pregnant women being prescribed tacrolimus for immunosuppression. Methods Blood, plasma and urine samples were collected over one steady-state dosing interval from women treated with oral tacrolimus during early to late pregnancy (n = 10) and postpartum (n = 5). Total and unbound tacrolimus as well as metabolite concentrations in blood and plasma were assayed by a validated LC/MS/MS method. A mixed effect linear model was used for comparison across gestational age and using postpartum as the reference group. Results The mean oral clearance (CL/F) based on whole blood tacrolimus concentration was 39% higher during mid- and late-pregnancy compared to postpartum (47.4 ± 12.6 vs. 34.2 ± 14.8 L/h, P Tacrolimus free fraction increased by 91% in plasma (fP) and by 100% in blood (fB) during pregnancy (P = 0.0007 and 0.002, respectively). Increased fP was inversely associated with serum albumin concentration (r = − 0.7, P = 0.003), which decreased by 27% during pregnancy. Pregnancy related changes in fP and fB contributed significantly to the observed gestational increase in tacrolimus whole blood CL/F (r2 = 0.36 and 0.47 respectively, P tacrolimus whole blood CL/F was inversely correlated with both hematocrit and red blood cell counts, suggesting that binding of tacrolimus to erythrocytes restricts its availability for metabolism. Treating physicians increased tacrolimus dosages in study participants during pregnancy by an average of 45% in order to maintain tacrolimus whole blood trough concentrations in the therapeutic range. This led to striking increases in unbound tacrolimus trough concentrations and unbound AUC, by 112% and 173%, respectively during pregnancy (P = 0.02 and 0.03, respectively). Conclusions Tacrolimus pharmacokinetics are altered during pregnancy. Dose adjustment to maintain whole blood tacrolimus concentration

  6. Genotypes Affecting the Pharmacokinetics of Anticancer Drugs.

    Science.gov (United States)

    Bertholee, Daphne; Maring, Jan Gerard; van Kuilenburg, André B P

    2017-04-01

    Cancer treatment is becoming more and more individually based as a result of the large inter-individual differences that exist in treatment outcome and toxicity when patients are treated using population-based drug doses. Polymorphisms in genes encoding drug-metabolizing enzymes and transporters can significantly influence uptake, metabolism, and elimination of anticancer drugs. As a result, the altered pharmacokinetics can greatly influence drug efficacy and toxicity. Pharmacogenetic screening and/or drug-specific phenotyping of cancer patients eligible for treatment with chemotherapeutic drugs, prior to the start of anticancer treatment, can identify patients with tumors that are likely to be responsive or resistant to the proposed drugs. Similarly, the identification of patients with an increased risk of developing toxicity would allow either dose adaptation or the application of other targeted therapies. This review focuses on the role of genetic polymorphisms significantly altering the pharmacokinetics of anticancer drugs. Polymorphisms in DPYD, TPMT, and UGT1A1 have been described that have a major impact on the pharmacokinetics of 5-fluorouracil, mercaptopurine, and irinotecan, respectively. For other drugs, however, the association of polymorphisms with pharmacokinetics is less clear. To date, the influence of genetic variations on the pharmacokinetics of the increasingly used monoclonal antibodies has hardly been investigated. Some studies indicate that genes encoding the Fcγ-receptor family are of interest, but more research is needed to establish if screening before the start of therapy is beneficial. Considering the profound impact of polymorphisms in drug transporters and drug-metabolizing enzymes on the pharmacokinetics of chemotherapeutic drugs and hence, their toxicity and efficacy, pharmacogenetic and pharmacokinetic profiling should become the standard of care.

  7. New comprehensive studies of a gold(III) Dithiocarbamate complex with proven anticancer properties: Aqueous dissolution with cyclodextrins, pharmacokinetics and upstream inhibition of the ubiquitin-proteasome pathway.

    Science.gov (United States)

    Tomasello, Marianna F; Nardon, Chiara; Lanza, Valeria; Di Natale, Giuseppe; Pettenuzzo, Nicolò; Salmaso, Stefano; Milardi, Danilo; Caliceti, Paolo; Pappalardo, Giuseppe; Fregona, Dolores

    2017-09-29

    The gold(III)-dithiocarbamate complex AuL12 (dibromo [ethyl-N-(dithiocarboxy-kS,kS')-N-methylglycinate] gold(III)), is endowed with promising in vitro/in vivo antitumor activity and toxicological profile. Here, we report our recent strategies to improve its water solubility and stability under physiological conditions along with our efforts for unravelling its tangled mechanism of action. We used three types of α-cyclodextrins (CDs), namely β-CD, Me-β-CD and HP-β-CD to prepare aqueous solutions of AuL12. The ability of these natural oligosaccharide carriers to enhance water solubility of hydrophobic compounds, allowed drug stability of AuL12 to be investigated. Moreover, pharmacokinetic experiments were first carried out for a gold(III) coordination compound, after i.v. injection of the nanoformulation AuL12/HP-β-CD to female mice. The gold content in the blood samples was detected at scheduled times by AAS (atomic absorption spectrometry) analysis, highlighting a fast biodistribution with a t β1/2 of few minutes and a slow escretion (t α1/2 of 14.3 h). The in vitro cytotoxic activity of AuL12 was compared with the AuL12/HP-β-CD mixture against a panel of three human tumor cell lines (i.e., HeLa, KB and MCF7). Concerning the mechanism of action, we previously reported the proteasome-inhibitory activity of some our gold(III)-based compounds. In this work, we moved from the proteasome target to upstream of the important ubiquitin-proteasome pathway, testing the effects of AuL12 on the polyubiquitination reactions involving the Ub-activating (E1) and -conjugating (E2) enzymes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen.

    Science.gov (United States)

    Zhao, Yanli; Harmatz, Jerold S; Epstein, Carol R; Nakagawa, Yukako; Kurosaki, Chie; Nakamura, Tetsuro; Kadota, Takumi; Giesing, Dennis; Court, Michael H; Greenblatt, David J

    2015-11-01

    The antiviral agent favipiravir is likely to be co-prescribed with acetaminophen (paracetamol). The present study evaluated the possiblility of a pharmacokinetic interaction between favipiravir and acetaminophen, in vitro and in vivo. The effect of favipivir on the transformation of acetaminophen to its glucuronide and sulfate metabolites was studied using a pooled human hepatic S9 fraction in vitro. The effect of acute and extended adminstration of favipiravir on the pharmacokinetics of acetaminophen and metabolites was evaluated in human volunteers. Favipiravir inhibited the in vitro formation of acetaminophen sulfate, but not acetaminophen glucuronide. In human volunteers, both acute (1 day) and extended (6 days) administration of favipiravir slightly but significantly increased (by about 20 %) systemic exposure to acetaminophen (total AUC), whereas Cmax was not significantly changed. AUC for acetaminophen glucuronide was increased by 23 to 35 % above control by favipiravir, while AUC for acetaminophen sulfate was reduced by about 20 % compared to control. Urinary excretion of acetaminophen sulfate was likewise reduced to 44 to 65 % of control values during favipiravir co-administration, while excretion of acetaminophen glucuronide increased to 17 to 32 % above control. Favipiravir inhibits acetaminophen sulfate formation in vitro and in vivo. However the increase in systemic exposure to acetaminophen due to favipiravir co-administration, though statistically significant, is small in magnitude and unlikely to be of clinical importance. © 2015 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  9. Pre-formulation characterization and pharmacokinetic evaluation of resveratrol

    Science.gov (United States)

    Robinson-Barnes, Keila Delores

    Resveratrol, a natural compound found in grapes has potential chemotherapy effects but very low oral bioavailability in humans. The objectives of this study are to quantitatively characterized and understand the physiochemical properties and the pharmacokinetic evaluation of resveratrol. Solubility of resveratrol was measured in 10 common solvents at 25°C using HPLC. The solution state pH stability of resveratrol was assessed in various USP buffers ranging from pH 2-10 for 24 hours at 37 °C. Human plasma protein binding was determined using ultracentrifugation technique. Stability of resveratrol in human and rat plasma was also assessed at 37°C. Aliquots of blank plasma were spiked with a standard drug concentration to yield final plasma concentration of 50 mug/mL. Samples were analyzed for resveratrol concentration up to 96 hours. A group (n=8) of jugular vein-cannulated adult male Sprague-Dawley rats were evaluated and received intravenous dose of 20 mg/kg resveratrol. Serial blood samples were collected up to 8 hours after the dose. Plasma concentrations of resveratrol were measured by an established LC-MS/MS method. Pharmacokinetic parameters were assessed using noncompartmental methods. Resveratrol is more soluble in alcohol and PEG-400, and stable in acidic pH. It binds highly to plasma proteins, and degrades slower in human then rat plasma. Resveratrol exhibits bioexponential disposition after intravenous administration and has a short elimination half-life. Resveratrol displays bioexponential disposition following intravenous administration. The estimated mean maximum concentration was 1045.5 ng/mL and rapidly dropped below 100 ng/mL within 30 minutes. The area under the concentration time curve (AUC) for resveratrol was 13888.7 min*ng/mL The mean terminal elimination half-life was 50.9 minutes. The mean total body clearance (Cl) and volume of distribution of trans-resveratrol were 1711.9mL/min/kg and 91087.8 mL/kg, respectively. Pre

  10. Theophylline: a review of population pharmacokinetic analyses.

    Science.gov (United States)

    Ma, Y J; Jiang, D Q; Meng, J X; Li, M X; Zhao, H H; Wang, Y; Wang, L Q

    2016-12-01

    Numerous population pharmacokinetic studies of theophylline have been conducted in paediatric and adult patients. The purpose of this review was to summarize the published studies concerning population pharmacokinetics of theophylline in patients of different ages and discuss factors that might cause the large variability in the pharmacokinetics of theophylline. A literature search was conducted in PubMed using the following keywords: 'theophylline', 'population pharmacokinetic(s)' and 'nonlinear mixed effect model'. Additionally, the relevant references listed in the retrieved articles were manually reviewed. All of the studies that reported the population pharmacokinetics of theophylline in humans were included in this review. However, articles were excluded if they were not written in English. Sixteen articles were included in this review. Among them, 11 were conducted on paediatric patients, and five were conducted on adults. A one-compartment model with first-order elimination was employed in most of the included articles. A nonlinear mixed effect modelling approach (NONMEM) was the most commonly used software to develop a population pharmacokinetic model. Body weight and age (post-conceptional age and post-natal age) were the most important factors associated with the clearance (CL) of theophylline in paediatric patients. Body weight (ideal body weight and lean body mass), age and smoking status were most frequently used to estimate the CL of theophylline in adults. The median (range) estimate values of CL for paediatric and adult patients were 0·062 (0·0056-0·0949) L/h/kg and 0·053 (0·0493-0·0517) L/h/kg, respectively. The median values of the interindividual variability of CL were 33·5% in adults and 25·8% in paediatric patients. The mean values of the residual variability were 21% in paediatric patients and 14·3% in adults. This review concludes that body weight and age were the most important factors associated with the clearance of theophylline

  11. Predicting Oral Drug Absorption: Mini Review on Physiologically-Based Pharmacokinetic Models

    Directory of Open Access Journals (Sweden)

    Louis Lin

    2017-09-01

    Full Text Available Most marketed drugs are administered orally, despite the complex process of oral absorption that is difficult to predict. Oral bioavailability is dependent on the interplay between many processes that are dependent on both compound and physiological properties. Because of this complexity, computational oral physiologically-based pharmacokinetic (PBPK models have emerged as a tool to integrate these factors in an attempt to mechanistically capture the process of oral absorption. These models use inputs from in vitro assays to predict the pharmacokinetic behavior of drugs in the human body. The most common oral PBPK models are compartmental approaches, in which the gastrointestinal tract is characterized as a series of compartments through which the drug transits. The focus of this review is on the development of oral absorption PBPK models, followed by a brief discussion of the major applications of oral PBPK models in the pharmaceutical industry.

  12. Comparison of gastroretentive microspheres and sustained-release preparations using theophylline pharmacokinetics.

    Science.gov (United States)

    Miyazaki, Yasunori; Yakou, Shigeru; Takayama, Kozo

    2008-06-01

    The objective of this study was to use the pharmacokinetics of theophylline to compare various gastroretentive microspheres. Three types of theophylline microspheres prepared from a hydrophobic dextran derivative were characterized in terms of drug release in-vitro and floating and mucoadhesive properties. Theophylline pharmacokinetic studies were conducted in Beagle dogs, comparing bulk powder, commercial sustained-release granules (Theodur), sustained-release microspheres, floatable microspheres and mucoadhesive microspheres. Theodur and sustained-release microspheres resulted in a lower maximum concentration (Cmax) (P mucoadhesive microspheres indicated an increase in AUC without decreasing the rate of bioavailability. Overall, the gastroretentive microspheres improved the extent of bioavailability of theophylline, which is absorbable from the entire gastrointestinal tract. The mucoadhesive microsphere showed a prolonged serum drug level, indicating a superior sustained-release delivery system for theophylline.

