WorldWideScience

Sample records for model hydrophilic drug

  1. Kinetic Modelling of Drug Release from Pentoxifylline Matrix Tablets based on Hydrophilic, Lipophilic and Inert Polymers

    Directory of Open Access Journals (Sweden)

    Mircia Eleonora

    2015-12-01

    Full Text Available Pentoxifylline is a xanthine derivative used in the treatment of peripheral vascular disease, which because of its pharmacokinetic and pharmacologic profile is an ideal candidate for the development of extended release formulations. The aim of this study is to present a kinetic analysis of the pentoxifylline release from different extended release tablets formulations, using mechanistic and empirical kinetic models. A number of 28 formulations were prepared and analysed; the analysed formulations differed in the nature of the matrix forming polymers (hydrophilic, lipophilic, inert and in their concentrations. Measurements were conducted in comparison with the reference product Trental 400 mg (Aventis Pharma. The conditions for the dissolution study were according to official regulations of USP 36: apparatus no. 2, dissolution medium water, volume of dissolution medium is 1,000 mL, rotation speed is 50 rpm, spectrophotometric assay at 274 nm. Six mathematical models, five mechanistic (0 orders, 1st-order release, Higuchi, Hopfenberg, Hixson-Crowell and one empirical (Peppas, were fitted to pentoxifylline dissolution profile from each pharmaceutical formulation. The representative model describing the kinetics of pentoxifylline release was the 1st-order release, and its characteristic parameters were calculated and analysed.

  2. Influence of chitosan and polycarbophil on permeation of a model hydrophilic drug into the urinary bladder wall.

    Science.gov (United States)

    Grabnar, I; Bogataj, M; Mrhar, A

    2003-04-30

    Influence of dispersions of mucoadhesive polymers chitosan and polycarbophil on permeability properties of urinary bladder was investigated in vitro on isolated porcine urinary bladder. Pipemidic acid as a model hydrophilic drug was used. Its distribution in the bladder wall was determined from actual tissue concentrations by a method based on sectioning of frozen tissue and extraction of tissue slices. Pipemidic acid tissue concentration versus tissue depth profiles were evaluated by a diffusion model assuming constant diffusion coefficient. Increase in bladder wall permeability was observed in the presence of both polymers. Apparent permeability (mean+/-S.D.) of urinary bladder wall was increased 2.7+/-2.9 and 2.8+/-2.0 times for chitosan, and 2.3+/-2.0 and 4.3+/-4.2 times for polycarbophil at 0.5 and 1.0%, w/v polymer concentration, respectively. This increase is a consequence of the increased permeability of urothelium. These findings support investigations on application of chitosan and polycarbophil in development of mucoadhesive intravesical drug delivery systems. Experimental model may be applied to evaluate the results of experiments with drugs used in intravesical therapy.

  3. Improving Drug Loading of Mucosal Solvent Cast Films Using a Combination of Hydrophilic Polymers with Amoxicillin and Paracetamol as Model Drugs

    Directory of Open Access Journals (Sweden)

    Joshua Boateng

    2013-01-01

    Full Text Available Solvent cast mucosal films with improved drug loading have been developed by combining carboxymethyl cellulose (CMC, sodium alginate (SA, and carrageenan (CAR using paracetamol and amoxicillin as model drugs and glycerol (GLY as plasticizer. Films were characterized using X-ray powder diffraction (XRPD, scanning electron microscopy (SEM, folding resilience, swelling capacity, mucoadhesivity, and drug dissolution studies. SA, CMC, and GLY (5 : 3 : 6 films showed maximum amoxicillin loading of 26.3% whilst CAR, CMC, and GLY (1 : 2 : 3 films had a maximum paracetamol loading of 40%. XRPD analysis showed different physical forms of the drugs depending on the amount loaded. Films containing 29.4% paracetamol and 26.3% amoxicillin showed molecular dispersion of the drugs while excess paracetamol was observed on the film surface when the maximum 40% was loaded. Work of adhesion was similar for blank films with slightly higher cohesiveness for CAR and CMC based films, but the differences were significant between paracetamol and amoxicillin containing films. The stickiness and cohesiveness for drug loaded films were generally similar with no significant differences. The maximum percentage cumulative drug release was 84.65% and 70.59% for paracetamol and amoxicillin, respectively, with anomalous case two transport mechanism involving both drug diffusion and polymer erosion.

  4. Exploring the effect of hydrophilic and hydrophobic structure of grafted polymeric micelles on drug loading.

    Science.gov (United States)

    Shi, Chenjun; Sun, Yujiao; Wu, Haiyang; Zhu, Chengyun; Wei, Guoguang; Li, Jinfeng; Chan, Tenglan; Ouyang, Defang; Mao, Shirui

    2016-10-15

    The objective of this paper is to explore the effect of hydrophilic and hydrophobic structure of grafted polymeric micelles on drug loading, and elucidate whether drug-polymer compatibility, as predicted by Hansen solubility parameters (HSPs), can be used as a tool for drug-polymer pairs screening and guide the design of grafted polymeric micelles. HSPs of 27 drugs and three grafted copolymers were calculated according to group contribution method. The drug-polymer compatibilities were evaluated using the approaches of Flory-Huggins interaction parameters (χFH) and polarity difference (△Xp). Two models, model A and B, were put forward for drug-polymer compatibility prediction. In model A, hydrophilic/hydrophobic part as a whole was regarded as one segment. And, in model B, hydrophilic and hydrophobic segments were evaluated individually. First of all, using chitosan (CS)-grafted-glyceryl monooeate (GMO) based micelle as an example, the suitability of model A and model B for predicating drug-polymer compatibility was evaluated theoretically. Thereafter, corresponding experiments were carried out to check the validity of the theoretical prediction. It was demonstrated that Model B, which evaluates drug compatibility with both hydrophilic and hydrophobic segments of the copolymer, is more reliable for drug-polymer compatibility prediction. Moreover, the approach of model B allows for the selection of a defined grafted polymer with for a specific drug and vice versa. Thus, drug compatibility evaluation via HSPs with both hydrophilic and hydrophobic segments is a suitable tool for the rational design of grafted polymeric micelles. The molecular dynamics (MD) simulation study provided further support to the established model and experimental results.

  5. CHARACTERIZATION OF TERNARY SYSTEM OF POORLY SOLUBLE DRUG IN VARIOUS HYDROPHILIC CARRIERS

    OpenAIRE

    Vijay Kumar; Shankaraiah MM; Venkatesh JS; Rangaraju D; Nagesh, C.

    2011-01-01

    The present study aims to experiment the solid dispersion of poorly water soluble drug fenbendazole as model drug. Fenbendazole is an Antihelmintic drug (BCS class 2).The purpose of this study was to enhance the dissolution of Fenbendazole by solid dispersions consisting of the drug, a polymeric carrier, Binary and ternary system were prepared by kneading method using hydrophilic polymers like polyvinylpyrrolidone K-25 (PVP K25), beta-cyclodextrin (BCD),mannitol and urea. The prepared form...

  6. Syntheses and self-assembly of novel asparagine-derived amphiphiles: Applications in the encapsulation of proteins, hydrophobic, and hydrophilic drug models

    Science.gov (United States)

    Mfuh, Adelphe Mbufung

    This thesis focuses mainly on the synthesis, characterization, and self-assembly of a novel series of asparagine-derived amphiphiles and their use in the preparation and stabilization of nano and microcapsules for the encapsulation of proteins, and hydrophilic and hydrophobic drug models. Chapter 1 gives a brief literature overview of lipid molecular assembly, which covers some aspects of morphological analyses, encapsulation of chemical entity and some reported characterization techniques of supramolecular assemblies. It introduces the scope of this dissertation and contains some information on stimulus responsive liposomal systems for controlled release of drug models. Chapter 2 introduces a novel asparagine-derived lipid bearing two fatty chains (C11 and C17) and a tetrahydropyrimidinone head group. It presents information on the synthesis and characterization of this lipid and describes the self-assembly and effects of this lipid in distearoyl phosphatidyl choline bilayer. Chapter 3 presents the synthesis and characterization of a series of ALAn,m (where n and m represent the length of the hydrocarbon chains on the asparagine-derived, heterocyclic head group). It contains data on the effect of chain length, solvent media and head group ionization on the conformational equilibrium about a tertiary amide bond in ALAn,m. The chapter also examines the influence of chain length on ALAn,m on the colloidal stability of DSPC liposomes. Chapter 4 presents the first example of an N,N-acetal linkage in a novel pH responsive nanocarrier system obtained from the cyclocondensation of dodecanal with sodium asparaginate. Data is presented on the spontaneous self-assembly, encapsulation studies and morphological characterization of the nano-systems with the inclusion of cholesterol as additive. Chapter 5 presents the development of a photoresponsive nanocarrier via the self- assembly of an asparagine-derived lipid containing a coumarin unit in the hydrophobic domain. The

  7. Biodegradable hydrophobic-hydrophilic hybrid hydrogels: swelling behavior and controlled drug release.

    Science.gov (United States)

    Wu, Da-Qing; Chu, Chih-Chang

    2008-01-01

    The objective of this work was to investigate a new family of hydrophobic-hydrophilic biodegradable hybrid hydrogels as drug carriers. A series of hydrophobic-hydrophilic biodegradable hybrid hydrogels was formulated via photo means from hydrophobic three-arm poly (epsilon-caprolactone) maleic acid (PGCL-Ma) and hydrophilic dextran maleic acid (Dex-Ma) precursors over a wide range of the two precursors' feed ratio (PGCL-Ma/Dex-Ma at 100:0, 70:30, 50:50, 30:70 and 0:100). A low-molecular-weight and hydrophilic drug, the alpha-7 agonist cocaine methiodide, was used as the model drug for the release study from the hybrid hydrogels in pH 7.4 phosphate buffer solution at 37 degrees C. The swelling data of these hybrid hydrogels depended on the hydrophobic to hydrophilic precursors' feed ratio, and there were several-fold differences in swelling ratios between a pure hydrophilic Dex-Ma and a pure hydrophobic PGCL-Ma hydrogels. The presence of the hydrophobic PGCL-Ma component significantly reduced the initial burst swelling of the hybrid hydrogels. Depending on the two precursors' feed ratios, the swelling data during the early period obeyed either Fickian diffusion (for 50:50 PGCL-Ma/Dex-Ma hydrogel), non-Fickian or anomalous transport (for 70:30 and 100:0 PGCL-Ma/Dex-Ma), or relaxation-controlled (for 30:70 and 0:100 PGCL-Ma/Dex-Ma). A wide range of cocaine methiodide release profiles was achieved by controlling hydrophobic to hydrophilic precursors' feed ratios. Initial drug burst release was significantly reduced as the concentration of the hydrophobic PGCL-Ma component increased in the hybrid hydrogels. The bulk of cocaine methiodide released during the 160-h period was via diffusion-controlled mechanism, while degradation-controlled mechanism dominated thereafter.

  8. Iontophoretic delivery of lipophilic and hydrophilic drugs from lipid nanoparticles across human skin.

    Science.gov (United States)

    Charoenputtakun, Ponwanit; Li, S Kevin; Ngawhirunpat, Tanansait

    2015-11-10

    The combined effects of iontophoresis and lipid nanoparticles on drug delivery across human epidermal membrane (HEM) were investigated. The delivery of lipophilic and hydrophilic drugs, all trans-retinoic acid (ATRA), salicylate (SA), and acyclovir (ACV), across HEM from lipid nanoparticles, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), was compared in passive and iontophoresis experiments in vitro. Iontophoresis experiments were also performed with synthetic Nuclepore membrane for comparison. Drug distribution in the skin after iontophoretic delivery with the lipid nanoparticles was examined using a model probe rhodamine B base (RhoB). The drug-loaded lipid nanoparticles had average sizes of ∼ 118-169 nm and a negative zeta potential. Iontophoresis did not enhance the delivery of ATRA across HEM from SLN and NLC. However, HEM distribution study of RhoB suggested that lipophilic drugs could be delivered into the deeper layer of the skin following iontophoretic delivery of the drugs from the lipid nanoparticles. Iontophoresis enhanced the delivery of hydrophilic drug SA with the lipid nanoparticles. Similarly, iontophoresis enhanced the delivery of ACV when it was loaded in SLN. These results suggest that lipid nanoparticles are a promising drug delivery method that can be combined with iontophoresis to improve skin delivery of hydrophilic drugs.

  9. Solid lipid nanoparticles for encapsulation of hydrophilic drugs by an organic solvent free double emulsion technique.

    Science.gov (United States)

    Becker Peres, Luana; Becker Peres, Laize; de Araújo, Pedro Henrique Hermes; Sayer, Claudia

    2016-04-01

    Encapsulation of hydrophilic compounds for drug delivery systems with high loading efficiency is not easily feasible and remains a challenge, mainly due to the leaking of the drug to the outer aqueous phase during nanoparticle production. Usually, encapsulation of hydrophilic drugs is achieved by using double emulsion or inverse miniemulsion systems that often require the use of organic solvents, which may generate toxicological issues arising from solvent residues. Herein, we present the preparation of solid lipid nanoparticles loaded with a hydrophilic compound by a novel organic solvent free double emulsion/melt dispersion technique. The main objective of this study was to investigate the influence of important process and formulation variables, such as lipid composition, surfactant type, sonication parameters and lipid solidification conditions over physicochemical characteristics of SLN dispersion. Particle size and dispersity, as well as dispersion stability were used as responses. SLN dispersions with average size ranging from 277 to 550 nm were obtained, showing stability for over 60 days at 4 °C depending on the chosen emulsifying system. Entrapment efficiency of fluorescent dyes used as model markers was assessed by fluorescence microscopy and UV-vis spectrophotometry and results suggest that the obtained lipid based nanoparticles could be potentially applied as a delivery system of water soluble drugs.

  10. Formation of controllable hydrophilic/hydrophobic drug delivery systems by electrospinning of vesicles.

    Science.gov (United States)

    Li, Wei; Luo, Tian; Yang, Yanjuan; Tan, Xiuniang; Liu, Lifei

    2015-05-12

    Novel multifunctional poly(ethylene oxide) (PEO) nanofibrous membrane, which contains vesicles constructed by mixed surfactant cetyltrimethylammonium bromide (CTAB)/sodium dodecylbenzenesulfonate (SDBS), has been designed as dual drug-delivery system and fabricated via the electrospinning process. 5-FU and paeonolum, which are hydrophilic and hydrophobic anticancer model drugs, can be dissolved in vesicle solution's bond water and lipid bilayer membranes, respectively. The physicochemical properties of the electrospun nanofibrous membrane were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), and X-ray diffraction (XRD). Drug release behaviors of the electrospun nanofibrous membrane fabricated with different molar ratio of CTAB/SDBS vesicle solution were investigated. The result showed that the releasing amount of hydrophilic drug presented an ascending release manner, while the hydrophobic one showed a descending release behavior with increasing of the molar ratio of CTAB/SDBS. Moreover, the release amount of drugs from drug delivery system can be controlled by the molar ratio of CTAB/SDBS in the vesicle solution easily and conveniently. The distinct properties can be utilized to encapsulate environmental demanding and quantificational materials.

  11. Study of the critical points of HPMC hydrophilic matrices for controlled drug delivery.

    Science.gov (United States)

    Miranda, Antonia; Millán, Mónica; Caraballo, Isidoro

    2006-03-27

    The knowledge of the percolation thresholds of a system results in a clear improvement of the design of controlled release dosage forms such as inert matrices. Despite hydrophilic matrices are one of the most used controlled delivery systems in the world, but actuality, the mechanisms of drug release from these systems continue to be a matter of debate nowadays. The objective of the present paper is to apply the percolation theory to study the release and hydration rate of hydrophilic matrices. Matrix tablets have been prepared using KCl as a drug model and HPMC K4M as matrix-forming material, employing five different excipient/drug particle size ratios (ranging from 0.42 to 2.33). The formulations studied containing a drug loading in the range of 20-90% (w/w). Dissolution studies were carried out using the paddle method and the water uptake measurements were performed using a modified Enslin apparatus. In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to the volumetric fraction of each component at time zero, was studied. The percolation theory has been applied for the first time to the study of matrix type controlled delivery systems. The application of this theory allowed to explain changes in the release and hydration kinetics of these matrices. The critical points observed in dissolution and water uptake studies can be attributed to the excipient percolation threshold, being this threshold one of the main factors governing the gel layer formation and consequently, the drug release control from hydrophilic matrices.

  12. Silk fibroin/copolymer composite hydrogels for the controlled and sustained release of hydrophobic/hydrophilic drugs.

    Science.gov (United States)

    Zhong, Tianyi; Jiang, Zhijuan; Wang, Peng; Bie, Shiyu; Zhang, Feng; Zuo, Baoqi

    2015-10-15

    In the present study, a composite system for the controlled and sustained release of hydrophobic/hydrophilic drugs is described. Composite hydrogels were prepared by blending silk fibroin (SF) with PLA-PEG-PLA copolymer under mild aqueous condition. Aspirin and indomethacin were incorporated into SF/Copolymer hydrogels as two model drugs with different water-solubility. The degradation of composite hydrogels during the drug release was mainly caused by the hydrolysis of copolymers. SF with stable β-sheet-rich structure was not easily degraded which maintained the mechanical integrity of composite hydrogel. The hydrophobic/hydrophilic interactions of copolymers with model drugs would significantly alter the morphological features of composite hydrogels. Various parameters such as drug load, concentration ratio, and composition of copolymer were considered in vitro drug release. Aspirin as a hydrophilic drug could be controlled release from composite hydrogel at a constant rate for 5 days. Its release was mainly driven by diffusion-based mechanism. Hydrophobic indomethacin could be encapsulated in copolymer nanoparticles distributing in the composite hydrogel. Its sustained release was mainly degradation controlled which could last up to two weeks. SF/Copolymer hydrogel has potential as a useful composite system widely applying for controlled and sustained release of various drugs.

  13. CHARACTERIZATION OF TERNARY SYSTEM OF POORLY SOLUBLE DRUG IN VARIOUS HYDROPHILIC CARRIERS

    Directory of Open Access Journals (Sweden)

    Vijay Kumar

    2011-09-01

    Full Text Available The present study aims to experiment the solid dispersion of poorly water soluble drug fenbendazole as model drug. Fenbendazole is an Antihelmintic drug (BCS class 2.The purpose of this study was to enhance the dissolution of Fenbendazole by solid dispersions consisting of the drug, a polymeric carrier, Binary and ternary system were prepared by kneading method using hydrophilic polymers like polyvinylpyrrolidone K-25 (PVP K25, beta-cyclodextrin (BCD,mannitol and urea. The prepared formulations were characterized by polymer compatibility by using FT-IR.The drug content uniformity was found to be good in all formulations. The influence of various factors (type of polymer, ratio of the polymer on the solubility and dissolution rate of the drug were also evaluated. The solubility of fenbendazole was greater with fenbendazole-betacyclodextrin-PVP K-25 system. Dissolution rates of fenbendazole were significantly increased by binary and ternary system. Among all the formulations, fenbendazole-betacyclodextrin-polyvinylpyrrolidone K-25 (VK3 Formulation was found to be better amorphous nature in relation with in-vitro release. The result confirmed that ternary system showed better solubility and dissolution characteristics when compared to binary system.

  14. Novel drug nanocarriers combining hydrophilic cyclodextrins and chitosan

    Energy Technology Data Exchange (ETDEWEB)

    Trapani, A; Garcia-Fuentes, M; Alonso, M J [Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain)], E-mail: ffmjalon@usc.es

    2008-05-07

    The aim of this study was to explore the possibility of obtaining nanoparticles (NPs) containing high amounts of cyclodextrin (CD) derivatives such as carboxymethyl-{beta}-CD and sulphobutyl ether-{beta}-CD. The rationale used was to combine the drug solubilizing and stabilizing properties of cyclodextrins (CDs) with the mucoadhesive properties of chitosan (CS) in a unique nanoparticulate drug delivery system. The size of the resulting NPs was affected by the nature of the CDs, ranging between 275 and 550 nm, whereas the zeta potential of the NPs was always positive and close to +35 mV. The positive zeta values, together with the results from NMR studies, suggest that CS is the major compound on the surface of the NPs, while CD molecules are strongly associated with the NP matrix. The empirical composition of the NPs was quantified by elemental analysis and the results indicated that the amount of CD associated with the NPs was strictly dependent on its electrostatic charge. Finally, in vitro stability studies indicated that the presence of CDs in the NP structure can prevent the aggregation of this nanometric carrier system in simulated intestinal fluid. Overall, this new type of NP represents an attractive drug delivery platform of particular interest for the oral administration of drugs with low bioavailability.

  15. Controlled release from thermo-sensitive PNVCL-co-MAA electrospun nanofibers: The effects of hydrophilicity/hydrophobicity of a drug.

    Science.gov (United States)

    Liu, Lin; Bai, Shaoqing; Yang, Huiqin; Li, Shubai; Quan, Jing; Zhu, Limin; Nie, Huali

    2016-10-01

    The thermo-sensitive copolymer poly(N-vinylcaprolactam-co-methacrylic acid) (PNVCL-co-MAA) was synthesized by free radical polymerization and the resulting nanofibers were fabricated using an electrospinning process. The molecular weight of the copolymer was adjusted by varying the content of methacrylic acid (MAA) while keeping that of N-vinylcaprolactam (NVCL) constant. Hydrophilic captopril and hydrophobic ketoprofen were used as model drugs, and PNVCL-co-MAA nanofibers were used as the drug carrier to investigate the effects of drug on its release properties from nanofibers at different temperatures. The results showed that slow release over several hours was observed at 40°C (above the lower critical solution temperature (LCST) of PNVCL-co-MAA), while the drugs exhibited a burst release of several seconds at 20°C (below the LCST). Drug release slowed with increasing content of the hydrophobic monomer NVCL. The hydrophilic captopril was released at a higher rate than the hydrophobic ketoprofen. The drug release characteristics were dependent on the temperature, the portion of hydrophilic groups and hydrophobic groups in the copolymer and hydrophilicity/hydrophobicity of drug. Study on the mechanism of release showed that Korsmeyer-Peppas model as a major drug release mechanism. Given these results, the PNVCL-co-MAA copolymers are proposed to have useful applications in intellectual drug delivery systems.

  16. Lipid-drug conjugate nanoparticles of the hydrophilic drug diminazene-cytotoxicity testing and mouse serum adsorption

    NARCIS (Netherlands)

    Olbrich, C.; Gessner, A.; Schroder, W.; Kayser, Oliver; Muller, R.H.

    2004-01-01

    Sleeping sickness is a widely distributed disease in great parts of Africa. It is caused by Trypanosoma brucei gambiense and rhodiense, transmitted by the Tse-Tse fly. After a hemolymphatic stage, the parasites enter the central nervous system where they cannot be reached by hydrophilic drugs. To

  17. Lipid-drug conjugate nanoparticles of the hydrophilic drug diminazene-cytotoxicity testing and mouse serum adsorption

    NARCIS (Netherlands)

    Olbrich, C.; Gessner, A.; Schroder, W.; Kayser, Oliver; Muller, R.H.

    2004-01-01

    Sleeping sickness is a widely distributed disease in great parts of Africa. It is caused by Trypanosoma brucei gambiense and rhodiense, transmitted by the Tse-Tse fly. After a hemolymphatic stage, the parasites enter the central nervous system where they cannot be reached by hydrophilic drugs. To po

  18. Drug release property of a pH-responsive double-hydrophilic hyperbranched graft copolymer

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    In this paper, we report the synthesis and self-assembly of double-hydrophilic hyperbranched graft copolymers of HPG-g-PDMAEMA, which consist of a hyperbranched polyglycerol (HPG) core and several grafted poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) arms. HPG was synthesized by cationic polymerization. Then HPG-Br macroinitiator was obtained by esterification of HPG with 2-bromoisobutyryl bromide, which was subsequently used in the preparation of HPG-g-PDMAEMA graft copolymers through atom transfer radical polymerization (ATRP) of DMAEMA monomers. The molecular structures were studied by 1H NMR and GPC. The pyrene-based fluorescent probe method, 1H NMR and DLS were used to study the self-assembly behavior of HPG-g-PDMAEMA. The drug loading and pH-responsive release properties of HPG-g-PDMAEMA were also investigated by using coumarin 102 as a model drug. The results show that the HPG-g-PDMAEMA micelles can continuously release and re-encapsulate coumarin 102 as the pH continuously changes from 11.5 to 2.5; however, this process is not totally reversible.

  19. Recent advances in amphiphilic polymers for simultaneous delivery of hydrophobic and hydrophilic drugs.

    Science.gov (United States)

    Martin, Chloe; Aibani, Noorjahan; Callan, John F; Callan, Bridgeen

    2016-01-01

    Nanomedicine has evolved with the use of biological compounds such as proteins, peptides and DNA. These hydrophilic and often highly charged compounds require a delivery system to allow effective transport and release at the site of action. These new biological therapeutics have not replaced the more traditional smaller molecule, but instead are working synergistically to the benefit of the end user. To that end, drug delivery systems are now required to encapsulate both larger hydrophilic compounds as well as the smaller and generally more hydrophobic compound. This review highlights the emerging role in drug delivery of amphiphilic polymers that by their very nature can associate with compounds of differing physicochemical properties, in particular the role of micelles, polymersomes and nanocapsules.

  20. Drug release-modulating mechanism of hydrophilic hydroxypropylmethylcellulose matrix tablets: distribution of atoms and carrier and texture analysis.

    Science.gov (United States)

    Park, Jun-Bom; Lim, Jisung; Kang, Chin-Yang; Lee, Beom-Jin

    2013-12-01

    Although release profiles of drug from hydrophilic matrices have been well recognized, the visual distribution of hydroxypropylmethylcellulose (HPMC) and atoms inside of internal structures of hydrophilic HPMC matrices has not been characterized. In this paper, drug release mechanism from HPMC matrix tablet was investigated based on the release behaviors of HPMC, physical properties of gelled HPMC tablet and atomic distributions of formulation components using diverse instruments. A matrix tablet consisting of hydroxypropyl methylcellulose (HPMC 6, 4,000 and 100,000 mPa·s), chlorpheniramine maleate (CPM) as a model and fumed silicon dioxide (Aerosil(®) 200) was prepared via direct compression. The distribution of atoms and HPMC imaging were characterized using scanning electron microscope (SEM)/ energy-dispersive X-ray spectroscopy (EDX), and near-infrared (NIR) analysis, respectively as a function of time. A texture analyzer was also used to characterize the thickness and maintenance of gel layer of HPMC matrix tablet. The HPMC matrix tablets showed Higuchi release kinetics with no lag time against the square root of time. High viscosity grades of HPMC gave retarded release rate because of the greater swelling and gel thickness as characterized by texture analyzer. According to the NIR imaging, low-viscosity-grade HPMC (6 mPa·s) quickly leached out onto the surface of the tablet, while the high-viscosity-grade HPMC (4000 mPa·s) formed much thicker gel layer around the tablet and maintained longer via slow erosion, resulting in retarded drug release. The atomic distribution of the drug (chlorine, carbon, oxygen), HPMC (carbon, oxygen) and silicon dioxide (silica, oxygen) and NIR imaging of HPMC corresponded with the dissolution behaviors of drug as a function of time. The use of imaging and texture analyses could be applicable to explain the release- modulating mechanism of hydrophilic HPMC matrix tablets.

  1. PLA-PEG-PLA copolymer-based polymersomes as nanocarriers for delivery of hydrophilic and hydrophobic drugs: preparation and evaluation with atorvastatin and lisinopril.

    Science.gov (United States)

    Danafar, H; Rostamizadeh, K; Davaran, S; Hamidi, M

    2014-10-01

    Tri-block poly(lactide)-poly(ethylene glycol)-poly(lactide) (PLA-PEG-PLA) copolymers were synthesized and used to prepare polymersomes loaded separately by the hydrophobic and hydrophilic model drugs, atorvastatin and lisinopril, respectively. The resulting nanostructures were characterized by various techniques such as FTIR, DSC, PCS and AFM. The polymersomes exhibited high encapsulation efficiencies of almost 78% and 70.8% for atorvastatin and lisinopril, respectively. Investigation on FTIR and DSC results revealed that such a high encapsulation efficiency is due to strong interaction between atorvastatin and the copolymer. The impact of drug/copolymer ratio and copolymer composition on drug-loading efficiency and drug release behavior were also studied. The results showed that in case of lisinopril, polymersomes exhibited a triphasic drug release, while for atorvastatin a biphasic release profile was obtained. Overall, the results indicated that PLA-PEG-PLA polymersomes can be considered as a promising carrier for both hydrophilic and hydrophobic drugs.

  2. Thermochemical Properties of Hydrophilic Polymers from Cashew and Khaya Exudates and Their Implications on Drug Delivery.

    Science.gov (United States)

    Olorunsola, Emmanuel O; Bhatia, Partap G; Tytler, Babajide A; Adikwu, Michael U

    2016-01-01

    Characterization of a polymer is essential for determining its suitability for a particular purpose. Thermochemical properties of cashew gum (CSG) extracted from exudates of Anacardium occidentale L. and khaya gum (KYG) extracted from exudates of Khaya senegalensis were determined and compared with those of acacia gum BP (ACG). The polymers were subjected to different thermal and chemical analyses. Exudates of CSG contained higher amount of hydrophilic polymer. The pH of 2% w/v gum dispersions was in the order KYG application of cashew gum for formulation of basic and oxidizable drugs while using khaya gum for acidic drugs.

  3. Losartan potassium loaded sustained release matrix tablets: Influence of various hydrophilic and hydrophobic polymers on drug release behaviour

    Directory of Open Access Journals (Sweden)

    D D Vohra

    2012-01-01

    Full Text Available Losartan potassium is an angiotensin II receptor antagonist readily absorbed from the GIT, following oral administration. It has low bioavailability as it undergoes extensive first pass metabolism and low elimination half-life. The present study was aimed at studying sustained release behaviour of the drug using hydrophilic and hydrophobic polymers and to optimise using a 32 full factorial design. Eudragit and HPMC were used to evaluate the effect of hydrophilic and hydrophobic polymers on the release pattern of the drug. A full factorial was implemented at 20, 30 and 40% concentration of hydrophilic polymer and 2.5, 5 and 7.5% of hydrophobic polymer correlating with the release behaviour. Process variables were investigated and the results showed excellent adaptability in releasing drug over prolonged periods. Based on the results, it was found suitable to formulate a dosage form using optimum concentration of hydrophobic polymer along with hydrophilic polymer to vary the release behaviour for over 12 hours.

  4. Formulation of gastroretentive floating drug delivery system using hydrophilic polymers and its in vitro characterization

    Directory of Open Access Journals (Sweden)

    Venkata Srikanth Meka

    2014-04-01

    Full Text Available The aim of the present research is to formulate and evaluate the gastroretentive floating drug delivery system of antihypertensive drug, propranolol HCl. Gastroretentive floating tablets (GRFT were prepared by using a synthetic hydrophilic polymer polyethylene oxide of different grades such as PEO WSR N-12 K and PEO 18 NF as release retarding polymers and calcium carbonate as gas generating agent. The GRFT were compressed by direct compression strategy and the tablets were evaluated for physico-chemical properties, in vitro buoyancy, swelling studies, in vitro dissolution studies and release mechanism studies. From the dissolution and buoyancy studies, F 9 was selected as an optimized formulation. The optimized formulation followed zero order rate kinetics with non-Fickian diffusion mechanism. The optimized formulation was characterised with FTIR studies and observed no interaction between the drug and the polymers.

  5. Triggered in situ drug supersaturation and hydrophilic matrix self-assembly.

    Science.gov (United States)

    Benaouda, F; Brown, M B; Martin, G P; Jones, S A

    2012-12-01

    To understand in situ drug thermodynamic activity when embedded in a supramolecular structured hydrophilic matrix that simultaneously self-assembled during drug supersaturation. A propylene glycol (PG)/water, hydroxypropyl methyl cellulose matrix containing ethanol was used to support diclofenac supersaturation. Phase behaviour, thermodynamics and drug transport were assessed through the determination of evaporation kinetics, supersaturation kinetics and transmembrane penetration. Initial ethanol evaporation from the drug loaded matrix (2.9 ± 0.4 mg.min(-1).cm(-2)) was comparable to that of the pure solvent (ca. 3 mg.min(-1).cm(-2)). When 25% w/w of the total ethanol from the applied phase was lost (ethanol/water/PG molar ratio of 7:5:1.2), an inflection point in the evaporation profile and a sudden decrease in drug solubility demonstrated that a defined supramolecular structure was formed. The 55-fold decrease in drug solubility observed over the subsequent 8 h drove in situ supersaturation, the rate of which was a function of the drug load in the matrix (y = 0.0078x, R(2) 24 h, but did not hinder mobility and this allowed the thermodynamic activity of the drug to be directly translated into highly efficient transmembrane penetration.

  6. A novel experimental design method to optimize hydrophilic matrix formulations with drug release profiles and mechanical properties.

    Science.gov (United States)

    Choi, Du Hyung; Lim, Jun Yeul; Shin, Sangmun; Choi, Won Jun; Jeong, Seong Hoon; Lee, Sangkil

    2014-10-01

    To investigate the effects of hydrophilic polymers on the matrix system, an experimental design method was developed to integrate response surface methodology and the time series modeling. Moreover, the relationships among polymers on the matrix system were studied with the evaluation of physical properties including water uptake, mass loss, diffusion, and gelling index. A mixture simplex lattice design was proposed while considering eight input control factors: Polyethylene glycol 6000 (x1 ), polyethylene oxide (PEO) N-10 (x2 ), PEO 301 (x3 ), PEO coagulant (x4 ), PEO 303 (x5 ), hydroxypropyl methylcellulose (HPMC) 100SR (x6 ), HPMC 4000SR (x7 ), and HPMC 10(5) SR (x8 ). With the modeling, optimal formulations were obtained depending on the four types of targets. The optimal formulations showed the four significant factors (x1 , x2 , x3 , and x8 ) and other four input factors (x4 , x5 , x6 , and x7 ) were not significant based on drug release profiles. Moreover, the optimization results were analyzed with estimated values, targets values, absolute biases, and relative biases based on observed times for the drug release rates with four different targets. The result showed that optimal solutions and target values had consistent patterns with small biases. On the basis of the physical properties of the optimal solutions, the type and ratio of the hydrophilic polymer and the relationships between polymers significantly influenced the physical properties of the system and drug release. This experimental design method is very useful in formulating a matrix system with optimal drug release. Moreover, it can distinctly confirm the relationships between excipients and the effects on the system with extensive and intensive evaluations.

  7. Self-degrading niosomes for encapsulation of hydrophilic and hydrophobic drugs: An efficient carrier for cancer multi-drug delivery.

    Science.gov (United States)

    Sharma, Varsha; Anandhakumar, Sundaramurthy; Sasidharan, Manickam

    2015-11-01

    In this study, we have examined the encapsulation and release of hydrophilic and hydrophobic drugs in self-degrading niosomes as a unique method for anticancer therapy. Niosomes were prepared by amphiphilic self-assembly of Tween 80 and cholesterol through film hydration method. Encapsulation studies with two active molecules curcumin and doxorubicin hydrochloride (Dox) showed that curcumin is supposed to accumulate in the shell whereas Dox accumulates in the inner aqueous core of the niosome. Confocal studies indicated that nile red adsorbs preferentially to the head group of the Tween 80 and forms two separate layers in the shell. It was also seen that the niosomes undergo self-degradation in PBS through a sequential process, forming interconnected pores followed by complete collapse after 1week. The release profile shows two phases: i) initial Dox release in the first two days, followed by ii) curcumin release over 7days. Enhanced (synergistic) cytotoxicity was observed for dual-drug loaded niosomes against HeLa cell lines. Thus these niosomes are shown to offer a promising delivery system for hydrophobic and hydrophilic drugs collectively.

  8. Study of the effect of formulation parameters/variables to control the nanoencapsulation of hydrophilic drug via double emulsion technique.