  13. Forsythiae Fructus: A Review on its Phytochemistry, Quality Control, Pharmacology and Pharmacokinetics.

    Science.gov (United States)

    Dong, Zhanglu; Lu, Xianyuan; Tong, Xueli; Dong, Yaqian; Tang, Lan; Liu, Menghua

    2017-09-04

    Forsythiae Fructus , as a traditional Chinese medicine, has been widely used both as a single herb and in compound prescriptions in Asia, mainly due to its heat-clearing and detoxifying effects. Modern pharmacology has proved Forsythiae Fructus possesses various therapeutic effects, both in vitro and in vivo, such as anti-inflammatory, antibacterial and antiviral activities. Up to now, three hundred and twenty-one compounds have been identified and sensitive analytical methods have been established for its quality control. Recently, the pharmacokinetics of Forsythiae Fructus and its bioactive compounds have been reported, providing valuable information for its clinical application. Therefore, this systematic review focused on the newest scientific reports on Forsythiae Fructus and extensively summarizes its phytochemistry, pharmacology, pharmacokinetics and standardization procedures, especially the difference between the two applied types-unripe Forsythiae Fructus and ripe Forsythiae Fructus -in the hope of providing a helpful reference and guide for its clinical applications and further studies.

  14. Pharmacokinetics: an analysis of the method.

    Science.gov (United States)

    Staubus, A E

    1980-01-01

    The field of radiology in general, and gastrointestinal radiology in particular, can and has benefited by the application of pharmacokinetic principles in contrast agent research and development. The application of basic pharmacokinetic principles can aid in the design of new synthetic analogues. In many cases, the presence or the absence of certain functional groups in particular locations on the aromatic ring system can predictively influence the binding, clearance and half-life values of these compounds. Detailed pharmacokinetic understanding of gastrointestinal contrast agents, particularly cholecystopaques, hold the key for unlocking the "black box" aspects of hepatic/biliary functions. Specific agents are currently quantitating and characterizing hepatic uptake, enzyme transformations, and biliary excretion functions of the liver. Pharmacokinetic principles can also be applied within the clinical radiology setting. Studies are currently underway to correlate blood iodine levels following iopanoic acid (Telepaque) administration with the causes of gallbladder nonvisualization. In summary, the use of pharmacokinetics has and will continue to assist the gastrointestinal radiologist interested in developmental, basic, and/or clinical research.

  15. Modulation of Pharmacokinetic and Cytotoxicity Profile of Imatinib Base by Employing Optimized Nanostructured Lipid Carriers.

    Science.gov (United States)

    Gupta, Biki; Poudel, Bijay Kumar; Tran, Tuan Hiep; Pradhan, Roshan; Cho, Hyuk-Jun; Jeong, Jee-Heon; Shin, Beom Soo; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2015-09-01

    To prepare, optimize and characterize imatinib-loaded nanostructured lipid carriers (IMT-NLC), and evaluate their pharmacokinetic and cytotoxicity characteristics. IMT-NLC was prepared by hot homogenization method, and optimized by an approach involving Plackett-Burman design (PBD) and central composite design (CCD). An in vivo pharmacokinetic study was conducted in rats after both oral and intravenous administration. The in vitro cytotoxicity was evaluated by MTT assay on NCI-H727 cell-lines. PBD screening, followed by optimization by CCD and desirability function, yielded an optimized condition of 0.054, 6% w/w, 2.5% w/w and 1.25% w/v for organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (D/L), amount of lecithin (Lec) and amount of Tween® 20 (Tw20) respectively. The optimized IMT-NLC exhibited a particle size (Sz) of 148.80 ± 1.37 nm, polydispersity index (PDI) 0.191 ± 0.017 of and ζ-potential of -23.0 ± 1.5 mV, with a drug loading (DL) of 5.48 ± 0.01% and encapsulation efficiency (EE) of 97.93 ± 0.03%. IMT-NLC displayed sustained IMT release in vitro, significantly enhanced in vivo bioavailability of IMT after intravenous and oral administration, and greater in vitro cytotoxicity on NCI-H727 cells, compared with free IMT. A combined DoE approach enabled accurate optimization and successful preparation of IMT-NLC with enhanced in vivo pharmacokinetic and in vitro cytotoxicity characteristics.

  16. Biophysical characterization of Met-G-CSF: effects of different site-specific mono-pegylations on protein stability and aggregation.

    Directory of Open Access Journals (Sweden)

    Antonino Natalello

    Full Text Available The limited stability of proteins in vitro and in vivo reduces their conversion into effective biopharmaceuticals. To overcome this problem several strategies can be exploited, as the conjugation of the protein of interest with polyethylene glycol, in most cases, improves its stability and pharmacokinetics. In this work, we report a biophysical characterization of the non-pegylated and of two different site-specific mono-pegylated forms of recombinant human methionyl-granulocyte colony stimulating factor (Met-G-CSF, a protein used in chemotherapy and bone marrow transplantation. In particular, we found that the two mono-pegylations of Met-G-CSF at the N-terminal methionine and at glutamine 135 increase the protein thermal stability, reduce the aggregation propensity, preventing also protein precipitation, as revealed by circular dichroism (CD, Fourier transform infrared (FTIR, intrinsic fluorescence spectroscopies and dynamic light scattering (DLS. Interestingly, the two pegylation strategies were found to drastically reduce the polydispersity of Met-G-CSF, when incubated under conditions favouring protein aggregation, as indicated by DLS measurements. Our in vitro results are in agreement with preclinical studies, underlining that preliminary biophysical analyses, performed in the early stages of the development of new biopharmaceutical variants, might offer a useful tool for the identification of protein variants with improved therapeutic values.

  17. Steady-state pharmacokinetics of lithium carbonate in healthy subjects.

    OpenAIRE

    Hunter, R

    1988-01-01

    1. The pharmacokinetics of lithium in six healthy volunteers stabilised on lithium were investigated and appropriate pharmacokinetic parameters calculated. 2. The results illustrate important differences in single and multiple dose lithium pharmacokinetics; the implications for minimising lithium-induced renal damage are discussed.

  18. Pharmacokinetics of EDP-420 after ascending single oral doses in healthy adult volunteers.

    Science.gov (United States)

    Jiang, Li-Juan; Wang, Michelle; Or, Yat Sun

    2009-05-01

    EDP-420 (EP-013420, S-013420) is a first-in-class bicyclolide (bridged bicyclic macrolide) currently in clinical development for the treatment of respiratory tract infections. It has good preclinical pharmacokinetic properties across multiple species and potent in vitro and in vivo activity against respiratory tract infection pathogens, including Haemophilus influenzae, atypical organisms (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila), and multidrug-resistant streptococci. The safety, tolerability, and pharmacokinetics of an orally administered EDP-420 suspension in 40 healthy adult subjects were assessed in a randomized, double-blind, placebo-controlled, ascending single-dose study. Eligible subjects were sequentially randomized into one of five study groups (i.e., 100-, 200-, 400-, 800-, or 1,200-mg dosing groups) consisting of eight subjects (six active and two placebo) each. EDP-420 was well tolerated. There were no serious adverse events reported, nor were there any dose-limiting clinical or laboratory adverse events reported. EDP-420 was rapidly absorbed after a single oral dose. The mean plasma terminal half-life ranged from 15.6 to 20.1 h with low clearance. At the 400-mg dose, the area under the curve was 14.4 microg x h/ml, which well exceeded the required area under the concentration-time curve to cover common respiratory tract infection pathogens based on preclinical pharmacokinetic/pharmacodynamic modeling. The long half-life and high systemic exposure of EDP-420 support once-daily dosing and may allow for shorter treatment durations compared to other macrolide antibiotics. Based on its human pharmacokinetic profiles, taken together with its in vitro/in vivo activity against common respiratory pathogens, EDP-420 warrants efficacy trials for the treatment of respiratory tract infections.

  19. Pharmacokinetics of EDP-420 after Ascending Single Oral Doses in Healthy Adult Volunteers▿

    Science.gov (United States)

    Jiang, Li-Juan; Wang, Michelle; Or, Yat Sun

    2009-01-01

    EDP-420 (EP-013420, S-013420) is a first-in-class bicyclolide (bridged bicyclic macrolide) currently in clinical development for the treatment of respiratory tract infections. It has good preclinical pharmacokinetic properties across multiple species and potent in vitro and in vivo activity against respiratory tract infection pathogens, including Haemophilus influenzae, atypical organisms (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila), and multidrug-resistant streptococci. The safety, tolerability, and pharmacokinetics of an orally administered EDP-420 suspension in 40 healthy adult subjects were assessed in a randomized, double-blind, placebo-controlled, ascending single-dose study. Eligible subjects were sequentially randomized into one of five study groups (i.e., 100-, 200-, 400-, 800-, or 1,200-mg dosing groups) consisting of eight subjects (six active and two placebo) each. EDP-420 was well tolerated. There were no serious adverse events reported, nor were there any dose-limiting clinical or laboratory adverse events reported. EDP-420 was rapidly absorbed after a single oral dose. The mean plasma terminal half-life ranged from 15.6 to 20.1 h with low clearance. At the 400-mg dose, the area under the curve was 14.4 μg·h/ml, which well exceeded the required area under the concentration-time curve to cover common respiratory tract infection pathogens based on preclinical pharmacokinetic/pharmacodynamic modeling. The long half-life and high systemic exposure of EDP-420 support once-daily dosing and may allow for shorter treatment durations compared to other macrolide antibiotics. Based on its human pharmacokinetic profiles, taken together with its in vitro/in vivo activity against common respiratory pathogens, EDP-420 warrants efficacy trials for the treatment of respiratory tract infections. PMID:19223626

  20. Pharmacokinetics of amantadine in cats.

    Science.gov (United States)

    Siao, K T; Pypendop, B H; Stanley, S D; Ilkiw, J E

    2011-12-01

    This study reports the pharmacokinetics of amantadine in cats, after both i.v. and oral administration. Six healthy adult domestic shorthair female cats were used. Amantadine HCl (5 mg/kg, equivalent to 4 mg/kg amantadine base) was administered either intravenously or orally in a crossover randomized design. Blood samples were collected immediately prior to amantadine administration, and at various times up to 1440 min following intravenous, or up to 2880 min following oral administration. Plasma amantadine concentrations were determined by liquid chromatography-mass spectrometry, and plasma amantadine concentration-time data were fitted to compartmental models. A two-compartment model with elimination from the central compartment best described the disposition of amantadine administered intravenously in cats, and a one-compartment model best described the disposition of oral amantadine in cats. After i.v. administration, the apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state [mean ± SEM (range)], and the clearance and terminal half-life [harmonic mean ± jackknife pseudo-SD (range)] were 1.5 ± 0.3 (0.7-2.5) L/kg, 4.3 ± 0.2 (3.7-5.0) L/kg, 8.2 ± 2.1 (5.9-11.4) mL·min/kg, and 348 ± 49 (307-465) min, respectively. Systemic availability [mean ± SEM (range)] and terminal half-life after oral administration [harmonic mean ± jackknife pseudo-SD (range)] were 130 ± 11 (86-160)% and 324 ± 41 (277-381) min, respectively. © 2011 Blackwell Publishing Ltd.

  1. Pharmacokinetic of 3 H-deacetylasperulosidic acid in mice

    Directory of Open Access Journals (Sweden)

    Simla Basar-Maurer

    2016-08-01

    Full Text Available Background: An investigation was conducted to determine the fate of the iridoid derivative deacetylasperulosidic acid (DAA after oral application to mice. Methods: DAA was extracted from Morinda citrifolia leaf and purified by preparative HPLC. The identity was verified by MS and NMR spectroscopy. A sample of DAA was radioactively labelled with tritium and applied to mice by gavage. The pharmacokinetic of the radioactivity was investigated in blood, organs, urine and feces. Metabolites were isolated in blood and urine by HPLC and identified by LC-MS. In vitro incubation of DAA with mouse duodenum and liver homogenate and human fecal bacteria was performed and possible metabolites were separated by HPLC. Results: DAA was rapidly absorbed and excreted mainly via the kidneys with a half-life of 30 minutes. Radioactivity was present in all organs with highest concentrations in kidney and liver. Almost 100% of the radioactivity isolated from urine and organs could be identified as unchanged DAA. Additionally, no metabolism could be observed after in vitro incubation of DAA with mouse small intestine or liver homogenate. However, a total breakdown of the molecule was observed after incubation of DAA with human intestinal bacteria. Conclusion: The absorption and excretion of glycosides such as DAA in mammals without hydrolysis is a potential defense mechanism of animals against the toxicity of these compounds.

  2. Pharmacokinetic and pharmacodynamic evaluation of phencyclidine and its decadeutero variant

    Energy Technology Data Exchange (ETDEWEB)

    Cho, A.K.; Hiramatsu, M.; Pechnick, R.N.; Di Stefano, E.

    1989-07-01

    The role of metabolism in the in vivo actions of phencyclidine (PCP) was examined by comparing deuterium-substituted drug with drug of normal isotopic abundance. PCP elicits two responses that differ in their time course, ataxia, which is observable immediately after dosage, and hypothermia, which peaks approximately 90 to 120 min after drug administration. The role of metabolism in these responses was determined by comparing bioavailabilities of deuterium enriched (d10) and normal (d0) PCP with the two responses. Plasma concentration was determined after the i.v. and i.p. administration of d10 and d0 drug and the bioavailability of the d10 was found to be 1.3 to 1.5 times the d0. The clearance of the d10 was also smaller than the d0. The d10, which is pharmacologically equivalent in vitro, is metabolized more slowly than the d0 in vitro. The pharmacokinetic and pharmacodynamic bioavailabilities exhibited comparable isotope effects, indicating that both responses are due to the actions of the parent drug.