    Science.gov (United States)

    Ayoub, Mohamed; Ahmed, Naveed; Kalaji, Nader; Charcosset, Catherine; Magdy, Ayoub; Fessi, Hatem; Elaissari, Abdelhamid

    2011-04-01

    Preparation of biodegradable nanoparticles containing active molecule is now taking much attention of researchers. The aim of the present work is to achieve the nanosize particles for the first time by double emulsion (W1/O/W2,) evaporation method to encapsulate hydrophilic substance using high performance stirring apparatus. A fluorescent stable hydrophilic agent (Stilbene derivative) was used as a model drug to be encapsulated. For this purpose, PCL (polycaprolactone) was chosen as polymer in this study. Several kinds of stabilizers [triton-405, tween 80, poloxamer, PVP (polyvinylpyrrolidone), PEG (poly ethylene glycol) & PVA (poly vinyl alcohol)] were investigated and the results indicate that the PVA (0.5% concentration) leads to the most stable double emulsion with the particle size in nano range. Different parameters affecting the size of particles have been studied such as stirring time (for 1st and 2nd emulsion), stirring speed (for 1st and 2nd emulsion), polymer and stabilizer concentrations etc. After duration of one month, the encapsulation efficiency of obtained particles was estimated using U.V. analysis. Transmission Electron Microscopy (TEM) showed that the prepared particles were spherical in shape. The size and size distribution were found to be submicron and ranging from 150 to 400 nm.

  9. Synthesis of novel polymeric nanoparticles for hydrophobic and hydrophilic drug delivery

    Science.gov (United States)

    Sartor, Marta

    Modern medicine has achieved extraordinary results with the use of nanotechnologies. The combination of the two disciplines created the modern field of nanomedicine, in which drug delivery is one of the most prominent branches. Several aspects are involved in drug delivery; this work will focus on the drug delivery vehicle. In particular three aspects will be investigated: building material, internal structure and material compatibility. In a first project DNA was proposed as an innovative building material. DNA nanoparticles were made from self-folding of long concatameric repeats of a single strand sequence. Nanoparticles with different sequences created a library that was biopanned against dendritic cells (DC). Particles from the enriched library were sequenced and individually tested for affinity towards DC. The use of DNA as building material offers several advantages. For instance DNA binding drugs (such as Doxorubicin) can be easily incorporated, and immunostimulatory sequences (such as GpC) and any other encoding sequence can be integrated within the concatamers. In addition, any other molecule or small particle of interest can be conjugated to a short complementary sequence and hybridized on the outer layer of the DNA nanoparticle. DNA nanoparticles' payloads are limited to hydrophilic drugs. In addition to an hydrophobic payload, some therapies require a high loading and steady release. To achieve such results a gradient structure was created within the core of a polymeric nanoparticle. Physical and chemical gradient were considered. A chemical gradient was created by combining a low molecular weigh polycaprolactone (PCL) to a higher molecular weigh poly(lactic-co-glycolic acid) (PLGA). PCL and PLGA have different degradation rate and hydrophobicity. The particles created by combining the two polymers showed properties (such as loading) dependent on the two polymers' proportion into the composition. The chemical gradient nanoparticles are characterized by

  10. Efficient "green" encapsulation of a highly hydrophilic anticancer drug in metal-organic framework nanoparticles.

    Science.gov (United States)

    Rodriguez-Ruiz, Violeta; Maksimenko, Andrei; Anand, Resmi; Monti, Sandra; Agostoni, Valentina; Couvreur, Patrick; Lampropoulou, Maria; Yannakopoulou, Konstantina; Gref, Ruxandra

    2015-01-01

    Metal-organic frameworks (MOFs) are coordination polymers of interest for biomedical applications. Of particular importance, nanoparticles made of iron(III) trimesate (MIL-100, MIL standing for Material Institut Lavoisier) (nanoMOFs) can be conveniently synthesised under mild and green conditions. They were shown to be biodegradable, biocompatible and efficient to encapsulate a variety of active molecules. We have addressed here the challenges to encapsulate a highly hydrophilic anticancer prodrug, phosphated gemcitabin (Gem-MP) known for its instability and inability to bypass cell membranes. MIL-100 nanoMOFs acted as efficient "nanosponges", soaking Gem-MP from its aqueous solution with almost perfect efficiency (>98%). Maximal loadings reached ∼30 wt% reflecting the strong interaction between the drug and the iron trimesate matrices. Neither degradation nor loss of crystalline structure was observed after the loading process. Storage of the loaded nanoMOFs in water did not result in drug release over three days. However, Gem-MP was released in media containing phosphates, as a consequence to particle degradation. Drug-loaded nanoMOFs were effective against pancreatic PANC-1 cells, in contrast to free drug and empty nanoMOFs. However, an efflux phenomenon could contribute to reduce the efficacy of the nanocarriers. Size optimization and surface modification of the nanoMOFs are expected to further improve these findings.

  11. Fluorescent graphene oxide via polymer grafting: an efficient nanocarrier for both hydrophilic and hydrophobic drugs.

    Science.gov (United States)

    Kundu, Aniruddha; Nandi, Sudipta; Das, Pradip; Nandi, Arun K

    2015-02-18

    Functionalized graphene-based drug delivery vehicles have conquered a significant position because functionalization improves its biocompatibility and stability in cell medium, leaving sufficient graphitic basal plane for drug loading through π-π stacking. In this study, poly(N-isopropylacrylamide) (PNIPAM) is covalently grafted from the surface of graphene oxide (GO) via a facile, eco-friendly and an easy procedure of free radical polymerization (FRP) using ammonium persulfate initiator. Various spectroscopic and microscopic studies confirm the successful grafting of PNIPAM from GO surface. PNIPAM-grafted GO (GPNM) exhibits enhanced thermal stability, improved dispersibility both in aqueous and cell medium, and better biocompatibility and cell viability compared to GO. Interestingly, GPNM displays an exciting fluorescence property in aqueous medium, which is a hike of intensity at 36 °C due to the lower critical solution temperature (LCST) of PNIPAM chains (32 °C). Moreover both hydrophilic (doxorubicin (DOX)) and hydrophobic (indomethacin (IMC)) drugs loaded on the surface of GPNM hybrid exhibits its efficacy as an efficient carrier for both types of drugs. Cellular uptakes of free DOX and DOX-loaded GPNM (GPNM-DOX) are evidenced both from optical and fluorescence imaging of live cells, and the efficiency of drug is significantly improved in the loaded system. The release of DOX from GPNM-DOX was achieved at pH 4, relevant to the environment of cancer cells. The pH-triggered release of hydrophobic drug was also studied using UV-vis spectroscopy via alginate encapsulation, showing a great enhancement at pH = 7.4. The IMC is also found to be released by human serum albumin using dialysis technique. The GPNM nanomaterial shows the property of simultaneous loading of DOX and IMC as well as pH-triggered simultaneous release of both of the drugs.

  12. Thermochemical Properties of Hydrophilic Polymers from Cashew and Khaya Exudates and Their Implications on Drug Delivery

    Directory of Open Access Journals (Sweden)

    Emmanuel O. Olorunsola

    2016-01-01

    Full Text Available Characterization of a polymer is essential for determining its suitability for a particular purpose. Thermochemical properties of cashew gum (CSG extracted from exudates of Anacardium occidentale L. and khaya gum (KYG extracted from exudates of Khaya senegalensis were determined and compared with those of acacia gum BP (ACG. The polymers were subjected to different thermal and chemical analyses. Exudates of CSG contained higher amount of hydrophilic polymer. The pH of 2% w/v gum dispersions was in the order KYG < CSG < ACG. Calcium was the predominant ion in CSG while potassium was predominant in KYG. The FTIR spectra of CSG and KYG were similar and slightly different from that of ACG. Acacia and khaya gums exhibited the same thermal behaviour which is different from that of CSG. X-ray diffraction revealed that the three gums are the same type of polymer, the major difference being the concentration of metal ions. This work suggests the application of cashew gum for formulation of basic and oxidizable drugs while using khaya gum for acidic drugs.

  13. Thermochemical Properties of Hydrophilic Polymers from Cashew and Khaya Exudates and Their Implications on Drug Delivery

    Science.gov (United States)

    Bhatia, Partap G.; Tytler, Babajide A.; Adikwu, Michael U.

    2016-01-01

    Characterization of a polymer is essential for determining its suitability for a particular purpose. Thermochemical properties of cashew gum (CSG) extracted from exudates of Anacardium occidentale L. and khaya gum (KYG) extracted from exudates of Khaya senegalensis were determined and compared with those of acacia gum BP (ACG). The polymers were subjected to different thermal and chemical analyses. Exudates of CSG contained higher amount of hydrophilic polymer. The pH of 2% w/v gum dispersions was in the order KYG < CSG < ACG. Calcium was the predominant ion in CSG while potassium was predominant in KYG. The FTIR spectra of CSG and KYG were similar and slightly different from that of ACG. Acacia and khaya gums exhibited the same thermal behaviour which is different from that of CSG. X-ray diffraction revealed that the three gums are the same type of polymer, the major difference being the concentration of metal ions. This work suggests the application of cashew gum for formulation of basic and oxidizable drugs while using khaya gum for acidic drugs. PMID:27990303

  14. A water-like model under confinement for hydrophobic and hydrophilic particle-plate interaction potentials

    OpenAIRE

    Krott, Leandro B.; BARBOSA, Marcia C.

    2013-01-01

    Molecular dynamic simulations were employed to study a water-like model confined between hydrophobic and hydrophilic plates. The phase behavior of this system is obtained for different distances between the plates and particle-plate potentials. For both hydrophobic and hydrophilic walls there are the formation of layers. Crystallization occurs at lower temperature at the contact layer than at the middle layer. In addition, the melting temperature decreases as the plates become more hydrophobi...

  15. Hydrophilic drug encapsulation in shell-core microcarriers by two stage polyelectrolyte complexation method.

    Science.gov (United States)

    Dalmoro, Annalisa; Sitenkov, Alexander Y; Cascone, Sara; Lamberti, Gaetano; Barba, Anna Angela; Moustafine, Rouslan I

    2017-02-25

    In this study a protocol exploiting the combination of the ultrasonic atomization and the complexation between polyelectrolytes was developed to efficiently encapsulate a hydrophilic chemotherapeutic agent essentially used in the treatment of colon cancer, 5-fluorouracil, in enteric shell-core alginate-based microcarriers. The atomization assisted by ultrasound allowed to obtain small droplets by supplying low energy and avoiding drug degradation. In particular microcarriers were produced in a home-made apparatus where both the core (composed of alginate, drug, and Pluronic F127) and shell (composed of only alginate) feed were separately sent to the coaxial ultrasonic atomizer where they were nebulized and placed in contact with the complexation bulk. With the aim to obtain microstructured particles of alginate encapsulating 5-fluorouracil, different formulations of the first complexation bulk were tested; at last an emulsion made of a calcium chloride aqueous solution and dichloromethane allowed to reach an encapsulation efficiency of about 50%. This result can be considered very interesting considering that in literature similar techniques gave 5-fluorouracil encapsulation efficiencies of about 10%. Since a single complexation stage was not able to assure microcarriers gastroresistance, the formulation of a second complexation bulk was evaluated. The solution of cationic and pH-insoluble Eudragit® RS 100 in dichloromethane was chosen as bulk of second-stage complexation obtaining good enteric properties of shell-core microcarriers, i.e. a 5-FU cumulative release at pH 1 (simulating gastric pH) lower than 35%. The formation of interpolyelectrolyte complex (IPEC) between countercharged polymers and the chemical stability of 5-FU in microcarriers were confirmed by FTIR analysis, the presence of an amorphous dispersion of 5-FU in prepared microparticles was also confirmed by DSC. Finally, shell-core enteric coated microcarriers encapsulating 5-fluorouracil were used

  16. Development of polymeric nanoparticles with highly entrapped herbal hydrophilic drug using nanoprecipitation technique: an approach of quality by design.

    Science.gov (United States)

    Vuddanda, Parameswara Rao; Mishra, Amit; Singh, Sanjay Kumar; Singh, Sanjay

    2015-01-01

    The intention of this study is to achieve higher entrapment efficiency (EE) of berberine chloride (selected hydrophilic drug) using nanoprecipitation technique. The solubility of drug was studied in various pH buffers (1.2-7.2) for selection of aqueous phase and stabilizer. Quality by design (QbD)-based 3(2) factorial design were employed for optimization of formulation variables; drug to polymer ratio (X1) and surfactant concentration (X2) on entrapment efficiency (EE), particle size (PS) and polydispersity index (PDI) of the nanoparticles. The nanoparticles were subjected to solid state analysis, in vitro drug release and stability study. The aqueous phase and stabilizer selected for the formulations were pH 4.5 phthalate buffer and surfactant F-68, respectively. The formulation (F-6) containing drug to polymer ratio (1:3) and stabilizer (F-68) concentration of 50 mM exhibited best EE (82.12%), PS (196.71 nm), PDI (0.153). The various solid state characterizations assured that entrapped drug is amorphous and nanoparticles are fairly spherical in shape. In vitro drug release of the F-6 exhibited sustained release with non-Fickian diffusion and stable at storage condition. This work illustrates that the proper selection of aqueous phase and optimization of formulation variables could be helpful in improving the EE of hydrophilic drugs by nanoprecipitation technique.

  17. Self-assembled silk sericin/poloxamer nanoparticles as nanocarriers of hydrophobic and hydrophilic drugs for targeted delivery

    Energy Technology Data Exchange (ETDEWEB)

    Mandal, Biman B; Kundu, S C, E-mail: kundu@hijli.iitkgp.ernet.i [Department of Biotechnology, Indian Institute of Technology, Kharagpur 721302 (India)

    2009-09-02

    In recent times self-assembled micellar nanoparticles have been successfully employed in tissue engineering for targeted drug delivery applications. In this review, silk sericin protein from non-mulberry Antheraea mylitta tropical tasar silk cocoons was blended with pluronic F-127 and F-87 in the presence of solvents to achieve self-assembled micellar nanostructures capable of carrying both hydrophilic (FITC-inulin) and hydrophobic (anticancer drug paclitaxel) drugs. The fabricated nanoparticles were subsequently characterized for their size distribution, drug loading capability, cellular uptake and cytotoxicity. Nanoparticle sizes ranged between 100 and 110 nm in diameter as confirmed by dynamic light scattering. Rapid uptake of these particles into cells was observed in in vitro cellular uptake studies using breast cancer MCF-7 cells. In vitro cytotoxicity assay using paclitaxel-loaded nanoparticles against breast cancer cells showed promising results comparable to free paclitaxel drugs. Drug-encapsulated nanoparticle-induced apoptosis in MCF-7 cells was confirmed by FACS and confocal microscopic studies using Annexin V staining. Up-regulation of pro-apoptotic protein Bax, down-regulation of anti-apoptotic protein Bcl-2 and cleavage of regulatory protein PARP through Western blot analysis suggested further drug-induced apoptosis in cells. This study projects silk sericin protein as an alternative natural biomaterial for fabrication of self-assembled nanoparticles in the presence of poloxamer for successful delivery of both hydrophobic and hydrophilic drugs to target sites.

  18. Combinational delivery of hydrophobic and hydrophilic anticancer drugs in single nanoemulsions to treat MDR in cancer.

    Science.gov (United States)

    Ma, Yan; Liu, Dan; Wang, Dun; Wang, Yongjun; Fu, Qiang; Fallon, John K; Yang, Xinggang; He, Zhonggui; Liu, Feng

    2014-08-04

    In this study, we developed the core-matched nanoemulsions (NEs) functionalized by vitamin E (VE) and tocopherol poly(ethylene glycol)succinate (TPGS) to codeliver hydrophobic and hydrophilic drugs, paclitaxel (PTX) and 5-fluoroucacil (5-FU), in order to achieve synergistic effects and overcome PTX resistance in a multi-drug-resistant (MDR) human epidermal carcinoma cell line KB-8-5. Antitumor effect of the combination therapy based on core-matched technology (CMT) was evaluated in vitro and in vivo in mice. The core-matched NEs showed entrapment efficiency of >90% and were of nanoscale particle size and negative zeta-potential. The combined core-matched NEs exhibited concentration and time-dependent cytotoxicity against PTX-sensitive KB-3-1 cells and PTX-resistant KB-8-5 cells as well as an obviously increased G2/M phase block. The improvements in therapeutic response over either PTX-VE or 5-FU-TPGS therapy alone were demonstrated by the ability to effectively induce the apoptosis of tumor cells via up-regulation of tumor suppressor p53 and β-tubulin and by the significant inhibition of cell cycle progression. The combination therapy led to dramatic inhibition of tumor growth with little toxicity in vivo, especially in the PTX-resistant KB-8-5 tumors, whereas Taxol had little therapeutic effect. This was mainly ascribed to the synergism of PTX and 5-FU and the reverse of MDR by the inhibition of ATPase activity by VE and TPGS. Coencapsulation of two chemotherapeutic agents with different mechanisms allows simultaneous interruption of diverse anticancer pathways, resulting in increased therapeutic response and low toxicity. The CMT markedly facilitated the long circulation of PTX and 5-FU, which was closely associated with the high accumulation of chemotherapeutic agents within the tumors and the improvement of antitumor efficacy. The current study demonstrated the feasibility of incorporating PTX and 5-FU targeting to different pathways into a single core

  19. The effect of urea and taurine as hydrophilic penetration enhancers on stratum corneum lipid models.

    Science.gov (United States)

    Mueller, J; Oliveira, J S L; Barker, R; Trapp, M; Schroeter, A; Brezesinski, G; Neubert, R H H

    2016-09-01

    To optimize transdermal application of drugs, the barrier function of the skin, especially the stratum corneum (SC), needs to be reduced reversibly. For this purpose, penetration enhancers like urea or taurine are applied. Until now, it is unclear if this penetration enhancement is caused by an interaction with the SC lipid matrix or related to effects within the corneocytes. Therefore, the effects of both hydrophilic enhancers on SC models with different dimensionality, ranging from monolayers to multilayers, have been investigated in this study. Many sophisticated methods were applied to ascertain the mode of action of both substances on a molecular scale. The experiments reveal that there is no specific interaction when 10% urea or 5% taurine solutions are added to the SC model systems. No additional water uptake in the head group region and no decrease of the lipid chain packing density have been observed. Consequently, we suppose that the penetration enhancing effect of both substances might be based on the introduction of large amounts of water into the corneocytes, caused by the enormous water binding capacity of urea and a resulting osmotic pressure in case of taurine.

  20. Model of waterlike fluid under confinement for hydrophobic and hydrophilic particle-plate interaction potentials.

    Science.gov (United States)

    Krott, Leandro B; Barbosa, Marcia C

    2014-01-01

    Molecular dynamic simulations were employed to study a waterlike model confined between hydrophobic and hydrophilic plates. The phase behavior of this system is obtained for different distances between the plates and particle-plate potentials. For both hydrophobic and hydrophilic walls, there are the formation of layers. Crystallization occurs at lower temperature at the contact layer than at the middle layer. In addition, the melting temperature decreases as the plates become more hydrophobic. Similarly, the temperatures of maximum density and extremum diffusivity decrease with hydrophobicity.

  1. Evaluating the hydrophilic-lipophilic nature of asphaltenic oils and naphthenic amphiphiles using microemulsion models.

    Science.gov (United States)

    Kiran, Sumit K; Acosta, Edgar J; Moran, Kevin

    2009-08-01

    Asphaltenes and naphthenic acid derivatives, which are polar and surface-active species, are known to interfere with the recovery of heavy crude oil by promoting the formation of stable emulsions. In this study, previously established microemulsion phase behavior models were applied to quantify the hydrophilic-lipophilic nature of asphaltenic oils (bitumen, deasphalted bitumen, asphalt, naphthalene) and surface-active species found in heavy oils (naphthenic compounds and asphaltenes). For the test oils, the equivalent alkane carbon number (EACN) was determined by evaluating the "salinity shifts" of microemulsions formulated with a reference surfactant (sodium dihexyl sulfosuccinate--SDHS) and a reference oil (toluene) as a function of test oil volume fraction. Similarly, the characteristic curvature (C(C)) of surface-active species was determined by evaluating the salinity shifts as a function of the molar fraction of the surface-active species in mixture with SDHS. As a part of the oil phase, asphaltenes and asphaltene-like species are highly hydrophilic, which lead to low EACN values despite their large molecular weight. As a surface-active material, asphaltenes are hydrophobic species that lead to the formation of water-in-oil emulsions. Naphthenates, particularly sodium naphthenates, are highly hydrophilic compounds that lead to the formation of oil-in-water emulsions. These hydrophilic-lipophilic characterization parameters, and the methods used to determine them, can be used in the future to understand the phase behavior of complex oil-water systems.

  2. Solid lipid nanoparticles for hydrophilic biotech drugs: optimization and cell viability studies (Caco-2 & HEPG-2 cell lines).

    Science.gov (United States)

    Severino, Patrícia; Andreani, Tatiana; Jäger, Alessandro; Chaud, Marco V; Santana, Maria Helena A; Silva, Amélia M; Souto, Eliana B

    2014-06-23

    Insulin was used as model protein to developed innovative Solid Lipid Nanoparticles (SLNs) for the delivery of hydrophilic biotech drugs, with potential use in medicinal chemistry. SLNs were prepared by double emulsion with the purpose of promoting stability and enhancing the protein bioavailability. Softisan(®)100 was selected as solid lipid matrix. The surfactants (Tween(®)80, Span(®)80 and Lipoid(®)S75) and insulin were chosen applying a 2(2) factorial design with triplicate of central point, evaluating the influence of dependents variables as polydispersity index (PI), mean particle size (z-AVE), zeta potential (ZP) and encapsulation efficiency (EE) by factorial design using the ANOVA test. Therefore, thermodynamic stability, polymorphism and matrix crystallinity were checked by Differential Scanning Calorimetry (DSC) and Wide Angle X-ray Diffraction (WAXD), whereas the effect of toxicity of SLNs was check in HepG2 and Caco-2 cells. Results showed a mean particle size (z-AVE) width between 294.6 nm and 627.0 nm, a PI in the range of 0.425-0.750, ZP about -3 mV, and the EE between 38.39% and 81.20%. After tempering the bulk lipid (mimicking the end process of production), the lipid showed amorphous characteristics, with a melting point of ca. 30 °C. The toxicity of SLNs was evaluated in two distinct cell lines (HEPG-2 and Caco-2), showing to be dependent on the concentration of particles in HEPG-2 cells, while no toxicity in was reported in Caco-2 cells. SLNs were stable for 24 h in in vitro human serum albumin (HSA) solution. The resulting SLNs fabricated by double emulsion may provide a promising approach for administration of protein therapeutics and antigens.

  3. Hydrophilic magnetic nanoclusters with thermo-responsive properties and their drug controlled release

    Energy Technology Data Exchange (ETDEWEB)

    Meerod, Siraprapa [Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Naresuan University, Phitsanulok 65000 (Thailand); Rutnakornpituk, Boonjira; Wichai, Uthai [Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Naresuan University, Phitsanulok 65000 (Thailand); Center of Excellence in Biomaterials, Faculty of Science, Naresuan University, Phitsanulok 65000 Thailand (Thailand); Rutnakornpituk, Metha, E-mail: methar@nu.ac.th [Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Naresuan University, Phitsanulok 65000 (Thailand); Center of Excellence in Biomaterials, Faculty of Science, Naresuan University, Phitsanulok 65000 Thailand (Thailand)

    2015-10-15

    Synthesis and drug controlled release properties of thermo-responsive magnetic nanoclusters grafted with poly(N-isopropylacrylamide) (poly(NIPAAm)) and poly(NIPAAm-co-poly(ethylene glycol) methyl ether methacrylate) (PEGMA) copolymers were described. These magnetic nanoclusters were synthesized via an in situ radical polymerization in the presence of acrylamide-grafted magnetic nanoparticles (MNPs). Poly(NIPAAm) provided thermo-responsive properties, while PEGMA played a role in good water dispersibility to the nanoclusters. The ratios of PEGMA to NIPAAm in the (co)polymerization in the presence of the MNPs were fine-tuned such that the nanoclusters with good water dispersibility, good magnetic sensitivity and thermo responsiveness were obtained. The size of the nanoclusters was in the range of 50–100 nm in diameter with about 100–200 particles/cluster. The nanoclusters were well dispersible in water at room temperature and can be suddenly agglomerated when temperature was increased beyond the lower critical solution temperature (LCST) (32 °C). The release behavior of an indomethacin model drug from the nanoclusters was also investigated. These novel magnetic nanoclusters with good dispersibility in water and reversible thermo-responsive properties might be good candidates for the targeting drug controlled release applications. - Highlights: • Nanoclusters with good water dispersibility and magnetic response were prepared. • They were grafted with thermo-responsive poly(NIPAAm) and/or poly(PEGMA). • Poly(NIPAAm) provided thermo-responsive properties to the nanoclusters. • Poly(PEGMA) provided good water dispersibilityto the nanoclusters. • Accelerated and controllable releases of a drug from the nanoclusters were shown.

  4. Drug release property of a pH-responsive double-hydrophilic hyperbranched graft copolymer

    Institute of Scientific and Technical Information of China (English)

    SUN XiaoYi; ZHOU YongFeng; YAN DeYue

    2009-01-01

    In this paper, we report the synthesis and self-assembly of double-hydrophilie hyperbranched graft copolymers of HPG-g-PDMAEMA, which consist of a hyperbranched polyglycerol (HPG) core and several grafted poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) arms. HPG was synthesized by cationic polymerization. Then HPG-Br macroinitiator was obtained by esterification of HPG with 2-bromoisobutyryl bromide, which was subsequently used in the preparation of HPG-g-PDMAEMA graft copolymers through atom transfer radical polymerization (ATRP) of DMAEMA monomers. The molecular structures were studied by 1H NMR arid GPC. The pyrene-based fluorescent probe method, 1H NMR and DLS were used to study the self-assembly behavior of HPG-g-PDMAEMA. The drug loading and pH-responsive release properties of HPG-g-PDMAEMA were also investigated by using coumarin 102 as a model drug. The results show that the HPG-g-PDMAEMA micelles can continuously release and re-encapsulate coumarin 102 as the pH continuously changes from 11.5 to 2.5; however, this process is not totally reversible.

  5. Hydrophilic interaction chromatography of seized drugs and related compounds with sub 2 μm particle columns.

    Science.gov (United States)

    Lurie, Ira S; Li, Li; Toske, Steven G

    2011-12-30

    The use of hydrophilic interaction chromatography (HILIC) with sub 2 μm particle columns for the analysis of drugs and related compounds of forensic interest is described. This technique uses a high organic/low aqueous buffered mobile phase with a polar stationary phase, and is excellent for the separation of many of the charged solutes that are found in forensic drug exhibits. In this study, HILIC is investigated for 11 solutes of forensic interest, including weak bases, weak acids, and a neutral solute. In addition, for columns containing either ethylene bridged hybrid particles with or without an amide bonded phase, the effects of acetonitrile concentration, buffer type, buffer concentration, linear velocity, and sample concentration were studied. Based on these studies, HILIC with sub 2 μm particle columns can offer highly efficient, selective, and rapid isocratic separations of drugs and related compounds of forensic interest, with excellent peak shapes and low back pressures. This is in contrast to reverse phase chromatography (RPLC), where gradient elution is usually required, which can result in extensive overlap between acidic, neutral, and basic solutes. In addition, since HILIC exhibits a much greater loading capacity than RPLC, it could be a preferred technique for drug profiling. Furthermore, because high organic content mobile phases are highly amenable to mass spectrometric detection, the use of HILIC with tandem mass spectrometric detection for the analysis of seized drugs is described.

  6. Design of smart GE11-PLGA/PEG-PLGA blend nanoparticulate platforms for parenteral administration of hydrophilic macromolecular drugs: synthesis, preparation and in vitro/ex vivo characterization.

    Science.gov (United States)

    Colzani, Barbara; Speranza, Giovanna; Dorati, Rossella; Conti, Bice; Modena, Tiziana; Bruni, Giovanna; Zagato, Elisa; Vermeulen, Lotte; Dakwar, George R; Braeckmans, Kevin; Genta, Ida

    2016-09-25

    Active drug targeting and controlled release of hydrophilic macromolecular drugs represent crucial points in designing efficient polymeric drug delivery nanoplatforms. In the present work EGFR-targeted polylactide-co-glycolide (PLGA) nanoparticles were made by a blend of two different PLGA-based polymers. The first, GE11-PLGA, in which PLGA was functionalized with GE11, a small peptide and EGFR allosteric ligand, able to give nanoparticles selective targeting features. The second polymer was a PEGylated PLGA (PEG-PLGA) aimed at improving nanoparticles hydrophilicity and stealth features. GE11 and GE11-PLGA were custom synthetized through a simple and inexpensive method. The nanoprecipitation technique was exploited for the preparation of polymeric nanoparticles composed by a 1:1weight ratio between GE11-PLGA and PEG-PLGA, obtaining smart nanoplatforms with proper size for parenteral administration (143.9±5.0nm). In vitro cellular uptake in EGFR-overexpressing cell line (A549) demonstrated an active internalization of GE11-functionalized nanoparticles. GE11-PLGA/PEG-PLGA blend nanoparticles were loaded with Myoglobin, a model hydrophilic macromolecule, reaching a good loading (2.42% respect to the theoretical 4.00% w/w) and a prolonged release over 60days. GE11-PLGA/PEG-PLGA blend nanoparticles showed good in vitro stability for 30days in physiological saline solution at 4°C and for 24h in pH 7.4 or pH 5.0 buffer at 37°C respectively, giving indications about potential storage and administration conditions. Furthermore ex vivo stability study in human plasma using fluorescence Single Particle Tracking (fSPT) assessed good GE11-PLGA/PEG-PLGA nanoparticles dimensional stability after 1 and 4h. Thanks to the versatility in polymeric composition and relative tunable nanoparticles features in terms of drug incorporation and release, GE11-PLGA/PEG-PLGA blend NPs can be considered highly promising as smart nanoparticulate platforms for the treatment of diseases

  7. HIGH MOLECULAR CELLULOSE ESTERS. MECHANISM OF ACTION IN SUSTAINED RELEASE MATRIX TABLETS. DISSOLUTION PROFILE OF ACTIVE DRUG DEPENDING ON MOLECULAR WEIGHT AND HYDROPHILIC PROPERTIES OF POLYMERS

    Directory of Open Access Journals (Sweden)

    S. V. Trofimov

    2015-01-01

    Full Text Available This article reviews cellulose esters as important excipients in development of dosage forms with sustained release. We have studied modern methods of drug development, based on technological, and physical and chemical properties of excipients to provide a sustained release effect and the mechanism of interaction between active substance and excipients for justification of choice of the optimum prolonging agent in compliance with desirable result. Different cellulose esters were used as model excipients. They were hydroxypropylmethylcellulose (HPMC and hydroxyethylcellulose (HEC. we have studied an effect of molecular weight and hydrophilic properties on dissolution rate of active substance from the tablets with sustained release.

  8. Influence of the hydrophilicity of suppository bases on rectal absorption of carprofen, a lipophilic nonsteroidal anti-inflammatory drug.

    Science.gov (United States)

    Schmitt, M; Guentert, T W

    1990-04-01

    The influence of the hydrophilicity of fatty suppository bases on the rectal absorption of the lipophilic drug carprofen (octanol-buffer, pH 7.4; partition coefficient, 40) was investigated in dogs. Five animals received each of six carprofen formulations in a random sequence: intravenous, oral, and rectal solutions, and three suppository formulations. The suppository vehicles tested were semisynthetic glycerides containing saturated fatty acids mainly in the range of C10 to C18 [Massa Estarinum A (MEA), Massa Estarinum B (MEB), and Massa Estarinum 299 (ME299)]; their hydroxyl values increased from 1 for ME299, through 24 for MEB, to 45 for MEA. Following every drug administration, blood samples were collected over a period of 104 h and carprofen plasma concentrations were measured by a specific HPLC method with UV detection. The rate and extent of carprofen absorption were characterized by evaluation of the maximum plasma concentrations (Cmax), the time of their occurrence (tmax), absolute bioavailabilities, statistical moments, and by deconvolution. Carprofen was rapidly and completely absorbed from the oral solution. The maximum concentrations obtained with oral solutions were significantly higher than those observed with rectal solutions and with the three suppository formulations. Results obtained with the rectal solution exhibited a high degree of intersubject variability. After rectal administration of suppositories, the rate and extent of carprofen absorption increased with the hydroxyl value of the suppository base; the mean absorption times (MAT) and tmax were shorter with MEA (2.15 and 1.7 h, respectively) than with the less hydrophilic vehicles (MEB: 4.09 and 2.1 h, respectively; ME299: 4.22 and 2.4 h, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Coencapsulation of hydrophobic and hydrophilic antituberculosis drugs in synergistic Brij 96 microemulsions: a biophysical characterization.

    Science.gov (United States)

    Kaur, Gurpreet; Mehta, S K; Kumar, Sandeep; Bhanjana, Gaurav; Dilbaghi, Neeraj

    2015-07-01

    A microemulsion has been formulated to coencapsulate antituberculosis drugs to solve the issue of stability of rifampicin (RIF) in the presence of isoniazid (INH) and pyrazinamide (PZA). The structural transition, solubilization locus, and quantitative release of drugs without interference have been estimated. Derivative absorbance spectroscopy, especially ratio derivative and double divisor ratio derivative methods, has been employed for estimating the release. The coencapsulation of the anti-tuberculosis drugs were carried out in single, binary, or ternary mixtures and occupy the same solubilization sites in multiple drugs microemulsion systems as in the case of single drug-loaded systems. INH and PZA obey the diffusional (Fickian) release mechanism, whereas RIF shows anomalous release. Resazurin assay and agar well diffusion method were adopted for cytotoxicity analysis and antimicrobial activity, respectively. Cytotoxicity was found to be dependent on concentration and on colloidal structure of microemulsion.

  10. Interaction mechanism between hydrophobic and hydrophilic surfaces: using polystyrene and mica as a model system.

    Science.gov (United States)

    Faghihnejad, Ali; Zeng, Hongbo

    2013-10-08

    The interactions between hydrophobic and hydrophilic molecules, particles, or surfaces occur in many biological phenomena and industrial processes. In this work, polystyrene (PS) and mica were chosen as a model system to investigate the interaction mechanism between hydrophilic and hydrophobic surfaces. Using a surface forces apparatus (SFA) coupled with a top-view optical microscope, interaction forces between PS and mica surfaces were directly probed in five different electrolyte solutions (i.e., NaCl, CaCl2, NaOH, HCl, and CH3COOH) of various concentrations. Long-range repulsion was observed in low electrolyte concentration (e.g., 0.001 M) which was mainly due to the presence of microscopic and submicroscopic bubbles on PS surface. A modified Derjaguin-Landau-Verwey-Overbeek (DLVO) theory well fits the interaction forces by taking into account the effect of bubbles on PS surface. The range of the repulsion was dramatically reduced in 1.0 M solutions of NaCl, CaCl2, and NaOH but did not significantly change in 1.0 M HCl and CH3COOH, which was due to ion specificity effect on the formation and stability of bubbles on PS surface. The range of repulsion was also significantly reduced to forces dominate the interaction between hydrophilic surface (i.e., mica) and hydrophobic polymer (i.e., PS), while the types of electrolytes (ion specificity), electrolyte concentration, degassing, and surface hydrophobicity can significantly affect the formation and stability of bubbles on the interacting surfaces, thus affecting the range and magnitude of the interaction forces.

  11. Development of a Physiologically Based Computational Kidney Model to Describe the Renal Excretion of Hydrophilic Agents in Rats

    Science.gov (United States)

    Niederalt, Christoph; Wendl, Thomas; Kuepfer, Lars; Claassen, Karina; Loosen, Roland; Willmann, Stefan; Lippert, Joerg; Schultze-Mosgau, Marcus; Winkler, Julia; Burghaus, Rolf; Bräutigam, Matthias; Pietsch, Hubertus; Lengsfeld, Philipp

    2013-01-01

    A physiologically based kidney model was developed to analyze the renal excretion and kidney exposure of hydrophilic agents, in particular contrast media, in rats. In order to study the influence of osmolality and viscosity changes, the model mechanistically represents urine concentration by water reabsorption in different segments of kidney tubules and viscosity dependent tubular fluid flow. The model was established using experimental data on the physiological steady state without administration of any contrast media or drugs. These data included the sodium and urea concentration gradient along the cortico-medullary axis, water reabsorption, urine flow, and sodium as well as urea urine concentrations for a normal hydration state. The model was evaluated by predicting the effects of mannitol and contrast media administration and comparing to experimental data on cortico-medullary concentration gradients, urine flow, urine viscosity, hydrostatic tubular pressures and single nephron glomerular filtration rate. Finally the model was used to analyze and compare typical examples of ionic and non-ionic monomeric as well as non-ionic dimeric contrast media with respect to their osmolality and viscosity. With the computational kidney model, urine flow depended mainly on osmolality, while osmolality and viscosity were important determinants for tubular hydrostatic pressure and kidney exposure. The low diuretic effect of dimeric contrast media in combination with their high intrinsic viscosity resulted in a high viscosity within the tubular fluid. In comparison to monomeric contrast media, this led to a higher increase in tubular pressure, to a reduction in glomerular filtration rate and tubular flow and to an increase in kidney exposure. The presented kidney model can be implemented into whole body physiologically based pharmacokinetic models and extended in order to simulate the renal excretion of lipophilic drugs which may also undergo active secretion and reabsorption

  12. Preparation and In Vitro Evaluation of Ethylcellulose and Polymethacrylate Resins Loaded Microparticles Containing Hydrophilic Drug

    Directory of Open Access Journals (Sweden)

    Satish Pandav

    2014-01-01

    Full Text Available Objective. The purpose of the recent study was to prepare and estimate sustained release of Ethylcellulose (300 cps and Eudragit (RS 100 and RL 100 microparticles containing Propranolol hydrochloride used as a treatment of cardiovascular system, especially hypertension. Method. Propranolol hydrochloride was microencapsulated with different polymers (Ethylcellulose, Eudragit RS, and Eudragit RL using modified hydrophobic (O/O solvent evaporation method using 1 : 1 combination of acetone and isopropanol as the internal phase. Obtained microparticles were showing higher batch yield with higher encapsulation efficiency. Microparticles were prepared with different ratios of 1 : 1, 1 : 3, 1 : 5, and 1 : 7 (%, wt/wt using span 80 (%, v/v as a surfactant. Results. The influence of formulation factors like drug: polymer ratio, internal phase, and type of polymers on obtained microparticles was characterized with respect to particle size distribution, encapsulation efficiency, percentage yield, FTIR, and FE-SEM. Higher encapsulation efficiencies were obtained with various polymers like Ethylcellulose (96.63 ± 0.5 compared to Eudragit RS 100 (83.70 ± 0.6 and RL 100 (89.62 ± 0.6. The in vitro release study was characterized by initial burst. Conclusion. The result of study displays that Ethylcellulose and Eudragit loaded microparticles of Propranolol hydrochloride can be effectively prepared using modified hydrophobic emulsification solvent evaporation technique. Therefore, the modified hydrophobic emulsion technique can also be applied to the preparation of microparticles for low molecular weight and highly water soluble drugs.

  13. Efficient one-pot synthesis of hydrophilic and fluorescent molecularly imprinted polymer nanoparticles for direct drug quantification in real biological samples.

    Science.gov (United States)

    Niu, Hui; Yang, Yaqiong; Zhang, Huiqi

    2015-12-15

    Efficient one-pot synthesis of hydrophilic and fluorescent molecularly imprinted polymer (MIP) nanoparticles and their application as optical chemosensor for direct drug quantification in real, undiluted biological samples are described. The general principle was demonstrated by preparing tetracycline (Tc, a broad-spectrum antibiotic)-imprinted fluorescent polymer nanoparticles bearing hydrophilic polymer brushes via poly(2-hydroxyethyl methacrylate) (PHEMA) macromolecular chain transfer agent-mediated reversible addition-fragmentation chain transfer (RAFT) precipitation polymerization in the presence of a fluorescent monomer. The introduction of hydrophilic PHEMA brushes and fluorescence labeling onto/into the MIP nanoparticles proved to not only significantly improve their surface hydrophilicity and lead to their obvious specific binding and high selectivity toward Tc in the undiluted bovine serum, but also impart them with strong fluorescent properties. In particular, significant fluorescence quenching was observed upon their binding with Tc in such complex biological milieu, which makes these Tc-MIP nanoparticles useful optical chemosensor with a detection limit of 0.26 μM. Furthermore, such advanced functional MIP nanoparticles-based chemosensor was also successfully utilized for the direct, sensitive, and accurate determination of Tc in another biological medium (i.e., the undiluted pig serum) with average recoveries ranging from 98% to 102%, even in the presence of several interfering drugs.

  14. Absorption-enhancing effects of gemini surfactant on the intestinal absorption of poorly absorbed hydrophilic drugs including peptide and protein drugs in rats.

    Science.gov (United States)

    Alama, Tammam; Kusamori, Kosuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

    2016-02-29

    In general, the intestinal absorption of small hydrophilic molecules and macromolecules like peptides, after oral administration is very poor. Absorption enhancers are considered to be one of the most promising agents to enhance the intestinal absorption of drugs. In this research, we focused on a gemini surfactant, a new type of absorption enhancer. The intestinal absorption of drugs, with or without sodium dilauramidoglutamide lysine (SLG-30), a gemini surfactant, was examined by an in situ closed-loop method in rats. The intestinal absorption of 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-dextrans (FDs) was significantly enhanced in the presence of SLG-30, such effect being reversible. Furthermore, the calcium levels in the plasma significantly decreased when calcitonin was co-administered with SLG-30, suggestive of the increased intestinal absorption of calcitonin. In addition, no significant increase in the of lactate dehydrogenase (LDH) activity or in protein release from the intestinal epithelium was observed in the presence of SLG-30, suggestive of the safety of this compound. These findings indicate that SLG-30 is an effective absorption-enhancer for improving the intestinal absorption of poorly absorbed drugs, without causing serious damage to the intestinal epithelium.

  15. Microemulsions as model fluids for enhanced oil recovery: dynamics adjacent to planar hydrophilic walls

    Directory of Open Access Journals (Sweden)

    Mattauch S.

    2012-10-01

    Full Text Available After the dynamics of microemulsions adjacent to a planar hydrophilic wall have been characterized using grazing incidence neutron spin echo spectroscopy, the model of Seifert was employed to explain the discovered acceleration for the surface near lamellar ordered membranes. Reflections of hydrodynamic waves by the wall – or the volume conservation between the membrane and the wall – explain faster relaxations and, therefore, a lubrication effect that is important for flow fields in narrow pores. The whole scenery is now spectated by using different scenarios of a bicontinuous microemulsion exposed to clay particles and of a lamellar microemulsion adjacent to a planar wall. The Seifert concept could successfully be transferred to the new problems.

  16. Dynamic Mathematical Modelling of the Removal of Hydrophilic VOCs by Biotrickling Filters

    Directory of Open Access Journals (Sweden)

    Pau San-Valero

    2015-01-01

    Full Text Available A mathematical model for the simulation of the removal of hydrophilic compounds using biotrickling filtration was developed. The model takes into account that biotrickling filters operate by using an intermittent spraying pattern. During spraying periods, a mobile liquid phase was considered, while during non-spraying periods, a stagnant liquid phase was considered. The model was calibrated and validated with data from laboratory- and industrial-scale biotrickling filters. The laboratory experiments exhibited peaks of pollutants in the outlet of the biotrickling filter during spraying periods, while during non-spraying periods, near complete removal of the pollutant was achieved. The gaseous outlet emissions in the industrial biotrickling filter showed a buffered pattern; no peaks associated with spraying or with instantaneous variations of the flow rate or inlet emissions were observed. The model, which includes the prediction of the dissolved carbon in the water tank, has been proven as a very useful tool in identifying the governing processes of biotrickling filtration.

  17. Wang-Landau sampling in face-centered-cubic hydrophobic-hydrophilic lattice model proteins.

    Science.gov (United States)

    Liu, Jingfa; Song, Beibei; Yao, Yonglei; Xue, Yu; Liu, Wenjie; Liu, Zhaoxia

    2014-10-01

    Finding the global minimum-energy structure is one of the main problems of protein structure prediction. The face-centered-cubic (fcc) hydrophobic-hydrophilic (HP) lattice model can reach high approximation ratios of real protein structures, so the fcc lattice model is a good choice to predict the protein structures. The lacking of an effective global optimization method is the key obstacle in solving this problem. The Wang-Landau sampling method is especially useful for complex systems with a rough energy landscape and has been successfully applied to solving many optimization problems. We apply the improved Wang-Landau (IWL) sampling method, which incorporates the generation of an initial conformation based on the greedy strategy and the neighborhood strategy based on pull moves into the Wang-Landau sampling method to predict the protein structures on the fcc HP lattice model. Unlike conventional Monte Carlo simulations that generate a probability distribution at a given temperature, the Wang-Landau sampling method can estimate the density of states accurately via a random walk, which produces a flat histogram in energy space. We test 12 general benchmark instances on both two-dimensional and three-dimensional (3D) fcc HP lattice models. The lowest energies by the IWL sampling method are as good as or better than those of other methods in the literature for all instances. We then test five sets of larger-scale instances, denoted by the S, R, F90, F180, and CASP target instances on the 3D fcc HP lattice model. The numerical results show that our algorithm performs better than the other five methods in the literature on both the lowest energies and the average lowest energies in all runs. The IWL sampling method turns out to be a powerful tool to study the structure prediction of the fcc HP lattice model proteins.

  18. Drug models of schizophrenia

    Science.gov (United States)

    Steeds, Hannah; Carhart-Harris, Robin L.

    2015-01-01

    Schizophrenia is a complex mental health disorder with positive, negative and cognitive symptom domains. Approximately one third of patients are resistant to currently available medication. New therapeutic targets and a better understanding of the basic biological processes that drive pathogenesis are needed in order to develop therapies that will improve quality of life for these patients. Several drugs that act on neurotransmitter systems in the brain have been suggested to model aspects of schizophrenia in animals and in man. In this paper, we selectively review findings from dopaminergic, glutamatergic, serotonergic, cannabinoid, GABA, cholinergic and kappa opioid pharmacological drug models to evaluate their similarity to schizophrenia. Understanding the interactions between these different neurotransmitter systems and their relationship with symptoms will be an important step towards building a coherent hypothesis for the pathogenesis of schizophrenia. PMID:25653831

  19. 新型不饱和聚酯基亲水性药物缓释材料的制备%Preparation of novel unsaturated polyester based hydrophilic material for drug controlled release

    Institute of Scientific and Technical Information of China (English)

    高鹏; 郭文迅; 李丹

    2012-01-01

    采用本体熔融聚合方法,以三羟甲基丙烷二烯丙基醚(TMPDE)对不饱和聚酯酰胺脲树脂进行封端,得到了一种药物缓释载体的亲水性预聚物,以盐酸环丙沙星为模型药物,制备了盐酸环丙沙星-不饱和聚酯酰胺脲树脂药片.研究了尿素含量和饱和二元酸对材料降解性能和亲水性的影响.体外降解和药物释放(37℃,pH 7.4 PBS缓冲溶液)结果表明,该空白材料的降解速率可通过改变尿素含量来调节;缓释药片释药平稳,持续释药时间可达30 d.%The unsaturated polyester-urea amide (UU) copolymer was terminated at both chain ends with trimethylolpropane diallyl ether (TMPDE) by melt polycondensation to obtain a hydrophilic prepolymer which could be used as drug carriers. The ciprofloxacin hydrochloride-unsaturated polyester-urea amide tablets was successfully prepared through the prepolymer as drug delivery material, ciprofloxacin hydro-chloride as a model drug. The effects of urea content and saturated dicarboxylic acids on degradable and hydrophilic properties were also studied. Studies demonstrated that those copolymers were degradable in phosphate buffer (pH =7.4) at 37℃ and the mass loss profiles of the resulting polymer could be easily tailored by altering the molar ratio of urea in the structure. The copolymers had proper drug release rate and the sustained drug release time was 30 d.

  20. Polymer micelle with pH-triggered hydrophobic-hydrophilic transition and de-cross-linking process in the core and its application for targeted anticancer drug delivery.

    Science.gov (United States)

    Fan, Jianquan; Zeng, Fang; Wu, Shuizhu; Wang, Xiaodan

    2012-12-10

    In this study, an novel amphiphilic block copolymer P[PEGMA-b-(DEMA-co-APMA)]-FA and its cross-linker uracil-(CH2)6-uracil (U-(CH2)6-U) were synthesized and used as the targeted and pH-responsive nanocarriers for anticancer drug delivery. The hydrophobic block of the copolymer contains adenine (A) and tertiary amine moieties and the hydrophilic block is terminated with a targeting ligand folic acid (FA). Under neutral pH, the hydrophobic chain segments of the copolymer are cross-linked by U-(CH2)6-U through the A-U nucleobase pairing based on complementary multiple hydrogen bonding, and the copolymer forms stable micelles with their mean diameter of around 170 nm in water. While under acidic pH, the micelles dissociate as a result of protonation of tertiary amines and disruption of the A-U nucleobase pairing. Flow cytometry and fluorescent microscope observation show that, when loaded with an anticancer drug DOX, the micelles can preferably enter folate receptor (FR)-positive cancer cells and kill the cells via intracellular release of the anticancer drug. Cytotoxicity tests (MTT tests) indicate that the micelles with FA on their surfaces exhibit higher cytotoxicity toward FR-positive cells than those without FA. This study provides useful insights on designing and improving the applicability of copolymer micelles for other targeted drug delivery systems.

  1. Definition of formulation design space, in vitro bioactivity and in vivo biodistribution for hydrophilic drug loaded PLGA/PEO-PPO-PEO nanoparticles using OFAT experiments.

    Science.gov (United States)

    Simonoska Crcarevska, M; Geskovski, N; Calis, S; Dimchevska, S; Kuzmanovska, S; Petruševski, G; Kajdžanoska, M; Ugarkovic, S; Goracinova, K

    2013-04-11

    Modified nanoprecipitation method was used for improved incorporation of hydrophilic drug (irinotecan hydrochloride) into the PLGA/PEO-PPO-PEO blended and blended/adsorbed nanoparticles. One factor at a time (OFAT) variation experiments were conducted in order to determine key formulation factors (concentration and volume of drug solution, evaporation rate and PLGA/PEO-PPO-PEO ratio) influencing nanoparticle properties (particle size and size distribution, encapsulation efficiency, drug content, zeta potential, drug dissolution rate, as well as protein binding capacity). The insight into in vivo behavior of prepared nanoparticles and their potential for effective anticancer treatment was gained by performing biodistribution and cell culture studies as part of OFAT experiments. The mean particle size, mainly dependent upon PLGA/PEO-PPO-PEO ratio, was in the range of 112-125 nm, with narrow unimodal distribution (PDI∼0.1). Encapsulation efficiency (32-63%) was impacted by evaporation rate and PLGA/PEO-PPO-PEO ratio. Drug content (0.2-1.51%) and controlled release properties were related to the influence of all tested formulation factors. Structural information for the studied nanoparticles was obtained using DSC and FT-IR spectroscopy. Zeta potential values indicated that presence of PEO-PPO-PEO in the formulations shielded the high surface negative charge of PLGA. PEO-PPO-PEO surface coverage of PLGA/PEO-PPO-PEO blended as well as blended/adsorbed nanoparticles depended upon amount of used PEO-PPO-PEO during preparation procedure and was related to the protein resistant characteristics of nanoparticles. Results from in vivo studies evidenced prolonged blood circulation time of the prepared nanoparticles, while cell culture studies indicated higher in vitro bioefficacy compared to free drug. Performed experiments defined possible design space and justified further optimization of formulation using experimental design studies.

  2. 21 CFR 872.3300 - Hydrophilic resin coating for dentures.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Hydrophilic resin coating for dentures. 872.3300... (CONTINUED) MEDICAL DEVICES DENTAL DEVICES Prosthetic Devices § 872.3300 Hydrophilic resin coating for dentures. (a) Identification. A hydrophilic resin coating for dentures is a device that consists of a...

  3. Animal models of drug addiction.

    Science.gov (United States)

    García Pardo, María Pilar; Roger Sánchez, Concepción; De la Rubia Ortí, José Enrique; Aguilar Calpe, María Asunción

    2017-01-12

    The development of animal models of drug reward and addiction is an essential factor for progress in understanding the biological basis of this disorder and for the identification of new therapeutic targets. Depending on the component of reward to be studied, one type of animal model or another may be used. There are models of reinforcement based on the primary hedonic effect produced by the consumption of the addictive substance, such as the self-administration (SA) and intracranial self-stimulation (ICSS) paradigms, and there are models based on the component of reward related to associative learning and cognitive ability to make predictions about obtaining reward in the future, such as the conditioned place preference (CPP) paradigm. In recent years these models have incorporated methodological modifications to study extinction, reinstatement and reconsolidation processes, or to model specific aspects of addictive behavior such as motivation to consume drugs, compulsive consumption or drug seeking under punishment situations. There are also models that link different reinforcement components or model voluntary motivation to consume (two-bottle choice, or drinking in the dark tests). In short, innovations in these models allow progress in scientific knowledge regarding the different aspects that lead individuals to consume a drug and develop compulsive consumption, providing a target for future treatments of addiction.

  4. Nonlinear Porous Diffusion Modeling of Hydrophilic Ionic Agrochemicals in Astomatous Plant Cuticle Aqueous Pores: A Mechanistic Approach

    Directory of Open Access Journals (Sweden)

    Eloise C. Tredenick

    2017-05-01

    Full Text Available The agricultural industry requires improved efficacy of sprays being applied to crops and weeds in order to reduce their environmental impact and deliver improved financial returns. Enhanced foliar uptake is one means of improving efficacy. The plant leaf cuticle is known to be the main barrier to diffusion of agrochemicals within the leaf. The usefulness of a mathematical model to simulate uptake of agrochemicals in plant cuticles has been noted previously in the literature, as the results of each uptake experiment are specific to each formulation of active ingredient, plant species and environmental conditions. In this work we develop a mathematical model and numerical simulation for the uptake of hydrophilic ionic agrochemicals through aqueous pores in plant cuticles. We propose a novel, nonlinear, porous diffusion model for ionic agrochemicals in isolated cuticles, which extends simple diffusion through the incorporation of parameters capable of simulating: plant species variations, evaporation of surface droplet solutions, ion binding effects on the cuticle surface and swelling of the aqueous pores with water. We validate our theoretical results against appropriate experimental data, discuss the key sensitivities in the model and relate theoretical predictions to appropriate physical mechanisms. Major influencing factors have been found to be cuticle structure, including tortuosity and density of the aqueous pores, and to a lesser extent humidity and cuticle surface ion binding effects.

  5. A comparative study on the effects of amphiphilic and hydrophilic polymers on the release profiles of a poorly water-soluble drug.

    Science.gov (United States)

    Irwan, Anastasia W; Berania, Jacqueline E; Liu, Xueming

    2016-03-01

    This paper reports the use of two crystalline polymers, an amphiphilic Pluronic® F-127 (PF-127) and a hydrophilic poly(ethylene glycol) (PEG6000) as drug delivery carriers for improving the drug release of a poorly water-soluble drug, fenofibrate (FEN), via micelle formation and formation of a solid dispersion (SD). In 10% PF-127 (aq.), FEN showed an equilibrium solubility of ca. 0.6 mg/mL, due to micelle formation. In contrast, in 10% PEG6000 (aq.), FEN only exhibited an equilibrium solubility of 0.0037 mg/mL. FEN-loaded micelles in PF-127 were prepared by direct dissolution and membrane dialysis. Both methods only yielded a highest drug loading (DL) of 0.5%. SDs of FEN in PF-127 and PEG6000, at DLs of 5-80%, were prepared by solvent evaporation. In-vitro dissolution testing showed that both micelles and SDs significantly improved FEN's release rate. The SDs of FEN in PF-127 showed significantly faster release than crystalline FEN, when the DL was as high as 50%, whereas SDs of PEG6000 showed similar enhancement in the release rate when the DL was not more than 20%. The DSC thermograms of SDs of PF-127 exhibited a single phase transition peak at ca. 55-57 °C when the DL was not more than 50%, whereas those in PEG6000 exhibited a similar peak at ca. 61-63 °C when the DL was not more than 35%. When the DL exceeded 50% for SDs of PF-127 and 35% for SDs of PEG6000, DSC thermograms showed two melting peaks for the carrier polymer and FEN, respectively. FT-IR studies revealed that PF-127 has a stronger hydrophobic-hydrophobic interaction with FEN than PEG6000. It is likely that both dispersion and micelle formation contributed to the stronger effect of PF-127 on enhancing the release rate of FEN in its SDs.

  6. 4-氨基吡啶凝胶骨架缓释片的制备及体外释放%Preparation and drug release in vitro of 4-aminopyridine hydrophilic matrics sustained release tablets

    Institute of Scientific and Technical Information of China (English)

    叶小玲; 关世侠; 周郁斌; 袁中文; 杨艳; 胡波; 卢舒凡; 张怡; 欧汝静

    2012-01-01

    OBJECTIVE To prepare 4-aminopyridine (4-AP) hydrophilic matrics sustained release tablets. METHODS The formula of 4-aminopyridine (4-AP) hydrophilic matrics sustained release tablets was optimized by orthogonal experiment with the kind of HPMC and the amount of HPMC and lactose as factors and with the in vitro release rates as index. Meanwhile, the verification test on the intra-and inter-batch release rates of the samples was performed. Weibull model was used to make in vitro release fitting curve, and the influence of in vitro release conditions on the drug release was investigated. RESULTS The optimum formula could be seen as follows: the ratios of HPMC K100LV and lactose were 54% and 16% respectively. The formula achieved a sustained drug release of up to 12h, and both the intra- batch homogenicity and the inter- batch reproducibility were satisfactory. Weibull curve fitting equations showed that the drug release met level 1 rate process. The results of in vitro release test showed that drug release rate could be affected by the stirring rate, while the kind of media and device had no significant effect on it. CONCLUSION The preparation procedure of self-prepared 4-aminopyridine hydrophilic matrics sustained release tablets is feasible and rcpeatablc. The tablets have obviously sustained property.%目的:制备4-氨基吡啶(4-aminopyridine,4-AP)亲水凝胶骨架缓释片.方法:以羟丙甲纤维素的规格、处方用量及乳糖处方用量为因素设计正交试验,以体外释放度为考察指标,优化4-AP凝胶骨架片的处方,并进行批内和批间体外释放度验证试验.采用Origin软件对筛选出的最优处方释放度进行Weibull曲线拟合.考察体外释放条件对药物释放的影响.结果:优化处方为HPMC规格为K100LV,处方用量为54%0,乳糖的处方用量为16%.所制得4-AP凝胶骨架片可持续释药12 h,批内释放均一性及批间重复性均良好.Weibull模型拟合方程得出药物释放符合一级

  7. Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics.

    Science.gov (United States)

    Hu, Yuan; Sinha, Sudipta Kumar; Patel, Sandeep

    2015-06-23

    Cell-penetrating and antimicrobial peptides show a remarkable ability to translocate across physiological membranes. Along with factors such as electric-potential-induced perturbations of membrane structure and surface tension effects, experiments invoke porelike membrane configurations during the solute transfer process into vesicles and cells. The initiation and formation of pores are associated with a nontrivial free-energy cost, thus necessitating a consideration of the factors associated with pore formation and the attendant free energies. Because of experimental and modeling challenges related to the long time scales of the translocation process, we use umbrella sampling molecular dynamics simulations with a lipid-density-based order parameter to investigate membrane-pore-formation free energy employing Martini coarse-grained models. We investigate structure and thermodynamic features of the pore in 18 lipids spanning a range of headgroups, charge states, acyl chain lengths, and saturation. We probe the dependence of pore-formation barriers on the area per lipid, lipid bilayer thickness, and membrane bending rigidities in three different lipid classes. The pore-formation free energy in pure bilayers and peptide translocating scenarios are significantly coupled with bilayer thickness. Thicker bilayers require more reversible work to create pores. The pore-formation free energy is higher in peptide-lipid systems than in peptide-free lipid systems due to penalties to maintain the solvation of charged hydrophilic solutes within the membrane environment.

  8. Blends of hydrophobic and swelling agents in the swelling layer in the preparation of delayed-release pellets of a hydrophilic drug with low MW: Physicochemical characterizations and in-vivo evaluations

    Directory of Open Access Journals (Sweden)

    Chang You

    2014-08-01

    Full Text Available In this study, a hydrophobic material, ethylcellulose, which was used as its aqueous suspension Surelease®, was combined with a swelling agent as the swelling layer to prepare delayed-release pellets for Danshensu, which is a hydrophilic drug with low MW. A rupturable, delayed-release pellet consists of a drug core, a swelling layer containing a swelling agent (cross-linked sodium carboxymethyl cellulose with a hydrophobic agent (Surelease®, and a controlled layer composed by an insoluble, water-permeable polymeric coating (aqueous ethylcellulose dispersions was developed in a fluidised bed. Results showed that blending Surelease® into the swelling layer could effectively extend the release of Danshensu from the pellets, which may be attributed to the slowed swelling rate by reduction of water penetration and improvement of mechanical integrity of the swelling layer. Drug in the delayed pellets showed sustained release in beagle dogs after oral administration with comparable in-vivo exposure to the uncoated drug pellets. In conclusion, blends of hydrophobic and swelling agents in the swelling layer in double-membrane pellets could achieve a delayed drug-release profile in vitro, as well as delayed and sustained absorption in vivo for highly soluble, low-MW drug. The present study highlighted the potential use of a delayed-release system for other hydrophilic, low-MW drugs to meet the formulation requirements for chronopharmacological diseases.

  9. Influence of hydrophilic polymers on the complexation of carbamazepine with hydroxypropyl-β-cyclodextrin.

    Science.gov (United States)

    Medarević, Djordje; Kachrimanis, Kyriakos; Djurić, Zorica; Ibrić, Svetlana

    2015-10-12

    In this study binary carbamazepine-hydroxypropyl-β-cyclodextrin, as well as ternary carbamazepine-hydroxypropyl-β-cyclodextrin-hydrophilic polymer systems were used to improve dissolution rate of carbamazepine. It has been shown that addition of hydrophilic polymers (Soluplus® and two types of hydroxypropyl methylcellulose-Metolose® 90SH-100 and Metolose® 65SH-1500) significantly increased solubilization capacity of hydroxypropyl-β-cyclodextrin for carbamazepine. Evaluation of carbamazepine-hydroxypropyl-β-cyclodextrin-hydrophilic polymer interactions using molecular modeling techniques showed interactions between carbamazepine, which dissociates from inclusion complexes and hydroxypropyl methylcellulose that can prevent crystallization of dissolved carbamazepine. These results can contribute to better understanding of drug-cyclodextrin-hydrophilic polymer interactions which are still not well understood. After evaluation of carbamazepine solubilization with hydroxypropyl-β-cyclodextrin and hydrophilic polymers, both binary carbamazepine-hydroxypropyl-β-cyclodextrin and ternary carbamazepine-hydroxypropyl-β-cyclodextrin-hydrophilic polymer systems were prepared by spray drying. The results of solid state characterization methods showed amorphous nature of carbamazepine in all spray dried systems, which together with the results of molecular modeling techniques indicates inclusion complex formation. Carbamazepine dissolution rate was significantly improved from spray dried formulations compared to pure drug. Binary carbamazepine-hydroxypropyl-β-cyclodextrin and ternary carbamazepine-hydroxypropyl-β-cyclodextrin-Soluplus® systems exhibited the fastest carbamazepine release, wherein the entire amount of carbamazepine was released during first 5 min.

  10. Evaluation of the drug solubility and rush ageing on drug release performance of various model drugs from the modified release polyethylene oxide matrix tablets.

    Science.gov (United States)

    Shojaee, Saeed; Nokhodchi, Ali; Maniruzzaman, Mohammed

    2017-02-01

    Hydrophilic matrix systems are currently some of the most widely used drug delivery systems for controlled-release oral dosage forms. Amongst a variety of polymers, polyethylene oxide (PEO) is considered an important material used in pharmaceutical formulations. As PEO is sensitive to thermal oxidation, it is susceptible to free radical oxidative attack. The aim of this study was to investigate the stability of PEO based formulations containing different model drugs with different water solubility, namely propranolol HCl, theophylline and zonisamide. Both polyox matrices 750 and 303 grade were used as model carriers for the manufacture of tablets stored at 40 °C. The results of the present study suggest that the drug release from the matrix was affected by the length of storage conditions, solubility of drugs and the molecular weight of the polymers. Generally, increased drug release rates were prevalent in soluble drug formulations (propranolol) when stored at the elevated temperature (40 °C). In contrast, it was not observed with semi soluble (theophylline) and poorly soluble (zonisamide) drugs especially when formulated with PEO 303 polymer. This indicates that the main parameters controlling the drug release from fresh polyox matrices are the solubility of the drug in the dissolution medium and the molecular weight of the polymer. DSC traces indicated that that there was a big difference in the enthalpy and melting points of fresh and aged PEO samples containing propranolol, whereas the melting point of the aged polyox samples containing theophylline and zonisamide was unaffected. Graphical abstract ᅟ.

  11. Clustering drug-drug interaction networks with energy model layouts: community analysis and drug repurposing

    OpenAIRE

    Lucreţia Udrescu; Laura Sbârcea; Alexandru Topîrceanu; Alexandru Iovanovici; Ludovic Kurunczi; Paul Bogdan; Mihai Udrescu

    2016-01-01

    Analyzing drug-drug interactions may unravel previously unknown drug action patterns, leading to the development of new drug discovery tools. We present a new approach to analyzing drug-drug interaction networks, based on clustering and topological community detection techniques that are specific to complex network science. Our methodology uncovers functional drug categories along with the intricate relationships between them. Using modularity-based and energy-model layout community detection...

  12. Molecular modelling and drug design.

    Science.gov (United States)

    Meyer, E F; Swanson, S M; Williams, J A

    2000-03-01

    Drug design is a creative act of the same magnitude as composing, sculpting, or writing. The results can touch the lives of millions, but the creator is rarely one scientist and the rewards are distributed differently in the arts than in the sciences. The mechanisms of creativity are the same, i.e., incremental (plodding from darkness to dawn) or sudden (the "Eureka" effect) realization, but both are poorly understood. Creativity remains a human characteristic, but it is directly related to the tools available, especially computer software and hardware. While modelling software continues to mature, very little new has evolved in terms of hardware. Here, we discuss the history of molecular modelling and describe two novel modelling tools, a haptic device and a program, SCULPT, to generate solid molecular models at atomic resolution.

  13. Hydrophilic Carotenoids: Recent Progress

    Directory of Open Access Journals (Sweden)

    Attila Agócs

    2012-04-01

    Full Text Available Carotenoids are substantially hydrophobic antioxidants. Hydrophobicity is this context is rather a disadvantage, because their utilization in medicine as antioxidants or in food chemistry as colorants would require some water dispersibility for their effective uptake or use in many other ways. In the past 15 years several attempts were made to synthetize partially hydrophilic carotenoids. This review compiles the recently synthetized hydrophilic carotenoid derivatives.

  14. Correlation of in vitro and in vivo models for the oral absorption of peptide drugs.

    Science.gov (United States)

    Föger, F; Kopf, A; Loretz, B; Albrecht, K; Bernkop-Schnürch, A

    2008-06-01

    The aim of this study was to evaluate two in vitro models, Caco-2 monolayer and rat intestinal mucosa, regarding their linear correlation with in vivo bioavailability data of therapeutic peptide drugs after oral administration in rat and human. Furthermore the impact of molecular mass (Mm) of the according peptides on their permeability was evaluated. Transport experiments with commercially available water soluble peptide drugs were conducted using Caco-2 cell monolayer grown on transwell filter membranes and with freshly excised rat intestinal mucosa mounted in Using type chambers. Apparent permeability coefficients (P (app)) were calculated and compared with in vivo data derived from the literature. It was shown that, besides a few exceptions, the Mm of peptides linearly correlates with permeability across rat intestinal mucosa (R (2) = 0.86; y = -196.22x + 1354.24), with rat oral bioavailability (R (2) = 0.64; y = -401.90x + 1268.86) as well as with human oral bioavailability (R (2) = 0.91; y = -359.43x + 1103.83). Furthermore it was shown that P (app) values of investigated hydrophilic peptides across Caco-2 monolayer displayed lower permeability than across rat intestinal mucosa. A correlation between P (app) values across rat intestinal mucosa and in vivo oral bioavailability in human (R (2) = 0.98; y = 2.11x + 0.34) attests the rat in vitro model to be a very useful prediction model for human oral bioavailability of hydrophilic peptide drugs. Presented correlations encourage the use of the rat in vitro model for the prediction of human oral bioavailabilities of hydrophilic peptide drugs.

  15. Recent development on the microencapsulation of hydrophilic small molecular drugs%亲水性小分子药物缓释微球制备方法的研究进展

    Institute of Scientific and Technical Information of China (English)

    李静涵; 魏振平

    2016-01-01

    Because of their short half-life,hydrophilic small molecule drugs need frequent administration and sustained release microspheres can control the release of drug and therefore overcome this disadvantage. This article reviewed the present preparation status and development direction of microencapsulating hydrophilic small molecule drugs,and introduced the advantages and disadvantages of different preparation methods from the view of using different support materials. Emulsion solvent evaporation method and phase separation method were elaborated for water-insoluble support materials,while for water-soluble support materials,emulsion crosslinking method and spray drying method were discussed. Then the technical principles and preparation procedures of layer-by-layer self-assembly method and solvent evaporation method with magnetic particles were analyzed. It was pointed out that the development of encapsulating hydrophilic small molecule drugs would favor simple,safe and effective and intelligent target operation.%缓释微球可以延长药物的作用时间,从而能够解决亲水性小分子药物由于半衰期较短需要长期频繁给药的问题。本文综述了亲水性小分子药物缓释微球制备方法的研究现状和发展方向,分别从使用非水溶性载体材料和水溶性载体材料两个方面介绍了亲水性小分子微球制备方法的优缺点。使用非水溶性载体材料方面,重点阐述了乳化溶剂挥发法和相分离法;使用水溶性载体材料方面,重点阐述了乳化交联法和喷雾干燥法。并着重分析了层层自组装法以及结合磁性粒子的溶剂挥发法的技术原理和制备过程。最后指出亲水性小分子药物缓释微球的制备方法将朝着操作简单、安全有效和智能靶向的方向发展。

  16. Findings of an experimental study in a rabbit model on posterior capsule opacification after implantation of hydrophobic acrylic and hydrophilic acrylic intraocular lenses

    Directory of Open Access Journals (Sweden)

    Nikolaos Trakos

    2009-01-01

    Full Text Available Nikolaos Trakos1, Elli Ioachim2, Elena Tsanou2, Miltiadis Aspiotis1, Konstantinos Psilas1, Chris Kalogeropoulos11University Eye Clinic of Ioannina, Ioannina, Greece; 2Pathology Department, University of Ioannina, Ioannina, GreecePurpose: Study on cell growth on the posterior capsule after implantation of hydrophobic acrylic (Acrysof SA 60 AT and hydrophilic acrylic (Akreos Disc intraocular lenses (IOL in a rabbit model and comparison of posterior capsule opacification (PCO.Methods: Phacoemulsification was performed in 22 rabbit eyes, and two different IOL types (Acrysof SA60 AT and Akreos Disc were implanted. These IOLs had the same optic geometry (square edged but different material and design. Central PCO (CPCO, peripheral PCO (PPCO, Sommering’s ring (SR formation, type of growth, extension of PCO, cell type, inhibition, and fibrosis were evaluated three weeks after surgery. Histological sections of each globe were prepared to document the evaluation of PCO.Results: No statistically significant difference was observed between a hydrophobic acrylic IOL and a hydrophilic acrylic IOL in relation to the CPCO, PPCO, type of growth, extension, cell type, inhibition, and fibrosis. Statistically significant difference was observed in relation to the formation of SR with Acrysof SA 60 AT group presenting more SR than Akreos Disc group.Conclusion: PCO was not influenced by the material of the IOL or the design of the haptics of the IOLs we studied.Keywords: posterior capsule opacification, intraocular lenses, rabbit model

  17. Hydrophilic-hydrophobic polymer blend for modulation of crystalline changes and molecular interactions in solid dispersion.