  3. Effect of carbamazepine on the pharmacokinetics of promazine.

    Science.gov (United States)

    Syrek, M; Wójcikowski, J; Daniel, W

    1996-01-01

    Combinations of neuroleptics and carbamazepine are administered to psychiatric patients in the therapy of mania, manic-depressive illness and schizophrenia. The present study was aimed at assessing the influence of carbamazepine on the pharmacokinetics of promazine. Male Wistar rats received promazine and/or carbamazepine twice daily for two weeks (promazine, 10 mg/kg ip; carbamazepine, 15 mg/kg ip during the 1st, and 20 mg/kg ip during the 2nd week of treatment). In a short time (1 h) after administration, carbamazepine had a tendency to increase the concentration of promazine in the blood plasma and brain. Lineweaver-Burk's analysis showed that carbamazepine added in vitro competitively inhibited the N-demethylation of promazine in liver microsomes, without affecting the sulphoxidation process. The effect was reflected in vivo (1 h) by an increased promazine/desmethylpromazine ratio. After a long time interval (6 h, 12 h), carbamazepine decreased the concentration of promazine and its metabolites. In vitro studies into the promazine metabolism, conducted on microsomes from rats treated with promazine and/or carbamazepine, did not show acceleration of its demethylation or sulphoxidation by carbamazepine. The obtained results suggest that induction of promazine metabolism by carbamazepine involves metabolic pathways other than N-demethylation or sulphoxidation. It has been concluded that when a phenothiazine neuroleptic, such as promazine, is administered jointly with carbamazepine, a slight increase in the neuroleptic concentration may be expected in a short time after administration, followed by its significant decrease.

  4. In Vitro Mouse and Human Serum Stability of a Heterobivalent Dual-Target Probe That Has Strong Affinity to Gastrin-Releasing Peptide and Neuropeptide Y1 Receptors on Tumor Cells.

    Science.gov (United States)

    Ghosh, Arijit; Raju, Natarajan; Tweedle, Michael; Kumar, Krishan

    2017-02-01

    Receptor-targeting radiolabeled molecular probes with high affinity and specificity are useful in studying and monitoring biological processes and responses. Dual- or multiple-targeting probes, using radiolabeled metal chelates conjugated to peptides, have potential advantages over single-targeting probes as they can recognize multiple targets leading to better sensitivity for imaging and radiotherapy when target heterogeneity is present. Two natural hormone peptide receptors, gastrin-releasing peptide (GRP) and Y1, are specifically interesting as their expression is upregulated in most breast and prostate cancers. One of our goals has been to develop a dual-target probe that can bind both GRP and Y1 receptors. Consequently, a heterobivalent dual-target probe, t-BBN/BVD15-DO3A (where a GRP targeting ligand J-G-Abz4-QWAVGHLM-NH2 and Y1 targeting ligand INP-K [ɛ-J-(α-DO3A-ɛ-DGa)-K] YRLRY-NH2 were coupled), that recognizes both GRP and Y1 receptors was synthesized, purified, and characterized in the past. Competitive displacement cell binding assay studies with the probe demonstrated strong affinity (IC50 values given in parentheses) for GRP receptors in T-47D cells (18 ± 0.7 nM) and for Y1 receptors in MCF7 cells (80 ± 11 nM). As a further evaluation of the heterobivalent dual-target probe t-BBN/BVD15-DO3A, the objective of this study was to determine its mouse and human serum stability at 37°C. The in vitro metabolic degradation of the dual-target probe in mouse and human serum was studied by using a 153Gd-labeled t-BBN/BVD15-DO3A and a high-performance liquid chromatography/radioisotope detector analytical method. The half-life (t1/2) of degradation of the dual-target probe in mouse serum was calculated as 7 hours and only ∼20% degradation was seen after 6 hours incubation in human serum. The slow in vitro metabolic degradation of the dual-target probe can be compared with the degradation t1/2 of the corresponding monomeric probes, BVD15-DO3A

  5. [Lead compound optimization strategy (1)--changing metabolic pathways and optimizing metabolism stability].

    Science.gov (United States)

    Wang, Jiang; Liu, Hong

    2013-10-01

    Lead compound optimization plays an important role in new drug discovery and development. The strategies for changing metabolic pathways can modulate pharmacokinetic properties, prolong the half life, improve metabolism stability and bioavailability of lead compounds. The strategies for changing metabolic pathways and improving metabolism stability are reviewed. These methods include blocking metabolic site, reduing lipophilicity, changing ring size, bioisosterism, and prodrug.

  6. Stabilization of TRAIL, an all-{beta}-sheet multimeric protein, using computational redesign

    NARCIS (Netherlands)

    van der Sloot, Almer Martinus; Mullally, Margaret; Fernandez-Ballester, G.; Serrano, L.; Quax, Wim

    2004-01-01

    Protein thermal stability is important for therapeutic proteins, both influencing the pharmacokinetic and pharmacodynamic properties and for stability during production and shelf-life of the final product. In this paper we show the redesign of a therapeutically interesting trimeric all-beta-sheet

  7. Stabilization of TRAIL, an all-beta-sheet multimeric protein, using computational redesign

    NARCIS (Netherlands)

    van der Sloot, AM; Mullally, MM; Fernandez-Ballester, G; Serrano, L; Quax, WJ

    Protein thermal stability is important for therapeutic proteins, both influencing the pharmacokinetic and pharmacodynamic properties and for stability during production and shelf-life of the final product. In this paper we show the redesign of a therapeutically interesting trimeric all-beta-sheet

  8. Oral and intravenous pharmacokinetics of taurine in sprague-dawley rats

    DEFF Research Database (Denmark)

    Nielsen, Carsten Uhd; Bjerg, Maria; Ulaganathan, Nithiya

    2017-01-01

    Taurine is involved in various physiological processes, and one of the most abundant amino acids in human. The aim was to investigate the mechanism for intestinal absorption of taurine in vivo using also in vitro mechanistic studies. Taurine absorption was measured in male Sprague-Dawley rats at 10...... (BCH) (200 mg/kg). BCH is not an inhibitor of PAT1 or the taurine transporter, TauT, hence it was included as a negative control. In vitro studies investigating the transport mechanism of taurine were conducted in human intestinal Caco-2 cells. The pharmacokinetic investigations showed that intestinal...... taurine absorption was not saturable at the investigated doses, but that the time (tmax) to reach the maximal plasma concentration (Cmax) increased with dose. Furthermore, Sar and Pro, but not BCH, decreased taurine Cmax. In vitro it was clearly shown that PAT1 mediated the cellular uptake of taurine...

  9. Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo.

    Science.gov (United States)

    Asakura, Mitsutoshi; Fukami, Tatsuki; Nakajima, Miki; Fujii, Hideaki; Atsuda, Koichiro; Itoh, Tomoo; Fujiwara, Ryoichi

    2017-02-01

    The main route of elimination of vildagliptin, which is an inhibitor of dipeptidyl peptidase-4 (DPP-4), in humans is cyano group hydrolysis to produce a carboxylic acid metabolite M20.7. Our in vitro study previously demonstrated that DPP-4 itself greatly contributed to the hydrolysis of vildagliptin in mouse, rat, and human livers. To investigate whether hepatic DPP-4 contributes to the hydrolysis of vildagliptin in vivo, in the present study, we conducted in vivo pharmacokinetics studies of vildagliptin in mice coadministered with vildagliptin and sitagliptin, which is another DPP-4 inhibitor, and also in streptozotocin (STZ)-induced diabetic mice. The area under the plasma concentration-time curve (AUC) value of M20.7 in mice coadministered with vildagliptin and sitagliptin was significantly lower than that in mice administered vildagliptin alone (P < 0.01). Although plasma DPP-4 expression level was increased 1.9-fold, hepatic DPP-4 activity was decreased in STZ-induced diabetic mice. The AUC values of M20.7 in STZ-induced diabetic mice were lower than those in control mice (P < 0.01). Additionally, the AUC values of M20.7 significantly positively correlated with hepatic DPP-4 activities in the individual mice (Rs = 0.943, P < 0.05). These findings indicated that DPP-4 greatly contributed to the hydrolysis of vildagliptin in vivo and that not plasma, but hepatic DPP-4 controlled pharmacokinetics of vildagliptin. Furthermore, enzyme assays of 23 individual human liver samples showed that there was a 3.6-fold interindividual variability in vildagliptin-hydrolyzing activities. Predetermination of the interindividual variability of hepatic vildagliptin-hydrolyzing activity might be useful for the prediction of blood vildagliptin concentrations in vivo. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  10. Pharmacokinetics and tolerability of oseltamivir combined with probenecid.

    Science.gov (United States)

    Holodniy, Mark; Penzak, Scott R; Straight, Timothy M; Davey, Richard T; Lee, Kelvin K; Goetz, Matthew Bidwell; Raisch, Dennis W; Cunningham, Francesca; Lin, Emil T; Olivo, Noemi; Deyton, Lawrence R

    2008-09-01

    Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further.

  11. Pharmacokinetics and Tolerability of Oseltamivir Combined with Probenecid▿ †

    Science.gov (United States)

    Holodniy, Mark; Penzak, Scott R.; Straight, Timothy M.; Davey, Richard T.; Lee, Kelvin K.; Goetz, Matthew Bidwell; Raisch, Dennis W.; Cunningham, Francesca; Lin, Emil T.; Olivo, Noemi; Deyton, Lawrence R.

    2008-01-01

    Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further. PMID:18559644

  12. Staurosporine analysis and its pharmacokinetics in the blood of rats

    Energy Technology Data Exchange (ETDEWEB)

    Gurley, L.R.; Umbarger, K.O.; Kim, J.M.; Bradbury, E.M.; Lehnert, B.E.

    1994-07-01

    Staurosporine (Stsp), a protein kinase inhibitor, has been found to have a differential effect on the proliferation of normal and transformed cells in vitro. Essentially nothing is known about the distribution and pharmacokinetics of Stsp in the body. To facilitate such investigations, we have developed a High-Performance Liquid Chromatography method for measuring the levels of Stsp in blood. Stsp was measured in both plasma and RBC of rat blood. In vivo, Stsp was rapidly sequestered in some other tissue compartment, which rapidly decreased the concentration of Stsp in plasma to nondetectable levels. Using a postchromatography computerized analysis program that amplified the Stsp UV absorption peak from the HPLC. nanogram levels of Stsp were detected in vivo. Using this detection system for pharmacokinetic studies it was found that, in vivo, Stsp had a half-life of 51.6 min in plasma and 75.3 min in RBC. Tissue adsorption studies demonstrated that up to 99% of the Stsp was adsorbed by the heart and lung tissue in one pass through these organs. Extrapolation of the data from these studies suggest that 1{minus}g Stsp injections should produce a 2- to 7-ng/ml plasma Stsp level in vivo which is in the effective range to produce G1 arrest in normal cells. The short half-life of Stsp in plasma indicates that it will be necessary to infuse Stsp at some low level following the initial bolus injection in order to maintain Stsp levels in plasma at the 1- to 10-ng/ml level for the 2- to 3-day period necessary to achieve G1 arrest in vivo.

  13. Dissolution and pharmacokinetics of baicalin-polyvinylpyrrolidone coprecipitate.

    Science.gov (United States)

    Li, Bibo; He, Mei; Li, Wei; Luo, Zhibin; Guo, Ying; Li, Yajun; Zang, Chunbao; Wang, Bo; Li, Fang; Li, Shaolin; Ji, Ping

    2013-11-01

    Baicalin-polyvinylpyrrolidone coprecipitate was prepared with the aim of improving the dissolution and bioavailability of the baicalin. The dissolution of the coprecipitate in capsule form was tested and compared with baicalin active pharmaceutical ingredient (API) capsules. A sensitive high-performance liquid chromatography-ultraviolet detection method was established to determine the concentration of baicalin in plasma. The liquid-liquid extraction and solid phase extraction methods were used to pretreat the baicalin plasma sample. The pharmacokinetics of the coprecipitate capsules were tested and compared with the API capsules in six beagle dogs after crossover oral administration. The results of the dissolution demonstrated that the dissolution of the coprecipitate capsules was 21.02, 2.02 and 3.29 times that of the API capsules in 0.1 mol/l HCl solution, pH 4.5 solution and water, respectively, but it was slightly lower than that of the API capsules in a pH 6.8 solution. The calibration curve showed a good linearity at concentrations between 3.648 ng/mL and 364.8 ng/mL (r = 0.998). The baicalin plasma sample was successfully pretreated, with endogenous impurities almost completely removed. The pharmacokinetics of the coprecipitate capsules and the API capsules indicated that the mean values of Cmax were 127.04 ± 10.6 and 27.49 ± 36 μg/l, and those of AUC(0-24h) were 1080.23 ± 336.43 and 337.84 ± 127.64 μg/l × h, respectively. Compared with the baicalin API capsules, the relative bioavailability of the coprecipitate capsules was 338.2% ± 93.2%. From these observations of improved dissolution and pharmacokinetic behaviours, a good relationship was found in vitro and in vivo, indicating that the coprecipitate could be a promising formulation strategy for insoluble baicalin. © 2013 Royal Pharmaceutical Society.