    Science.gov (United States)

    Van Ngo, Hai; Nguyen, Phuc Kien; Van Vo, Toi; Duan, Wei; Tran, Van-Thanh; Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh

    2016-11-20

    This research study aimed to develop a new strategy for using a polymer blend in solid dispersion (SD) for dissolution enhancement of poorly water-soluble drugs. SDs with different blends of hydrophilic-hydrophobic polymers (zein/hydroxypropyl methylcellulose - zein/HPMC) were prepared using spray drying to modulate the drug crystal and polymer-drug interactions in SDs. Physicochemical characterizations, including power X-ray diffraction and Fourier transform infrared spectroscopy, were performed to elucidate the roles of the blends in SDs. Although hydrophobic polymers played a key role in changing the model drug from a crystal to an amorphous state, the dissolution rate was limited due to the wetting property. Fortunately, the hydrophilic-hydrophobic blend not only reduced the drug crystallinity but also resulted in a hydrogen bonding interaction between the drugs and the polymer for a dissolution rate improvement. This work may contribute to a new generation of solid dispersion using a blend of hydrophilic-hydrophobic polymers for an effective dissolution enhancement of poorly water-soluble drugs.

  18. Hydrophilic interaction liquid chromatography-tandem mass spectrometry quantitative method for the cellular analysis of varying structures of gemini surfactants designed as nanomaterial drug carriers.

    Science.gov (United States)

    Donkuru, McDonald; Michel, Deborah; Awad, Hanan; Katselis, George; El-Aneed, Anas

    2016-05-13

    Diquaternary gemini surfactants have successfully been used to form lipid-based nanoparticles that are able to compact, protect, and deliver genetic materials into cells. However, what happens to the gemini surfactants after they have released their therapeutic cargo is unknown. Such knowledge is critical to assess the quality, safety, and efficacy of gemini surfactant nanoparticles. We have developed a simple and rapid liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method for the quantitative determination of various structures of gemini surfactants in cells. Hydrophilic interaction liquid chromatography (HILIC) was employed allowing for a short simple isocratic run of only 4min. The lower limit of detection (LLOD) was 3ng/mL. The method was valid to 18 structures of gemini surfactants belonging to two different structural families. A full method validation was performed for two lead compounds according to USFDA guidelines. The HILIC-MS/MS method was compatible with the physicochemical properties of gemini surfactants that bear a permanent positive charge with both hydrophilic and hydrophobic elements within their molecular structure. In addition, an effective liquid-liquid extraction method (98% recovery) was employed surpassing previously used extraction methods. The analysis of nanoparticle-treated cells showed an initial rise in the analyte intracellular concentration followed by a maximum and a somewhat more gradual decrease of the intracellular concentration. The observed intracellular depletion of the gemini surfactants may be attributable to their bio-transformation into metabolites and exocytosis from the host cells. Obtained cellular data showed a pattern that grants additional investigations, evaluating metabolite formation and assessing the subcellular distribution of tested compounds.

  19. Drug: D05237 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05237 Drug Hydrophilic ointment (JP16); Ointment, hydrophilic (USP); Hydrophilic o...intment (TN) Pharmaceutic aid [ointment base, oil-in-water emulsion] Therapeutic category: 7122 Therapeutic category of dr...712 Ointment bases 7122 Emulsion bases D05237 Hydrophilic ointment (JP16); Ointment, hydrophilic (USP) CAS: 8022-61-5 PubChem: 17398254 ...

  20. Hydrophilic nanoporous materials

    DEFF Research Database (Denmark)

    2010-01-01

    The present application discloses a method for preparing and rendering hydrophilic a nanoporous material of a polymer matrix which has a porosity of 0.1-90 percent (v/v), such that the ratio between the final water absorption (percent (w/w)) and the porosity (percent (v/v)) is at least 0.05, the ......The present application discloses a method for preparing and rendering hydrophilic a nanoporous material of a polymer matrix which has a porosity of 0.1-90 percent (v/v), such that the ratio between the final water absorption (percent (w/w)) and the porosity (percent (v/v)) is at least 0.......05, the method comprising the steps of: (a) preparing a precursor material comprising at least one polymeric component and having a first phase and a second phase; (b) removal of at least a part of the first phase of the precursor material prepared in step (a) so as to leave behind a nanoporous material...... of the polymer matrix; (c) irradiating at least a part of said nanoporous material with light of a wave length of in the range of 250-400 nm (or 200-700 nm) in the presence of oxygen and/or ozone. Corresponding hydrophilic nanoporous materials are also disclosed. L...

  1. Characteristics and degradation of chitosan/cellulose acetate microspheres with different model drugs

    Institute of Scientific and Technical Information of China (English)

    Hui-yun ZHOU; Xi-guang CHEN

    2008-01-01

    In this study, chitosan/cellulose acetate micro-spheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggre-gated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The load-ing efficiency of 6-mercaptopurine (6-MP) was more than 30% whereas that of ranitidine hydrochloride (RT) or acetaminophen (ACP) was only 10%. The pH values of solution affected the swelling ability of CCAM and the relative humidity had little effect on the characteristics of CCAM when it was not more than 75%. The CCAM system had a good effect on the controlled release of dif-ferent model drugs. However, the release rate became slower with the increase of the hydrophobicity of drugs. The release rate of CCAM loaded with hydrophilic RT was almost 60% during 48 h and the release rate of CCAM loaded with hydrophobic drug of 6-MP was not more than 30%. In the meantime, the CCAM system was degradable in vitro and the degradation rate was faster in lysozyme solution than that in the medium of PBS. So the CCAM system was a degradable promising drug delivery system especially for hydrophobic drugs.

  2. Development and evaluation of biodegradable microspheres embedded in in situ gel for controlled delivery of hydrophilic drug for treating oral infections: In vitro and in vivo studies

    Directory of Open Access Journals (Sweden)

    Neha Manish Munot

    2014-01-01

    Full Text Available Present investigation was aimed at developing biodegradable polymeric microspheres of Tetracycline hydrochloride to treat oral infections by using Poly (D, L lactic-co-glycolic acid (50:50 as polymer. Microspheres were prepared using oil-in-oil (O/O and water-in-oil-in-water (W/O/W double emulsion solvent evaporation method. Microspheres prepared by W/O/W were spherical in shape compared those prepared with O/O method. Thus, the microspheres formulated by W/O/W method were further evaluated for particle size, morphology, entrapment efficiency, and percent drug release. Effects of salt addition, polymer concentration on the characteristics of microspheres and tetracycline release profile were investigated. An increase in polymer concentration decreased drug release and increased entrapment efficiency of drug. In vitro studies indicated that release of drug from microspheres could be controlled for 10-15 days depending on drug: Polymer concentration. Formulation E released 99.10% of drug from microspheres in 10 days. Addition of sodium chloride to outer aqueous phase produced spherical microspheres with smooth surface and also increased entrapment efficiency. Microspheres were further dispersed in optimized formulation of mucoadhesive in situ gel of Pluronic F127, which acts as carrier for microspheres. In vivo studies were conducted on patients who underwent molar tooth extraction to check efficacy of designed formulation.

  3. MODELING OF TARGETED DRUG DELIVERY PART II. MULTIPLE DRUG ADMINISTRATION

    Directory of Open Access Journals (Sweden)

    A. V. Zaborovskiy

    2017-01-01

    Full Text Available In oncology practice, despite significant advances in early cancer detection, surgery, radiotherapy, laser therapy, targeted therapy, etc., chemotherapy is unlikely to lose its relevance in the near future. In this context, the development of new antitumor agents is one of the most important problems of cancer research. In spite of the importance of searching for new compounds with antitumor activity, the possibilities of the “old” agents have not been fully exhausted. Targeted delivery of antitumor agents can give them a “second life”. When developing new targeted drugs and their further introduction into clinical practice, the change in their pharmacodynamics and pharmacokinetics plays a special role. The paper describes a pharmacokinetic model of the targeted drug delivery. The conditions under which it is meaningful to search for a delivery vehicle for the active substance were described. Primary screening of antitumor agents was undertaken to modify them for the targeted delivery based on underlying assumptions of the model.

  4. Development of Novel Delivery System for Cardiovascular Drug Molsidomine: Influence of Synthesis Method and Conditions on Molsidomine Release From Its Composites With Hydrophilic Silica In Vitro.

    Science.gov (United States)

    Dolinina, Ekaterina S; Parfenyuk, Elena V

    2016-06-01

    Composites of cardiovascular drug molsidomine with silica materials (unmodified and mercaptopropyl modified) were prepared by 2 methods, adsorption and sol-gel technology. The effects of sol pH and release medium pH (1.6 and 7.4) as well as molsidomine loading on the drug release kinetics were also investigated. Mechanisms of molsidomine release from all the synthesized composites were elucidated. The obtained results showed that different principles of the composites formation (adsorption or sol-gel) lead to their different release behavior because the composites obtained by the indicated methods differ by distribution of the drug over the silica matrixes and their capability to degradation. The drug release from the composites prepared by adsorption is characterized by a high burst effect, sustained release up to 36 h irrespective of release medium pH. The release behavior of sol-gel composites depends on the amount of the loaded drug and release medium pH. These effects were explained by different stability of the sol-gel composites with high and low loading in acidic and neutral media. In general case, the ascertained effects are independent on chemistry of the silica surface organic groups.

  5. Recent applications of hydrophilic interaction liquid chromatography in pharmaceutical analysis.

    Science.gov (United States)

    Zhang, Qian; Yang, Feng-Qing; Ge, Liya; Hu, Yuan-Jia; Xia, Zhi-Ning

    2017-01-01

    Hydrophilic interaction liquid chromatography, an alternative liquid chromatography mode, is of particular interest in separating hydrophilic and polar ionic compounds. Compared with traditional liquid chromatography techniques, hydrophilic interaction liquid chromatography offers specific advantages mainly including: (1) relatively green and water-soluble mobile phase composition, which enhances the solubility of hydrophilic and polar ionic compounds; (2) no need for ion-pairing reagents and high content of organic solvent, which benefits mass spectrometry detection; (3) high orthogonality to reverse-phase liquid chromatography, well adapted to two-dimensional liquid chromatography for complicated samples. Therefore, hydrophilic interaction liquid chromatography has been rapidly developed in many areas over the past decades. This review summarizes the recent progress (from 2012 to July 2016) of hydrophilic interaction liquid chromatography in pharmaceutical analysis, with the focus on detecting chemical drugs in various matrices, charactering active compounds of natural products and assessing biotherapeutics through typical structure unit. Moreover, the retention mechanism and behavior of analytes in hydrophilic interaction liquid chromatography as well as some novel hydrophilic interaction liquid chromatography columns used for pharmaceutical analysis are also described.

  6. Animal models in drug development for MRSA.

    Science.gov (United States)

    Marra, Andrea

    2014-01-01

    One of the foremost challenges of drug discovery in any therapeutic area is that of solidifying the correlation between in vitro activity and clinical efficacy. Between these is the confirmation that affecting a particular target in vivo will lead to a therapeutic benefit. In antibacterial drug discovery, there is a key advantage from the start, since the targets are bacteria-therefore, it is simple to ascertain in vitro whether a drug has the desired effect, i.e., bacterial cell inhibition or killing, and to understand the mechanism by which that occurs. The downstream criteria, whether a compound reaches the infection site and achieves appropriately high levels to affect bacterial viability, can be evaluated in animal models of infection. In this way animal models of infection can be a highly valuable and predictive bridge between in vitro drug discovery and early clinical evaluation.The Gram-positive pathogen Staphylococcus aureus causes a wide variety of infections in humans (Archer, Clin Infect Dis 26:1179-1181, 1998) and has been said to be able to infect every tissue type. Fortunately, over the years a great deal of effort has been expended toward developing infection models in rodents using this organism, with good success. This chapter will describe the advantages, methods, and outcome measurements of the rodent models most used in drug discovery for S. aureus. Mouse models will be the focus of this chapter, as they are the most economical and thus most commonly used, but a rat infection model is included as well.

  7. A novel nuclear magnetic resonance (NMR) imaging method for measuring the water front penetration rate in hydrophilic polymer matrix capsule plugs and its role in drug release.

    Science.gov (United States)

    Ashraf, M; Iuorno, V L; Coffin-Beach, D; Evans, C A; Augsburger, L L

    1994-05-01

    An NMR imaging method was developed to estimate the rate of water movement in slow-release capsule matrices of pseudoephdrine HCl and hydroxypropyl cellulose (HPC). Test capsules were first placed in a USP method 2 (paddles, 50 rpm) dissolution apparatus. Each plug was removed from the dissolution medium at predetermined times, blotted dry, and placed within the magnetic field of a General Electric 400-MHz wide-bore NMR spectrometer equipped with a microimaging accessory. Images were recorded along the transverse plane of each plug. The water penetration rate was determined by comparison of the cut and weighed contour plots of the images acquired. After 1 hr, the plugs tamped to 200 N exhibited water penetration to the center, while only 45% of the drug was released. The percentage dry matrix was fitted to the Jost equation to obtain a diffusion coefficient of 4.15 x 10(-6) cm2/sec. NMR imaging is set forth as an important and practicable technique to investigate drug formulations. In the HPC matrix system of this study, the NMR imaging results convincingly revealed the rate of hydration front penetration not to be a rate-limiting step in the drug release process.

  8. Animal models of alcohol and drug dependence

    Directory of Open Access Journals (Sweden)

    Cleopatra S. Planeta

    2013-01-01

    Full Text Available Drug addiction has serious health and social consequences. In the last 50 years, a wide range of techniques have been developed to model specific aspects of drug-taking behaviors and have greatly contributed to the understanding of the neurobiological basis of drug abuse and addiction. In the last two decades, new models have been proposed in an attempt to capture the more genuine aspects of addiction-like behaviors in laboratory animals. The goal of the present review is to provide an overview of the preclinical procedures used to study drug abuse and dependence and describe recent progress that has been made in studying more specific aspects of addictive behavior in animals.

  9. Mathematical modelling of magnetically targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Grief, Andrew D. [Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD (United Kingdom)]. E-mail: andrew.grief@nottingham.ac.uk; Richardson, Giles [Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD (United Kingdom)]. E-mail: giles.richardson@nottingham.ac.uk

    2005-05-15

    A mathematical model for targeted drug delivery using magnetic particles is developed. This includes a diffusive flux of particles arising from interactions between erythrocytes in the microcirculation. The model is used to track particles in a vessel network. Magnetic field design is discussed and we show that it is impossible to specifically target internal regions using an externally applied field.

  10. An invertebrate model for CNS drug discovery

    DEFF Research Database (Denmark)

    Al-Qadi, Sonia; Schiøtt, Morten; Hansen, Steen Honoré

    2015-01-01

    BACKGROUND: ABC efflux transporters at the blood brain barrier (BBB), namely the P-glycoprotein (P-gp), restrain the development of central nervous system (CNS) drugs. Consequently, early screening of CNS drug candidates is pivotal to identify those affected by efflux activity. Therefore, simple,...... barriers. CONCLUSION: Findings suggest a conserved mechanism of brain efflux activity between insects and vertebrates, confirming that this model holds promise for inexpensive and high-throughput screening relative to in vivo models, for CNS drug discovery......., high-throughput and predictive screening models are required. The grasshopper (locust) has been developed as an invertebrate in situ model for BBB permeability assessment, as it has shown similarities to vertebrate models. METHODS: Transcriptome profiling of ABC efflux transporters in the locust brain......BACKGROUND: ABC efflux transporters at the blood brain barrier (BBB), namely the P-glycoprotein (P-gp), restrain the development of central nervous system (CNS) drugs. Consequently, early screening of CNS drug candidates is pivotal to identify those affected by efflux activity. Therefore, simple...

  11. Effects of Hydrophilic Polymers on the Stability of Self-microemulsifying Drug Delivery Systems%亲水性聚合物对自乳化药物传递系统稳定性的影响

    Institute of Scientific and Technical Information of China (English)

    靖博宇; 郑霞; 杨瑞; 赵佳; 于绍军

    2016-01-01

    OBJECTIVE:To investigate the effects of hydrophilic polymers on the stability of self-microemulsifying drug deliv-ery systems (SMEDDS). METHODS:Taking felodipine (FDP) as model drug,the content of FDP was determined by HPLC method. The effects of pure water,0.5% Kollidon VA64,HPMC E5,HPMC K100LV,HPMC K4M,PVP K30 solution,while 0.1%,0.5% and 1.0% HPMC E5 and Kollidon VA64 on residual content of dissolved FDP were determined in SMEDDS. RE-SULTS:The residual contents of dissolved FDP in SMEDDS placed in Kollidon VA64,HPMC E5,HPMC K100LV,PVP K30, HPMC K4M and pure water for 1 h were 92.7%,63.6%,50.2%,46.2%,36.0%and 24.0%,respectively. The order of maintain-ing the supersaturation state was Kollidon VA64>HPMC E5>HPMC K100LV>PVP K30>HPMC K4M>pure water. The residu-al contents of dissolved FDP in SMEDDS placed in 0.1%,0.5%,1% Kollidon VA64 and HPMC E5 and pure water for 1 h were 93.2%,95.1%,96.0% and 48.4%,62.1%,75.1%. CONCLUSIONS:Kollidon VA64 and HPMC E5 can significantly inhibit drug release in SMEDDS and be used as stabilizer of SMEDDS,wherein Kollidon VA64 was better.%目的:研究亲水性聚合物对自乳化药物传递系统(SMEDDS)稳定性的影响。方法:以非洛地平(FDP)为模型药物,采用高效液相色谱法测定FDP含量,考察不同介质种类[纯水和0.5%的共聚维酮VA64、羟丙基甲基纤维素(HPMC)E5、HPMC K100LV、HPMC K4M、聚乙烯吡咯烷酮(PVP)K30水溶液],以及不同介质浓度[0.1%、0.5%、1.0%的HPMC E5和共聚维酮VA64水溶液]对SMEDDS中剩余溶解状态FDP含量的影响。结果:SMEDDS在共聚维酮VA64、HPMC E5、HPMC K100LV、PVP K30、HPMC K4M、纯水中室温放置1 h时剩余溶解状态FDP的含量分别为92.7%、63.6%、50.2%、46.2%、36.0%和24.0%,表明维持系统过饱和能力的顺序为共聚维酮VA64>HPMC E5>HPMC K100LV>PVP K30>HPMC K4M>纯水。SMEDDS在0.1%、0.5%、1%的共聚维酮VA64和HPMC E5水溶液中室温放置1

  12. Applicability of the one-step DVS method for the determination of amorphous amounts for further different hydrophilic and hydrophobic drugs.

    Science.gov (United States)

    Müller, Thorsten; Scherließ, Regina; Schiewe, Jörg; Smal, Rüdiger; Weiler, Claudius; Steckel, Hartwig

    2015-08-01

    In a former publication the authors showed that low amounts of amorphous content (LOQ of 0.5%) in a hydrophobic model API (Ciclesonide) can be measured with an individually adjusted one-step dynamic organic vapor sorption (DVS). In this investigation the applicability is tested on various APIs which differ in lipophilicity (poor water solubility) and hygroscopicity (absorption of water). The vapor sorption method proved to be applicable in almost all cases. Moisture sorption isotherms were determined for all five investigated crystalline and amorphous APIs. However, it was necessary to select the parameters individually for each API. The used solvents (water, methanol, isopropanol and methylene chloride) and the humidity-levels (0.05 p/p0 until 0.5 p/p0) were chosen carefully because otherwise the amorphous amounts switch to their crystalline counterparts and are not detectable. The production of fully amorphous samples (absence of crystalline material measured by DSC, mDSC and XRPD) was optimized over several trials. As successfully methods proved ball-milling, freeze-drying, spray-drying and/or quench cooling. In the next step these fully amorphous amounts were blended with crystalline starting material to calibration curves (Turbula blender, influence of electrostatic charge to homogeneity) for the calculation of amorphous content. In summary, the following presented methods were used to determine and quantify low amorphous amounts (between 1.5% and 17.0%) in jet-milled powders (grinding pressure of 8bar, 1-3 grinding cycles), respectively.

  13. Bayesian hierarchical modeling of drug stability data.

    Science.gov (United States)

    Chen, Jie; Zhong, Jinglin; Nie, Lei

    2008-06-15

    Stability data are commonly analyzed using linear fixed or random effect model. The linear fixed effect model does not take into account the batch-to-batch variation, whereas the random effect model may suffer from the unreliable shelf-life estimates due to small sample size. Moreover, both methods do not utilize any prior information that might have been available. In this article, we propose a Bayesian hierarchical approach to modeling drug stability data. Under this hierarchical structure, we first use Bayes factor to test the poolability of batches. Given the decision on poolability of batches, we then estimate the shelf-life that applies to all batches. The approach is illustrated with two example data sets and its performance is compared in simulation studies with that of the commonly used frequentist methods. (c) 2008 John Wiley & Sons, Ltd.

  14. Swelling and drug releasing properties of poly(N-isopropylacrylamide) thermo-sensitive copolymer gels

    Institute of Scientific and Technical Information of China (English)

    Chunyue PAN; Qingde LONG; Dian YU; Yanping RAO; Nianqian WU; Xingcui LI

    2008-01-01

    A series of N,isopropylacrylamide (NIPAAm)copolymer gels with different hydrophilicities were prepared from NIPAAm, hydrophilic acrylamide (AAm) and hydrophobic butyl methacrylate (BMA). The swelling and thermo,responsive properties of PNIPAAm P (NIPAm,co,BMA) and P(NIPAm,co,AAm) copolymer hydrogels were investigated. The drug loading and releasing behaviors for two kinds of model drug with different hydrophilicities were studied. The result shows that the copolymer gels present negative thermo,sensitivities. The lower critical solution temperature (LCST), equilibrium swelling degree and the initial swelling rate increase as the hydrophilicity of gels increases when the temperature is below the LCST. With increasing gel hydrophilicity the loading ratio for sodium salicylate increases, while for salicylic acid, the reverse is observed. The initial drug releasing rate of sodium salicylate and salicylic acid also increase with increasing gel hydrophilicity. The initial drug releasing rate of sodium salicylate is significantly higher than that of salicylic acid. For salicylic acid which is less hydrophilic, the equilibrium releasing ratio at high temperature is lower than that at low temperature while for sodium salicylate which is more hydrophilic, the equilibrium releasing ratio at high temperature is almost the same as that at low temperature. Equilibrium releasing ratios of the three gels are significantly different from each other for salicylic acid when the temperature is below LCST while the equilibrium releasing ratios of the three gels are all 100% for sodium salicylate.

  15. Modelling Simple Experimental Platform for In Vitro Study of Drug Elution from Drug Eluting Stents (DES)

    Science.gov (United States)

    Kalachev, L. V.

    2016-06-01

    We present a simple model of experimental setup for in vitro study of drug release from drug eluting stents and drug propagation in artificial tissue samples representing blood vessels. The model is further reduced using the assumption on vastly different characteristic diffusion times in the stent coating and in the artificial tissue. The model is used to derive a relationship between the times at which the measurements have to be taken for two experimental platforms, with corresponding artificial tissue samples made of different materials with different drug diffusion coefficients, to properly compare the drug release characteristics of drug eluting stents.

  16. Modulation of tight junctions does not predict oral absorption of hydrophilic compounds: use of Caco-2 and Calu-3 cells.

    Science.gov (United States)

    Kamath, Amrita V; Morrison, Richard A; Mathias, Neil R; Dando, Sandra A; Marino, Anthony M; Chong, Saeho

    2007-08-01

    Permeability estimates using Caco-2 cells do not accurately predict the absorption of hydrophilic drugs that are primarily absorbed via the paracellular pathway. The objective of this study was to investigate whether modulation of tight junctions would help differentiation of paracellularly absorbed compounds. Tight junctions in Caco-2 cell monolayers were manipulated using calcium depletion approaches to decrease the transepithelial electrical resistance (TEER) of the monolayers, and permeability of hydrophilic compounds were measured under these conditions. Permeability of these compounds were also measured in Calu-3 cells, which have tighter junctions than Caco-2 cells. Calcium depletion loosened the tight junctions of Caco-2 cells to varying levels as measured by the decrease in TEER values of the monolayers. While the absolute permeability of all the model compounds increased as the tight junctions were loosened, the ratios of their permeability relative to mannitol permeability were similar. The permeability of these compounds in the tighter Calu-3 cells were also found to be similar to each other. Altering the tight junctions of Caco-2 cells to obtain leakier cell monolayers, or using a cell line with tighter junctions like Calu-3 cells, did not improve differentiation between well absorbed and poorly absorbed hydrophilic drugs. Mere manipulation of the tight junctions to increase or decrease transepithelial electrical resistance does not appear to be a viable approach to predict human absorption for hydrophilic compounds that are primarily absorbed via the paracellular pathway.

  17. Investigating critical effects of variegated lubricants, glidants and hydrophilic additives on lag time of press coated ethylcellulose tablets.

    Science.gov (United States)

    Patadia, Riddhish; Vora, Chintan; Mittal, Karan; Mashru, Rajashree

    2016-01-01

    The research envisaged focuses on vital impacts of variegated lubricants, glidants and hydrophilic additives on lag time of press coated ethylcellulose (EC) tablets using prednisone as a model drug. Several lubricants and glidants such as magnesium stearate, colloidal SiO2, sodium stearyl fumarate, talc, stearic acid, polyethylene glycol (6000) and glyceryl behenate were investigated to understand their effects on lag time by changing their concentrations in outer coat. Further, the effects of hydrophilic additives on lag time were examined for hydroxypropylmethylcellulose (E5), hydroxypropylcellulose (EF and SSL), povidone (K30), copovidone, polyethylene glycol (4000), lactose and mannitol. In vitro drug release testing revealed that each selected lubricant/glidant, if present even at concentration of 0.25% w/w, significantly reduced the lag time of press coated tablets. Specifically, colloidal SiO2 and/or magnesium stearate were detrimental while other lubricants/glidants were relatively less injurious. Among hydrophilic additives, freely water soluble fillers had utmost influence in lag time, whereas, comparatively less impact was observed with polymeric binders. Concisely, glidant and lubricant should be chosen to have minimal impact on lag time and further judicious selection of hydrophilic additives should be exercised for modulating lag time of pulsatile release formulations.

  18. A Learning Model for Drug Dependent Behaviors.

    Science.gov (United States)

    Bremkamp, Steven

    1982-01-01

    Presents the complex factors, i.e., social determinants, drug types, personality characteristics, reasons for drug use and misuse, which characterize the drug experience. Defines awareness of these characteristics as a developmental approach to treatment and prevention of addiction. (RC)

  19. Exceptionally high protection of photocarcinogenesis by topical application of (--)-epigallocatechin-3-gallate in hydrophilic cream in SKH-1 hairless mouse model: relationship to inhibition of UVB-induced global DNA hypomethylation.

    Science.gov (United States)

    Mittal, Anshu; Piyathilake, Chandrika; Hara, Yukihiko; Katiyar, Santosh K

    2003-01-01

    (--)-Epigallocatechin-3-gallate (EGCG) has been shown to have potent antiphotocarcinogenic activity, but it was required to develop a cream-based formulation for topical application. For topical application, we tested hydrophilic cream as a vehicle for EGCG. Treatment with EGCG ( approximately 1 mg/cm(2) skin area) in hydrophilic cream resulted in exceptionally high protection against photocarcinogenesis when determined in terms of tumor incidence, tumor multiplicity, and tumor size in a SKH-1 hairless mouse model. EGCG also inhibited malignant transformation of ultraviolet B (UVB)-induced papillomas to carcinomas. In order to determine the mechanism of prevention of photocarcinogenesis, we determined the effect of EGCG on global DNA methylation pattern using monoclonal antibodies against 5-methyl cytosine and DNA methyltransferase in the long-term UV-irradiated skin because altered DNA methylation silencing is recognized as a molecular hallmark of human cancer. We found that treatment with EGCG resulted in significant inhibition of UVB-induced global DNA hypomethylation pattern. Long-term application of EGCG did not show any apparent sign of toxicity in mice when determined in terms of skin appearance, lean mass, total bone mineral content, and total bone mineral density but showed reduction in fat mass when analyzed using dual-energy X-ray absorptiometry. These data suggest that hydrophilic cream could be a suitable vehicle for topical application of EGCG, and that EGCG is a promising candidate for future cancer therapies based on its influence on the epigenetic pathway.

  20. Exceptionally High Protection of Photocarcinogenesis by Topical Application of (--Epi gal locatechin-3-Gal late in Hydrophilic Cream in SKH-1 Hairless Mouse Model: Relationship to Inhibition of UVB-Induced Global DNA Hypomethylation

    Directory of Open Access Journals (Sweden)

    Anshu Mittal

    2003-11-01

    Full Text Available (--Epigallocatechin-3-gal late (EGCG has been shown to have potent antiphotocarcinogenic activity, but it was required to develop a cream-based formulation for topical application. For topical application, we tested hydrophilic cream as a vehicle for EGCG. Treatment with EGCG (≈ 1 mg/cm2 skin area in hydrophilic cream resulted in exceptionally high protection against photocarcinogenesis when determined in terms of tumor incidence, tumor multiplicity, and tumor size in a SKI-11-11 hairless mouse model. EGCG also inhibited malignant transformation of ultraviolet B (UVB-induced papillomas to carcinomas. In order to determine the mechanism of prevention of photocarcinogenesis, we determined the effect of EGCG on global DNA methylation pattern using monoclonal antibodies against 5-methyl cytosine and DNA methyltransferase in the long-term UV-irradiated skin because altered DNA methylation silencing is recognized as a molecular hallmark of human cancer. We found that treatment with EGCG resulted in significant inhibition of UVBinduced global DNA hypomethylation pattern. Longterm application of EGCG did not show any apparent sign of toxicity in mice when determined in terms of skin appearance, lean mass, total bone mineral content, and total bone mineral density but showed reduction in fat mass when analyzed using dual-energy X-ray absorptiometry. These data suggest that hydrophilic cream could be a suitable vehicle for topical application of EGCG, and that EGCG is a promising candidate for future cancer therapies based on its influence on the epigenetic pathway.

  1. Permeation of Hydrophilic Molecules across Glycated Skin Is Differentially Regulated by the Stratum Corneum and Epidermis-Dermis.

    Science.gov (United States)

    Yokota, Mami; Tokudome, Yoshihiro

    2015-01-01

    The effects of glycation on skin permeation and accumulation of compounds were evaluated using an in vitro glycated skin model. Glycation of the skin of hairless mice was induced using vertical diffusion cells and incubation with phosphate-buffered saline containing 50 mM glyoxal for 24 h. Flux and accumulation in the skin were determined by applying hydrophilic and lipophilic molecules (Sodium fluorescein; FL-Na and Nile red, respectively) to this in vitro glycated skin model. Furthermore, to investigate the effect of glycation on epidermal-dermal barrier properties, we conducted diffusion experiments with FL-Na and fluorescein isothiocyanate-dextran using stratum corneum (SC)-stripped glycated skin. The in vitro glycated skin model demonstrated characteristic glycation alterations like a yellowish change in skin color and surface roughness. For low-molecular weight (MW) hydrophilic molecules, flux across glycated full-thickness skin was higher than that across normal skin, although there was no difference with lipophilic molecules. However, glycated epidermis-dermis showed lower flux, and the difference increased with the MW of the compound. Furthermore, the amount of high-MW hydrophilic molecules accumulated in glycated epidermis-dermis was decreased. These results suggest that glycated SC and epidermis-dermis differentially regulate the permeability of hydrophilic molecules and highlight the importance of controlling drug delivery by modifying the formulation or method of application depending on skin condition.

  2. Challenges in modelling nanoparticles for drug delivery

    Science.gov (United States)

    Barnard, Amanda S.

    2016-01-01

    Although there have been significant advances in the fields of theoretical condensed matter and computational physics, when confronted with the complexity and diversity of nanoparticles available in conventional laboratories a number of modeling challenges remain. These challenges are generally shared among application domains, but the impacts of the limitations and approximations we make to overcome them (or circumvent them) can be more significant one area than another. In the case of nanoparticles for drug delivery applications some immediate challenges include the incompatibility of length-scales, our ability to model weak interactions and solvation, the complexity of the thermochemical environment surrounding the nanoparticles, and the role of polydispersivity in determining properties and performance. Some of these challenges can be met with existing technologies, others with emerging technologies including the data-driven sciences; some others require new methods to be developed. In this article we will briefly review some simple methods and techniques that can be applied to these (and other) challenges, and demonstrate some results using nanodiamond-based drug delivery platforms as an exemplar.

  3. Mathematical modelling of the release of drug from porous, nonswelling transdermal drug-delivery devices.

    Science.gov (United States)

    Lee, A J; King, J R; Hibberd, S

    1998-06-01

    A general model is presented for the release of drug from porous nonswelling, transdermal drug-delivery devices and it is shown to reduce to previously proposed models in suitable limits. The processes which govern the release of drug are considered to be diffusion of dissolved drug and dissolution of dispersed drug, both in the body of the device and in the device pores, and transfer of drug between the two domains. In the classical limit of large dissolution rates, the problem reduces to one of the moving-boundary type, and solution of this problem in the case where the initial drug loading is much greater than the drug solubility in the device yields expressions for the flux of drug to a perfect sink (modelling in vitro conditions). It is shown that behaviour greatly differing from the classical first-order drug delivery (alpha t 1/2) may be exhibited, depending upon the parameter regime. In some situations the dissolution rates may not be so large and solutions of the general model are derived in the case where the dispersed drug is considered to be undepleted and the diffusivity in the solvent-filled pores is much larger than in the body of the delivery device. Numerical studies are undertaken, and the coupling of delivery device and skin-diffusion models (in order to model the complete transdermal drug-delivery process) is also considered.

  4. Morphologic characterization and properties of a nanocomposite matrix of polyvinylpyrrolidone and sodium bentonite for hydrophilic drug controlled release; Caracterizacao morfologica e propriedades de uma matriz de nanocomposito de polivinilpirrolidona e bentonita sodica para potencial uso como matriz para liberacao controlada de farmacos hidrofilicos

    Energy Technology Data Exchange (ETDEWEB)

    Almeida, Dario B.R. de; Tavares, Maria I.B.; Iulianelli, Gisele C.V., E-mail: dario@ima.ufrj.br [Universidade Federal do Rio de Janeiro (IMA/UFRJ), Rio de Janeiro, RJ (Brazil). Instituto de Macromoleculas

    2015-07-01

    For several years, research in drug formulation field have been focused in seeking systems that enable a more efficient release of drug and greater time of acting. Aiming to bring numerous benefits to the patient and advantages for the pharmaceutical industry. Leading to greater acceptance and use by society. In this study polymer nanocomposites based on PVP and bentonite clay will be obtained with the drug Metformin, a known hydrophilic hypoglycemiating drug, in order to improve its properties and pharmacokinetics. This mixture will be obtained through spray drying, especially suited for administration of tablets. The characteristics of these materials are being studied by scanning electron microscopy (SEM), nuclear magnetic resonance (NMR), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). (author)

  5. Hydrophilic-Core Microcapsules and Their Formation

    Science.gov (United States)

    Calle, Luz M. (Inventor); Li, Wenyan (Inventor); Buhrow, Jerry W. (Inventor); Jolley, Scott T. (Inventor)

    2016-01-01

    Hydrophilic-core microcapsules and methods of their formation are provided. A hydrophilic-core microcapsule may include a shell that encapsulates water with the core substance dissolved or dispersed therein. The hydrophilic-core microcapsules may be formed from an emulsion having hydrophilic-phase droplets dispersed in a hydrophobic phase, with shell-forming compound contained in the hydrophilic phase or the hydrophobic phase and the core substance contained in the hydrophilic phase. The shells of the microcapsules may be capable of being broken down in response to being contacted by an alkali, e.g., produced during corrosion, contacting the shell.

  6. Alternative methods for estimating common descriptors for QSAR studies of dyes and fluorescent probes using molecular modeling software. 2. Correlations between log P and the hydrophilic/lipophilic index, and new methods for estimating degrees of amphiphilicity.

    Science.gov (United States)

    Dapson, Richard W; Horobin, Richard W

    2013-11-01

    The log P descriptor, despite its usefulness, can be difficult to use, especially for researchers lacking skills in physical chemistry. Moreover this classic measure has been determined in numerous ways, which can result in inconsistant estimates of log P values, especially for relatively complex molecules such as fluorescent probes. Novel measures of hydrophilicity/lipophilicity (the Hydrophilic/Lipophilic Index, HLI) and amphiphilicity (hydrophilic/lipophilic indices for the head group and tail, HLIT and HLIHG, respectively) therefore have been devised. We compare these descriptors with measures based on log P, the standard method for quantitative structure activity relationships (QSAR) studies. HLI can be determined using widely available molecular modeling software, coupled with simple arithmetic calculations. It is based on partial atomic charges and is intended to be a stand-alone measure of hydrophilicity/lipophilicity. Given the wide application of log P, however, we investigated the correlation between HLI and log P using a test set of 56 fluorescent probes of widely different physicochemical character. Overall correlation was poor; however, correlation of HLI and log P for probes of narrowly specified charge types, i.e., non-ionic compounds, anions, conjugated cations, or zwitterions, was excellent. Values for probes with additional nonconjugated quaternary cations, however, were less well correlated. The newly devised HLI can be divided into domain-specific descriptors, HLIT and HLIHG in amphiphilic probes. Determinations of amphiphilicity, made independently by the authors using their respective methods, showed excellent agreement. Quantifying amphiphilicity from partial log P values of the head group (head group hydrophilicity; HGH) and tail (amphiphilicity index; AI) has proved useful for understanding fluorescent probe action. The same limitations of log P apply to HGH and AI, however. The novel descriptors, HLIT and HLIHG, offer analogous advantages

  7. Animal models of social contact and drug self-administration.

    Science.gov (United States)

    Strickland, Justin C; Smith, Mark A

    2015-09-01

    Social learning theories of drug abuse propose that individuals imitate drug use behaviors modeled by social peers, and that these behaviors are selectively reinforced and/or punished depending on group norms. Historically, animal models of social influence have focused on distal factors (i.e., those factors outside the drug-taking context) in drug self-administration studies. Recently, several investigators have developed novel models, or significantly modified existing models, to examine the role of proximal factors (i.e., those factors that are immediately present at the time of drug taking) on measures of drug self-administration. Studies using these newer models have revealed several important conclusions regarding the effects of social learning on drug abuse: 1) the presence of a social partner influences drug self-administration, 2) the behavior of a social partner determines whether social contact will increase or decrease drug intake, and 3) social partners can model and imitate specific patterns of drug self-administration. These findings are congruent with those obtained in the human laboratory, providing support for the cross-species generality and validity of these preclinical models. This mini-review describes in detail some of the preclinical animal models used to study social contact and drug self-administration to guide future research on social learning and drug abuse.

  8. Softec HD hydrophilic acrylic intraocular lens: biocompatibility and precision

    Directory of Open Access Journals (Sweden)

    Ladan Espandar

    2011-01-01

    Full Text Available Ladan Espandar1, Shameema Sikder2, Majid Moshirfar31Department of Ophthalmology, Tulane University, New Orleans, LA, USA; 2Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA; 3John A Moran Eye Center, University of Utah, Salt Lake City, UT, USAAbstract: Intraocular lens development is driven by higher patient expectations for ideal visual outcomes. The recently US Food and Drug Administration-approved Softec HD™ lens is an aspheric, hydrophilic acrylic intraocular lens (IOL. The hydrophilic design of the lens is optimized to address dysphotopsia while maintaining biocompatibility, optical clarity, resistance to damage, and resistance to biocontamination. Aspheric lenses decrease postoperative spherical aberration. The addition of the Softec lens provides clinicians with another option for IOL placement; however, randomized comparative studies of this lens to others already on the market remain to be completed.Keywords: hydrophilic acrylic intraocular lens, Softec HD intraocular lens, aspheric intraocular lens, IOL

  9. A Model for Random Student Drug Testing

    Science.gov (United States)

    Nelson, Judith A.; Rose, Nancy L.; Lutz, Danielle

    2011-01-01

    The purpose of this case study was to examine random student drug testing in one school district relevant to: (a) the perceptions of students participating in competitive extracurricular activities regarding drug use and abuse; (b) the attitudes and perceptions of parents, school staff, and community members regarding student drug involvement; (c)…

  10. A quality by design (QbD) case study on liposomes containing hydrophilic API: I. Formulation, processing design and risk assessment.

    Science.gov (United States)

    Xu, Xiaoming; Khan, Mansoor A; Burgess, Diane J

    2011-10-31

    The purpose of this study was to extend QbD principles to liposomal drug products containing a hydrophilic active pharmaceutical ingredient (API) to demonstrate both the feasibility and the advantages of applying QbD concepts to liposome based complex parenteral controlled release systems. The anti-viral drug Tenofovir was selected as a model compound. Desired properties for two of the key liposome drug product qualities, namely the particle size and drug encapsulation efficiency, were defined and evaluated. It was observed that the liposome preparation process significantly affects liposome particle size, and this resulted in considerable variation in the drug encapsulation efficiency. Lipid chain length did not have a significant effect on drug encapsulation efficiency. However, lipid concentration did affect the drug encapsulation efficiency with higher lipid concentrations resulting in higher drug encapsulation. The use of risk assessment in this study assisted the identification of eight high risk factors that may impact liposome drug encapsulation efficiency and particle size.

  11. Drug release profile in core-shell nanofibrous structures: a study on Peppas equation and artificial neural network modeling.

    Science.gov (United States)

    Maleki, Mahboubeh; Amani-Tehran, Mohammad; Latifi, Masoud; Mathur, Sanjay

    2014-01-01

    Release profile of drug constituent encapsulated in electrospun core-shell nanofibrous mats was modeled by Peppas equation and artificial neural network. Core-shell fibers were fabricated by co-axial electrospinning process using tetracycline hydrochloride (TCH) as the core and poly(l-lactide-co-glycolide) (PLGA) or polycaprolactone (PCL) as the shell materials. The density and hydrophilicity of the shell polymers, feed rates and concentrations of core and shell phases, the contribution of TCH in core material and electrical field were the parameters fed to the perceptron network to predict Peppas constants in order to derive release pattern. This study demonstrated the viability of the prediction tool in determining drug release profile of electrospun core-shell nanofibrous scaffolds.

  12. Hydrophilic structures for condensation management in appliances

    Science.gov (United States)

    Kuehl, Steven John; Vonderhaar, John J.; Wu, Guolian; Wu, Mianxue

    2016-02-02

    An appliance that includes a cabinet having an exterior surface; a refrigeration compartment located within the cabinet; and a hydrophilic structure disposed on the exterior surface. The hydrophilic structure is configured to spread condensation. The appliance further includes a wicking structure located in proximity to the hydrophilic structure, and the wicking structure is configured to receive the condensation.

  13. Multiscale Modeling in the Clinic: Drug Design and Development

    Energy Technology Data Exchange (ETDEWEB)

    Clancy, Colleen E.; An, Gary; Cannon, William R.; Liu, Yaling; May, Elebeoba E.; Ortoleva, Peter; Popel, Aleksander S.; Sluka, James P.; Su, Jing; Vicini, Paolo; Zhou, Xiaobo; Eckmann, David M.

    2016-02-17

    A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multi-scale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multi-scale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multi-scale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical techniques employed for multi-scale modeling approaches used in pharmacology and present several examples illustrating the current state-of-the-art regarding drug development for: Excitable Systems (Heart); Cancer (Metastasis and Differentiation); Cancer (Angiogenesis and Drug Targeting); Metabolic Disorders; and Inflammation and Sepsis. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multi-scale models.

  14. Multiscale Modeling in the Clinic: Drug Design and Development.

    Science.gov (United States)

    Clancy, Colleen E; An, Gary; Cannon, William R; Liu, Yaling; May, Elebeoba E; Ortoleva, Peter; Popel, Aleksander S; Sluka, James P; Su, Jing; Vicini, Paolo; Zhou, Xiaobo; Eckmann, David M

    2016-09-01

    A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multiscale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multiscale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multiscale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical and computational techniques employed for multiscale modeling approaches used in pharmacometric and systems pharmacology models in drug development and present several examples illustrating the current state-of-the-art models for (1) excitable systems and applications in cardiac disease; (2) stem cell driven complex biosystems; (3) nanoparticle delivery, with applications to angiogenesis and cancer therapy; (4) host-pathogen interactions and their use in metabolic disorders, inflammation and sepsis; and (5) computer-aided design of nanomedical systems. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multiscale models.

  15. Controlled Release of Multiple Hydrophilic and Hydrophobic Drugs and in vitro Cytotoxicity of Electrospun Poly(lactic-co-glycolic acid)/ZnO Nanofibers Encapsulated with Dual Drugs%聚乳酸-乙醇酸/纳米氧化锌复合电纺纤维装载亲疏水药物的控释及体外细胞毒性

    Institute of Scientific and Technical Information of China (English)

    曾莉; 胡俊; 魏俊超

    2014-01-01

    利用静电纺丝技术制备了负载亲水性药物阿霉素( DOX)以及疏水性药物喜树碱( CPT)的复合纳米纤维。先用巯基封端的普朗尼克(F127)修饰纳米氧化锌(FZnO),再将FZnO负载盐酸阿霉素(DOX@FZnO),最后将DOX@FZnO与CPT一起纺入聚乳酸-乙醇酸( PLGA)纤维中。体外药物释放结果表明,复合纳米纤维能够减小亲水性药物的突释,减缓药物释放速率,延长药物释放时间。体外细胞活性结果表明,双载药复合纤维比单载药复合纤维具有更强的细胞毒性,能够有效抑制癌细胞生长。%A novel poly( lactic-co-glycolic acid) ( PLGA)/ZnO electrospun composite fibers encapsulated with both hydrophilic drug(doxorubicin hydrochloride, DOX) and hydrophobic drug(camptothecin, CPT) were fabricated via electrospinning method. Primarily, the ZnO was decorat with F127 and then used to encapsulate DOX. Finally, the DOX-loaded ZnO( DOX@ZnO) and CPT were mixed with PLGA solution to fabricate elec-trospun hybrid nanofibers. The in vitro release results demonstrated the composite fibers decreased the burst release and increased the time of release, which showed a long-term and sustained release. The cell cytotoxici-ty test demonstated that the composite nanofiber with two drugs showed stronger antitumor efficacy against HepG-2 cells than the nanofiber with single drug. Thus, the composite nanofibers with two anticancer drugs could be a versatile drug delivery system as local implantable scaffolds for potential postsurgical cancer treat-ment.

  16. Predicting Anticancer Drug Responses Using a Dual-Layer Integrated Cell Line-Drug Network Model.

    Directory of Open Access Journals (Sweden)

    Naiqian Zhang

    Full Text Available The ability to predict the response of a cancer patient to a therapeutic agent is a major goal in modern oncology that should ultimately lead to personalized treatment. Existing approaches to predicting drug sensitivity rely primarily on profiling of cancer cell line panels that have been treated with different drugs and selecting genomic or functional genomic features to regress or classify the drug response. Here, we propose a dual-layer integrated cell line-drug network model, which uses both cell line similarity network (CSN data and drug similarity network (DSN data to predict the drug response of a given cell line using a weighted model. Using the Cancer Cell Line Encyclopedia (CCLE and Cancer Genome Project (CGP studies as benchmark datasets, our single-layer model with CSN or DSN and only a single parameter achieved a prediction performance comparable to the previously generated elastic net model. When using the dual-layer model integrating both CSN and DSN, our predicted response reached a 0.6 Pearson correlation coefficient with observed responses for most drugs, which is significantly better than the previous results using the elastic net model. We have also applied the dual-layer cell line-drug integrated network model to fill in the missing drug response values in the CGP dataset. Even though the dual-layer integrated cell line-drug network model does not specifically model mutation information, it correctly predicted that BRAF mutant cell lines would be more sensitive than BRAF wild-type cell lines to three MEK1/2 inhibitors tested.

  17. Wetting of soap bubbles on hydrophilic, hydrophobic and superhydrophobic surfaces

    CERN Document Server

    Arscott, Steve

    2013-01-01

    Wetting of sessile bubbles on solid and liquid surfaces has been studied. A model is presented for the contact angle of a sessile bubble based on a modified Young equation - the experimental results agree with the model. A hydrophilic surface results in a bubble contact angle of 90 deg whereas on a superhydrophobic surface one observes 134 deg. For hydrophilic surfaces, the bubble angle diminishes with bubble radius - whereas on a superhydrophobic surface, the bubble angle increases. The size of the Plateau borders governs the bubble contact angle - depending on the wetting of the surface.

  18. A Molecular Communication System Model for Particulate Drug Delivery Systems.

    Science.gov (United States)

    Chahibi, Youssef; Pierobon, Massimiliano; Song, Sang Ok; Akyildiz, Ian F

    2013-12-01

    The goal of a drug delivery system (DDS) is to convey a drug where the medication is needed, while, at the same time, preventing the drug from affecting other healthy parts of the body. Drugs composed of micro- or nano-sized particles (particulate DDS) that are able to cross barriers which prevent large particles from escaping the bloodstream are used in the most advanced solutions. Molecular communication (MC) is used as an abstraction of the propagation of drug particles in the body. MC is a new paradigm in communication research where the exchange of information is achieved through the propagation of molecules. Here, the transmitter is the drug injection, the receiver is the drug delivery, and the channel is realized by the transport of drug particles, thus enabling the analysis and design of a particulate DDS using communication tools. This is achieved by modeling the MC channel as two separate contributions, namely, the cardiovascular network model and the drug propagation network. The cardiovascular network model allows to analytically compute the blood velocity profile in every location of the cardiovascular system given the flow input by the heart. The drug propagation network model allows the analytical expression of the drug delivery rate at the targeted site given the drug injection rate. Numerical results are also presented to assess the flexibility and accuracy of the developed model. The study of novel optimization techniques for a more effective and less invasive drug delivery will be aided by this model, while paving the way for novel communication techniques for Intrabody communication networks.

  19. Drugs and Crime: An Empirically Based, Interdisciplinary Model

    Science.gov (United States)

    Quinn, James F.; Sneed, Zach

    2008-01-01

    This article synthesizes neuroscience findings with long-standing criminological models and data into a comprehensive explanation of the relationship between drug use and crime. The innate factors that make some people vulnerable to drug use are conceptually similar to those that predict criminality, supporting a spurious reciprocal model of the…

  20. Drugs and Crime: An Empirically Based, Interdisciplinary Model

    Science.gov (United States)

    Quinn, James F.; Sneed, Zach

    2008-01-01

    This article synthesizes neuroscience findings with long-standing criminological models and data into a comprehensive explanation of the relationship between drug use and crime. The innate factors that make some people vulnerable to drug use are conceptually similar to those that predict criminality, supporting a spurious reciprocal model of the…

  1. A new experimental design method to optimize formulations focusing on a lubricant for hydrophilic matrix tablets.

    Science.gov (United States)

    Choi, Du Hyung; Shin, Sangmun; Khoa Viet Truong, Nguyen; Jeong, Seong Hoon

    2012-09-01

    A robust experimental design method was developed with the well-established response surface methodology and time series modeling to facilitate the formulation development process with magnesium stearate incorporated into hydrophilic matrix tablets. Two directional analyses and a time-oriented model were utilized to optimize the experimental responses. Evaluations of tablet gelation and drug release were conducted with two factors x₁ and x₂: one was a formulation factor (the amount of magnesium stearate) and the other was a processing factor (mixing time), respectively. Moreover, different batch sizes (100 and 500 tablet batches) were also evaluated to investigate an effect of batch size. The selected input control factors were arranged in a mixture simplex lattice design with 13 experimental runs. The obtained optimal settings of magnesium stearate for gelation were 0.46 g, 2.76 min (mixing time) for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The optimal settings for drug release were 0.33 g, 7.99 min for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The exact ratio and mixing time of magnesium stearate could be formulated according to the resulting hydrophilic matrix tablet properties. The newly designed experimental method provided very useful information for characterizing significant factors and hence to obtain optimum formulations allowing for a systematic and reliable experimental design method.

  2. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  3. Spread of anti-malarial drug resistance: mathematical model with implications for ACT drug policies.

    Science.gov (United States)

    Pongtavornpinyo, Wirichada; Yeung, Shunmay; Hastings, Ian M; Dondorp, Arjen M; Day, Nicholas P J; White, Nicholas J

    2008-11-02

    Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT). The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria

  4. Preparation and in vitro evaluation of hydrophilic fenretinide nanoparticles.

    Science.gov (United States)

    Ledet, Grace A; Graves, Richard A; Glotser, Elena Y; Mandal, Tarun K; Bostanian, Levon A

    2015-02-20

    Fenretinide is an effective anti-cancer drug with high in vitro cytotoxicity and low in vivo systemic toxicity. In clinical trials, fenretinide has shown poor therapeutic efficacy following oral administration - attributed to its low bioavailability and solubility. The long term goal of this project is to develop a formulation for the oral delivery of fenretinide. The purpose of this part of the study was to prepare and characterize hydrophilic nanoparticle formulations of fenretinide. Three different ratios of polyvinyl pyrrolidone (PVP) to fenretinide were used, namely, 3:1, 4:1, and 5:1. Both drug and polymer were dissolved in a mixture of methanol and dichloromethane (2:23 v/v). Rotary evaporation was used to remove the solvents, and, following reconstitution with water, a high pressure homogenizer was used to form nanoparticles. The particle size and polydispersity index were measured before and after lyophilization. The formulations were studied by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The effectiveness of the formulations was assessed by release studies and Caco-2 cell permeability assays. As the PVP content increased, the recovered particle size following lyophilization became more consistent with the pre-lyophilization particle size, especially for those formulations with less lactose. The DSC scans of the formulations did not show any fenretinide melting endotherms, indicating that the drug was either present in an amorphous form in the formulation or that a solid solution of the drug in PVP had formed. For the release studies, the highest drug release among the formulations was 249.2±35.5ng/mL for the formulation with 4:1 polymer-to-drug. When the permeability of the formulations was evaluated in a Caco-2 cell model, the mean normalized flux for each treatment group was significantly higher (p<0.05) from the fenretinide control. The formulation containing 4:1 polymer-to-drug

  5. Softec HD hydrophilic acrylic intraocular lens: biocompatibility and precision

    OpenAIRE

    Ladan Espandar; Shameema Sikder; Majid Moshirfar

    2011-01-01

    Ladan Espandar1, Shameema Sikder2, Majid Moshirfar31Department of Ophthalmology, Tulane University, New Orleans, LA, USA; 2Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA; 3John A Moran Eye Center, University of Utah, Salt Lake City, UT, USAAbstract: Intraocular lens development is driven by higher patient expectations for ideal visual outcomes. The recently US Food and Drug Administration-approved Softec HD™ lens is an aspheric, hydrophilic acrylic intraocular le...

  6. Systems pharmacology modeling: an approach to improving drug safety.

    Science.gov (United States)

    Bai, Jane P F; Fontana, Robert J; Price, Nathan D; Sangar, Vineet

    2014-01-01

    Advances in systems biology in conjunction with the expansion in knowledge of drug effects and diseases present an unprecedented opportunity to extend traditional pharmacokinetic and pharmacodynamic modeling/analysis to conduct systems pharmacology modeling. Many drugs that cause liver injury and myopathies have been studied extensively. Mitochondrion-centric systems pharmacology modeling is important since drug toxicity across a large number of pharmacological classes converges to mitochondrial injury and death. Approaches to systems pharmacology modeling of drug effects need to consider drug exposure, organelle and cellular phenotypes across all key cell types of human organs, organ-specific clinical biomarkers/phenotypes, gene-drug interaction and immune responses. Systems modeling approaches, that leverage the knowledge base constructed from curating a selected list of drugs across a wide range of pharmacological classes, will provide a critically needed blueprint for making informed decisions to reduce the rate of attrition for drugs in development and increase the number of drugs with an acceptable benefit/risk ratio.

  7. Development and validation of an alternative disturbed skin model by mechanical abrasion to study drug penetration

    Directory of Open Access Journals (Sweden)

    P. Schlupp

    2014-01-01

    Skin permeation of the three substances was increased in tape-stripped and abraded skin compared to untreated skin due to the reduced barrier integrity. Enhancement of drug uptake was highest for the most hydrophilic substance, caffeine, followed by sorbic acid and lipophilic testosterone. No significant difference in drug uptake studies was observed between the new abrasion method with an aluminum-coated sponge and the tape-stripping method. The obtained results demonstrate that this abrasion method is an alternative way to achieve a disturbed skin barrier for drug and chemical uptake studies.

  8. Hydrodynamic modeling of ferrofluid flow in magnetic targeting drug delivery

    Institute of Scientific and Technical Information of China (English)

    LIU Han-dan; XU Wei; WANG Shi-gang; KE Zun-ji

    2008-01-01

    Among the proposed techniques for delivering drugs to specific locations within human body, magnetic drug targeting prevails due to its non-invasive character and its high targeting efficiency. Magnetic targeting drug delivery is a method of carrying drug-loaded magnetic nanoparticles to a target tissue target under the applied magnetic field. This method increases the drug concentration in the target while reducing the adverse side-effects. Although there have been some theoretical analyses for magnetic drug targeting, very few researchers have addressed the hydrodynamic models of magnetic fluids in the blood vessel. A mathematical model is presented to describe the hydrodynamics of ferrofluids as drug carriers flowing in a blood vessel under the applied magnetic field. In this model, magnetic force and asymmetrical force are added, and an angular momentum equation of magnetic nanoparticles in the applied magnetic field is modeled. Engineering approximations are achieved by retaining the physically most significant items in the model due to the mathematical complexity of the motion equations. Numerical simulations are performed to obtain better insight into the theoretical model with computational fluid dynamics. Simulation results demonstrate the important parameters leading to adequate drug delivery to the target site depending on the magnetic field intensity, which coincident with those of animal experiments. Results of the analysis provide important information and suggest strategies for improving delivery in clinical application.

  9. Drug: D05332 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05332 Mixture, Drug Hydrophilic petrolatum (JP16); Petrolatum, hydrophilic (USP) W...hite beewax [DR:D04969], Stearyl alcohol [DR:D01924], Cholesterol [DR:D00040], White petrolatum [DR:D05304] ...71 Dispensing medicines 712 Ointment bases 7121 Oil bases D05332 Hydrophilic petrolatum (JP16); Petrolatum, hydrophilic (USP) CAS: 8027-64-3 PubChem: 17398285 ...

  10. Integrating Multiscale Modeling with Drug Effects for Cancer Treatment.

    Science.gov (United States)

    Li, Xiangfang L; Oduola, Wasiu O; Qian, Lijun; Dougherty, Edward R

    2015-01-01

    In this paper, we review multiscale modeling for cancer treatment with the incorporation of drug effects from an applied system's pharmacology perspective. Both the classical pharmacology and systems biology are inherently quantitative; however, systems biology focuses more on networks and multi factorial controls over biological processes rather than on drugs and targets in isolation, whereas systems pharmacology has a strong focus on studying drugs with regard to the pharmacokinetic (PK) and pharmacodynamic (PD) relations accompanying drug interactions with multiscale physiology as well as the prediction of dosage-exposure responses and economic potentials of drugs. Thus, it requires multiscale methods to address the need for integrating models from the molecular levels to the cellular, tissue, and organism levels. It is a common belief that tumorigenesis and tumor growth can be best understood and tackled by employing and integrating a multifaceted approach that includes in vivo and in vitro experiments, in silico models, multiscale tumor modeling, continuous/discrete modeling, agent-based modeling, and multiscale modeling with PK/PD drug effect inputs. We provide an example application of multiscale modeling employing stochastic hybrid system for a colon cancer cell line HCT-116 with the application of Lapatinib drug. It is observed that the simulation results are similar to those observed from the setup of the wet-lab experiments at the Translational Genomics Research Institute.

  11. Property profiling of biosimilar mucus in a novel mucus-containing in vitro model for assessment of intestinal drug absorption.

    Science.gov (United States)

    Boegh, Marie; Baldursdóttir, Stefania G; Müllertz, Anette; Nielsen, Hanne M

    2014-07-01

    Oral delivery of drugs, including peptide and protein therapeutics, can be impeded by the presence of the mucus surface-lining the intestinal epithelium. The aim of the present project was to design and characterize biosimilar mucus compatible with Caco-2 cell monolayers cultured in vitro to establish a more representative in vitro model for the intestinal mucosa. The rheological profile of a biosimilar mucus mixture composed of purified gastric mucin, lipids and protein in buffer was optimized by supplementing with an anionic polymer to display viscoelastic properties and a microstructure comparable to freshly isolated porcine intestinal mucus (PIM). Further, this multicomponent biosimilar mucus mixture was optimized with regard to the lipid content in order to obtain cellular compatibility with well-differentiated Caco-2 cell monolayers. In contrast, PIM was found to severely disrupt the Caco-2 cell monolayer. When combined with the Caco-2 cell monolayers, the final biosimilar mucus was found to significantly affect the permeability profiles for hydrophobic and hydrophilic small and large model drug compounds in different ways. In conclusion, the present study describes an improvement of the biorelevance of the Caco-2 cell culture model by application of mucus, resulting in an in vitro model of oral mucosa suitable for future assessment of innovative drug delivery approaches. Copyright © 2014. Published by Elsevier B.V.

  12. Tumor Growth Model with PK Input for Neuroblastoma Drug Development

    Science.gov (United States)

    2015-09-01

    9/2012 - 4/30/2017 2.40 calendar NCI Anticancer Drug Pharmacology in Very Young Children The proposed studies will use pharmacokinetic... anticancer drugs . DOD W81XWH-14-1-0103 CA130396 (Stewart) 9/1/2014 - 8/31/2016 .60 calendar DOD-DEPARTMENT OF THE ARMY Tumor Growth Model with PK... anticancer drugs . .60 calendar V Foundation Translational (Stewart) 11/1/2012-10/31/2015 THE V FDN FOR CA RES Identification & preclinical testing

  13. In silico modeling to predict drug-induced phospholipidosis

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Sydney S.; Kim, Jae S.; Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov; Sadrieh, Nakissa

    2013-06-01

    Drug-induced phospholipidosis (DIPL) is a preclinical finding during pharmaceutical drug development that has implications on the course of drug development and regulatory safety review. A principal characteristic of drugs inducing DIPL is known to be a cationic amphiphilic structure. This provides evidence for a structure-based explanation and opportunity to analyze properties and structures of drugs with the histopathologic findings for DIPL. In previous work from the FDA, in silico quantitative structure–activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the construction and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80–81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ≥ 80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL. - Highlights: • New in silico models for predicting drug-induced phospholipidosis (DIPL) are described. • The training set data in the models is derived from the FDA's phospholipidosis database. • We find excellent predictivity values of the models based on external validation. • The models can support drug screening and regulatory decision-making on DIPL.

  14. A unified multicomponent stress-diffusion model of drug release from non-biodegradable polymeric matrix tablets.

    Science.gov (United States)

    Salehi, Ali; Zhao, Jin; Cabelka, Tim D; Larson, Ronald G

    2016-02-28

    We propose a new transport model of drug release from hydrophilic polymeric matrices, based on Stefan-Maxwell flux laws for multicomponent transport. Polymer stress is incorporated in the total mixing free energy, which contributes directly to the diffusion driving force while leading to time-dependent boundary conditions at the tablet interface. Given that hydrated matrix tablets are dense multicomponent systems, extended Stefan-Maxwell (ESM) flux laws are adopted to ensure consistency with the Onsager reciprocity principle and the Gibbs-Duhem thermodynamic constraint. The ESM flux law for any given component takes into account the friction exerted by all other species and is invariant with respect to reference velocity, thus satisfying Galilean translational invariance. Our model demonstrates that penetrant-induced plasticization of polymer chains partially or even entirely offsets the steady decline of chemical potential gradients at the tablet-medium interface that drive drug release. Utilizing a Flory-Huggins thermodynamic model, a modified form of the upper convected Maxwell constitutive equation for polymer stress and a Fujita-type dependence of mutual diffusivities on composition, depending on parameters, Fickian, anomalous or case II drug transport arises naturally from the model, which are characterized by quasi-power-law release profiles with exponents ranging from 0.5 to 1, respectively. A necessary requirement for non-Fickian release in our model is that the matrix stress relaxation time is comparable to the time scale for water diffusion. Mutual diffusivities and their composition dependence are the most decisive factors in controlling drug release characteristics in our model. Regression of the experimental polymer dissolution and drug release profiles in a system of Theophylline/cellulose (K15M) demonstrate that API-water mutual diffusivity in the presence of excipient cannot generally be taken as a constant.

  15. A two-dimensional mathematical model of percutaneous drug absorption

    Directory of Open Access Journals (Sweden)

    Kubota K

    2004-06-01

    Full Text Available Abstract Background When a drug is applied on the skin surface, the concentration of the drug accumulated in the skin and the amount of the drug eliminated into the blood vessel depend on the value of a parameter, r. The values of r depend on the amount of diffusion and the normalized skin-capillary clearence. It is defined as the ratio of the steady-state drug concentration at the skin-capillary boundary to that at the skin-surface in one-dimensional models. The present paper studies the effect of the parameter values, when the region of contact of the skin with the drug, is a line segment on the skin surface. Methods Though a simple one-dimensional model is often useful to describe percutaneous drug absorption, it may be better represented by multi-dimensional models. A two-dimensional mathematical model is developed for percutaneous absorption of a drug, which may be used when the diffusion of the drug in the direction parallel to the skin surface must be examined, as well as in the direction into the skin, examined in one-dimensional models. This model consists of a linear second-order parabolic equation with appropriate initial conditions and boundary conditions. These boundary conditions are of Dirichlet type, Neumann type or Robin type. A finite-difference method which maintains second-order accuracy in space along the boundary, is developed to solve the parabolic equation. Extrapolation in time is applied to improve the accuracy in time. Solution of the parabolic equation gives the concentration of the drug in the skin at a given time. Results Simulation of the numerical methods described is carried out with various values of the parameter r. The illustrations are given in the form of figures. Conclusion Based on the values of r, conclusions are drawn about (1 the flow rate of the drug, (2 the flux and the cumulative amount of drug eliminated into the receptor cell, (3 the steady-state value of the flux, (4 the time to reach the steady

  16. Solid state drug-polymer miscibility studies using the model drug ABT-102.

    Science.gov (United States)

    Jog, Rajan; Gokhale, Rajeev; Burgess, Diane J

    2016-07-25

    Amorphous solid dispersions typically suffer storage stability issues due to: their amorphous nature, high drug loading, uneven drug:stabilizer ratio and plasticization effects as a result of hygroscopic excipients. An extensive solid state miscibility study was conducted to aid in understanding the mechanisms involved in drug/stabilizer interactions. ABT-102 (model drug) and nine different polymers with different molecular weights and viscosities were selected to investigate drug/polymer miscibility. Three different polymer:drug ratios (1:3, 1:1 and 3:1, w/w) were analyzed using: DSC, FTIR and PXRD. Three different techniques were used to prepare the amorphous solid dispersions: serial dilution, solvent evaporation and spray drying. Spray drying was the best method to obtain amorphous solid dispersions. However, under certain conditions amorphous formulations could be obtained using solvent evaporation. Melting point depression was used to calculate interaction parameters and free energy of mixing for the various drug polymer mixtures. The spray dried solid dispersions yielded a negative free energy of mixing which indicated strong drug-polymer miscibility compared to the solvent evaporation and serial dilution method. Soluplus was the best stabilizer compared to PVP and HPMC, which is probably a consequence of strong hydrogen bonding between the two CO moieties of soluplus and the drug NH moieities. Copyright © 2016. Published by Elsevier B.V.

  17. Towards a pragmatic human migraine model for drug testing

    DEFF Research Database (Denmark)

    Hansen, Emma Katrine; Olesen, Jes

    2017-01-01

    BACKGROUND: A model for the testing of novel anti-migraine drugs should preferably use healthy volunteers for ease of recruiting. Isosorbide-5-mononitrate (5-ISMN) provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity...... drug testing....

  18. A Mathematical Model for HIV Drug-Resistance

    Science.gov (United States)

    Faedo, Ivan; Raimundo, Silvia Martorano; Venturino, Ezio

    2010-09-01

    In this paper we present a mathematical model of the transmission of HIV infection here the individuals receive antiretroviral drugs but may not respond to treatment. In such case the latter can be changed to a different therapy, and individuals may or may not respond also to this second set of drugs.

  19. The Øie-Tozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior.

    Science.gov (United States)

    Stepensky, David

    2011-10-01

    Drug distribution is a major pharmacokinetic process that affects the time course of drug concentrations in tissues, biological fluids and the resulting pharmacological activities. Drug distribution may follow different pathways and patterns, and is governed by the drug's physicochemical properties and the body's physiology. The classical Øie-Tozer model is frequently used for predicting volume of drug distribution and for pharmacokinetic calculations. In this review, the suitability of the Øie-Tozer model for drugs that exhibit different distribution patterns is critically analyzed and illustrated. The method used is a pharmacokinetic modeling and simulation approach. It is demonstrated that the major limitation of the Øie-Tozer model stems from its focus on the total drug concentrations and not on the active (unbound) concentrations. Moreover, the Øie-Tozer model may be inappropriate for drugs with nonlinear or complex pharmacokinetic behavior, such as biopharmaceuticals, drug conjugates or for drugs incorporated into drug delivery systems. Distribution mechanisms and alternative distribution models for these drugs are discussed. The Øie-Tozer model can serve for predicting unbound volume of drug distribution for 'classical' small molecular mass drugs with linear pharmacokinetics. However, more detailed mechanism-based distribution models should be used in preclinical and clinical settings for drugs that exhibit more complex pharmacokinetic behavior.

  20. Restricted access molecularly imprinted polymers obtained by bovine serum albumin and/or hydrophilic monomers' external layers: a comparison related to physical and chemical properties.

    Science.gov (United States)

    Santos, Mariane Gonçalves; Moraes, Gabriel de Oliveira Isac; Nakamura, Maurício Gustavo; dos Santos-Neto, Álvaro José; Figueiredo, Eduardo Costa

    2015-11-21

    Molecularly imprinting polymers (MIPs) can be modified with external layers in order to obtain restricted access molecularly imprinted polymers (RAMIPs) able to exclude macromolecules and retain low weight compounds. These modifications have been frequently achieved using hydrophilic monomers, chemically bound on the MIP surface. Recently, our group proposed a new biocompatible RAMIP based on the formation of a bovine serum albumin coating on the surface of MIP particles. This material has been used to extract drugs directly from untreated human plasma samples, but its physicochemical evaluation has not been carried out yet, mainly in comparison with RAMIPs obtained by hydrophilic monomers. Thus, we proposed in this paper a comparative study involving the surface composition, microscopic aspect, selectivity, binding kinetics, adsorption and macromolecule elimination ability of these different materials. We concluded that the synthesis procedure influences the size and shape of particles and that hydrophilic co-monomer addition as well as coating with BSA do not alter the chemical recognition ability of the material. The difference between imprinted and non-imprinted polymers' adsorption was evident (suggesting that imprinted polymers have a better capacity to bind the template than the non-imprinted ones). The Langmuir model presents the best fit to describe the materials' adsorption profile. The polymer covered with hydrophilic monomers presented the best adsorption for the template in an aqueous medium, probably due to a hydrophilic layer on its surface. We also concluded that an association of the hydrophilic monomers with the bovine serum albumin coating is important to obtain materials with higher capacity of macromolecule exclusion.