  14. In vitro and in vivo assessment of matrix type transdermal therapeutic system of labetalol hydrochloride.

    Science.gov (United States)

    Mittal, Ashu; Parmar, Shikha; Singh, Brijendra

    2009-10-01

    The aim of the investigation was to develop and evaluate matrix type transdermal therapeutic systems containing new polymeric combinations (Eudragit E PO/Eudragit RL 100 & Plasdone S 630) as polymers and Labetalol Hydrochloride (LBHCl) as a model drug. The matrix type TTS of LBHCl were prepared by film casting technique. The patches were characterized for physical, in vitro release studies & ex-vivo permeation studies (human cadaver skin). On the basis of in vitro drug release and skin permeation performance, formulation A1 was found to be better than the other formulations and it was selected as the optimized formulation. The optimized patch was assessed for its pharmacokinetic, pharmacodynamic, skin irritation potential, and stability studies. The maximum percentage drug release & Permeation in 48 hrs were 92.43 % and 76.24 % respectively for optimized patch. The Korsmeyer peppas release exponent value of 0.604 suggested release mechanism towards first order release in the optimized formulation. The results obtained from the in vivo characterization of the optimized patch showed sustained action of the developed formulation. The interaction studies analysis indicated no chemical interaction between the drug and polymers. The optimized patch was seemingly free of potentially hazardous skin irritation as suggested by skin irritation score of 0.915<2.00 (under Draize score test). The optimized formulation was found to be stable at ambient storage conditions. The above TTS holds promise for improved bioavailability and better management of hypertension on long term basis.

  15. Ethnic and genetic factors in methadone pharmacokinetics: A population pharmacokinetic study☆

    Science.gov (United States)

    Bart, Gavin; Lenz, Scott; Straka, Robert J.; Brundage, Richard C.

    2014-01-01

    Background Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population. Methods Plasma levels of the opiate-active R-methadone and opiate-inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of racmethadone. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics. Results In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G > T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G > T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R-methadone. Conclusion This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability. PMID:25456329

  16. Pharmacokinetics and pharmacodynamics of cannabinoids.

    Science.gov (United States)

    Grotenhermen, Franjo

    2003-01-01

    Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial

  17. Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics.

    Science.gov (United States)

    Vorrink, Sabine U; Ullah, Shahid; Schmidt, Staffan; Nandania, Jatin; Velagapudi, Vidya; Beck, Olof; Ingelman-Sundberg, Magnus; Lauschke, Volker M

    2017-06-01

    Adverse reactions or lack of response to medications are important concerns for drug development programs. However, faithful predictions of drug metabolism and toxicity are difficult because animal models show only limited translatability to humans. Furthermore, current in vitro systems, such as hepatic cell lines or primary human hepatocyte (PHH) 2-dimensional (2D) monolayer cultures, can be used only for acute toxicity tests because of their immature phenotypes and inherent instability. Therefore, the migration to novel phenotypically stable models is of prime importance for the pharmaceutical industry. Novel 3-dimensional (3D) culture systems have been shown to accurately mimic in vivo hepatic phenotypes on transcriptomic and proteomic level, but information about their metabolic stability is lacking. Using a combination of targeted and untargeted high-resolution mass spectrometry, we found that PHHs in 3D spheroid cultures remained metabolically stable for multiple weeks, whereas metabolic patterns of PHHs from the same donors cultured as conventional 2D monolayers rapidly deteriorated. Furthermore, pharmacokinetic differences between donors were maintained in 3D spheroid cultures, enabling studies of interindividual variability in drug metabolism and toxicity. We conclude that the 3D spheroid system is metabolically stable and constitutes a suitable model for in vitro studies of long-term drug metabolism and pharmacokinetics.-Vorrink, S. U., Ullah, S., Schmid, S., Nandania, J., Velagapudi, V., Beck, O., Ingelman-Sundberg, M., Lauschke, V. M. Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics. © The Author(s).

  18. Obstetric pharmacokinetic dosing studies are urgently needed

    Directory of Open Access Journals (Sweden)

    Shelley A. McCormack

    2014-02-01

    Full Text Available Use of pharmacotherapy during pregnancy is common and increasing. Physiologic changes during pregnancy may significantly alter overall systemic drug exposure, necessitating dose changes. A search of PubMed for pharmacokinetic studies showed 494 publications during pregnancy out of 35,921 total pharmacokinetic published studies (1.29%, from the late 1960s through August 31, 2013. Closer examination of pharmacokinetic studies in pregnant women published since 2008 (81 studies revealed that about a third of the trials were for treatment of acute labor and delivery issues, a third included studies of infectious disease treatment during pregnancy, and the remaining third were for varied antepartum indications. Approximately two-thirds of these recent studies were primarily funded by government agencies worldwide, one quarter were supported by private non-profit foundations or combinations of government and private funding, and slightly less than 10% were supported by pharmaceutical industry. As highlighted in this review, vast gaps exist in pharmacology information and evidence for appropriate dosing of medications in pregnant women. This lack of knowledge and understanding of drug disposition throughout pregnancy place both the mother and the fetus at risk for avoidable therapeutic misadventures – suboptimal efficacy or excess toxicity – with medication use in pregnancy. Increased efforts to perform and support obstetric dosing and pharmacokinetic studies are greatly needed.

  19. Pharmacokinetics of Chloramphenicol in Sheep after Intramuscular ...

    African Journals Online (AJOL)

    Following a 25 mg/kg intramuscular dose of CAP, the drug was absorbed rapidly from the injection site and by one week post drug administration the mean serum concentration was 0.26±0.03 ng/ml. Significant (p<0.05) individual differences were observed in the serum drug concentrations and pharmacokinetic parameters.

  20. A Terminal Pharmaceutics Course in Clinical Pharmacokinetics.

    Science.gov (United States)

    Reuning, Richard H.; Krautheim, Daniel

    1978-01-01

    At Ohio State University, an undergraduate course extends the course sequence in biopharmaceutics and pharmacokinetics to application to problems in optimizing drug therapy. Course content, structure, instructional methods, and student term projects are described, and a course outline, typical projects, and some behavioral objectives are appended.…

  1. Comparative pharmacokinetic analysis with two omeprazole ...

    African Journals Online (AJOL)

    The pharmacokinetics of omeprazole pharmaceutical products Proceptin® 20mg capsule and Losec® 20mg MUPS tablet were compared in healthy subjects. The study was an open-‐label, randomized, two-‐treatment, two-sequence, two-way crossover, single-dose bioavailability study conducted under fasting conditions ...

  2. Glipizide Pharmacokinetics in Healthy and Diabetic Volunteers

    African Journals Online (AJOL)

    Erah

    3Discipline of Social and Administrative Pharmacy, School of Pharmaceutical Sciences, University Sains Malaysia,. 11800, Penang, Malaysia, 4Ministry of Health ... be by increasing the secretion of insulin from the islets of Langerhans in both normal ..... obesity on the pharmacokinetics and pharmacodynamics of glipizide in ...

  3. Population pharmacokinetic and pharmacodynamic analysis of bosutinib.

    Science.gov (United States)

    Hsyu, Poe-Hirr; Mould, Diane R; Abbas, Richat; Amantea, Michael

    2014-01-01

    Bosutinib is an orally active, competitive inhibitor of Src/Abl tyrosine kinases. A population pharmacokinetic model was developed using data pooled from 3 studies of patients (n = 870) with solid tumors or Philadelphia chromosome-positive leukemia. Patients (aged 18-91 y, weighing 35-221 kg) who received bosutinib 50 to 600 mg orally with food each contributed 6-9 pharmacokinetic samples. The final pharmacokinetic model was a linear two-compartment model with first-order absorption, an absorption lag-time, and dose-dependent bioavailability. Oral absorption was relatively slow, with a half-time of 1.14 h and a lag-time of 0.87 h; time to peak concentration was 5-6 h. Apparent clearance was 120 L/h. The apparent volume of the peripheral compartment was large with a slow turnover; alpha and beta half-lives were 19 h and 290 days, respectively. All parameters were estimated with acceptable precision (standard error bosutinib pharmacokinetics. Therefore, adjusting bosutinib dose for body size (weight, surface area) would not provide benefit over fixed dosing. Using this exposure model in pharmacodynamic assessment of one study, adverse event incidence was shown to be similar in overall and bosutinib-responsive populations.

  4. Pharmacokinetic interaction studies between felbamate and vigabatrin

    Science.gov (United States)

    Reidenberg, P.; Glue, P.; Banfield, C.; Colucci, R.; Meehan, J.; Rey, E.; Radwanski, E.; Nomeir, A.; Lim, J.; Lin, C.; Guillaume, M.; Affrime, M. B.

    1995-01-01

    To assess the possible occurrence of pharmacokinetic interactions between the antiepileptic agents felbamate and vigabatrin, two randomized, double-blind, placebo-controlled, crossover studies were conducted in healthy male volunteers. In Study I, 18 subjects received oral vigabatrin 1000 mg every 12 h for two 8 day periods with felbamate 1200 mg every 12 h or placebo. In Study II, 18 other volunteers were administered oral felbamate 1200 mg every 12 h for two 8 day periods with vigabatrin 1000 mg every 12 h or placebo. On the eighth day of each treatment period, blood and urine samples were collected over 12 h for determination of the active S(+)- and inactive R(-)-vigabatrin enantiomer concentrations (Study I) or felbamate concentrations (Study II). In Study I, the pharmacokinetic parameters of R(-)-vigabatrin were similar during co-administration with felbamate or placebo. Felbamate produced a 13% increase in AUC(0,12 h) and an 8% increase in urinary excretion of S(+)-vigabatrin. Although these changes were statistically significant, their magnitude was small. In Study II, the pharmacokinetic parameters of felbamate were similar during concurrent administration with vigabatrin or placebo. These data indicate that there are no clinically relevant pharmacokinetic interactions between felbamate and vigabatrin in man PMID:8562299

  5. Synergism in Pharmacokinetics of Retagliptin and Metformin ...

    African Journals Online (AJOL)

    Keywords: Retagliptin, Metformin, Pharmacokinetic interaction, Synergism, Type 2 diabetes. Tropical Journal of Pharmaceutical Research is ... chemical structure was shown in the Figure 1. Retagliptin has entered into clinical trial ... allergies or hypersensitivity to the study drugs or their excipients; abuse of drugs or alcohol ...

  6. Pharmacokinetics of chloroquine in diabetic rabbits | Adelusi ...

    African Journals Online (AJOL)

    The pharmacokinetic parameters derived from diabetic rabbits have been compared to those of normal rabbits. Two sets of rabbits were used, normal rabbits and diabetic rabbits. The diabetic rabbits were obtained by inducing diabetes in rabbits using streptozotocin. Chloroquine at a dose of 10 mg/kg was administered to ...

  7. Pharmacokinetics Of Artemether-Lumefantrine Combination ...

    African Journals Online (AJOL)

    Objectives: The therapeutic effects of artemether monotherapy compared to artemether-lumefantrine combined therapy in malaria based on their pharmacokinetic parameters such as absorption, elimination constants, area under the curve, bioavailability, volume of distribution and half-lives were investigated. Methods: ...

  8. Pharmacokinetic comparison of seven 8-methoxypsoralen brands

    DEFF Research Database (Denmark)

    Menne, T; Andersen, Klaus Ejner; Larsen, E

    1981-01-01

    The pharmacokinetics of seven 8-MOP brands were evaluated in 7 volunteers using an incomplete bloc design. After a single oral dose the 8-MOP plasma level was followed for 3 hours. The plasma concentration was measured with a gas chromatographic - mass spectrometric method, using an isotopic...

  9. Pharmacokinetic Studies on Metoprolol - Eudragit Matrix Tablets ...

    African Journals Online (AJOL)

    Purpose: To investigate the pharmacokinetics of of a developed metoprolol and a reference standard (Mepressor®). Methods: Metoprolol tartrate-loaded Eudragit® FS microparticles were formulated and compressed into tablets. The tablets were tested for their physicochemical properties according to United States ...

  10. A General Purpose Pharmacokinetic Model for Propofol

    NARCIS (Netherlands)

    Eleveld, Douglas J.; Proost, Johannes H.; Cortinez, Luis I.; Absalom, Anthony R.; Struys, Michel M. R. F.

    BACKGROUND: Pharmacokinetic (PK) models are used to predict drug concentrations for infusion regimens for intraoperative displays and to calculate infusion rates in target-controlled infusion systems. For propofol, the PK models available in the literature were mostly developed from particular

  11. Self-emulsifying drug delivery system developed by the HLB-RSM approach: Characterization by transmission electron microscopy and pharmacokinetic study.

    Science.gov (United States)

    Bahloul, Badr; Lassoued, Mohamed Ali; Seguin, Johanne; Lai-Kuen, René; Dhotel, Hélène; Sfar, Souad; Mignet, Nathalie

    2015-06-20

    Recently, we developed a new approach to rationalize an optimized design for self-emulsifying drug delivery system (SEDDS) by introducing the HLB and the response surface as determinant factors in SEDDS development. The aim of this current paper is to assess the suitability of this HLB-RSM approach to enhance the oral bioavailability of BCS class II compounds using fenofibrate as drug model. Eight SEDDS formulations (I→VIII) were pre-selected regarding their self-emulsification capacity and their effect on increasing in vitro drug release. They were firstly evaluated for their thermodynamic stability and zeta potential. Unstable SEDDS were discarded meanwhile the structural morphology of the stable ones (I, VI and VIII) was characterized using transmission electron microscopy (TEM). A pharmacokinetic study was then undertaken on male BALB/cJRj mices. The in vivo results showed a significant increase of fenofibrate absorption for all the three stable SEDDS formulations compared to the commercialized form, (LIPANTHYL micronized(®) (pHLB-RSM approach could be considered as a promising method for the development of efficient and highly stable SEDDS aiming to increase the poor bioavailability of BCS class II molecules. Copyright © 2015. Published by Elsevier B.V.

  12. Population pharmacokinetics of cyclosporine in chinese cardiac transplant recipients.

    Science.gov (United States)

    Yin, Ophelia Q P; Lau, So-Kei; Chow, Moses S S

    2006-06-01

    To characterize the population pharmacokinetics of cyclosporine in Chinese patients undergoing cardiac transplantation and to identify the demographic and clinical covariates affecting cyclosporine clearance. Population pharmacokinetic analysis using data from a retrospective chart review. Specialty hospital in Hong Kong for treatment of cardiac and pulmonary diseases. Thirty-eight Chinese adult patients (mean age 46 yrs) who had undergone routine cyclosporine therapeutic drug monitoring after cardiac transplantation between January 1, 1991, and December 31, 2003. Data regarding dosing, demographics, clinical laboratory values, and concurrent drugs were collected retrospectively. Data were included if patients had blood cyclosporine concentrations determined for at least 12 weeks after transplantation; an average of 18 blood samples/patient were collected. Population modeling was performed using a one-compartment linear model with first-order absorption and elimination. Various demographic and clinical covariates were tested for their significant effects on the apparent oral clearance (Cl/F) of cyclosporine. The stability of the final population model was evaluated by using the bootstrap resampling method. Statistically significant associations were observed between Cl/F and each of the following covariates: body weight (BW), use of diltiazem (DIL), and hematocrit value (HCT). The final model was Cl/F=5.00*(1-DIL)+365/HCT+(0.144*BW). The interindividual variabilities of Cl/F and apparent volume of distribution were 14.5% and 40.2%, respectively. The mean parameter estimates obtained from bootstrap analyses were highly consistent with those obtained with the original data set. The estimated Cl/F values of cyclosporine in our Chinese cardiac transplant recipients appeared to be similar to those reported for Caucasian cardiac transplant recipients. Thus, our data provide support that a cyclosporine dosage regimen similar to that in Caucasian patients may be needed in

  13. Does Critical Illness Change Levofloxacin Pharmacokinetics?

    Science.gov (United States)

    Roberts, Jason A; Cotta, Menino Osbert; Cojutti, Piergiorgio; Lugano, Manuela; Della Rocca, Giorgio; Pea, Federico

    2015-12-14

    Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  14. A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform.

    Science.gov (United States)

    Choi, Y; Jiang, F; An, H; Park, H J; Choi, J H; Lee, H

    2017-03-01

    Genetic association studies on the pharmacokinetics of tacrolimus have reported conflicting results, except for the role of the CYP3A5*3 polymorphism. The objective of this study was to identify genetic variants affecting the pharmacokinetics of tacrolimus using the DMETTM Plus microarray in 42 healthy males. Aside from CYP3A5*3, the rs3814055 polymorphism in the NR1I2 gene was associated with the tacrolimus pharmacokinetics based on false discovery rate-corrected multiple tests and the least absolute shrinkage and selection operator analysis. The area under the concentration-time curve to the last quantifiable time point (AUClast) was 3.42 times greater in subjects with homozygous mutations in both genes (CYP3A5*3/*3 and NR1I2 T/T) than in wild-type subjects. The two variants explained the 54% variability in the tacrolimus AUClast. An in vitro luciferase reporter assay indicated that downregulation of PXR expression is the likely molecular mechanism responsible for the increased exposure to tacrolimus in subjects carrying the rs3814055 C>T variant.

  15. Docetaxel and ketoconazole in advanced hormone-refractory prostate carcinoma: a phase I and pharmacokinetic study.

    Science.gov (United States)

    Van Veldhuizen, Peter J; Reed, Gregory; Aggarwal, Arvind; Baranda, Joaquina; Zulfiqar, Muhammad; Williamson, Stephen

    2003-11-01

    Docetaxel has significant single-agent activity in patients with prostate carcinoma, and ketoconazole has activity as a second-line hormonal agent. In vitro, ketoconazole exhibits synergy with several chemotherapeutic agents. A potential drug interaction exists, however, because both docetaxel and ketoconazole are metabolized hepatically by the cytochrome p450 system (CYP3A4). The authors performed a Phase I study and a pharmacokinetic study evaluating the both tolerability of a docetaxel/ketoconazole combination as well as this potential drug interaction. For all initial patients, docetaxel was administered intravenously at a dose of 55 mg/m(2) over 1 hour every 21 days. Starting on Day 8 after their first docetaxel dose, cohorts of at least 3-5 new patients were enrolled to receive escalating doses of ketoconazole. When the maximally tolerated dose (MTD) of ketoconazole was reached, the subsequent cohort of patients received an escalating dose of docetaxel. Pharmacokinetic studies were performed after docetaxel infusions on Day 1 (prior to ketoconazole) and Day 22 (after starting ketoconazole). Twenty-six patients were enrolled and completed at least 2 cycles of treatment. The MTD was ketoconazole 400 mg twice daily and docetaxel 55 mg/m(2). Dose-limiting toxicities included neutropenia and fatigue. Ketoconazole did not cause a consistent effect on docetaxel pharmacokinetics, although there was significant intrapatient and interpatient variability in serum levels. The recommended Phase II dose for this combination is ketoconazole 400 mg twice daily and docetaxel 55 mg/m(2) every 21 days.

  16. Biodegradable nanoparticles for improved kidney bioavailability of rhein: preparation, characterization, plasma, and kidney pharmacokinetics.

    Science.gov (United States)

    Wei, Yinghui; Luo, Xiaoting; Guan, Jiani; Ma, Jianping; Zhong, Yicong; Luo, Jingwen; Li, Fanzhu

    2017-11-01

    The aim of this work is to develop biodegradable nanoparticles for improved kidney bioavailability of rhein (RH). RH-loaded nanoparticles were prepared using an emulsification solvent evaporation method and fully characterized by several techniques. Kidney pharmacokinetics was assessed by implanting a microdialysis probe in rat's kidney cortex. Blood samples were simultaneously collected (via femoral artery) for assessing plasma pharmacokinetics. Optimized nanoparticles were small, with a mean particle size of 132.6 ± 5.95 nm, and homogeneously dispersed. The charge on the particles was nearly zero, the encapsulation efficiency was 62.71 ± 3.02%, and the drug loading was 1.56 ± 0.15%. In vitro release of RH from the nanoparticles showed an initial burst release followed by a sustained release. Plasma and kidney pharmacokinetics showed that encapsulation of RH into nanoparticles significantly increased its kidney bioavailability (AUCkidney/AUCplasma = 0.586 ± 0.072), clearly indicating that nanoparticles are a promising strategy for kidney drug delivery.

  17. Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites.

    Directory of Open Access Journals (Sweden)

    Yang-Ji Kim

    Full Text Available Allyl-isothiocyanate (AITC is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH or N-acetylcysteine (NAC and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis.

  18. Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics.

    Science.gov (United States)

    Hirvensalo, Päivi; Tornio, Aleksi; Neuvonen, Mikko; Tapaninen, Tuija; Paile-Hyvärinen, Maria; Kärjä, Vesa; Männistö, Ville T; Pihlajamäki, Jussi; Backman, Janne T; Niemi, Mikko

    2017-09-23

    To identify the genetic basis of interindividual variability in montelukast exposure, we determined its pharmacokinetics and sequenced 379 pharmacokinetic genes in 191 healthy volunteers. An intronic single nucleotide variation (SNV), strongly linked with UGT1A3*2, associated with reduced area under the plasma concentration-time curve (AUC0-∞ ) of montelukast (by 18% per copy of the minor allele; P = 1.83 × 10(-10) ). UGT1A3*2 was associated with increased AUC0-∞ of montelukast acyl-glucuronide M1 and decreased AUC0-∞ of hydroxymetabolites M5R, M5S, and M6 (P montelukast. The found UGT1A3 and ABCC9 variants associated with increased expression of the respective genes in human liver samples. Montelukast and its hydroxymetabolites were glucuronidated by UGT1A3 in vitro. These results indicate that UGT1A3 plays an important role in montelukast pharmacokinetics, especially in UGT1A3*2 carriers. © 2017, The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  19. Factors involved in the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer: clinical and experimental studies.

    Science.gov (United States)

    Rudek, Michelle A; Venitz, Jürgen; Ando, Yuichi; Reed, Eddie; Pluda, James M; Figg, William D

    2003-10-01

    COL-3 is an oral, lipophilic, tetracycline analog that has been administered to patients with metastatic cancer. Preliminary assessment of COL-3 in 35 patients with refractory metastatic carcinoma demonstrated apparent nonlinear pharmacokinetics with highly variable oral clearance (63.9% coefficient of variance [CV]). To elucidate possible sources of variability of COL-3 pharmacokinetics in vivo, in vitro plasma protein binding and in vitro metabolism were explored along with in vivo pharmacokinetics using compartmental modeling. The variability in the overall clearance and urinary excretion of COL-3 was also assessed. COL-3 had a long terminal half-life (median = 59.8 h), large apparent volume of distribution (median = 50.2 L), and low apparent clearance (median = 9.93 mL/min). Only adjusted ideal body weight decreased the variability in total apparent clearance. There was nonsaturable plasma protein binding of COL-3 (fu = 5.5%), with the majority of binding to albumin. The renal route of elimination is negligible, with 0.06% of unchanged COL-3 and 3.31% COL-3 glucuronide excreted in the first 6 days. COL-3 is not metabolized by phase I metabolism but does undergo glucuronidation in vitro by UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and in vivo, as evidenced by COL-3 glucuronides in the urine (median = 13.6% of the total dose). COL-3 exhibits nonlinear pharmacokinetics, possibly due to dissolution rate-limited absorption.

  20. Single daily dosing of antibiotics: importance of in vitro killing rate, serum half-life, and protein binding.

    OpenAIRE

    Potel, G.; Chau, N P; Pangon, B; Fantin, B; Vallois, J M; Faurisson, F; Carbon, C.

    1991-01-01

    The relative importance of pharmacokinetic and pharmacodynamic parameters for the feasibility of a single daily dose (SDD) of antibiotics remains to be established. Therefore, we studied the relationship between in vitro bacteriological parameters (MIC, MBC, and killing rate [KR], defined as the reduction in the inoculum within 3 h), pharmacokinetic parameters (t1/2 and protein binding [PB], and in vivo antibacterial effect of a single antibiotic dose in an experimental rabbit model of Escher...

  1. Formulation and pharmacokinetics of colon-specific double-compression coated mini-tablets: Chronopharmaceutical delivery of ketorolac tromethamine.

    Science.gov (United States)

    Vemula, Sateesh Kumar

    2015-08-01

    The present study is designed and significantly planned to study the effect of double-compression coating on core mini-tablets to attain the chronopharmaceutical delivery of ketorolac tromethamine to colon. Double-compression coated tablets were prepared based on time-controlled hydroxypropyl methylcellulose K100M inner compression coat and pH-sensitive Eudragit S100 outer compression coat. From the in vitro drug release studies, F6 tablets was considered as the optimized formulation, which retarded the drug release in stomach and small intestine (3.51 ± 0.15% in 5h) and progressively released to colon (99.82 ± 0.69% in 24h). The release process followed supercase-II transport with zero order release kinetics. Similarity factor calculated from stability studies was found to be 84.73. From the pharmacokinetic evaluation, the immediate release core mini-tablets reached peak plasma concentration (Cmax of 4532.68 ± 28.14 ng/ml) at 2h Tmax and colon targeted tablets showed Cmax=3782.29 ± 17.83 ng/ml at 12h Tmax. The area under the curve and mean resident time of core mini-tablets were found to be 11,278.26 ± 132.67 ng-h/ml and 3.68 h respectively while 17,324.48 ± 56.32 ng-h/ml and 10.39 h for compression coated tablets. Hence the development of double-compression coated tablets is a promising way to gain the chronopharmaceutical delivery of ketorolac tromethamine to colon. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Pharmacokinetics and Pharmacodynamics of Antifungals in Children and their Clinical Implications

    Science.gov (United States)

    Stockmann, Chris; Constance, Jonathan E.; Roberts, Jessica K.; Olson, Jared; Doby, Elizabeth H.; Ampofo, Krow; Stiers, Justin; Spigarelli, Michael G.

    2017-01-01

    by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination. PMID:24595533

  3. Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine.

    Science.gov (United States)

    Zandvliet, Anthe S; Huitema, Alwin D R; de Jonge, Milly E; den Hoed, Rob; Sparidans, Rolf W; Hendriks, Vincent M; van den Brink, Wim; van Ree, Jan M; Beijnen, Jos H

    2005-01-01

    The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr(-1) for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.