  1. Pharmacological modeling and biostatistical analysis of a new drug

    Directory of Open Access Journals (Sweden)

    Revathi Ananthakrishnan

    2010-04-01

    Full Text Available Revathi Ananthakrishnan1, Philimon Gona21Cambridge, MA, USA; 2Boston University, Mathematics and Statistics Department, 111 Cummington St, Boston, MA-02215, USAAbstract: Clinical research and clinical trials of experimental drugs to treat human diseases have gained greater importance in recent years. Phase I–IV clinical trials offer patients the opportunity to gain access to a new, more efficacious and safer medication to alleviate or cure their disease. There are potential side effects of every new drug; however, such trials and studies are crucial for drug development and testing in humans. The US Food and Drug Administration (FDA regulated process of evaluating a new drug for treating a particular disease in humans is long, rigorous, and includes the stages starting from preclinical research through the entire human clinical trials process. This review synthesizes results from the above stages and describes the entire mechanism of the clinical study of a new drug for human disease. It emphasizes the associated mathematical modeling and statistical analyses, and bridges pharmacological modeling and biostatistics in clinical research and also provides a basic theoretical overview to biomedical experimentalists. The modern trend in clinical research involves a unified approach among several biomedical subspecialties and it is hoped that even more integrated studies of new drugs will continue to be carried out, leading to novel drugs that are highly effective in curing the associated condition.Keywords: PK/PD pharmacological modeling, biostatistical analyses of clinical trials data, clinical trials, phases of clinical trials, types and designs of clinical trials

  2. Teratogenic Potential of Antiepileptic Drugs in the Zebrafish Model

    Directory of Open Access Journals (Sweden)

    Sung Hak Lee

    2013-01-01

    Full Text Available The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ, ethosuximide (ETX, valproic acid (VPN, lamotrigine (LMT, lacosamide (LCM, levetiracetam (LVT, and topiramate (TPM in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf to termination of hatching (72 hpf which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data.

  3. Statistical Agent Based Modelization of the Phenomenon of Drug Abuse

    Science.gov (United States)

    di Clemente, Riccardo; Pietronero, Luciano

    2012-07-01

    We introduce a statistical agent based model to describe the phenomenon of drug abuse and its dynamical evolution at the individual and global level. The agents are heterogeneous with respect to their intrinsic inclination to drugs, to their budget attitude and social environment. The various levels of drug use were inspired by the professional description of the phenomenon and this permits a direct comparison with all available data. We show that certain elements have a great importance to start the use of drugs, for example the rare events in the personal experiences which permit to overcame the barrier of drug use occasionally. The analysis of how the system reacts to perturbations is very important to understand its key elements and it provides strategies for effective policy making. The present model represents the first step of a realistic description of this phenomenon and can be easily generalized in various directions.

  4. Statistical Agent Based Modelization of the Phenomenon of Drug Abuse

    CERN Document Server

    Di Clemente, Riccardo; 10.1038/srep00532

    2012-01-01

    We introduce a statistical agent based model to describe the phenomenon of drug abuse and its dynamical evolution at the individual and global level. The agents are heterogeneous with respect to their intrinsic inclination to drugs, to their budget attitude and social environment. The various levels of drug use were inspired by the professional description of the phenomenon and this permits a direct comparison with all available data. We show that certain elements have a great importance to start the use of drugs, for example the rare events in the personal experiences which permit to overcame the barrier of drug use occasionally. The analysis of how the system reacts to perturbations is very important to understand its key elements and it provides strategies for effective policy making. The present model represents the first step of a realistic description of this phenomenon and can be easily generalized in various directions.

  5. Use of a physiologically based pharmacokinetic model to simulate drug-drug interactions between antineoplastic and antiretroviral drugs.

    Science.gov (United States)

    Moltó, José; Rajoli, Rajith; Back, David; Valle, Marta; Miranda, Cristina; Owen, Andrew; Clotet, Bonaventura; Siccardi, Marco

    2017-03-01

    Co-administration of antineoplastics with ART is challenging due to potential drug-drug interactions (DDIs). However, trials specifically assessing such DDIs are lacking. Our objective was to simulate DDIs between the antineoplastics erlotinib and gefitinib with key antiretroviral drugs and to predict dose adjustments using a physiologically based pharmacokinetic (PBPK) model. In vitro data describing chemical properties and pharmacokinetic processes of each drug and their effect on cytochrome P450 isoforms were obtained from the literature. Plasma drug-concentration profiles were simulated in a virtual population of 50 individuals receiving erlotinib or gefitinib alone or with darunavir/ritonavir, efavirenz or etravirine. Simulated pharmacokinetic parameters and the magnitude of DDIs with probe drugs (midazolam, maraviroc) were compared with literature values. Erlotinib and gefitinib pharmacokinetics with and without antiretrovirals were compared and dose-adjustment strategies were evaluated. Simulated parameters of each drug and the magnitude of DDIs with probe drugs were in agreement with reference values. Darunavir/ritonavir increased erlotinib and gefitinib exposure, while efavirenz and etravirine decreased erlotinib and gefitinib concentrations. Based on our predictions, dose-adjustment strategies may consist of once-daily dosing erlotinib at 25 mg and gefitinib at 125 mg with darunavir/ritonavir; or erlotinib at 200 mg and gefitinib at 375 mg with etravirine. The interaction with efavirenz was not overcome even after doubling erlotinib or gefitinib doses. PBPK models predicted the in vivo pharmacokinetics of erlotinib, gefitinib and the antiretrovirals darunavir/ritonavir, efavirenz and etravirine, and the DDIs between them. The simulated dose-adjustments may represent valuable strategies to optimize antineoplastic therapy in HIV-infected patients.

  6. PBPK modeling and simulation in drug research and development

    OpenAIRE

    Xiaomei Zhuang; Chuang Lu

    2016-01-01

    Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the phar...

  7. Modeling and Simulation of In Vivo Drug Effects.

    Science.gov (United States)

    Lippert, Jörg; Burghaus, Rolf; Kuepfer, Lars; Ploeger, Bart; Schaller, Stephan; Schmitt, Walter; Willmann, Stefan

    2016-01-01

    The concept of a pharmacokinetics-pharmacodynamics (PK/PD) assessment of drug development candidates is well established in pharmaceutical research and development, and PK/PD modeling is common practice in all pharmaceutical companies. A recent analysis (Morgan et al., Drug Discov Today 17(9-10):419-424, 2012) revealed however that insufficient certainty in the integrity of the causal chain of fundamental pharmacological steps from drug dosing through systemic exposure, target tissue exposure, and engagement of molecular target to pharmacological response is still the major driver of failure in phase II of clinical drug development. Despite the rise of molecular biomarkers, ethical, scientific, and practical constraints very often still prevent a direct assessment of each necessary step ultimately leading to an intended drug effect or an unintended adverse reaction. Yet, incomplete investigation of the causality of drug responses is a major risk for translational assessments and the prediction of drug responses in different species or other populations. Mechanism-based modeling and simulation (M&S) offers a means to investigate complex physiological and pharmacological processes and to complement experimental data for non-accessible steps in the pharmacological causal chain. With the help of two examples, it is illustrated, what level of physiological detail, state-of-the-art models can represent, how predictive these models are and how mechanism-based approaches can be combined with empirical correlation-based concepts.

  8. Drug discovery and development for neglected diseases: the DNDi model

    Directory of Open Access Journals (Sweden)

    Eric Chatelain

    2011-03-01

    Full Text Available Eric Chatelain, Jean-Robert IosetDrugs for Neglected Diseases Initiative (DNDi, Geneva, SwitzerlandAbstract: New models of drug discovery have been developed to overcome the lack of modern and effective drugs for neglected diseases such as human African trypanosomiasis (HAT; sleeping sickness, leishmaniasis, and Chagas disease, which have no financial viability for the pharmaceutical industry. With the purpose of combining the skills and research capacity in academia, pharmaceutical industry, and contract researchers, public–private partnerships or product development partnerships aim to create focused research consortia that address all aspects of drug discovery and development. These consortia not only emulate the projects within pharmaceutical and biotechnology industries, eg, identification and screening of libraries, medicinal chemistry, pharmacology and pharmacodynamics, formulation development, and manufacturing, but also use and strengthen existing capacity in disease-endemic countries, particularly for the conduct of clinical trials. The Drugs for Neglected Diseases initiative (DNDi has adopted a model closely related to that of a virtual biotechnology company for the identification and optimization of drug leads. The application of this model to the development of drug candidates for the kinetoplastid infections of HAT, Chagas disease, and leishmaniasis has already led to the identification of new candidates issued from DNDi’s own discovery pipeline. This demonstrates that the model DNDi has been implementing is working but its DNDi, neglected diseases sustainability remains to be proven.Keywords: R&D, screening, lead optimization, human African trypanosomiasis, leishmaniasis, Chagas disease, product development partnerships

  9. Delivering hydrophilic and hydrophobic chemotherapeutics simultaneously by magnetic mesoporous silica nanoparticles to inhibit cancer cells.

    Science.gov (United States)

    Liu, Qian; Zhang, Jixi; Sun, Wei; Xie, Qian Reuben; Xia, Weiliang; Gu, Hongchen

    2012-01-01

    Using nanoparticles to deliver chemotherapeutics offers new opportunities for cancer therapy, but challenges still remain when they are used for the delivery of multiple drugs, especially for the synchronous delivery of hydrophilic and hydrophobic drugs in combination therapies. In this paper, we developed an approach to deliver hydrophilic-hydrophobic anticancer drug pairs by employing magnetic mesoporous silica nanoparticles (MMSNs). We prepared 50 nm-sized MMSNs with uniform pore size and evaluated their capability for the loading of two combinations of chemotherapeutics, namely doxorubicin-paclitaxel and doxorubicin-rapamycin, by means of sequential adsorption from the aqueous solution of doxorubicin and nonaqueous solutions of paclitaxel or rapamycin. Experimental results showed that the present strategy successfully realized the co-loading of hydrophilic and hydrophobic drugs with high-loading content and widely tunable ratio range. We elaborate on the theory behind the molecular interaction between the silica hydroxyl groups and drug molecules, which underlie the controllable loading, and the subsequent release of the drug pairs. Then we demonstrate that the multidrug-loaded MMSNs could be easily internalized by A549 human pulmonary adenocarcinoma cells, and produce enhanced tumor cell apoptosis and growth inhibition as compared to single-drug loaded MMSNs. Our study thus realized simultaneous and dose-tunable delivery of hydrophilic and hydrophobic drugs, which were endowed with improved anticancer efficacy. This strategy could be readily extended to other chemotherapeutic combinations and might have clinically translatable significance.

  10. Computational modeling in melanoma for novel drug discovery.

    Science.gov (United States)

    Pennisi, Marzio; Russo, Giulia; Di Salvatore, Valentina; Candido, Saverio; Libra, Massimo; Pappalardo, Francesco

    2016-06-01

    There is a growing body of evidence highlighting the applications of computational modeling in the field of biomedicine. It has recently been applied to the in silico analysis of cancer dynamics. In the era of precision medicine, this analysis may allow the discovery of new molecular targets useful for the design of novel therapies and for overcoming resistance to anticancer drugs. According to its molecular behavior, melanoma represents an interesting tumor model in which computational modeling can be applied. Melanoma is an aggressive tumor of the skin with a poor prognosis for patients with advanced disease as it is resistant to current therapeutic approaches. This review discusses the basics of computational modeling in melanoma drug discovery and development. Discussion includes the in silico discovery of novel molecular drug targets, the optimization of immunotherapies and personalized medicine trials. Mathematical and computational models are gradually being used to help understand biomedical data produced by high-throughput analysis. The use of advanced computer models allowing the simulation of complex biological processes provides hypotheses and supports experimental design. The research in fighting aggressive cancers, such as melanoma, is making great strides. Computational models represent the key component to complement these efforts. Due to the combinatorial complexity of new drug discovery, a systematic approach based only on experimentation is not possible. Computational and mathematical models are necessary for bringing cancer drug discovery into the era of omics, big data and personalized medicine.

  11. Chemical genetics and drug screening in Drosophila cancer models

    Institute of Scientific and Technical Information of China (English)

    Mara Gladstone; Tin Tin Su

    2011-01-01

    Drug candidates often fail in preclinical and clinical testing because of reasons of efficacy and/or safety.It would be time- and cost-efficient to have screening models that reduce the rate of such false positive candidates that appear promising at first but fail later.In this regard,it would be particularly useful to have a rapid and inexpensive whole animal model that can pre-select hits from high-throughput screens but before testing in costly rodent assays.Drosophila melanogaster has emerged as a potential whole animal model for drug screening.Of particular interest have been drugs that must act in the context of multi-cellularity such as those for neurological disorders and cancer.A recent review provides a comprehensive summary of drug screening in Drosophila,but with an emphasis on neurodegenerative disorders.Here,we review Drosophila screens in the literature aimed at cancer therapeutics.

  12. A novel evolutionary drug scheduling model in cancer chemotherapy.

    Science.gov (United States)

    Liang, Yong; Leung, Kwong-Sak; Mok, Tony Shu Kam

    2006-04-01

    In this paper, we introduce a modified optimal control model of drug scheduling in cancer chemotherapy and a new adaptive elitist-population-based genetic algorithm (AEGA) to solve it. Working closely with an oncologist, we first modify the existing model, because its equation for the cumulative drug toxicity is inconsistent with medical knowledge and clinical experience. To explore multiple efficient drug scheduling policies, we propose a novel variable representation--a cycle-wise representation, and modify the elitist genetic search operators in the AEGA. The simulation results obtained by the modified model match well with the clinical treatment experiences, and can provide multiple efficient solutions for oncologists to consider. Moreover, it has been shown that the evolutionary drug scheduling approach is simple, and capable of solving complex cancer chemotherapy problems by adapting multimodal versions of evolutionary algorithms.

  13. Animal Migraine Models for Drug Development

    DEFF Research Database (Denmark)

    Jansen-Olesen, Inger; Tfelt-Hansen, Peer; Olesen, Jes

    2013-01-01

    responses are likely to be behavioral, allowing multiple experiments in each individual animal. Distinction is made between acute and prophylactic models and how to validate each of them. Modern insight into neurobiological mechanisms of migraine is so good that it is only a question of resources...... for headache has almost come to a standstill partly because of a lack of valid animal models. Here we review previous models with emphasis on optimal characteristics of a future model. In addition to selection of animal species, the method of induction of migraine-like changes and the method of recording...

  14. Drug-loaded electrospun mats of poly(vinyl alcohol) fibres and their release characteristics of four model drugs

    Science.gov (United States)

    Taepaiboon, Pattama; Rungsardthong, Uracha; Supaphol, Pitt

    2006-05-01

    Mats of PVA nanofibres were successfully prepared by the electrospinning process and were developed as carriers of drugs for a transdermal drug delivery system. Four types of non-steroidal anti-inflammatory drug with varying water solubility property, i.e. sodium salicylate (freely soluble in water), diclofenac sodium (sparingly soluble in water), naproxen (NAP), and indomethacin (IND) (both insoluble in water), were selected as model drugs. The morphological appearance of the drug-loaded electrospun PVA mats depended on the nature of the model drugs. The 1H-nuclear magnetic resonance results confirmed that the electrospinning process did not affect the chemical integrity of the drugs. Thermal properties of the drug-loaded electrospun PVA mats were analysed by differential scanning calorimetry and thermogravimetric analysis. The molecular weight of the model drugs played a major role on both the rate and the total amount of drugs released from the as-prepared drug-loaded electrospun PVA mats, with the rate and the total amount of the drugs released decreasing with increasing molecular weight of the drugs. Lastly, the drug-loaded electrospun PVA mats exhibited much better release characteristics of the model drugs than drug-loaded as-cast films.

  15. Computational modeling of drug response with applications to neuroscience.

    Science.gov (United States)

    Herwig, Ralf

    2014-12-01

    The development of novel high-throughput technologies has opened up the opportunity to deeply characterize patient tissues at various molecular levels and has given rise to a paradigm shift in medicine towards personalized therapies. Computational analysis plays a pivotal role in integrating the various genome data and understanding the cellular response to a drug. Based on that data, molecular models can be constructed that incorporate the known downstream effects of drug-targeted receptor molecules and that predict optimal therapy decisions. In this article, we describe the different steps in the conceptual framework of computational modeling. We review resources that hold information on molecular pathways that build the basis for constructing the model interaction maps, highlight network analysis concepts that have been helpful in identifying predictive disease patterns, and introduce the basic concepts of kinetic modeling. Finally, we illustrate this framework with selected studies related to the modeling of important target pathways affected by drugs.

  16. Hydrophilic behavior of graphene and graphene-based materials.

    Science.gov (United States)

    Accordino, Sebastián R; Montes de Oca, Joan Manuel; Rodriguez Fris, J Ariel; Appignanesi, Gustavo A

    2015-10-21

    Graphene and the graphene-based materials like graphite, carbon nanotubes, and fullerenes are not only usually regarded as hydrophobic but also have been widely employed as paradigms for the investigation of the behavior of water under nonpolar confinement, a question of major concern for fields ranging from biology to materials design. However, some experimental and theoretical insights seem to contradict, at least partially, such a picture. In this work, we will provide firm evidence for a neat hydrophilic nature of graphene surfaces. Our molecular dynamics studies will demonstrate that parallel graphene sheets present a strong tendency to remain fully hydrated for moderately long times (even when the equilibrium state is indeed the collapse of the plates), and thus, they are less prone to self-assembly than model hydrophobic surfaces we shall employ as control which readily undergo a hydrophobic collapse. Potential of mean force calculations will indeed make evident that the solvent exerts a repulsive contribution on the self-assembly of graphene surfaces. Moreover, we shall also quantify graphene hydrophilicity by means of the calculation of water density at two pressures and water density fluctuations. This latter study has never been performed on graphene and represents a means both to confirm and to quantify its neat hydrophilic behavior. We shall also make evident the relevance of the mildly attractive water-carbon interactions, since their artificial weakening will be shown to revert from typically hydrophilic to typically hydrophobic behavior.

  17. Drug discovery and development for neglected diseases: the DNDi model.

    Science.gov (United States)

    Chatelain, Eric; Ioset, Jean-Robert

    2011-03-16

    New models of drug discovery have been developed to overcome the lack of modern and effective drugs for neglected diseases such as human African trypanosomiasis (HAT; sleeping sickness), leishmaniasis, and Chagas disease, which have no financial viability for the pharmaceutical industry. With the purpose of combining the skills and research capacity in academia, pharmaceutical industry, and contract researchers, public-private partnerships or product development partnerships aim to create focused research consortia that address all aspects of drug discovery and development. These consortia not only emulate the projects within pharmaceutical and biotechnology industries, eg, identification and screening of libraries, medicinal chemistry, pharmacology and pharmacodynamics, formulation development, and manufacturing, but also use and strengthen existing capacity in disease-endemic countries, particularly for the conduct of clinical trials. The Drugs for Neglected Diseases initiative (DNDi) has adopted a model closely related to that of a virtual biotechnology company for the identification and optimization of drug leads. The application of this model to the development of drug candidates for the kinetoplastid infections of HAT, Chagas disease, and leishmaniasis has already led to the identification of new candidates issued from DNDi's own discovery pipeline. This demonstrates that the model DNDi has been implementing is working but its DNDi, neglected diseases sustainability remains to be proven.

  18. Characterization of a clinical polymer-drug conjugate using multiscale modeling.

    Science.gov (United States)

    Peng, Lili X; Ivetac, Anthony; Chaudhari, Akshay S; Van, Sang; Zhao, Gang; Yu, Lei; Howell, Stephen B; McCammon, J Andrew; Gough, David A

    2010-11-01

    The molecular conformation of certain therapeutic agents has been shown to affect the ability to gain access to target cells, suggesting potential value in defining conformation of candidate molecules. This study explores how the shape and size of poly-γ-glutamyl-glutamate paclitaxel (PGG-PTX), an amphiphilic polymer-drug with potential chemotherapeutic applications, can be systematically controlled by varying hydrophobic and hydrophilic entities. Eighteen different formulations of PGG-PTX varying in three PTX loading fractions (f(PTX)) of 0.18, 0.24, and 0.37 and six spatial arrangements of PTX ('clusters', 'ends', 'even', 'middle', 'random', and 'side') were explored. Molecular dynamics (MD) simulations of all-atom (AA) models of PGG-PTX were run until a statistical equilibrium was reached at 100 ns and then continued as coarse-grained (CG) models until a statistical equilibrium was reached at an effective time of 800 ns. Circular dichroism spectroscopy was used to suggest initial modeling configurations. Results show that a PGG-PTX molecule has a strong tendency to form coil shapes, regardless of the PTX loading fraction and spatial PTX arrangement, although globular shapes exist at f(PTX) = 0.24. Also, less uniform PTX arrangements such as 'ends', 'middle', and 'side' produce coil geometries with more curvature. The prominence of coil shapes over globules suggests that PGG-PTX may confer a long circulation half-life and high propensity for accumulation to tumor endothelia. This multiscale modeling approach may be advantageous for the design of cancer therapeutic delivery systems. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 936-951, 2010.

  19. Modeling Illicit Drug Use Dynamics and Its Optimal Control Analysis

    Directory of Open Access Journals (Sweden)

    Steady Mushayabasa

    2015-01-01

    Full Text Available The global burden of death and disability attributable to illicit drug use, remains a significant threat to public health for both developed and developing nations. This paper presents a new mathematical modeling framework to investigate the effects of illicit drug use in the community. In our model the transmission process is captured as a social “contact” process between the susceptible individuals and illicit drug users. We conduct both epidemic and endemic analysis, with a focus on the threshold dynamics characterized by the basic reproduction number. Using our model, we present illustrative numerical results with a case study in Cape Town, Gauteng, Mpumalanga and Durban communities of South Africa. In addition, the basic model is extended to incorporate time dependent intervention strategies.

  20. A Cooperative Model to Improve Hospital Equipments and Drugs Management

    Science.gov (United States)

    Baffo, Ilaria; Confessore, Giuseppe; Liotta, Giacomo; Stecca, Giuseppe

    The cost of services provided by public and private healthcare systems is nowadays becoming critical. This work tackles the criticalities of hospital equipments and drugs management by emphasizing its implications on the whole healthcare system efficiency. The work presents a multi-agent based model for decisional cooperation in order to address the problem of integration of departments, wards and personnel for improving equipments, and drugs management. The proposed model faces the challenge of (i) gaining the benefits deriving from successful collaborative models already used in industrial systems and (ii) transferring the most appropriate industrial management practices to healthcare systems.

  1. Rat gingival model for testing drugs influencing inflammation

    Directory of Open Access Journals (Sweden)

    Shaju P Jacob

    2013-07-01

    Full Text Available Preclinical drug testing is an important areain new drug development where animals are used.An ideal animal model for this is one which is simple,reliable and can be extrapolated to humans. Topicaldrugs for inflammation are conventionally tested onthe skin of animals after induction of inflammation.A gingival model would be simple as inflammation canbe induced naturally by the action of plaque. Rats area popular animal model for testing drugs as well as tostudy various diseases of the periodontium. Periodontaldisease including gingival inflammation develops inrats in relation to indigenous plaque or experimentallyinduced bacterial products. A number of features ofrats ranging from anatomy, histology and response tobacterial insult can be seen mirrored to a great extentin humans. There is a lot similarity in the developmentand resolution of inflammation as well as the gingivalwound healing of rats and humans. This paper tries toexplore the feasibility of using the rat gingival modelfor preclinical testing of drugs acting on or influencinginflammation and concludes by identifying potentialareas of research using this model. The addition of sucha simple and inexpensive model for preclinical testing ofdrugs will be welcomed by the drug developers.

  2. PBPK modeling and simulation in drug research and development

    Directory of Open Access Journals (Sweden)

    Xiaomei Zhuang

    2016-09-01

    Full Text Available Physiologically based pharmacokinetic (PBPK modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development. In this mini-review, the concept and methodology of PBPK modeling are briefly introduced. Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development. These case studies are from our own work and the literature for better understanding of the absorption, distribution, metabolism and excretion (ADME of a drug candidate, and the applications to increase efficiency, reduce the need for animal studies, and perhaps to replace clinical trials. The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.

  3. Oral pulsatile delivery systems based on swellable hydrophilic polymers.

    Science.gov (United States)

    Gazzaniga, Andrea; Palugan, Luca; Foppoli, Anastasia; Sangalli, Maria Edvige

    2008-01-01

    Upon contact with aqueous fluids, swellable hydrophilic polymers undergo typical chain relaxation phenomena that coincide with a glassy-rubbery transition. In the rubbery phase, these polymers may be subject to swelling, dissolution and erosion processes or, alternatively, form an enduring gel barrier when cross-linked networks (hydrogels) are dealt with. Because of the peculiar hydration and biocompatibility properties, such materials are widely exploited in the pharmaceutical field, particularly as far as hydrophilic cellulose derivatives are concerned. In oral delivery, they have for long been employed in the manufacturing of prolonged release matrices and, more recently, for pulsatile (delayed) release devices as well. Pulsatile delivery, which is meant as the liberation of drugs following programmed lag phases, has drawn increasing interest especially in view of emerging chronotherapeutic approaches. In pursuit of pulsatile release, various design strategies have been proposed, chiefly including reservoir, capsular and osmotic formulations. In most cases, water-swellable polymers play a key role in the overall delivery mechanism after being activated by physiological media. Based on these premises, the aim of the present review is to survey the main oral pulsatile delivery systems, for which swelling, dissolution and/or erosion of hydrophilic polymers are primarily involved in the control of release.

  4. Detection of drug-drug interactions by modeling interaction profile fingerprints.

    Directory of Open Access Journals (Sweden)

    Santiago Vilar

    Full Text Available Drug-drug interactions (DDIs constitute an important problem in postmarketing pharmacovigilance and in the development of new drugs. The effectiveness or toxicity of a medication could be affected by the co-administration of other drugs that share pharmacokinetic or pharmacodynamic pathways. For this reason, a great effort is being made to develop new methodologies to detect and assess DDIs. In this article, we present a novel method based on drug interaction profile fingerprints (IPFs with successful application to DDI detection. IPFs were generated based on the DrugBank database, which provided 9,454 well-established DDIs as a primary source of interaction data. The model uses IPFs to measure the similarity of pairs of drugs and generates new putative DDIs from the non-intersecting interactions of a pair. We described as part of our analysis the pharmacological and biological effects associated with the putative interactions; for example, the interaction between haloperidol and dicyclomine can cause increased risk of psychosis and tardive dyskinesia. First, we evaluated the method through hold-out validation and then by using four independent test sets that did not overlap with DrugBank. Precision for the test sets ranged from 0.4-0.5 with more than two fold enrichment factor enhancement. In conclusion, we demonstrated the usefulness of the method in pharmacovigilance as a DDI predictor, and created a dataset of potential DDIs, highlighting the etiology or pharmacological effect of the DDI, and providing an exploratory tool to facilitate decision support in DDI detection and patient safety.

  5. Dissolution enhancement of poorly water-soluble APIs processed by hot-melt extrusion using hydrophilic polymers.

    Science.gov (United States)

    Maniruzzaman, M; Rana, M M; Boateng, J S; Mitchell, J C; Douroumis, D

    2013-02-01

    The aim of this study was to investigate the efficiency of hydrophilic polymers to enhance the dissolution rate of poorly water-soluble active pharmaceutical ingredients (APIs) processed by hot-melt extrusion (HME). Indomethacin (INM) and famotidine (FMT) were selected as model active substances while polyvinyl caprolactam graft copolymer, soluplus (SOL) and vinylpyrrolidone-vinyl acetate copolymer grades, Kollidon VA64 (VA64) and Plasdone S630 (S630) were used as hydrophilic polymeric carriers. For the purpose of the study, drug-polymer binary blends at various ratios were processed by a Randcastle single screw extruder. The physicochemical properties and the morphology of the extrudates were evaluated through X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Increased drug loadings of up to 40% were achieved in the extruded formulations for both drugs. INM and FMT exhibited strong plasticization effects with increasing concentrations and were found to be molecularly dispersed within the polymer blends. The in vitro dissolution studies showed increased INM/FMT release rates for all formulations compared to that of pure APIs alone.

  6. Testing a fall risk model for injection drug users.

    Science.gov (United States)

    Pieper, Barbara; Templin, Thomas N; Goldberg, Allon

    2012-01-01

    Fall risk is a critical component of clinical assessment and has not been examined for persons who have injected illicit drugs and are aging. The aim of this study was to test and develop the Fall Risk Model for Injection Drug Users by examining the relationships among injection drug use, chronic venous insufficiency, lower extremity impairments (i.e., decreased ankle range of motion, reduced calf muscle endurance, and leg pain), age and other covariates, and the Tinetti balance and gait total score as a measure of fall risk. A cross-sectional comparative design was used with four crossed factors. Standardized instruments were used to assess the variables. Moderated multiple regression with linear and quadratic trends in age was used to examine the nature of the relationship between the Tinetti balance and gait total and age and the potential moderating role of injection drug use. A prespecified series of models was tested. Participants (n = 713) were men (46.9%) and women with a mean age of 46.26 years and primarily African American (61.7%) in methadone treatment centers. The fall risk of a 48-year-old leg injector was comparable with the fall risk of a 69-year-old who had not injected drugs. Variables were added to the model sequentially, resulting in some lost significance of some when they were explained by subsequent variables. Final significant variables in the model were employment status, number of comorbidities, ankle range of motion, leg pain, and calf muscle endurance. Fall risk was associated with route of drug use. Lower extremity impairments accounted for the effects of injection drug use and chronic venous insufficiency on risk for falls. Further understanding of fall risk in injection users is necessary as they age, attempt to work, and participate in activities.

  7. Composite hydrophilic coating for conditioner aluminum fins

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    To solve the so-called "white rust" and 'water bridge" problems of the aluminum fins for heat exchanger of automobile air conditioner, aimed at nationalizing the art of hydrophilic coating technology, the choice of coating forming and curing materials was investigated. By measuring the water contact angle, SEM surface scanning and ingredients analysis of the coating, optimal parameters and composition are acquired. The coating forming mechanisms of the composition was also expatiated. The coating obtained has good hydrophilic and other properties.

  8. Bioresorbable polymer coated drug eluting stent: a model study.

    Science.gov (United States)

    Rossi, Filippo; Casalini, Tommaso; Raffa, Edoardo; Masi, Maurizio; Perale, Giuseppe

    2012-07-01

    In drug eluting stent technologies, an increased demand for better control, higher reliability, and enhanced performances of drug delivery systems emerged in the last years and thus offered the opportunity to introduce model-based approaches aimed to overcome the remarkable limits of trial-and-error methods. In this context a mathematical model was studied, based on detailed conservation equations and taking into account the main physical-chemical mechanisms involved in polymeric coating degradation, drug release, and restenosis inhibition. It allowed highlighting the interdependence between factors affecting each of these phenomena and, in particular, the influence of stent design parameters on drug antirestenotic efficacy. Therefore, the here-proposed model is aimed to simulate the diffusional release, for both in vitro and the in vivo conditions: results were verified against various literature data, confirming the reliability of the parameter estimation procedure. The hierarchical structure of this model also allows easily modifying the set of equations describing restenosis evolution to enhance model reliability and taking advantage of the deep understanding of physiological mechanisms governing the different stages of smooth muscle cell growth and proliferation. In addition, thanks to its simplicity and to the very low system requirements and central processing unit (CPU) time, our model allows obtaining immediate views of system behavior.

  9. Recent Applications of Mesoscale Modeling to Nanotechnology and Drug Delivery

    Energy Technology Data Exchange (ETDEWEB)

    Maiti, A; Wescott, J; Kung, P; Goldbeck-Wood, G

    2005-02-11

    Mesoscale simulations have traditionally been used to investigate structural morphology of polymer in solution, melts and blends. Recently we have been pushing such modeling methods to important areas of Nanotechnology and Drug delivery that are well out of reach of classical molecular dynamics. This paper summarizes our efforts in three important emerging areas: (1) polymer-nanotube composites; (2) drug diffusivity through cell membranes; and (3) solvent exchange in nanoporous membranes. The first two applications are based on a bead-spring-based approach as encoded in the Dissipative Particle Dynamics (DPD) module. The last application used density-based Mesoscale modeling as implemented in the Mesodyn module.

  10. Characterization of Chitosan Polymeric Ethosomes Capable of Encapsulating Hydrophobic and Hydrophilic Drugs Prepared by a Microemulsion Method%微乳液法制备可共载水溶和脂溶药物的壳聚糖季铵盐乙醇脂质体的载药性能表征

    Institute of Scientific and Technical Information of China (English)

    梁晓飞; 胡晶莹; 陈复华; 李宗海; 常津

    2012-01-01

    采用微乳液法制备了可包载脂溶性和水溶性药物的羧甲基壳聚糖十八烷基季铵盐(OQCMC)乙醇脂质体,研究了OQCMC乙醇高分子脂质体的相图、粒径和电位、对药物的包封及释放能力及共载水溶性和脂溶性荧光染料后的细胞内递送能力.结果表明:OQCMC上长链季铵盐分子的取代度和共乳化剂乙醇的加入量对相图中微乳区域的面积影响不大;微乳液法町制备包载水溶性长春新碱(VCR)、脂溶性消炎痛(IMC)或二者共载的OQCMC载药微球,微球粒径为(52.40+0.55) nm,分布均匀;微乳液体系对VCR的最大载药率为22.7%,对IMC的最大载药率为20.1%,二者共载时,VCR的最大载药率为12.2%,IMC的最大载药率为10.0%;载药微球对药物具有缓控释功能.OQCMC乙醇高聚物脂质体可有效地包载荧光染料异硫氰酸荧光素FITC(水溶性)和尼罗红(脂溶性),并将二者递送到卵巢癌H08901细胞内.%Polymeric ethosomes,formed from amphiphilic octadecyl quaternized carboxymethyl chitosan (OQCMC) with different degrees of quaternary substitution (DS),were prepared by the microemulsion (ME) method.These ethosomes could simultaneously encapsulate both the hydrophobic drug indomethacin (IMC) and the hydrophilic drug vincristine (VCR).The effects of the DS of the OQCMC and primary alcohols as cosurfactants on the phase diagram were elucidated.The prepared nanoparticles (NPs) were small ((52.40± 0.55) nm) and suitable as drug carriers for different drugs.The maximum drug loading efficiencies of VCR-loaded and IMC-Ioaded NPs were 22.7% and 20.1%,respectively.The drug loading capacities for co-delivery of VCR and IMC were 12.2% and 10.0%,respectively.OQCMC polymeric ethosomes were stable in aqueous solution and exhibited slow,steady drug release.Hydrophilic fluorescein isothiocyanate (FITC) and hydrophobic Nile Red were encapsulated by the OQCMC ME NPs and simultaneously delivered into HO8901 cells with green and

  11. Homology modeling: an important tool for the drug discovery.

    Science.gov (United States)

    França, Tanos Celmar Costa

    2015-01-01

    In the last decades, homology modeling has become a popular tool to access theoretical three-dimensional (3D) structures of molecular targets. So far several 3D models of proteins have been built by this technique and used in a great diversity of structural biology studies. But are those models consistent enough with experimental structures to make this technique an effective and reliable tool for drug discovery? Here we present, briefly, the fundamentals and current state-of-the-art of the homology modeling techniques used to build 3D structures of molecular targets, which experimental structures are not available in databases, and list some of the more important works, using this technique, available in literature today. In many cases those studies have afforded successful models for the drug design of more selective agonists/antagonists to the molecular targets in focus and guided promising experimental works, proving that, when the appropriate templates are available, useful models can be built using some of the several software available today for this purpose. Limitations of the experimental techniques used to solve 3D structures allied to constant improvements in the homology modeling software will maintain the need for theoretical models, establishing the homology modeling as a fundamental tool for the drug discovery.

  12. Modeling of transdermal drug delivery with a microneedle array

    Science.gov (United States)

    Lv, Y.-G.; Liu, J.; Gao, Y.-H.; Xu, B.

    2006-11-01

    Transdermal drug delivery is generally limited by the extraordinary barrier properties of the stratum corneum, the outer 10-15 µm layer of skin. A conventional needle inserted across this barrier and into deeper tissues could effectively deliver drugs. However, it would lead to infection and cause pain, thereby reducing patient compliance. In order to administer a frequent injection of insulin and other therapeutic agents more efficiently, integrated arrays with very short microneedles were recently proposed as very good candidates for painless injection or extraction. A variety of microneedle designs have thus been made available by employing the fabrication tools of the microelectronics industry and using materials such as silicon, metals, polymers and glass with feature sizes ranging from sub-micron to nanometers. At the same time, experiments were also made to test the capability of the microneedles to inject drugs into tissues. However, due to the difficulty encountered in measurement, a detailed understanding of the spatial and transient drug delivery process still remains unclear up to now. To better grasp the mechanisms involved, quantitative theoretical models were developed in this paper to simultaneously characterize the flow and drug transport, and numerical solutions were performed to predict the kinetics of dispersed drugs injected into the skin from a microneedle array. Calculations indicated that increasing the initial injection velocity and accelerating the blood circulation in skin tissue with high porosity are helpful to enhance the transdermal drug delivery. This study provides the first quantitative simulation of fluid injection through a microneedle array and drug species transport inside the skin. The modeling strategy can also possibly be extended to deal with a wider range of clinical issues such as targeted nanoparticle delivery for therapeutics or molecular imaging.

  13. Process Modeling of Ferrofluids Flowfor Magnetic Targeting Drug Delivery

    Institute of Scientific and Technical Information of China (English)

    LIU Handan; WANG Shigang; XU Wei

    2009-01-01

    Among the proposed techniques for delivering drugs to specific sites within the human body, magnetic targeting drug delivery surpasses due to its non-invasive character and its high targeting efficiency. Although there have been some analyses theoretically for magnetic drug targeting, very few researchers have addressed the hydrodynamic models of magnetic fluids in the blood vessel of human body. This paper presents a mathematical model to describe the hydrodynamics of ferrofluids as drug carriers flowing in a blood vessel under the applied magnetic field. A 3D flow field of magnetic particles in a blood vessel model is numerically simulated in order to further understand clinical application of magnetic targeting drug delivery. Simulation results show that magnetic nanoparticles can be enriched in a target region depending on the applied magnetic field intensity. Magnetic resonance imaging conftrms the enrichment of ferrofluids in a desired body tissue of Sprague-Dawley rats. The simulation results coincide with those animal experiments. Results of the analysis provide the important information and can suggest strategies for improving delivery in favor of the clinical application.

  14. Fluctuations of water near extended hydrophobic and hydrophilic surfaces

    OpenAIRE

    Patel, Amish J.; Chandler, David

    2009-01-01

    We use molecular dynamics simulations of the SPC-E model of liquid water to derive probability distributions for water density fluctuations in probe volumes of different shapes and sizes, both in the bulk as well as near hydrophobic and hydrophilic surfaces. To obtain our results, we introduce a biased sampling of coarse-grained densities, which in turn biases the actual solvent density. The technique is easily combined with molecular dynamics integration algorithms. Our principal result is t...

  15. Animal models of drug relapse and craving: From drug priming-induced reinstatement to incubation of craving after voluntary abstinence.

    Science.gov (United States)

    Venniro, Marco; Caprioli, Daniele; Shaham, Yavin

    2016-01-01

    High rates of relapse to drug use during abstinence is a defining feature of drug addiction. In abstinent drug users, drug relapse is often precipitated by acute exposure to the self-administered drug, drug-associated cues, stress, as well as by short-term and protracted withdrawal symptoms. In this review, we discuss different animal models that have been used to study behavioral and neuropharmacological mechanisms of these relapse-related phenomena. In the first part, we discuss relapse models in which abstinence is achieved through extinction training, including the established reinstatement model, as well as the reacquisition and resurgence models. In the second part, we discuss recent animal models in which drug relapse is assessed after either forced abstinence (e.g., the incubation of drug craving model) or voluntary (self-imposed) abstinence achieved either by introducing adverse consequences to ongoing drug self-administration (e.g., punishment) or by an alternative nondrug reward using a discrete choice (drug vs. palatable food) procedure. We conclude by briefly discussing the potential implications of the recent developments of animal models of drug relapse after voluntary abstinence to the development of medications for relapse prevention.

  16. Near-infrared labeled, ovalbumin loaded polymeric nanoparticles based on a hydrophilic polyester as model vaccine: In vivo tracking and evaluation of antigen-specific CD8(+) T cell immune response.

    Science.gov (United States)

    Rahimian, Sima; Kleinovink, Jan Willem; Fransen, Marieke F; Mezzanotte, Laura; Gold, Henrik; Wisse, Patrick; Overkleeft, Hermen; Amidi, Maryam; Jiskoot, Wim; Löwik, Clemens W; Ossendorp, Ferry; Hennink, Wim E

    2015-01-01

    Particulate antigen delivery systems aimed at the induction of antigen-specific T cells form a promising approach in immunotherapy to replace pharmacokinetically unfavorable soluble antigen formulations. In this study, we developed a delivery system using the model protein antigen ovalbumin (OVA) encapsulated in nanoparticles based on the hydrophilic polyester poly(lactide-co-hydroxymethylglycolic acid) (pLHMGA). Spherical nanoparticles with size 300-400 nm were prepared and characterized and showed a strong ability to deliver antigen to dendritic cells for cross-presentation to antigen-specific T cells in vitro. Using near-infrared (NIR) fluorescent dyes covalently linked to both the nanoparticle and the encapsulated OVA antigen, we tracked the fate of this formulation in mice. We observed that the antigen and the nanoparticles are efficiently co-transported from the injection site to the draining lymph nodes, in a more gradual and durable manner than soluble OVA protein. OVA-loaded pLHMGA nanoparticles efficiently induced antigen cross-presentation to OVA-specific CD8+ T cells in the lymph nodes, superior to soluble OVA vaccination. Together, these data show the potential of pLHMGA nanoparticles as attractive antigen delivery vehicles.

  17. Modeling mass drug treatment and resistant filaria disease transmission

    Science.gov (United States)

    Fuady, A. M.; Nuraini, N.; Soewono, E.; Tasman, H.; Supriatna, A. K.

    2014-03-01

    It has been indicated that a long term application of combined mass drug treatment may contribute to the development of drug resistance in lymphatic filariasis. This phenomenon is not well understood due to the complexity of filaria life cycle. In this paper we formulate a mathematical model for the spread of mass drug resistant in a filaria endemic region. The model is represented in a 13-dimensional Host-Vector system. The basic reproductive ratio of the system which is obtained from the next generation matrix, and analysis of stability of both the disease free equilibrium and the coexistence equilibria are shown. Numerical simulation for long term dynamics for possible field conditions is also shown.

  18. Characterization of lipid model membranes designed for studying impact of ceramide species on drug diffusion and penetration.

    Science.gov (United States)

    Ochalek, M; Heissler, S; Wohlrab, J; Neubert, R H H

    2012-05-01

    The stratum corneum (SC) intercellular lipid matrix plays a crucial role in the skin barrier function. In the present study, lipid model membranes mimicking its phase behavior were prepared and characterized using different analytical techniques (i.a. SAXD, HPTLC, ESEM, confocal Raman imaging, ATR-FTIR spectroscopy) in order to obtain well-standardized model membranes for diffusion and penetration studies. The lipid model membranes should be used in the future for studying the impact of each ceramide species on the diffusion and penetration of drugs. The SAXD study confirmed that the lipids within artificial lipid systems are arranged similarly to the lipids in the human SC. The polarization microscopic and ESEM images showed the homogenous deposition of lipids on the polycarbonate filter. Both the HPTLC and confocal Raman imaging studies proved the homogenous distribution of individual lipid classes within the lipid model membranes. First in vitro diffusion experiments (performed using an ATR-FTIR diffusion cell) of the hydrophilic compound, urea, revealed that the lipid model membrane represents even stronger diffusion barrier than the human SC. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. In silico ADME/T modelling for rational drug design.

    Science.gov (United States)

    Wang, Yulan; Xing, Jing; Xu, Yuan; Zhou, Nannan; Peng, Jianlong; Xiong, Zhaoping; Liu, Xian; Luo, Xiaomin; Luo, Cheng; Chen, Kaixian; Zheng, Mingyue; Jiang, Hualiang

    2015-11-01

    In recent decades, in silico absorption, distribution, metabolism, excretion (ADME), and toxicity (T) modelling as a tool for rational drug design has received considerable attention from pharmaceutical scientists, and various ADME/T-related prediction models have been reported. The high-throughput and low-cost nature of these models permits a more streamlined drug development process in which the identification of hits or their structural optimization can be guided based on a parallel investigation of bioavailability and safety, along with activity. However, the effectiveness of these tools is highly dependent on their capacity to cope with needs at different stages, e.g. their use in candidate selection has been limited due to their lack of the required predictability. For some events or endpoints involving more complex mechanisms, the current in silico approaches still need further improvement. In this review, we will briefly introduce the development of in silico models for some physicochemical parameters, ADME properties and toxicity evaluation, with an emphasis on the modelling approaches thereof, their application in drug discovery, and the potential merits or deficiencies of these models. Finally, the outlook for future ADME/T modelling based on big data analysis and systems sciences will be discussed.

  20. Toward a pragmatic migraine model for drug testing

    DEFF Research Database (Denmark)

    Hansen, Emma Katrine; Guo, Song; Ashina, Messoud

    2016-01-01

    BACKGROUND: A model for the testing of novel antimigraine drugs should ideally use healthy volunteers for ease of recruiting. Cilostazol provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache...

  1. New Hepatitis C Virus Drug Discovery Strategies and Model Systems

    Science.gov (United States)

    Hussain, Snawar; Barretto, Naina; Uprichard, Susan L

    2013-01-01

    Introduction Hepatitis C virus is a major cause of liver disease worldwide and the leading indication for liver transplantation in the United States. Current treatment options are expensive, not effective in all patients and are associated with serious side effects. While pre-clinical anti-HCV drug screening is still hampered by the lack of readily infectable small animal models, the development of cell culture HCV experimental model systems has driven a promising new wave of HCV antiviral drug discovery. Areas covered This review contains a concise overview of current HCV treatment options and limitations with a subsequent in-depth focus on the available experimental models and novel strategies that have and continue to enable important advances in HCV drug development. Expert opinion With a large cohort of chronically HCV infected patients progressively developing liver disease that puts them at risk for hepatocellular carcinoma and hepatic decompensation, there is an urgent need to develop effective therapeutics that are well-tolerated and effective in all patients and against all HCV genotypes. Significant advances in HCV experimental model development have expedited drug discovery; however, additional progress is needed. Importantly, the current trends and momentum in the field suggests that we will continue to overcome critical experimental challenges to reach this end goal. PMID:22861052

  2. Cell and small animal models for phenotypic drug discovery

    Directory of Open Access Journals (Sweden)

    Szabo M

    2017-06-01

    Full Text Available Mihaly Szabo,1 Sara Svensson Akusjärvi,1 Ankur Saxena,1 Jianping Liu,2 Gayathri Chandrasekar,1 Satish S Kitambi1 1Department of Microbiology Tumor, and Cell Biology, 2Department of Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden Abstract: The phenotype-based drug discovery (PDD approach is re-emerging as an alternative platform for drug discovery. This review provides an overview of the various model systems and technical advances in imaging and image analyses that strengthen the PDD platform. In PDD screens, compounds of therapeutic value are identified based on the phenotypic perturbations produced irrespective of target(s or mechanism of action. In this article, examples of phenotypic changes that can be detected and quantified with relative ease in a cell-based setup are discussed. In addition, a higher order of PDD screening setup using small animal models is also explored. As PDD screens integrate physiology and multiple signaling mechanisms during the screening process, the identified hits have higher biomedical applicability. Taken together, this review highlights the advantages gained by adopting a PDD approach in drug discovery. Such a PDD platform can complement target-based systems that are currently in practice to accelerate drug discovery. Keywords: phenotype, screening, PDD, discovery, zebrafish, drug

  3. A thermal analogy for modelling drug elution from cardiovascular stents.

    Science.gov (United States)

    Hose, D R; Narracott, A J; Griffiths, B; Mahmood, S; Gunn, J; Sweeney, D; Lawford, P V

    2004-10-01

    Restriction of blood flow by the narrowing or occlusion of arteries is one of the most common presentations of cardiovascular disease. One treatment involves the introduction of a metal scaffold, or stent, designed to prevent recoil and to provide structural stability to the vessel. On the occasions that this treatment is ineffective, failure is usually associated with re-invasion of tissue. This can be prevented by local delivery of drugs which inhibit tissue growth. The drug might be delivered locally in a polymer coating on the stent. This paper develops and explores the use of a thermal analogue of the drug delivery process and the associated three-dimensional convection-diffusion equation to model the spatial and temporal distribution of drug concentration within the vessel wall. This allows the routine use of commercial finite element analysis software to investigate the dynamics of drug distribution, assist in the understanding of the treatment process and develop improved delivery systems. Two applications illustrate how the model might be used to investigate the effects of controllable or measurable parameters on the progression of the process. It is demonstrated that the geometric characteristics of the stent can have significant impact on the homogeneity of the dosing in the vessel wall.

  4. Tuning surface hydrophilicity/hydrophobicity of hydrocarbon proton exchange membranes (PEMs).

    Science.gov (United States)

    He, Chenfeng; Mighri, Frej; Guiver, Michael D; Kaliaguine, Serge

    2016-03-15

    The effect of annealing on the surface hydrophilicity of various representative classes of hydrocarbon-based proton exchange membranes (PEMs) is investigated. In all cases, a more hydrophilic membrane surface develops after annealing at elevated temperatures. The annealing time also had some influence, but in different ways depending on the class of PEM. Longer annealing times resulted in more hydrophilic membrane surfaces for copolymerized sulfonated poly(ether ether ketone) (SPEEK-HQ), while the opposite behavior occurred in sulfonated poly(aryl ether ether ketone) (Ph-SPEEK), sulfonated poly(aryl ether ether ketone ketone) (Ph-m-SPEEKK) and sulfonated poly (aryl ether ether nitrile) (SPAEEN-B). Increased surface hydrophilicity upon annealing results from ionic cluster decomposition, according to the "Eisenberg-Hird-Moore model" (EHM). The increased surface hydrophilicity is supported by contact angle (CA) measurements, and the cluster decomposition is auxiliarily supported by probing the level of atomic sulfur (sulfonic acid) within different surface depths using angle-dependent XPS as well as ATR-FTIR. Membrane acidification leads to more hydrophilic surfaces by elimination of the hydrogen bonding that occurs between strongly-bound residual solvent (dimethylacetamide, DMAc) and PEM sulfonic acid groups. The study of physicochemical tuning of surface hydrophilicity/hydrophobicity of PEMs by annealing and acidification provides insights for improving membrane electrode assembly (MEA) fabrication in fuel cell (FC).

  5. The control of transmembrane helix transverse position in membranes by hydrophilic residues.

    Science.gov (United States)

    Krishnakumar, Shyam S; London, Erwin

    2007-12-14

    The ability of hydrophilic residues to shift the transverse position of transmembrane (TM) helices within bilayers was studied in model membrane vesicles. Transverse shifts were detected by fluorescence measurements of the membrane depth of a Trp residue at the center of a hydrophobic sequence. They were also estimated from the effective length of the TM-spanning sequence, derived from the stability of the TM configuration under conditions of negative hydrophobic mismatch. Hydrophilic residues (at the fifth position in a 21-residue hydrophobic sequence composed of alternating Leu and Ala residues and flanked on both ends by two Lys) induced transverse shifts that moved the hydrophilic residue closer to the membrane surface. At pH 7, the dependence of the extent of shift upon the identity of the hydrophilic residue increased in the order: L snorkeling). Additional experiments showed that shift was also modulated by the position of the hydrophilic residue in the sequence and the hydrophobicity of the sequence moved out of the bilayer core upon shifting. Combined, these studies show that the insertion boundaries of TM helices are very sensitive to sequence, and can be altered even by weakly hydrophilic residues. Thus, many TM helices may have the capacity to exist in more than one transverse position. Knowledge of the magnitudes of transverse shifts induced by different hydrophilic residues should be useful for design of mutagenesis studies measuring the effect of transverse TM helix position upon function.

  6. Review: US Spelling Colorectal cancer models for novel drug discovery

    Science.gov (United States)

    Golovko, Daniel; Kedrin, Dmitriy; Yilmaz, Omer H.; Roper, Jatin

    2016-01-01

    Introduction Despite increased screening rates and advances in targeted therapy, colorectal cancer (CRC) remains the third leading cause of cancer-related mortality. CRC models that recapitulate key features of human disease are essential to the development of novel and effective therapeutics. Classic methods of modeling CRC such as human cell lines and xenograft mice, while useful for many applications, carry significant limitations. Recently developed in vitro and in vivo models overcome some of these deficiencies and thus can be utilized to better model CRC for mechanistic and translational research. Areas Covered The authors review established models of in vitro cell culture and describe advances in organoid culture for studying normal and malignant intestine. They also discuss key features of classic xenograft models and describe other approaches for in vivo CRC research, including patient-derived xenograft, carcinogen-induced, orthotopic transplantation, and transgenic mouse models. We also describe mouse models of metastatic CRC. Expert opinion No single model is optimal for drug discovery in CRC. Genetically engineered models overcome many limitations of xenograft models. Three-dimensional organoids can be efficiently derived from both normal and malignant tissue for large-scale in vitro and in vivo (transplantation) studies, and are thus a significant advance in CRC drug discovery. PMID:26295972

  7. Quantitative modeling of selective lysosomal targeting for drug design

    DEFF Research Database (Denmark)

    Trapp, Stefan; Rosania, G.; Horobin, R.W.;

    2008-01-01

    Lysosomes are acidic organelles and are involved in various diseases, the most prominent is malaria. Accumulation of molecules in the cell by diffusion from the external solution into cytosol, lysosome and mitochondrium was calculated with the Fick–Nernst–Planck equation. The cell model considers....... This demonstrates that the cell model can be a useful tool for the design of effective lysosome-targeting drugs with minimal off-target interactions....

  8. Modeling drug- and chemical- induced hepatotoxicity with systems biology approaches

    Directory of Open Access Journals (Sweden)

    Sudin eBhattacharya

    2012-12-01

    Full Text Available We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of ‘toxicity pathways’ is described in the context of the 2007 US National Academies of Science report, Toxicity testing in the 21st Century: A Vision and A Strategy. Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically-based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular virtual tissue model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the AhR toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsymTM to understand drug-induced liver injury (DILI, the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

  9. Wetting failure of hydrophilic surfaces promoted by surface roughness

    Science.gov (United States)

    Zhao, Meng-Hua; Chen, Xiao-Peng; Wang, Qing

    2014-06-01

    Wetting failure is of vital importance to many physical phenomena, such as industrial coating and drop emission. Here we show when and how the surface roughness promotes the destabilization of a moving contact line on a hydrophilic surface. Beyond the balance of the driving force and viscous resistance where a stable wetting interface is sustained, wetting failure occurs and is modified by the roughness of the surface. The promoting effect arises only when the wetting velocity is high enough to create a gas-liquid-solid composite interface in the vicinity of the moving contact line, and it is a function of the intrinsic contact angle and proportion of solid tops. We propose a model to explain splashes of rough solid spheres impacting into liquids. It reveals a novel concept that dynamic wetting on hydrophilic rough surfaces can be similar to that on hydrophobic surfaces, and brings a new way to design surfaces with specific wetting properties.

  10. Development of Oral Dissolvable Films of Diclofenac Sodium for Osteoarthritis Using Albizia and Khaya Gums as Hydrophilic Film Formers

    Science.gov (United States)

    Bonsu, Martina Aduenimaa; Kipo, Samuel Lugrie; Boakye-Gyasi, Mariam El; Fosu, Mary-Ann

    2016-01-01

    Oral dissolvable films (ODFs) of diclofenac sodium intended for osteoarthritis were prepared using Albizia and Khaya gums as hydrophilic film formers. The physicochemical properties of the gums were characterized and the gums were used to prepare diclofenac sodium ODFs (~50 mg/4 cm2 film) by solvent casting. The two gums showed satisfactory film forming properties. The physicomechanical properties, drug-excipient compatibility, and in vitro drug release of the films in phosphate buffer pH 6.8 were studied. Khaya gum had higher extraction yield, moisture content, insoluble matter and true density while Albizia gum showed greater swelling capacity, solubility, and minerals content. The ODFs were thin, soft, and flexible with smooth glossy surfaces and possessed satisfactory physicomechanical properties. FTIR studies showed that no interaction occurred between the drug and the gums. The ODFs disintegrated in 75% drug release within 7 min with dissolution efficiencies of ~83–96%. Drug releases from F2, F3, F4, F5, and F6 were similar to F1 (p > 0.05; f1 15 and f2 < 50). Drug release followed the Higuchi kinetic model which is indicative of Fickian drug diffusion. PMID:27313894

  11. Development and evaluation of natural gum-based extended release matrix tablets of two model drugs of different water solubilities by direct compression.

    Science.gov (United States)

    Ofori-Kwakye, Kwabena; Mfoafo, Kwadwo Amanor; Kipo, Samuel Lugrie; Kuntworbe, Noble; Boakye-Gyasi, Mariam El

    2016-01-01

    The study was aimed at developing extended release matrix tablets of poorly water-soluble diclofenac sodium and highly water-soluble metformin hydrochloride by direct compression using cashew gum, xanthan gum and hydroxypropylmethylcellulose (HPMC) as release retardants. The suitability of light grade cashew gum as a direct compression excipient was studied using the SeDeM Diagram Expert System. Thirteen tablet formulations of diclofenac sodium (∼100 mg) and metformin hydrochloride (∼200 mg) were prepared with varying amounts of cashew gum, xanthan gum and HPMC by direct compression. The flow properties of blended powders and the uniformity of weight, crushing strength, friability, swelling index and drug content of compressed tablets were determined. In vitro drug release studies of the matrix tablets were conducted in phosphate buffer (diclofenac: pH 7.4; metformin: pH 6.8) and the kinetics of drug release was determined by fitting the release data to five kinetic models. Cashew gum was found to be suitable for direct compression, having a good compressibility index (ICG) value of 5.173. The diclofenac and metformin matrix tablets produced generally possessed fairly good physical properties. Tablet swelling and drug release in aqueous medium were dependent on the type and amount of release retarding polymer and the solubility of drug used. Extended release of diclofenac (∼24 h) and metformin (∼8-12 h) from the matrix tablets in aqueous medium was achieved using various blends of the polymers. Drug release from diclofenac tablets fitted zero order, first order or Higuchi model while release from metformin tablets followed Higuchi or Hixson-Crowell model. The mechanism of release of the two drugs was mostly through Fickian diffusion and anomalous non-Fickian diffusion. The study has demonstrated the potential of blended hydrophilic polymers in the design and optimization of extended release matrix tablets for soluble and poorly soluble drugs by direct

  12. Modification and Applications of Hydrophilic Polypropylene Membrane

    Science.gov (United States)

    Ariono, Danu; Kusuma Wardani, Anita

    2017-07-01

    Polypropylene (PP) is one of the most important polymers for microporous membrane due to its high void volume, well-controlled porosity, high thermal and chemical stability, and low cost. However, the hydrophobicity of PP becomes a limitation to broaden its applications. Furthermore, membrane fouling occurs more seriously on hydrophobic membranes than hydrophilic ones. To solve this problem, surface modifications have been developed to enhance PP membrane hydrophilicity without changing its bulk properties. Graft polymerization and plasma treatment are the most popular techniques for surface hydrophilization. Some studies showed that highly hydrophilic PP membranes with water contact angle less than 20° could be obtained by plasma treatment and graft polymerization. Furthermore, during plasma treatment, polar groups were formed on the PP membrane surface thus increased water uptake. To bring brief explanation on various research trends for PP modification, this paper provides a review of surface hydrophilization of microporous PP membrane, including plasma treatment and graft polymerization. The effects of surface modification on PP membrane performance such as porosity, water contact angle, and water flux are also discussed. In addition, the applications of modified PP membrane are presented as well.

  13. INVESTIGATION ON EFFECT OF DRUG DOSING REGIMENTS ON DRUG DELIVERY IN SOLID TUMOR VIA LUMPED PARAMETER MODELING AND ANIMAL EXPERIMENTS

    Institute of Scientific and Technical Information of China (English)

    GAO Ci-xiu; XU Shi-xiong; JIANG Yu-ping; TU Jiang-long

    2009-01-01

    This work aims to investigate the effects of dosing regiments on drug delivery in solid tumors and to validate them with experiments on rats.The lumped parameter models of pharmacokinetics and of drug delivery in tumor were developed to simulate time courses of average drug concentration(Ct)of tumor interstitium in two types of dosing regiments(i.e.,single-shot and triple-shot ones).The two regiments were performed via antitumor drug,hydroxycamptothecin(HCPT),on rats,to measure the drug concentration in the tumor.The simulations of the drug concentration in the tumor of the two dosing regiments were conducted and compared with the experimental data on rats.The coefficients in the models were investigated.It is concluded that the triple-shot method is more effective than that of single-shot injection.The present lumped-parameter model is quantitatively competent for drug delivery in solid tumor.

  14. Reinforcement, dopamine and rodent models in drug development for ADHD.

    Science.gov (United States)

    Tripp, Gail; Wickens, Jeff

    2012-07-01

    Attention deficit hyperactivity disorder (ADHD) presents special challenges for drug development. Current treatment with psychostimulants and nonstimulants is effective, but their mechanism of action beyond the cellular level is incompletely understood. We review evidence suggesting that altered reinforcement mechanisms are a fundamental characteristic of ADHD. We show that a deficit in the transfer of dopamine signals from established positive reinforcers to cues that predict such reinforcers may underlie these altered reinforcement mechanisms, and in turn explain key symptoms of ADHD. We argue that the neural substrates controlling the excitation and inhibition of dopamine neurons during the transfer process are a promising target for future drug development. There is a need to develop animal models and behavioral paradigms that can be used to experimentally investigate these mechanisms and their effects on sensitivity to reinforcement. More specific and selective targeting of drug development may be possible through this approach.

  15. Optimal Control of Drug Therapy in a Hepatitis B Model

    Directory of Open Access Journals (Sweden)

    Jonathan E. Forde

    2016-08-01

    Full Text Available Combination antiviral drug therapy improves the survival rates of patients chronically infected with hepatitis B virus by controlling viral replication and enhancing immune responses. Some of these drugs have side effects that make them unsuitable for long-term administration. To address the trade-off between the positive and negative effects of the combination therapy, we investigated an optimal control problem for a delay differential equation model of immune responses to hepatitis virus B infection. Our optimal control problem investigates the interplay between virological and immunomodulatory effects of therapy, the control of viremia and the administration of the minimal dosage over a short period of time. Our numerical results show that the high drug levels that induce immune modulation rather than suppression of virological factors are essential for the clearance of hepatitis B virus.

  16. Modeling energy intake by adding homeostatic feedback and drug intervention.

    Science.gov (United States)

    Gennemark, Peter; Hjorth, Stephan; Gabrielsson, Johan

    2015-02-01

    Energy intake (EI) is a pivotal biomarker used in quantification approaches to metabolic disease processes such as obesity, diabetes, and growth disorders. Eating behavior is however under both short-term and long-term control. This control system manifests itself as tolerance and rebound phenomena in EI, when challenged by drug treatment or diet restriction. The paper describes a model with the capability to capture physiological counter-regulatory feedback actions triggered by energy imbalances. This feedback is general as it handles tolerance to both increases and decreases in EI, and works in both acute and chronic settings. A drug mechanism function inhibits (or stimulates) EI. The deviation of EI relative to a reference level (set-point) serves as input to a non-linear appetite control signal which in turn impacts EI in parallel to the drug intervention. Three examples demonstrate the potential usefulness of the model in both acute and chronic dosing situations. The model shifts the predicted concentration-response relationship rightwardly at lower concentrations, in contrast to models that do not handle functional adaptation. A fourth example further shows that the model may qualitatively explain differences in rate and extent of adaptation in observed EI and its concomitants in both rodents and humans.

  17. A Model for Predicting the Interindividual Variability of Drug-Drug Interactions.

    Science.gov (United States)

    Tod, M; Bourguignon, L; Bleyzac, N; Goutelle, S

    2017-03-01

    Pharmacokinetic drug-drug interactions are frequently characterized and quantified by an AUC ratio (Rauc). The typical value of the AUC ratio in case of cytochrome-mediated interactions may be predicted by several approaches, based on in vitro or in vivo data. Prediction of the interindividual variability of Rauc would help to anticipate more completely the consequences of a drug-drug interaction. We propose and evaluate a simple approach for predicting the standard deviation (sd) of Ln(Rauc), a metric close to the interindividual coefficient of variation of Rauc. First, a model was derived to link sd(Ln Rauc) with the substrate fraction metabolized by each cytochrome and the potency of the interactors, in case of induction or inhibition. Second, the parameters involved in these equations were estimated by a Bayesian hierarchical model, using the data from 56 interaction studies retrieved from the literature. Third, the model was evaluated by several metrics based on the fold prediction error (PE) of sd(Ln Rauc). The median PE was 0.998 (the ideal value is 1) and the interquartile range was 0.96-1.03. The PE was in the acceptable interval (0.5 to 2) in 52 cases out of 56. Fourth, a surface plot of sd(Ln Rauc) as a function of the characteristics of the substrate and the interactor has been built. The minimal value of sd(Ln Rauc) was about 0.08 (obtained for Rauc = 1) while the maximal value, 0.7, was obtained for interactions involving highly metabolized substrates with strong interactors.

  18. A Two-Layer Mathematical Modelling of Drug Delivery to Biological Tissues

    CERN Document Server

    Chakravarty, Koyel

    2016-01-01

    Local drug delivery has received much recognition in recent years, yet it is still unpredictable how drug efficacy depends on physicochemical properties and delivery kinetics. The purpose of the current study is to provide a useful mathematical model for drug release from a drug delivery device and consecutive drug transport in biological tissue, thereby aiding the development of new therapeutic drug by a systemic approach. In order to study the complete process, a two-layer spatio-temporal model depicting drug transport between the coupled media is presented. Drug release is described by considering solubilisation dynamics of drug particle, diffusion of the solubilised drug through porous matrix and also some other processes like reversible dissociation / recrystallization, drug particle-receptor binding and internalization phenomena. The model has led to a system of partial differential equations describing the important properties of drug kinetics. This model contributes towards the perception of the roles...

  19. Animal models for testing anti-prion drugs.

    Science.gov (United States)

    Fernández-Borges, Natalia; Elezgarai, Saioa R; Eraña, Hasier; Castilla, Joaquín

    2013-01-01

    Prion diseases belong to a group of fatal infectious diseases with no effective therapies available. Throughout the last 35 years, less than 50 different drugs have been tested in different experimental animal models without hopeful results. An important limitation when searching for new drugs is the existence of appropriate models of the disease. The three different possible origins of prion diseases require the existence of different animal models for testing anti-prion compounds. Wild type, over-expressing transgenic mice and other more sophisticated animal models have been used to evaluate a diversity of compounds which some of them were previously tested in different in vitro experimental models. The complexity of prion diseases will require more pre-screening studies, reliable sporadic (or spontaneous) animal models and accurate chemical modifications of the selected compounds before having an effective therapy against human prion diseases. This review is intended to put on display the more relevant animal models that have been used in the search of new antiprion therapies and describe some possible procedures when handling chemical compounds presumed to have anti-prion activity prior to testing them in animal models.

  20. Homology Modeling a Fast Tool for Drug Discovery: Current Perspectives

    Science.gov (United States)

    Vyas, V. K.; Ukawala, R. D.; Ghate, M.; Chintha, C.

    2012-01-01

    Major goal of structural biology involve formation of protein-ligand complexes; in which the protein molecules act energetically in the course of binding. Therefore, perceptive of protein-ligand interaction will be very important for structure based drug design. Lack of knowledge of 3D structures has hindered efforts to understand the binding specificities of ligands with protein. With increasing in modeling software and the growing number of known protein structures, homology modeling is rapidly becoming the method of choice for obtaining 3D coordinates of proteins. Homology modeling is a representation of the similarity of environmental residues at topologically corresponding positions in the reference proteins. In the absence of experimental data, model building on the basis of a known 3D structure of a homologous protein is at present the only reliable method to obtain the structural information. Knowledge of the 3D structures of proteins provides invaluable insights into the molecular basis of their functions. The recent advances in homology modeling, particularly in detecting and aligning sequences with template structures, distant homologues, modeling of loops and side chains as well as detecting errors in a model contributed to consistent prediction of protein structure, which was not possible even several years ago. This review focused on the features and a role of homology modeling in predicting protein structure and described current developments in this field with victorious applications at the different stages of the drug design and discovery. PMID:23204616

  1. Animal models in therapeutic drug discovery for oculopharyngeal muscular dystrophy.

    Science.gov (United States)

    Chartier, Aymeric; Simonelig, Martine

    2013-01-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late onset disease which affects specific muscles. No pharmacological treatments are currently available for OPMD. In recent years, genetically tractable models of OPMD – Drosophila and Caenorhabditis elegans – have been generated. Although these models have not yet been used for large-scale primary drug screening, they have been very useful in candidate approaches for the identification of potential therapeutic compounds for OPMD. In this brief review, we summarize the data that validated active molecules for OPMD in animal models including Drosophila, C. elegans and mouse.

  2. Biomembrane models and drug-biomembrane interaction studies: Involvement in drug design and development

    Directory of Open Access Journals (Sweden)

    R Pignatello

    2011-01-01

    Full Text Available Contact with many different biological membranes goes along the destiny of a drug after its systemic administration. From the circulating macrophage cells to the vessel endothelium, to more complex absorption barriers, the interaction of a biomolecule with these membranes largely affects its rate and time of biodistribution in the body and at the target sites. Therefore, investigating the phenomena occurring on the cell membranes, as well as their different interaction with drugs in the physiological or pathological conditions, is important to exploit the molecular basis of many diseases and to identify new potential therapeutic strategies. Of course, the complexity of the structure and functions of biological and cell membranes, has pushed researchers toward the proposition and validation of simpler two- and three-dimensional membrane models, whose utility and drawbacks will be discussed. This review also describes the analytical methods used to look at the interactions among bioactive compounds with biological membrane models, with a particular accent on the calorimetric techniques. These studies can be considered as a powerful tool for medicinal chemistry and pharmaceutical technology, in the steps of designing new drugs and optimizing the activity and safety profile of compounds already used in the therapy.

  3. A hydrophilic dental implant surface exhibits thrombogenic properties in vitro.

    Science.gov (United States)

    Hong, Jaan; Kurt, Seta; Thor, Andreas

    2013-02-01

    Surface modifications of dental implants have gained attention during several years and the thrombotic response from blood components with these materials has become more important during recent years. The aims of this study were to evaluate the thrombogenic response of whole blood, in contact with clinically used dental surfaces, Sandblasted Large grit Acid etched titanium (SLA) and Sandblasted Large grit Acid etched, and chemically modified titanium with hydrophilic properties (SLActive). An in vitro slide chamber model, furnished with heparin, was used in which whole blood came in contact with slides of the test surfaces. After incubation (60-minute rotation at 22 rpm in a 37°C water bath), blood was mixed with ethylenediaminetetraacetic acid (EDTA) or citrate, further centrifuged at +4°C. Finally, plasma was collected pending analysis. Whole blood in contact with surfaces resulted in significantly higher binding of platelets to the hydrophilic surface, accompanied by a significant increase of contact activation of the coagulation cascade. In addition, the platelet activation showed a similar pattern with a significant elevated release of β-TG from platelet granule. The conclusion that can be drawn from the results in our study is that the hydrophilic modification seems to augment the thrombogenic properties of titanium with implications for healing into bone of, that is titanium dental implants. © 2011 Wiley Periodicals, Inc.