  4. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios.

    Science.gov (United States)

    Williams, J Andrew; Hyland, Ruth; Jones, Barry C; Smith, Dennis A; Hurst, Susan; Goosen, Theunis C; Peterkin, Vincent; Koup, Jeffrey R; Ball, Simon E

    2004-11-01

    Glucuronidation is a listed clearance mechanism for 1 in 10 of the top 200 prescribed drugs. The objective of this article is to encourage those studying ligand interactions with UDP-glucuronosyltransferases (UGTs) to adequately consider the potential consequences of in vitro UGT inhibition in humans. Spurred on by interest in developing potent and selective inhibitors for improved confidence around UGT reaction phenotyping, and the increased availability of recombinant forms of human UGTs, several recent studies have reported in vitro inhibition of UGT enzymes. In some cases, the observed potency of UGT inhibitors in vitro has been interpreted as having potential relevance in humans via pharmacokinetic drug-drug interactions. Although there are reported examples of clinically relevant drug-drug interactions for UGT substrates, exposure increases of the aglycone are rarely greater than 100% in the presence of an inhibitor relative to its absence (i.e., AUCi/AUC clinical relevance of potent in vitro inhibition of UGT enzymes will be assessed, taking the following into account: in vitro data on the enzymology of glucuronide formation from aglycone, pharmacokinetic principles based on empirical data for inhibition of metabolism, and clinical data on the pharmacokinetic drug-drug interactions of drugs primarily cleared by glucuronidation. Copyright 2004 The American Society for Pharmacology and Experimental Therapeutics

  5. Development of a physiologically based pharmacokinetic model for assessment of human exposure to bisphenol A.

    Science.gov (United States)

    Yang, Xiaoxia; Doerge, Daniel R; Teeguarden, Justin G; Fisher, Jeffrey W

    2015-12-15

    A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d6-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d6-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d6-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species. Published by Elsevier Inc.

  6. Stability study of Raloxifene tablets

    Directory of Open Access Journals (Sweden)

    Jorge Enrique Rodríguez Chanfrau

    Full Text Available Introduction: Raloxifene is a selective estrogen receptor modulator from the benzothiophene family. Several clinical trials have shown that raloxifene reduces bone loss rate in the spinal column and may increase bone mass at certain sites. Objective: to determine the physical and chemical stabilities of raloxifene tablets. Methods. three pilot scale batches of 5 kg each were prepared. In vitro dissolution, chemical stability, photostability and humidity studies were carried out. Samples were collected at 0, 1, 2, 3 and 6 months for the accelerated stability study and at 0, 6, 12, 18 and 24 months for the shelf life stability study. Chemical stability was determined using high performance liquid chromatography analytical method, which was developed and validated prior to the study. Results: in the accelerated stability study, the percentages of dissolved drug were more than 90 % and drug content porcentages were between 90 % and 110 %. Humidity conditions affected the chemical stability of the tablets. Conclusions: All raloxifene tablet batches formulations were stable for 24 months in the studied containers stored at 32 ± 2 ºC and waterproof. In vitro drug release dissolution showed good results for 24 months.

  7. Estabilidade e estudo de penetração cutânea in vitro da rutina veiculada em uma emulsão cosmética através de um modelo de biomembrana alternativo Stability and in vitro penetration study of rutin incorporated in a cosmetic emulsion through an alternative model biomembrane

    Directory of Open Access Journals (Sweden)

    André Rolim Baby

    2008-06-01

    employed as antioxidant and to prevent the capillary fragility and, when incorporated in cosmetic emulsions, it must target the action site. In vitro cutaneous penetration studies through human skin is the ideal situation, however, there are difficulties to obtain and to maintain this tissue viability. Among the membrane models, shed snake skin presents itself as pure stratum corneum, providing barrier function similar to human and it is obtained without the animal sacrifice. The objectives of this research were the development and stability evaluation of a cosmetic emulsion containing rutin and propylene glycol (penetration enhancer and the evaluation of rutin in vitro cutaneous penetration and retention from the emulsion, employing an alternative model biomembrane. Emulsion was developed with rutin and propylene glycol, both at 5.0% w/w. Active substance presented on the formulation was quantified by a validated spectrophotometric method at 361.0 nm. Rutin cutaneous penetration and retention was performed in vertical diffusion cells with shed snake skin of Crotalus durissus, as alternative model biomembrane, and distilled water and ethanol 99.5% (1:1, as receptor fluid. The experiment was conducted for six hours, at 37.0 ± 0.5 ºC with constant stirring of 300 rpm. Spectrophotometry at 410.0 nm, previously validated, determined the active substance after cutaneous penetration/retention. Emulsion did not promote rutin cutaneous penetration through C. durissus skin, retaining 0.931 ± 0.0391 mg rutin/mg shed snake skin. The referred formulation was chemically stable for 30 days after stored at 25.0 ± 2.0 ºC, 5.0 ± 0.5 ºC and 45.0 ± 0.5 ºC. In conclusion, it has not been verified the active cutaneous penetration through the model biomembrane, but only its retention on the Crotalus durissus stratum corneum, condition considered stable for 30 days.

  8. Pharmacokinetics of Alternative Administration Routes of Melatonin

    DEFF Research Database (Denmark)

    Zetner, D.; Andersen, L. P.H.; Rosenberg, J.

    2016-01-01

    Background: Melatonin is traditionally administered orally but has a poor and variable bioavailability. This study aims to present an overview of studies investigating the pharmacokinetics of alternative administration routes of melatonin. Methods: A systematic literature search was performed...... and included experimental or clinical studies, investigating pharmacokinetics of alternative administration routes of melatonin in vivo. Alternative administration routes were defined as all administration routes except oral and intravenous. Results: 10 studies were included in the review. Intranasal...... administration exhibited a quick absorption rate and high bioavailability. Transdermal administration displayed a variable absorption rate and possible deposition of melatonin in the skin. Oral transmucosal administration of melatonin exhibited a high plasma concentration compared to oral administration...

  9. PHARMACOKINETICS OF PIROXICAM IN CRANES (FAMILY GRUIDAE).

    Science.gov (United States)

    Keiper, Naomi L; Cox, Sherry K; Doss, Grayson A; Elsmo, Betsy; Franzen-Klein, Dana; Hartup, Barry K

    2017-09-01

    To investigate the pharmacokinetics of the nonsteroidal anti-inflammatory drug (NSAID) piroxicam in cranes, three brolgas (Antigone rubicunda) were administered piroxicam as a single oral dose at 0.5 mg/kg and 1.0 mg/kg during separate trials. Serial blood samples were collected for quantification of piroxicam in plasma. Piroxicam was readily absorbed at both dosages, and no adverse effects were observed. Plasma concentrations peaked at 3.67 hr with a concentration of 4.00 μg/ml for the lower dosage, and at 0.83 hr at 8.77 μg/ml for the higher dosage. Piroxicam may exhibit linear kinetics and dose proportionality in brolgas, but will require further study. Mean peak plasma concentrations in brolgas were comparable to concentrations demonstrated to be analgesic in humans. To the authors' knowledge, this study represents the first pharmacokinetic investigation of piroxicam in an avian species.

  10. Clinical Pharmacology and Pharmacokinetics of Levetiracetam

    Directory of Open Access Journals (Sweden)

    Chanin Clark Wright

    2013-12-01

    Full Text Available Status epilepticus and acute repetitive seizures still pose a management challenge despite the recent advances in the field of epilepsy. Parenteral formulations of old anticonvulsants are still a cornerstone in acute seizure management and are approved by the FDA. Intravenous levetiracetam, a second generation anticonvulsant, is approved by the FDA as an adjunctive treatment in patients 16 years or older when oral administration is not available. Data have shown that it has a unique mechanism of action, linear pharmacokinetics and no known drug interactions with other anticonvulsants. In this paper, we will review the current literature about the pharmacology and pharmacokinetics of intravenous levetiracetam and the safety profile of this new anticonvulsant in acute seizure management of both adults and children.

  11. Revisiting methadone: pharmacokinetics, pharmacodynamics and clinical indication

    OpenAIRE

    Barbosa Neto, José Osvaldo; Garcia, Marília Arrais; Garcia, João Batista Santos

    2015-01-01

    BACKGROUND AND OBJECTIVES: Methadone is a synthetic long-duration opioid with pharmacological properties qualitatively similar to morphine for its action on µ-opioid receptor. It is primarily used to treat cancer pain refractory to morphine. This study aimed at presenting a review of this drug with focus on pharmacokinetic and pharmacodynamic aspects, in addition to its clinical indication. CONTENTS: Articles available in Medline, Scielo, Cochrane library and Pubmed platforms until July 2014 ...

  12. Physiologic and pharmacokinetic changes in pregnancy

    OpenAIRE

    Maged eCostantine

    2014-01-01

    Physiologic changes in pregnancy induce profound alterations to the pharmacokinetic properties of many medications. These changes affect distribution, absorption, metabolism, and excretion of drugs, and thus may impact their pharmacodynamic properties during pregnancy. Pregnant women undergo several adaptations in many organ systems. Some adaptations are secondary to hormonal changes in pregnancy, while others occur to support the gravid woman and her developing fetus. Some of the changes in ...

  13. Current clinical evidence on topiramate pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Jakovljević Mihajlo

    2009-01-01

    Full Text Available Topiramate is biochemically classified as a fructopyranose sulphamate. Discovered as early as 1979, during middle 1980's it was approved in many countries for the treatment of epilepsies and migraine prevention. More recently, in the experimental stage, possible new indications have been disclosed: treatment of obesity, bipolar disorder, also cessation of smoking, neuropathic pain, cerebral pseudotumour, bulimia, periventricular leucomalatia in preterm infants and alcohol addiction. Most epileptologists consider it to be the first choice antiepileptic drug in severe pharmacoresistant epilepsies. A substantial corpus of evidence in paediatric population has been accumulated that confirms its efficiency in the treatment of generalised tonic-clonic seizures, Lenox-Gestaut syndrome, partial, absence and combined seizures. Having a unique monosaccharide chemical structure among other anticonvulsant drugs, characterizes it with special pharmacokinetic features. This substance exhibits a low interindividual variability in plasma levels and hence it features predictable pharmacokinetics. A steady state plasma concentration of topiramate increases linearly with higher dosages. Serum protein binding is approximately 15%, and biologic half-life in healthy volunteers is considered to range from 20 to 30 hours. Mean expected distribution volume rates from 0.55-0.8 l/kg, and accordingly, the drug shows a low and saturable binding capacity toward erythrocytes. It has not been present at the market for a sufficiently long time that would enable us to speak about a significant accumulation of data on its metabolism based on post-registration 4th stage clinical trials. For this purpose, we have done a literature review in order to summarise so far reported experience on topiramate pharmacokinetics in patients and healthy adults. Deeper understanding of its pharmacokinetic profile could enable a better technological design of the produced drug and the choice of

  14. Fully Bayesian Experimental Design for Pharmacokinetic Studies

    Directory of Open Access Journals (Sweden)

    Elizabeth G. Ryan

    2015-03-01

    Full Text Available Utility functions in Bayesian experimental design are usually based on the posterior distribution. When the posterior is found by simulation, it must be sampled from for each future dataset drawn from the prior predictive distribution. Many thousands of posterior distributions are often required. A popular technique in the Bayesian experimental design literature, which rapidly obtains samples from the posterior, is importance sampling, using the prior as the importance distribution. However, importance sampling from the prior will tend to break down if there is a reasonable number of experimental observations. In this paper, we explore the use of Laplace approximations in the design setting to overcome this drawback. Furthermore, we consider using the Laplace approximation to form the importance distribution to obtain a more efficient importance distribution than the prior. The methodology is motivated by a pharmacokinetic study, which investigates the effect of extracorporeal membrane oxygenation on the pharmacokinetics of antibiotics in sheep. The design problem is to find 10 near optimal plasma sampling times that produce precise estimates of pharmacokinetic model parameters/measures of interest. We consider several different utility functions of interest in these studies, which involve the posterior distribution of parameter functions.

  15. Pharmacokinetic profile of tert-butylaminoethanethiol

    Directory of Open Access Journals (Sweden)

    M. H. Guerra Andrade

    1990-09-01

    Full Text Available A preliminary study of the pharmacokinetic parameters of t-Butylaminoethanethiol (TBAESH was performed after administration of a single dose (35 mg/kg either orally or intravenously. Plasma or blood samples were treated with dithiothreitol, perchloric acid and, after filtration, submitted to further purification with anionic resin. In the final step the drug was retained on a cationic resin column, eluted with NaCl lM and detected according to the method of Ellman (1958. The results suggested a pharmacokinetic behavior related to a one open compartment model with the following values for the total drug: area under the intravenous curve (AUC i.v.: 443(+ ou - 24.0; AUC oral: 85.5(+ ou - 14.5 ug min.ml(elevado a -1; elimination rate constant: 0.069(+ ou - 0.0055 min(elevado a -1, biological half-life: 10.0(+ ou - 0.80 min; distribution volume 1.15(+ ou - 0.15 ml/g; biodisponibility: 0.19(+ ou - 0.02. From a pharmacokinetic standpoint, TBAESH seems to have no advantage over the analogous disulfide compound.

  16. Pharmacokinetics and dose proportionality of ceftibuten in men.

    Science.gov (United States)

    Lin, C; Lim, J; Radwanski, E; Marco, A; Affrime, M

    1995-01-01

    The pharmacokinetics and dose proportionality of ceftibuten were evaluated in healthy male volunteers receiving single oral doses of 200, 400, and 800 mg of ceftibuten. The drug was absorbed with similar times to the maximum concentration of drug in plasma for all three doses. Concentrations of ceftibuten in plasma increased with increasing dose. Analysis of variance was carried out on the dose-adjusted values for the maximum concentration of drug in plasma and the area under the plasma concentration-time curve; the results indicated that the concentrations in plasma after the 200- and 400-mg doses were dose proportional, and after the 800-mg of dose they were less than dose proportional. The elimination half-life from plasma ranged from 2.0 to 2.3 h and was independent of dose. The total excretion of unchanged ceftibuten in urine accounted for 53 to 68% of the dose, and the renal clearance was estimated to be 53 to 61 ml/min after all doses. The amount of ceftibuten-trans, the major in vitro and in vivo conversion product of ceftibuten, was low in both plasma and urine. PMID:7726498

  17. Pharmacokinetics and dose proportionality of ceftibuten in men.

    Science.gov (United States)

    Lin, C; Lim, J; Radwanski, E; Marco, A; Affrime, M

    1995-02-01

    The pharmacokinetics and dose proportionality of ceftibuten were evaluated in healthy male volunteers receiving single oral doses of 200, 400, and 800 mg of ceftibuten. The drug was absorbed with similar times to the maximum concentration of drug in plasma for all three doses. Concentrations of ceftibuten in plasma increased with increasing dose. Analysis of variance was carried out on the dose-adjusted values for the maximum concentration of drug in plasma and the area under the plasma concentration-time curve; the results indicated that the concentrations in plasma after the 200- and 400-mg doses were dose proportional, and after the 800-mg of dose they were less than dose proportional. The elimination half-life from plasma ranged from 2.0 to 2.3 h and was independent of dose. The total excretion of unchanged ceftibuten in urine accounted for 53 to 68% of the dose, and the renal clearance was estimated to be 53 to 61 ml/min after all doses. The amount of ceftibuten-trans, the major in vitro and in vivo conversion product of ceftibuten, was low in both plasma and urine.

  18. Pharmacokinetics and atherosclerotic lesions targeting effects of tanshinone IIA discoidal and spherical biomimetic high density lipoproteins.

    Science.gov (United States)

    Zhang, Wenli; He, Hongliang; Liu, Jianping; Wang, Ji; Zhang, Suyang; Zhang, Shuangshuang; Wu, Zimei

    2013-01-01

    High density lipoproteins (HDL) have been successfully reconstructed to deliver a large number of lipophilic drugs. Here, discoidal and spherical recombinant HDL loaded with cardiovascular drug tanshinone IIA (TA) were constructed (TA-d-rHDL and TA-s-rHDL), respectively. And next their in vitro physiochemical and biomimetic properties were characterized. Furthermore, pharmacokinetics, atherosclerotic lesions targeting effects and antiatherogenic efficacies were elaborately performed and compared in atherosclerotic New Zealand White (NZW) rabbits. In vitro characterizations results showed that both TA-d-rHDL and TA-s-rHDL had nano-size diameter, high entrapment efficiency (EE) and drug-loading capacity (DL). Additionally, similar to their native counterparts, TA-d-rHDL maintained remodeling behaviors induced by lecithin cholesterol acyltransferase (LCAT), and TA leaked during remodeling behaviors. Pharmacokinetic studies manifested that both TA-d-rHDL and TA-s-rHDL markedly improved pharmacokinetic behaviors of TA in vivo. Ex vivo imaging demonstrated that both d-rHDL and s-rHDL bound more avidly to atherosclerotic lesions than to normal vessel walls, and s-rHDL had better targeting effect than d-rHDL. Pharmacodynamic tests illustrated that both TA-d-rHDL and TA-s-rHDL had much stronger antiatherogenic efficacies than conventional TA nanostructured lipid carriers (TA-NLC), TA liposomes (TA-L) and commercially available preparation Sulfotanshinone Sodium Injection (SSI). Moreover, TA-s-rHDL had more potent antiatherogenic efficacies than TA-d-rHDL. Collectively our studies indicated that rHDL could be exploited as potential delivery vehicles of TA targeting atherosclerotic lesions as well as synergistically improving efficacies, especially for s-rHDL. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Comparable liraglutide pharmacokinetics in pediatric and adult populations with type 2 diabetes: a population pharmacokinetic analysis.

    Science.gov (United States)

    Petri, Kristin C Carlsson; Jacobsen, Lisbeth V; Klein, David J

    2015-06-01

    The safety, tolerability, and pharmacokinetics of the once-daily human glucagon-like peptide-1 (GLP-1) analog liraglutide have been evaluated in pediatric patients aged greater than 10 years with type 2 diabetes (T2D). In this study, a population pharmacokinetic analysis was compared to the pediatric pharmacokinetic data with those from two clinical pharmacology trials in adults with T2D. A one-compartment pharmacokinetic model previously found to adequately describe the pharmacokinetics of liraglutide in adults with T2D was applied to the evaluation of 13 pediatric subjects (10-17 years of age) with T2D. Steady-state estimates for apparent clearance (CL/F) for individual subjects and corresponding dose were used to derive the area under the plasma-concentration time curve from 0-24 h (AUC24) and investigate dose proportionality in the pediatric trial. A covariate analysis evaluated the effects of body weight, gender, and age category (pediatric/adult) on liraglutide exposure. Dose proportionality in the dose range of 0.3-1.8 mg was indicated by the model-derived AUC24 slope: 1.05 (95% CI 0.96-1.15). Consistent with findings from adult trials, body weight and gender were relevant covariates for liraglutide exposure in the pediatric population. The CL/F estimates, and thus exposure, for the pediatric subjects with T2D were similar to those in the adult trials. Based on this population pharmacokinetic analysis, the liraglutide dose regimen that was found to be clinically effective in adults is predicted to achieve the same range of exposure in the pediatric population (10-17 years of age) with a pre-trial body weight range of 57-214 kg.

  20. In Vivo and In Vitro Activities and ADME-Tox Profile of a Quinolizidine-Modified 4-Aminoquinoline: A Potent Anti-P. falciparum and Anti-P. vivax Blood-Stage Antimalarial

    Directory of Open Access Journals (Sweden)

    Nicoletta Basilico

    2017-12-01

    Full Text Available Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1 between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (Lupinus luteus. The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia, proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication. AM1 displayed a very attractive profile in terms of both in vitro and in vivo activity. By using standard in vitro antimalarial assays, AM1 showed low nanomolar inhibitory activity against chloroquine-sensitive and resistant P. falciparum strains (range IC50 16–53 nM, matched with a high potency against P. vivax field isolates (Mean IC50 29 nM. Low toxicity and additivity with artemisinin derivatives were also demonstrated in vitro. High in vivo oral efficacy was observed in both P. berghei and P. yoelii mouse models with IC50 values comparable or better than those of chloroquine. The metabolic stability in different species and the pharmacokinetic profile in the mouse model makes AM1 a compound worth further investigation as a potential novel schizonticidal agent.

  1. The effects of flavonoids on the ABC transporters: consequences for the pharmacokinetics of substrate drugs.

    Science.gov (United States)

    Li, Yan; Paxton, James W

    2013-03-01

    The flavonoids are a large group of dietary plant compounds with suggested health benefits. There is accumulating evidence that many of these flavonoids can interact with the major drug transporters (and metabolizing enzymes) in the body, leading to alterations in the pharmacokinetics of substrate drugs, and thus their efficacy and toxicity. This review summarizes and updates the reported in vitro and in vivo interactions between common dietary flavonoids and the major drug-effluxing ABC transporters; these include P-glycoprotein, breast cancer resistance protein and multidrug resistance proteins 1 and 2. In contrast to previous reviews, the ADME of flavonoids are considered, along with their glycosides and Phase II conjugates. The authors also consider their possible interactions with the ABC transporters in the oral absorption, distribution into pharmacological sanctuaries and excretion of substrate drugs. Electronic databases, including PubMed, Scopus and Google Scholar were searched to identify appropriate in vitro and in vivo ABC transporter-flavonoid interactions, particularly within the last 10 years. Caution is advised when taking flavonoid-containing supplements or herbal remedies concurrently with drugs. Further clinical studies are warranted to explore the impact of flavonoids and their metabolites on the pharmacokinetics, efficacy and toxicity of drugs.

  2. Pharmacokinetic profile of a sustained-delivery system for physostigmine in rats

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Donna [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117597 (Singapore); Zhao Bin [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117597 (Singapore); Moochhala, Shabbir [Defence Medical and Environmental Research Institute, DSO National Laboratories (Kent Ridge), 27 Medical Drive, 12-00, Singapore 117597 (Singapore)]. E-mail: mshabbir@dso.org.sg; Yang Yiyan [Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, 04-01, Singapore 138669 (Singapore)

    2006-07-25

    Physostigmine (PHY) is involved in clinical treatments of glaucoma, Alzheimer's disease and has been suggested as an alternative prophylactic treatment against organophosphate poisoning. However, one of the therapeutic uses of physostigmine is limited by short elimination half-life. In this study, PHY-loaded microparticles, prepared by a spray-drying method with biodegradable poly(D,L-lactide-co-glycolide) (PLGA) with a size ranging from 1 to 5 {mu}M was developed on a sustained release preparation to prevent multiple dosing and yet maintaining constant plasma level. The release of PHY-loaded microparticles was characterized in vitro and in vivo after oral administration in Sprague-Dawley rats. After oral administration of physostigmine-loaded microparticles in rats, the time course of physostigmine in blood plasma was followed over 48 h and samples were analysed using a validated high-performance liquid chromatography (HPLC) assay. In the pharmacokinetics profile of physostigmine for the elimination half-life and area-under-curve, PHY release was sustained in vitro for over 1 week with a low initial burst release. The pharmacokinetics results show a 15-fold increase in the elimination half-life of physostigmine microparticle formulation, coupled with a larger area under the concentration-time curve (AUC), without affecting the peak concentration and the latency to peak concentration, when compared to the standard formulation.

  3. Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform.

    Science.gov (United States)

    Choudhury, Hira; Gorain, Bapi; Karmakar, Sanmoy; Biswas, Easha; Dey, Goutam; Barik, Rajib; Mandal, Mahitosh; Pal, Tapan Kumar

    2014-01-02

    Paclitaxel, a potential anticancer agent against solid tumors has been restricted from its oral use due to poor water solubility as well as Pgp efflux property. The present study was aimed to improve the oral bioavailability of paclitaxel through development of (o/w) nanoemulsion consisting of Capryol 90 as internal phase with Tween 20 as emulsifier with water as an external phase. Formulations were selected from the nanoemulsion region of pseudo-ternary phase diagrams, formulated by aqueous titration method. The developed nanoemulsion has been characterized by its thermodynamic stability, morphology, droplet size, zeta potential, viscosity where in vitro release was evaluated through dialysis. Paclitaxel nanoemulsion exhibited thermodynamical stability with low viscosity, nano-sized oil droplets in water with low poly-dispersity index. The shelf life of the paclitaxel nanoemulsion was found to be approximately 2.38 years. Increased permeability through the Caco-2 cell monolayer and decreased efflux is great advantageous for nanoemulsion formulation. The effects of paclitaxel nanoemulsion on breast cancer cell proliferation, morphology and DNA fragmentation were analyzed in vitro which showed significant anti-proliferation and decreased IC50 values in nanoemulsion group which may be due to enhanced uptake of paclitaxel through the oil core. Moreover, the absolute oral bioavailability and sustained release profile of the paclitaxel nanoemulsion evaluated in mouse model was found to improve up to 55.9%. The concentration of paclitaxel in mice plasma was determined by our validated LC-MS/MS method. By reviewing the significant outcome of the present investigation based on stability study, Caco-2 permeability, cell proliferative assay and pharmacokinetic profile it may be concluded that the oral nanoemulsion has got encouraging advantages over the presently available formulations of this injectable chemotherapeutic drug. Copyright © 2013 Elsevier B.V. All rights

  4. Effects of dietary sodium butyrate on hepatic biotransformation and pharmacokinetics of erythromycin in chickens.

    Science.gov (United States)

    Csikó, G; Nagy, G; Mátis, G; Neogrády, Z; Kulcsár, Á; Jerzsele, A; Szekér, K; Gálfi, P

    2014-08-01

    Butyrate, a commonly applied feed additive in poultry nutrition, can modify the expression of certain genes, including those encoding cytochrome P450 (CYP) enzymes. In comparative in vitro and in vivo experiments, the effect of butyrate on hepatic CYP genes was examined in primary cultures of chicken hepatocytes and in liver samples of chickens collected from animals that had been given butyrate as a feed additive. Moreover, the effect of butyrate on the biotransformation of erythromycin, a marker substance for the activity of enzymes of the CYP3A family, was investigated in vitro and in vivo. Butyrate increased the expression of the avian-specific CYP2H1 both in vitro and in vivo. In contrast, the avian CYP3A37 expression was decreased in hepatocytes following butyrate exposure, but not in the in vivo model. CYP1A was suppressed by butyrate in the in vitro experiments, and overexpressed in vivo in butyrate-fed animals. The concomitant incubation of hepatocytes with butyrate and erythromycin led to an increased CYP2H1 expression and a less pronounced inhibition of CYP3A37. In in vivo pharmacokinetic experiments, butyrate-fed animals given a single i.m. injection of erythromycin, a slower absorption phase (longer T(half-abs) and delayed T(max)) but a rapid elimination phase of this marker substrate was observed. Although these measurable differences were detected in the pharmacokinetics of erythromycin, it is unlikely that a concomitant application of sodium butyrate with erythromycin or other CYP substrates will cause clinically significant feed-drug interaction in chickens. © 2014 John Wiley & Sons Ltd.

  5. A Physiologically Based Pharmacokinetic Model to Predict the Pharmacokinetics of Highly Protein-Bound Drugs and Impact of Errors in Plasma Protein Binding

    Science.gov (United States)

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2015-01-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data was often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for terminal elimination half-life (t1/2, 100% of drugs), peak plasma concentration (Cmax, 100%), area under the plasma concentration-time curve (AUC0–t, 95.4%), clearance (CLh, 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss, 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. PMID:26531057

  6. PLGA 50:50 nanoparticles of paclitaxel: Development, in vitro anti ...

    Indian Academy of Sciences (India)

    lation of novel drug delivery systems to deliver such extreme hydrophobic drug. To formulate nanoparticles which makes suitable to deliver hydrophobic drugs effectively (intravenous) with desired pharmacokinetic profile for breast cancer treatment; in this context in vitro cytotoxic activity was evaluated using BT-549 cell line.

  7. Anesthetic constituents of Zanthoxylum bungeanum Maxim.: A pharmacokinetic study.

    Science.gov (United States)

    Rong, Rong; Cui, Mei-Yu; Zhang, Qi-Li; Zhang, Mei-Yan; Yu, Yu-Ming; Zhou, Xian-Ying; Yu, Zhi-Guo; Zhao, Yun-Li

    2016-07-01

    A sensitive and selective ultra high performance liquid chromatography with tandem mass spectrometry method was established and validated for the simultaneous determination of hydroxy-α-sanshool, hydroxy-β-sanshool, and hydroxy-γ-sanshool in rat plasma after the subcutaneous and intravenous administration of an extract of the pericarp of Zanthoxylum bungeanum Maxim. Piperine was used as the internal standard. The analytes were extracted from rat plasma by liquid-liquid extraction with ethyl acetate and separated on a Thermo Hypersil GOLD C18 column (2.1 mm × 50 mm, 1.9 μm) with a gradient elution system at a flow rate of 0.4 mL/min. The mobile phase consisted of acetonitrile/0.05% formic acid in water and the total analysis time was 4 min. Positive electrospray ionization was performed using multiple reaction monitoring mode for the analytes. The calibration curves of the three analytes were linear over the tested concentration range. The intra- and interday precision was no more than 13.6%. Extraction recovery, matrix effect, and stability were satisfactory in rat plasma. The developed and validated method was suitable for the quantification of hydroxy-α-sanshool, hydroxy-β-sanshool, and hydroxy-γ-sanshool and successfully applied to a pharmacokinetic study of these analytes after subcutaneous and intravenous administration to rats. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. pharmacokinetics/pharmacodynamics; renal replacement therapy, continuous; antibiotics; antifungals.

    Science.gov (United States)

    Honore, Patrick M; Jacobs, Rita; De Waele, Elisabeth; Spapen, Herbert D

    2017-01-01

    Continuous renal replacement therapy (CRRT) is progressively supplanting intermittent haemodialysis (IHD) in critically ill patients. Although CRRT indeed offers more appropriate haemodynamic, fluid, and metabolic stability, concern is rising about its impact on concomitant drugs and, in particular, antimicrobial treatment. Antimicrobial dose recommendations have been elaborated to avoid drug accumulation and toxicity in patients undergoing IHD. However, these dosing regimens have resulted in significant underdosing in patients undergoing CRRT, thereby increasing the risk of treatment failure and development of resistance. Applying pharmacokinetic/pharmacodynamic (PK/PD) principles may aid one to obtain more adequate antimicrobial therapy during CRRT. Much progress has been made in recent years resulting in relevant changes in particular antimicrobial therapies. In this review, we discuss antimicrobials that are frequently used in an intensive care setting. Drugs are divided according to their PK/PD characteristics and, wherever possible, dose recommendations during CRRT are provided. Of course, while therapeutic drug monitoring remains the best way to cope with PK/PD variability within a critically ill CRRT population, its bedside use is actually limited to some specific antibiotics.

  9. Inhibition of cytochrome P450 3A enzyme by Millettia aboensis: its effect on the pharmacokinetic properties of efavirenz and nevirapine

    Directory of Open Access Journals (Sweden)

    Sunday O. Nduka

    Full Text Available ABSTRACT The chronic and comorbid nature of HIV infection necessitate the use of multiple drugs including herbs to relieve symptoms with a possible increase in herb–drug interaction cases. This study was designed to evaluate the effect of Millettia aboensis (Hook. f. Baker, Fabaceae, on cytochrome P450 3A isoenzyme and the influence of this effect on the bioavailability of two antiretroviral agents. In vitro effect of ethanol extract of M. aboensis on intestinal and liver microsomes extracted from female rats was assessed using erythromycin-N-demethylation assay method while in vivo effects were determined by estimating simvastatin plasma concentrations in rats. The effect of the extract on pharmacokinetic parameters of orally administered efavirenz (25 mg/kg and nevirapine (20 mg/kg was determined in rats divided into groups (n = 5. Plasma drug concentrations were assayed using HPLC and pharmacokinetic parameters determined through a non-compartmental analysis as implemented in WinNonlin pharmacokinetic program. The extract inhibited both intestinal and liver microsomal cytochrome P450 3A isoenzyme activities in vitro and enhanced simvastatin absorption in vivo with possible inhibition of metabolizing enzymes as indicated by significant (p 0.05 changes in the pharmacokinetic parameters of efavirenz and nevirapine. HPLC fingerprinting indicated the presence of quercetin and kaempferol in the extract. These findings revealed M. aboensis as an inhibitor of cytochrome P450 3A enzyme but, with no significant effect on the bioavailability of orally administered nevirapine and efavirenz.

  10. Pharmacokinetics of phenothiazine neuroleptics after chronic coadministration of carbamazepine.

    Science.gov (United States)

    Daniel, W A; Syrek, M; Haduch, A; Wójcikowski, J

    1998-01-01

    The aim of the present study was to assess the influence of carbamazepine on the pharmacokinetics of the two phenothiazine neuroleptics thioridazine and perazine in rats. The obtained results are compared with the results of analogical experiments concerning promazine. Thioridazine or perazine (10 mg/kg i.p.) were administered twice a day for two weeks alone or jointly with carbamazepine (15 mg/kg i.p. during the 1st week, and 20 mg/kg i.p. during the 2nd week of treatment). Concentrations of the neuroleptics and their main metabolites in the plasma and brain were measured at 30 min, 6 and 12 h after the last dose of the drugs. Carbamazepine decreased the concentrations of thioridazine and its metabolites (especially mesoridazine and sulforidazine) in plasma at 30 min and 6 h after the last dose of the drugs. Similar changes in the concentrations of thioridazine and its metabolites were observed at 6 h in the brain. Carbamazepine did not significantly influence the pharmacokinetics of perazine. In vitro studies with liver microsomes of control rats revealed that carbamazepine added to the incubation mixture inhibited N-demethylation of thioridazine via mixed mechanism, but it did not influence significantly 2- or 5-sulfoxidation of the neuroleptic. In the case of perazine, no distinct inhibition of its N-demethylation or sulfoxidation by carbamazepine was observed. Neither carbamazepine nor the neuroleptics, administered separately or jointly for two weeks, significantly influenced the concentrations of cytochromes P-450 and b-5 in the liver. Carbamazepine++ given chronically decreased the rate of N-demethylation and had a tendency to accelerate 2-sulfoxidation of thioridazine, both when given alone (as compared to the control) and when coadministered with thioridazine (as compared to the thioridazine-treated group). In contrast, chronic treatment with carbamazepine alone, significantly increased the rate of perazine N-demethylation. When carbamazepine was

  11. Transgene-host cell interactions mediate significant influences on the production, stability, and function of recombinant canine FVIII

    Directory of Open Access Journals (Sweden)

    Bredon Crawford

    2015-01-01

    Full Text Available Recombinant FVIII manufacturing is characterized by poor product stability and low yields. Codon-optimization of transgenes accelerates translation by exploiting the synonymous codon usage bias of a species. However, this can alter the performance of the final product. Additionally, the effects of transgene design across diverse cell types are not well understood and are of interest for next-generation protein and gene therapies. To investigate the effects of transgene design across different host cells, B-domain-deleted (BDD and modified codon-optimized (CO-N6 transgenes were inserted via lentiviral delivery into cBOECs, HEK293T, and MDCK cells. The CO-N6 cFVIII transgene produced threefold more protein per transgene in HEK293T cells, and sixfold more protein in the two canine cell lines. However, pharmacokinetic analysis in hemophilia A dogs demonstrated that cFVIII produced from cBOECs transduced with the CO-N6 transgene had significantly reduced in vivo recovery. Furthermore, this product showed reduced in vitro stability and activity on thrombin activation versus the BDD product. This trend was reversed in HEK293T lines. Overall, our results demonstrate the need for an integrated approach that not only assesses protein expression levels but also considers the influence that host-cells have on preserving the molecular and biochemical properties of the naturally occurring FVIII.

  12. Preparation, characterization and pharmacokinetics of doxycycline hydrochloride and florfenicol polyvinylpyrroliddone microparticle entrapped with hydroxypropyl-β-cyclodextrin inclusion complexes suspension.

    Science.gov (United States)

    Li, Xianqiang; Xie, Shuyu; Pan, Yuanhu; Qu, Wei; Tao, Yanfei; Chen, Dongmei; Huang, Lingli; Liu, Zhenli; Wang, Yulian; Yuan, Zonghui

    2016-05-01

    In order to effectively control the bacterial pneumonia in pigs, doxycycline hydrochloride (DoxHcl) and florfenicol (FF) microparticle suspension together with inclusion complexes was prepared by using hydroxypropyl-β-cyclodextrin (HP-β-CD) as host molecules, polyvinylpyrroliddone (PVP) as polymer carriers and hydroxypropyl methyl cellulose (HPMC) as suspending agents. In vitro antibacterial activity, properties, stability and pharmacokinetics of the suspension were studied. The results demonstrated that DoxHcl and FF had a synergistic or additive antibacterial activity against Streptococcus suis, Actinobacillus pleuropneumoniae and Haemophilus parasuis. The size, polydispersity index and zeta potential of microparticles were 1.46 ± 0.06 μm, 0.30 ± 0.02 and 1.53 ± 0.04 mV, respectively. The encapsulation efficiency (EE) of DoxHcl and FF was 45.28% ± 3.30% and 89.69% ± 2.71%, respectively. The re-dispersed time and sedimentation rate of the suspension were 1 min and 1. The suspension went through the 9-gage needle smoothly with withdrawal volume of 9.12 ± 0.87 mL/min. The suspension showed good stability when stored away from light, no irritation at the injection site and sustained release in PBS buffer. After intramuscular administration to pig, DoxHcl and FF could maintain over 0.15 μg/mL for 72 h. Compared to the control injection, the suspension increased the elimination half-life (T½ke) as well as mean residence time (MRT) of DoxHcl from 5.73 to 9.77 h and from 12.02 to 18.81 h, and those of FF from 12.02 to 26.19 h and from 12.02 to 28.16 h, respectively. The suspension increased the bioavailability of DoxHcl and FF by 1.74 and 1.13-fold, respectively. These results suggest that the compound suspension is a promising formulation for pig pneumonia therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Preparation, in-vitro and in-vivo evaluation of spray-dried ternary solid dispersion of biopharmaceutics classification system class II model drug.

    Science.gov (United States)

    Paidi, Sharan K; Jena, Sunil K; Ahuja, Bhupesh K; Devasari, Naresh; Suresh, Sarasija

    2015-05-01

    The objective of this study was to investigate the impact of a novel spray-dried ternary solid dispersion (TSD) on the dissolution rate and bioavailability of a biopharmaceutics classification system (BCS) class II model drug, atorvastatin calcium trihydrate (ATC), and evaluate its in-vitro and in-vivo performance. TSD of ATC was prepared by spray-drying method employing ethanol/water solvent systems. The TSD formulations, composed of hydroxypropyl methylcellulose (HPMC E5) and nicotinamide, were optimized by rotatable central composite design. Physicochemical characterization along with dissolution, stability and pharmacokinetic study of optimized TSD was evaluated. The optimized TSD was found to be amorphous with spherical shape morphology. It exhibited a fourfold increase in dissolution rate in comparison to ATC, with a considerable enhancement in oral bioavailability (relative bioavailability of 134.11%). Physicochemical characterization and dissolution study of optimized TSD at the end of stability studies clearly indicated that the stability of optimized TSD was due to hydrogen bonding between drug and HPMC E5 and nicotinamide. This bonding remained unaffected even under stressful