  4. Anionic and cationic Hofmeister effects on hydrophobic and hydrophilic surfaces.

    Science.gov (United States)

    Schwierz, Nadine; Horinek, Dominik; Netz, Roland R

    2013-02-26

    Using a two-step modeling approach, we address the full spectrum of direct, reversed, and altered ionic sequences as the charge of the ion, the charge of the surface, and the surface polarity are varied. From solvent-explicit molecular dynamics simulations, we extract single-ion surface interaction potentials for halide and alkali ions at hydrophilic and hydrophobic surfaces. These are used within Poisson-Boltzmann theory to calculate ion density and electrostatic potential distributions at mixed polar/unpolar surfaces for varying surface charge. The resulting interfacial tension increments agree quantitatively with experimental data and capture the Hofmeister series, especially the anomaly of lithium, which is difficult to obtain using continuum theory. Phase diagrams that feature different Hofmeister series as a function of surface charge, salt concentration, and surface polarity are constructed from the long-range force between two surfaces interacting across electrolyte solutions. Large anions such as iodide have a high hydrophobic surface affinity and increase the effective charge magnitude on negatively charged unpolar surfaces. Large cations such as cesium also have a large hydrophobic surface affinity and thereby compensate an external negative charge surface charge most efficiently, which explains the well-known asymmetry between cations and anions. On the hydrophilic surface, the size-dependence of the ion surface affinity is reversed, explaining the Hofmeister series reversal when comparing hydrophobic with hydrophilic surfaces.

  5. A Quantitative Model to Estimate Drug Resistance in Pathogens

    Directory of Open Access Journals (Sweden)

    Frazier N. Baker

    2016-12-01

    Full Text Available Pneumocystis pneumonia (PCP is an opportunistic infection that occurs in humans and other mammals with debilitated immune systems. These infections are caused by fungi in the genus Pneumocystis, which are not susceptible to standard antifungal agents. Despite decades of research and drug development, the primary treatment and prophylaxis for PCP remains a combination of trimethoprim (TMP and sulfamethoxazole (SMX that targets two enzymes in folic acid biosynthesis, dihydrofolate reductase (DHFR and dihydropteroate synthase (DHPS, respectively. There is growing evidence of emerging resistance by Pneumocystis jirovecii (the species that infects humans to TMP-SMX associated with mutations in the targeted enzymes. In the present study, we report the development of an accurate quantitative model to predict changes in the binding affinity of inhibitors (Ki, IC50 to the mutated proteins. The model is based on evolutionary information and amino acid covariance analysis. Predicted changes in binding affinity upon mutations highly correlate with the experimentally measured data. While trained on Pneumocystis jirovecii DHFR/TMP data, the model shows similar or better performance when evaluated on the resistance data for a different inhibitor of PjDFHR, another drug/target pair (PjDHPS/SMX and another organism (Staphylococcus aureus DHFR/TMP. Therefore, we anticipate that the developed prediction model will be useful in the evaluation of possible resistance of the newly sequenced variants of the pathogen and can be extended to other drug targets and organisms.

  6. Modeling HIV-1 drug resistance as episodic directional selection.

    Directory of Open Access Journals (Sweden)

    Ben Murrell

    Full Text Available The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.

  7. Tuning HERG out: antitarget QSAR models for drug development.

    Science.gov (United States)

    Braga, Rodolpho C; Alves, Vinicius M; Silva, Meryck F B; Muratov, Eugene; Fourches, Denis; Tropsha, Alexander; Andrade, Carolina H

    2014-01-01

    Several non-cardiovascular drugs have been withdrawn from the market due to their inhibition of hERG K+ channels that can potentially lead to severe heart arrhythmia and death. As hERG safety testing is a mandatory FDArequired procedure, there is a considerable interest for developing predictive computational tools to identify and filter out potential hERG blockers early in the drug discovery process. In this study, we aimed to generate predictive and well-characterized quantitative structure-activity relationship (QSAR) models for hERG blockage using the largest publicly available dataset of 11,958 compounds from the ChEMBL database. The models have been developed and validated according to OECD guidelines using four types of descriptors and four different machine-learning techniques. The classification accuracies discriminating blockers from non-blockers were as high as 0.83-0.93 on external set. Model interpretation revealed several SAR rules, which can guide structural optimization of some hERG blockers into non-blockers. We have also applied the generated models for screening the World Drug Index (WDI) database and identify putative hERG blockers and non-blockers among currently marketed drugs. The developed models can reliably identify blockers and non-blockers, which could be useful for the scientific community. A freely accessible web server has been developed allowing users to identify putative hERG blockers and non-blockers in chemical libraries of their interest (http://labmol.farmacia.ufg.br/predherg).

  8. Secondary Prevention Services for Clients Who Are Low Risk in Drug Court: A Conceptual Model

    Science.gov (United States)

    DeMatteo, David S.; Marlowe, Douglas B.; Festinger, David S.

    2006-01-01

    The drug court model assumes that most drug offenders are addicts, and that drug use fuels other criminal activity. As a result, drug court clients must satisfy an intensive regimen of treatment and supervisory obligations. However, research suggests that roughly one third of drug court clients do not have a clinically significant substance use…

  9. Development of a convenient ex vivo model for the study of the transcorneal permeation of drugs: histological and permeability evaluation.

    Science.gov (United States)

    Pescina, Silvia; Govoni, Paolo; Potenza, Arianna; Padula, Cristina; Santi, Patrizia; Nicoli, Sara

    2015-01-01

    In this paper, an ex vivo model for the study of the transcorneal permeation of drugs, based on porcine tissues, was evaluated. The setup is characterized by ease of realization, absence of O₂ and CO₂ bubbling and low cost; additionally, the large availability of porcine tissue permits a high throughput. Histological images showed the comparability between porcine and human corneas and confirmed the effectiveness of the isolation procedure. A new de-epithelization procedure based on a thermal approach was also set up to simulate cornea permeability in pathological conditions. The procedure did not affect the integrity of the underlying layers and allowed the characterization of the barrier properties of epithelium and stroma. Six compounds with different physicochemical properties were tested: fluorescein, atenolol, propranolol, diclofenac, ganciclovir and lidocaine. The model highlighted the barrier function played by epithelium toward the diffusion of hydrophilic compounds and the permselectivity with regard to more lipophilic molecules. In particular, positively charged compounds showed a significantly higher transcorneal permeability than negatively charged compounds. The comparability of results with literature data supports the goodness and the robustness of the model, especially taking into account the behavior of fluorescein, which is generally considered a marker of tissue integrity.

  10. Estimation of Liposome Penetration Barriers of Drug Molecules with All-Atom and Coarse-Grained Models.

    Science.gov (United States)

    Genheden, Samuel; Eriksson, Leif A

    2016-09-13

    Liposomes are common carriers of drug molecules, providing enhanced delivery and accumulation of hydrophilic agents or larger biomolecules. Molecular simulations can be used to estimate key features of the drug molecules upon interaction with the liposomes, such as penetration barriers and localization. Herein, we investigate several aspects of the computational estimation of penetration barriers, viz. the potential of mean force (PMFs) along a vector spanning the membrane. First, we provide an evaluation of the all-atom (AA) and coarse-grained (CG) parametrization of 5-aminolevulinic acid (5-ALA) and two of its alkyl esters by computing n-octanol/water partition coefficients. We find that the CG parametrization of the esters performs significantly better than the CG model of 5-ALA, highlighting the difficulty to coarse-grain small, polar molecules. However, the expected trend in partition coefficients is reproduced also with the CG models. Second, we compare PMFs in a small membrane slab described with either the AA or CG models. Here, we are able to reproduce the all-atom PMF of 5-ALA with CG. However, for the alkyl esters it is unfortunately not possible to correctly reproduce both the depth and the penetration barrier of the PMF seen in the AA simulations with any of the tested CG models. We argue that it is more important to choose a CG parametrization that reproduces the depth of the PMF. Third, we compare, using the CG model, PMFs in the membrane slab with PMFs in a large, realistic liposome. We find similar depths but slightly different penetration barriers most likely due to differences in the lipid density along the membrane axis. Finally, we compute PMFs in liposomes with three different lipid compositions. Unfortunately, differences in the PMFs could not be quantified, and it remains to be investigated to what extent liposome simulations can fully reproduce experimental findings.

  11. Preparation and characterization of PEG-modified polyurethane pressure-sensitive adhesives for transdermal drug delivery.

    Science.gov (United States)

    Chen, Xuemei; Liu, Wei; Zhao, Yanbing; Jiang, Lingyu; Xu, Huibi; Yang, Xiangliang

    2009-06-01

    The purpose of this work was to develop novel pressure-sensitive adhesives (PSAs) for transdermal drug-delivery systems (TDDS) with proper adhesive properties, hydrophilicity, biocompatibility and high drug loading. Polyethyleneglycol-modified polyurethane PSAs (PEG-PU-PSAs) were synthesized by prepolymerization method with PEG-modified co-polyether and hexamethylene diisocyanate. The effects of reaction temperature, catalyst, ratios of NCO/OH, co-polyether composition, and chain extender were investigated. Drug loading was studied by using thiamazole (hydrophilic drug), diclofenac sodium (slightly hydrophilic drug), and ibuprofen (lipophilic drug) as model drugs. In vitro drug-release kinetics obtained with Franz diffusion cell and dialysis membrane. The results showed that when reaction temperature at 80 degrees C, weight percentage of stannous octoate as catalyst at 0.05%, ratio of NCO/OH at 2.0-2.2, ratio of PEG/polypropylene glycol (PPG)/polytetramethylene ether glycol (PTMG) at 30/25-30/50-55, and weight percentage of glycol as chain extender at 4.5%, PEGPU-PSAs synthesized performed well on adhesive properties. Actually, PEG on the main chain of the PU could improve the hydrophilicity of PSAs, whereas PPG and PTMG could offer proper adhesive properties. Skin compatibility test on volunteers indicated that PEG-PU-PSAs would not cause any skin irritations. All the model drugs had excellent stabilizations in PEG-PU-PSAs. In vitro drug-release kinetics demonstrated that the drug release depended on drug-loading level and solubility of the drug. These experimental results indicated that PEG-PU-PSAs have good potential for applications in TDDS.

  12. Impulsivity in Animal Models for Drug Abuse Disorders

    OpenAIRE

    Jentsch, J. David

    2008-01-01

    Different conceptual frameworks have been generated to explain substance abuse; of relevance to this article, dysfunction of impulse control systems that are required for avoiding or stopping drug-seeking and –taking may play a key role in addiction. This review summarizes work in animal models that explains the pervasive association between impulse control and substance abuse. It further underscores the concept that impulse control may be a critical target for pharmacological intervention in...

  13. Optimization of matrix tablets controlled drug release using Elman dynamic neural networks and decision trees.

    Science.gov (United States)

    Petrović, Jelena; Ibrić, Svetlana; Betz, Gabriele; Đurić, Zorica

    2012-05-30

    The main objective of the study was to develop artificial intelligence methods for optimization of drug release from matrix tablets regardless of the matrix type. Static and dynamic artificial neural networks of the same topology were developed to model dissolution profiles of different matrix tablets types (hydrophilic/lipid) using formulation composition, compression force used for tableting and tablets porosity and tensile strength as input data. Potential application of decision trees in discovering knowledge from experimental data was also investigated. Polyethylene oxide polymer and glyceryl palmitostearate were used as matrix forming materials for hydrophilic and lipid matrix tablets, respectively whereas selected model drugs were diclofenac sodium and caffeine. Matrix tablets were prepared by direct compression method and tested for in vitro dissolution profiles. Optimization of static and dynamic neural networks used for modeling of drug release was performed using Monte Carlo simulations or genetic algorithms optimizer. Decision trees were constructed following discretization of data. Calculated difference (f(1)) and similarity (f(2)) factors for predicted and experimentally obtained dissolution profiles of test matrix tablets formulations indicate that Elman dynamic neural networks as well as decision trees are capable of accurate predictions of both hydrophilic and lipid matrix tablets dissolution profiles. Elman neural networks were compared to most frequently used static network, Multi-layered perceptron, and superiority of Elman networks have been demonstrated. Developed methods allow simple, yet very precise way of drug release predictions for both hydrophilic and lipid matrix tablets having controlled drug release.

  14. Formulation and evaluation of a sustained-release tablets of metformin hydrochloride using hydrophilic synthetic and hydrophobic natural polymers

    Directory of Open Access Journals (Sweden)

    K J Wadher

    2011-01-01

    Full Text Available Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study was to develop an oral sustained release metformin hydrochloride tablet by using hydrophilic Eudragit RSPO alone or its combination with hydrophobic natural polymers Gum copal and gum damar as rate controlling factor. The tablets were prepared by wet granulation method. The in vitro dissolution study was carried out using USP 22 apparatus I, paddle method and the data was analysed using zero order, first order, Higuchi, Korsmeyer and Hixson-Crowell equations. The drug release study revealed that Eudragit RSPO alone was unable to sustain the drug release. Combining Eudragit with gum Copal and gum Damar sustained the drug release for more than 12 h. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.

  15. Formulation and evaluation of a sustained-release tablets of metformin hydrochloride using hydrophilic synthetic and hydrophobic natural polymers.

    Science.gov (United States)

    Wadher, K J; Kakde, R B; Umekar, M J

    2011-03-01

    Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study was to develop an oral sustained release metformin hydrochloride tablet by using hydrophilic Eudragit RSPO alone or its combination with hydrophobic natural polymers Gum copal and gum damar as rate controlling factor. The tablets were prepared by wet granulation method. The in vitro dissolution study was carried out using USP 22 apparatus I, paddle method and the data was analysed using zero order, first order, Higuchi, Korsmeyer and Hixson-Crowell equations. The drug release study revealed that Eudragit RSPO alone was unable to sustain the drug release. Combining Eudragit with gum Copal and gum Damar sustained the drug release for more than 12 h. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism ranges from diffusion controlled or Fickian transport to anomalous type or non-Fickian transport. Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release.

  16. Mouse models for pre-clinical drug testing in leukemia.

    Science.gov (United States)

    Bhatia, Sanil; Daschkey, Svenja; Lang, Franziska; Borkhardt, Arndt; Hauer, Julia

    2016-11-01

    The development of novel drugs which specifically target leukemic cells, with the overall aim to increase complete remission and to reduce toxicity and morbidity, is the most important prerequisite for modern leukemia treatment. In this regard, the current transition rate of potential novel drugs from bench to bedside is remarkably low. Although many novel drugs show promising data in vitro and in vivo, testing of these medications in clinical phase I trials is often sobering with intolerable toxic side effects leading to failure in FDA approval. Areas covered: In this review, the authors discuss the development of murine model generation in the context of targeted therapy development for the treatment of childhood leukemia, aiming to decrease the attrition rate of progressively complex targeted therapies ranging from small molecules to cell therapy. As more complex therapeutic approaches develop, more complex murine models are needed, to recapitulate closely the human phenotype. Expert opinion: Combining xenograft models for efficacy testing and GEMMs for toxicity testing will be a global approach for pre-clinical testing of complex therapeutics and will contribute to the clinical approval of novel compounds. Finally, this approach is likely to increase clinical approval of novel compounds.

  17. Five-Factor Model personality profiles of drug users

    Directory of Open Access Journals (Sweden)

    Crum Rosa M

    2008-04-01

    Full Text Available Abstract Background Personality traits are considered risk factors for drug use, and, in turn, the psychoactive substances impact individuals' traits. Furthermore, there is increasing interest in developing treatment approaches that match an individual's personality profile. To advance our knowledge of the role of individual differences in drug use, the present study compares the personality profile of tobacco, marijuana, cocaine, and heroin users and non-users using the wide spectrum Five-Factor Model (FFM of personality in a diverse community sample. Method Participants (N = 1,102; mean age = 57 were part of the Epidemiologic Catchment Area (ECA program in Baltimore, MD, USA. The sample was drawn from a community with a wide range of socio-economic conditions. Personality traits were assessed with the Revised NEO Personality Inventory (NEO-PI-R, and psychoactive substance use was assessed with systematic interview. Results Compared to never smokers, current cigarette smokers score lower on Conscientiousness and higher on Neuroticism. Similar, but more extreme, is the profile of cocaine/heroin users, which score very high on Neuroticism, especially Vulnerability, and very low on Conscientiousness, particularly Competence, Achievement-Striving, and Deliberation. By contrast, marijuana users score high on Openness to Experience, average on Neuroticism, but low on Agreeableness and Conscientiousness. Conclusion In addition to confirming high levels of negative affect and impulsive traits, this study highlights the links between drug use and low Conscientiousness. These links provide insight into the etiology of drug use and have implications for public health interventions.

  18. Periodicity-dependent stiffness of periodic hydrophilic-hydrophobic heteropolymers

    Science.gov (United States)

    Chowdhury, Debashish; Stauffer, Dietrich; Strey, Reinhard

    1999-08-01

    From extensive Monte Carlo simulations of a Larson model of perfectly periodic heteropolymers (PHP) in water, a striking stiffening is observed as the period of the alternating hydrophobic and hydrophilic blocks is shortened. At short period and low temperature needlelike conformations are the stable conformations. As temperature is increased thermal fluctuations induce kinks and bends. At large periods compact oligomeric globules are observed. From the generalized Larson prescription, originally developed for modeling surfactant molecules in aqueous solutions, we find that the shorter the period is the more stretched the PHP is. This novel effect is expected to stimulate polymer synthesis and trigger research on the rheology of aqueous periodic heteropolymer solutions.

  19. Hydrophilic fluorescent nanogel thermometer for intracellular thermometry.

    Science.gov (United States)

    Gota, Chie; Okabe, Kohki; Funatsu, Takashi; Harada, Yoshie; Uchiyama, Seiichi

    2009-03-01

    The first methodology to measure intracellular temperature is described. A highly hydrophilic fluorescent nanogel thermometer developed for this purpose stays in the cytoplasm and emits stronger fluorescence at a higher temperature. Thus, intracellular temperature variations associated with biological processes can be monitored by this novel thermometer with a temperature resolution of better than 0.5 degrees C.

  20. Effect of hydrophilic polymers on isradipine complexation with hydroxypropyl β-cyclodextrin.

    Science.gov (United States)

    Mummidi, Varalakshmi; Jayanthi, Vijayaratna

    2013-07-01

    Complexation of isradipine with hydroxypropyl β-cyclodextrin (HPβCD) in the presence and absence of 3 hydrophilic polymers-polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG)-was investigated with an objective of evaluating the effect of hydrophilic polymers on the complexation and solubilizing efficiencies of HPβCD and on the dissolution rate of isradipine from the HPβCD complexes. The phase solubility studies indicated the formation of isradipine-HPβCD inclusion complexes at a 1:1M ratio in solution in both the presence and the absence of hydrophilic polymers. The complexes formed were quite stable. Addition of hydrophilic polymers markedly improved the complexation and solubilizing efficiencies of HPβCD. Solid inclusion complexes of isradipine-HPβCD were prepared in 1:1 and 1:2 ratios by the kneading method, with and without the addition of hydrophilic polymers. The solubility and dissolution rate of isradipine were significantly improved by complexation with HPβCD. The isradipine-HPβCD (1:2) inclusion complex yielded a 9.66-fold increase in the dissolution rate of isradipine. The addition of hydrophilic polymers also markedly improved the dissolution rate of isradipine from HPβCD complexes: a 11.72-, 17.01-, and 39.23-fold increase was observed with PVP, PEG, and HPMC respectively. X-ray diffractometry and differential scanning calorimetry indicated stronger drug amorphization and entrapment in HPβCD because of the combined action of HPβCD and the hydrophilic polymers.

  1. Co-delivery of a hydrophobic small molecule and a hydrophilic peptide by porous silicon nanoparticles.

    Science.gov (United States)

    Liu, Dongfei; Bimbo, Luis M; Mäkilä, Ermei; Villanova, Francesca; Kaasalainen, Martti; Herranz-Blanco, Barbara; Caramella, Carla M; Lehto, Vesa-Pekka; Salonen, Jarno; Herzig, Karl-Heinz; Hirvonen, Jouni; Santos, Hélder A

    2013-09-10

    Nanoparticulate drug delivery systems offer remarkable opportunities for clinical treatment. However, there are several challenges when they are employed to deliver multiple cargos/payloads, particularly concerning the synchronous delivery of small molecular weight drugs and relatively larger peptides. Since porous silicon (PSi) nanoparticles (NPs) can easily contain high payloads of drugs with various properties, we evaluated their carrier potential in multi-drug delivery for co-loading of the hydrophobic drug indomethacin and the hydrophilic human peptide YY3-36 (PYY3-36). Sequential loading of these two drugs into the PSi NPs enhanced the drug release rate of each drug and also their amount permeated across Caco-2 and Caco-2/HT29 cell monolayers. Regardless of the loading approach used, dual or single, the drug permeation profiles were in good correlation with their drug release behaviour. Furthermore, the permeation studies indicated the critical role of the mucus intestinal layer and the paracellular resistance in the permeation of the therapeutic compounds across the intestinal wall. Loading with PYY3-36 also greatly improved the cytocompatibility of the PSi NPs. Conformational analysis indicated that the PYY3-36 could still display biological activity after release from the PSi NPs and permeation across the intestinal cell monolayers. These results are the first demonstration of the promising potential of PSi NPs for simultaneous multi-drug delivery of both hydrophobic and hydrophilic compounds.

  2. 内水相结构对微球包封率及控释行为的影响%Influences of Microparticle Internal Phase on Hydrophilic Drug Loading Efficiency and Releasing

    Institute of Scientific and Technical Information of China (English)

    陈龙; 李红; 邓春林; 何显运; 魏坤; 吴刚

    2013-01-01

    Poly(lactic-co-glycolic acid) (PLGA) microspheres containing ofloxacine were made using the double-emulsion ( water-in-oil-in-water) solvent extraction/evaporation method. The influences of mesoporous silica, hyaluronic acid, polylysine in internal aqueous solution on the microparticle size distribution, surface morphology, ofloxacine loading efficiency and release behavior were investigated. SEM pictures indicate that microparticles with the microcavities inside are fabricated. The average particle size of Haluronic acid (HA) internal phase group is largest and the span index is smallest. Loading efficiency increases in both mesoporous silica (MS) and HA internal phase groups but decreases in polylysine group. The burst release of all groups is higher than that of the control group. Releasing profiles present the release rates of polylysine internal phase microparticle is fastest, while HA internal phase microparticles present the slowest release rates. The fit curves of the drug release pattern of the microparticles with different internal phases accord with the Slogistic mathematic mode.%采用水-油-水双乳化溶剂挥发法制备了聚乳酸-羟基乙酸共聚物(PLGA)/氧氟沙星载药微球,并考察了介孔硅、透明质酸、多聚赖氨酸不同内水相成分对微球粒径及其分布、表面形态、包封率以及释放特性的影响.研究结果表明,采用该方法制备出了内部具有多孔结构的载药微球;透明质酸内水相组微球平均粒度最大,粒径分布最小;介孔硅和透明质酸的加入提高了微球包封率;3种内水相组的初期爆释均高于对照组;多聚赖氨酸内水相组释放速率最快,透明质酸内水相组释放速率最慢.释放拟合曲线表明,4组不同内水相的微球,在释放区间内,释放行为都符合Slogistic方程式.

  3. Modeling the transport of drugs eluted from stents: physical phenomena driving drug distribution in the arterial wall.

    Science.gov (United States)

    Bozsak, Franz; Chomaz, Jean-Marc; Barakat, Abdul I

    2014-04-01

    Despite recent data that suggest that the overall performance of drug-eluting stents (DES) is superior to that of bare-metal stents, the long-term safety and efficacy of DES remain controversial. The risk of late stent thrombosis associated with the use of DES has also motivated the development of a new and promising treatment option in recent years, namely drug-coated balloons (DCB). Contrary to DES where the drug of choice is typically sirolimus and its derivatives, DCB use paclitaxel since the use of sirolimus does not appear to lead to satisfactory results. Since both sirolimus and paclitaxel are highly lipophilic drugs with similar transport properties, the reason for the success of paclitaxel but not sirolimus in DCB remains unclear. Computational models of the transport of drugs eluted from DES or DCB within the arterial wall promise to enhance our understanding of the performance of these devices. The present study develops a computational model of the transport of the two drugs paclitaxel and sirolimus eluted from DES in the arterial wall. The model takes into account the multilayered structure of the arterial wall and incorporates a reversible binding model to describe drug interactions with the constituents of the arterial wall. The present results demonstrate that the transport of paclitaxel in the arterial wall is dominated by convection while the transport of sirolimus is dominated by the binding process. These marked differences suggest that drug release kinetics of DES should be tailored to the type of drug used.

  4. Mathematical modeling of coupled drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls

    KAUST Repository

    Hossain, Shaolie S.

    2011-08-20

    The majority of heart attacks occur when there is a sudden rupture of atherosclerotic plaque, exposing prothrombotic emboli to coronary blood flow, forming clots that can cause blockages of the arterial lumen. Diseased arteries can be treated with drugs delivered locally to vulnerable plaques. The objective of this work was to develop a computational tool-set to support the design and analysis of a catheter-based nanoparticulate drug delivery system to treat vulnerable plaques and diffuse atherosclerosis. A threedimensional mathematical model of coupled mass transport of drug and drug-encapsulated nanoparticles was developed and solved numerically utilizing isogeometric finite element analysis. Simulations were run on a patient-specific multilayered coronary artery wall segment with a vulnerable plaque and the effect of artery and plaque inhomogeneity was analyzed. The method captured trends observed in local drug delivery and demonstrated potential for optimizing drug design parameters, including delivery location, nanoparticle surface properties, and drug release rate. © Springer-Verlag 2011.

  5. Mathematical modeling of coupled drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls

    Science.gov (United States)

    Hossain, Shaolie S.; Hossainy, Syed F. A.; Bazilevs, Yuri; Calo, Victor M.; Hughes, Thomas J. R.

    2012-02-01

    The majority of heart attacks occur when there is a sudden rupture of atherosclerotic plaque, exposing prothrombotic emboli to coronary blood flow, forming clots that can cause blockages of the arterial lumen. Diseased arteries can be treated with drugs delivered locally to vulnerable plaques. The objective of this work was to develop a computational tool-set to support the design and analysis of a catheter-based nanoparticulate drug delivery system to treat vulnerable plaques and diffuse atherosclerosis. A three-dimensional mathematical model of coupled mass transport of drug and drug-encapsulated nanoparticles was developed and solved numerically utilizing isogeometric finite element analysis. Simulations were run on a patient-specific multilayered coronary artery wall segment with a vulnerable plaque and the effect of artery and plaque inhomogeneity was analyzed. The method captured trends observed in local drug delivery and demonstrated potential for optimizing drug design parameters, including delivery location, nanoparticle surface properties, and drug release rate.

  6. Determining the polymer threshold amount for achieving robust drug release from HPMC and HPC matrix tablets containing a high-dose BCS class I model drug: in vitro and in vivo studies.

    Science.gov (United States)

    Klančar, Uroš; Baumgartner, Saša; Legen, Igor; Smrdel, Polona; Kampuš, Nataša Jeraj; Krajcar, Dejan; Markun, Boštjan; Kočevar, Klemen

    2015-04-01

    It is challenging to achieve mechanically robust drug-release profiles from hydrophilic matrices containing a high dose of a drug with good solubility. However, a mechanically robust drug release over prolonged period of time can be achieved, especially if the viscosity and amount of the polymer is sufficiently high, above the "threshold values." The goal of this research was to determine the hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) polymer threshold amount that would enable robust drug release from matrix tablets containing a high dose of levetiracetam as a class I model drug according to the Biopharmaceutical Classification System (BCS). For this purpose, formulations containing HPC or HPMC of similar viscosity range, but in different amounts, were prepared. Based on the dissolution results, two final formulations were selected for additional in vitro and in vivo evaluation to confirm the robustness and to show bioequivalence. Tablets were exposed to various stress conditions in vitro with the use of different mechanically stress-inducing dissolution methods. The in vitro results were compared with in vivo results obtained from fasted and fed bioequivalence studies. Under both conditions, the formulations were bioequivalent and food had a negligible influence on the pharmacokinetic parameters C max and area under the curve (AUC). It was concluded that the drug release from both selected formulations is mechanically robust and that HPC and HPMC polymers with intrinsic viscosities above 9 dL/g and in quantities above 30% enable good mechanical resistance, which ensures bioequivalence. In addition, HPC matrices were found to be more mechanically robust compared to HPMC.

  7. Xenograft model for therapeutic drug testing in recurrent respiratory papillomatosis.

    Science.gov (United States)

    Ahn, Julie; Bishop, Justin A; Akpeng, Belinda; Pai, Sara I; Best, Simon R A

    2015-02-01

    Identifying effective treatment for papillomatosis is limited by a lack of animal models, and there is currently no preclinical model for testing potential therapeutic agents. We hypothesized that xenografting of papilloma may facilitate in vivo drug testing to identify novel treatment options. A biopsy of fresh tracheal papilloma was xenografted into a NOD-scid-IL2Rgamma(null) (NSG) mouse. The xenograft began growing after 5 weeks and was serially passaged over multiple generations. Each generation showed a consistent log-growth pattern, and in all xenografts, the presence of the human papillomavirus (HPV) genome was confirmed by polymerase chain reaction (PCR). Histopathologic analysis demonstrated that the squamous architecture of the original papilloma was maintained in each generation. In vivo drug testing with bevacizumab (5 mg/kg i.p. twice weekly for 3 weeks) showed a dramatic therapeutic response compared to saline control. We report here the first successful case of serial xenografting of a tracheal papilloma in vivo with a therapeutic response observed with drug testing. In severely immunocompromised mice, the HPV genome and squamous differentiation of the papilloma can be maintained for multiple generations. This is a feasible approach to identify therapeutic agents in the treatment of recurrent respiratory papillomatosis. © The Author(s) 2014.

  8. Pharmacokinetic properties and in silico ADME modeling in drug discovery.

    Science.gov (United States)

    Honório, Kathia M; Moda, Tiago L; Andricopulo, Adriano D

    2013-03-01

    The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry.

  9. Applications and limitations of in silico models in drug discovery.

    Science.gov (United States)

    Sacan, Ahmet; Ekins, Sean; Kortagere, Sandhya

    2012-01-01

    Drug discovery in the late twentieth and early twenty-first century has witnessed a myriad of changes that were adopted to predict whether a compound is likely to be successful, or conversely enable identification of molecules with liabilities as early as possible. These changes include integration of in silico strategies for lead design and optimization that perform complementary roles to that of the traditional in vitro and in vivo approaches. The in silico models are facilitated by the availability of large datasets associated with high-throughput screening, bioinformatics algorithms to mine and annotate the data from a target perspective, and chemoinformatics methods to integrate chemistry methods into lead design process. This chapter highlights the applications of some of these methods and their limitations. We hope this serves as an introduction to in silico drug discovery.

  10. Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

    Directory of Open Access Journals (Sweden)

    Chandra Prakash

    2015-12-01

    Full Text Available Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs, and transport proteins coordinate drug influx (phase 0 and drug/drug-metabolite efflux (phase III. Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs, i.e. PXR (pregnane X receptor and CAR (constitutive androstane receptor, and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR, due to transactivation of xenobiotic-response elements (XREs present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug's impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse

  11. Comparative release studies of two cationic model drugs from different cellulose nanocrystal derivatives.

    Science.gov (United States)

    Akhlaghi, Seyedeh Parinaz; Tiong, Daryl; Berry, Richard M; Tam, Kam Chiu

    2014-09-01

    Native cellulose nanocrystal (CNC), oxidized CNC (CNC-OX) and chitosan oligosaccharide grafted CNC (CNC-CSOS) were evaluated as potential drug delivery carriers for two model drug compounds, procaine hydrochloride (PrHy) and imipramine hydrochloride (IMI). The loading of PrHy and IMI was performed at pH 8 and 7, respectively. IMI displayed higher binding to CNC derivatives than PrHy. Drug selective membranes were prepared for each model drug and a drug selective electrode system was used to measure the drug concentration in the filtrate and release medium. Isothermal Titration Calorimetry (ITC) was used to elucidate the types of interactions between model drugs and CNC and its derivatives. The complexation between model drugs and CNC derivatives was confirmed by zeta potential and transmittance measurements. The binding and release of these drugs correlated with the nature and types of interactions that exist between the CNC and drug molecules.

  12. Preparation of hydrophilic molecularly imprinted polymers for tetracycline antibiotics recognition

    Institute of Scientific and Technical Information of China (English)

    Peng Wang; Xiao Fang Fu; Jing Li; Jing Luo; Xiao Ya Zhao; Ming Jun Sun; Yin Zhu Shang; Cheng Ye

    2011-01-01

    Hydrophilic molecularly imprinted polymers (MIPs) were prepared using tetracycline as template, methacrylic acid as monomer and glycidilmethacrylate as pro-hydrophilic co-monomer. Compared with common MIPs, the imprinting effect and adsorption amounts of hydrophilic MIPs for tetracycline (TC) were greatly improved in water media. Furthermore, the electrochemical sensor fabricated by modifying hydrophilic MIPs on glassy carbon electrode was developed for the determination of TC in foodstuff samples.

  13. Stigma, sexual risks, and the war on drugs: Examining drug policy and HIV/AIDS inequities among African Americans using the Drug War HIV/AIDS Inequities Model.

    Science.gov (United States)

    Kerr, Jelani; Jackson, Trinidad

    2016-11-01

    The relationship between drug policy and HIV vulnerability is well documented. However, little research examines the links between racial/ethnic HIV disparities via the Drug War, sexual risk, and stigma. The Drug War HIV/AIDS Inequities Model has been developed to address this dearth. This model contends that inequitable policing and sentencing promotes sexual risks, resource deprivation, and ultimately greater HIV risk for African-Americans. The Drug War also socially marginalizes African Americans and compounds stigma for incarcerated and formerly incarcerated persons living with HIV/AIDS. This marginalization has implications for sexual risk-taking, access to health-promoting resources, and continuum of care participation. The Drug War HIV/AIDS Inequities Model may help illuminate mechanisms that promote increased HIV vulnerability as well as inform structural intervention development and targeting to address racial/ethnic disparities. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Switchable Hydrophobic-Hydrophilic Surfaces

    CERN Document Server

    Bunker, B C; Huber, D L; Kent, M S; Kushmerick, J G; Lopez, G P; Manginell, R P; Méndez, S E; Yim, H

    2002-01-01

    Tethered films of poly n-isopropylacrylamide (PNIPAM) films have been developed as materials that can be used to switch the chemistry of a surface in response to thermal activation. In water, PNIPAM exhibits a thermally-activated phase transition that is accompanied by significant changes in polymer volume, water contact angle, and protein adsorption characteristics. New synthesis routes have been developed to prepare PNIPAM films via in-situ polymerization on self-assembled monolayers. Swelling transitions in tethered films have been characterized using a wide range of techniques including surface plasmon resonance, attenuated total reflectance infrared spectroscopy, interfacial force microscopy, neutron reflectivity, and theoretical modeling. PNIPAM films have been deployed in integrated microfluidic systems. Switchable PNIPAM films have been investigated for a range of fluidic applications including fluid pumping via surface energy switching and switchable protein traps for pre-concentrating and separating...

  15. Scaling predictive modeling in drug development with cloud computing.

    Science.gov (United States)

    Moghadam, Behrooz Torabi; Alvarsson, Jonathan; Holm, Marcus; Eklund, Martin; Carlsson, Lars; Spjuth, Ola

    2015-01-26

    Growing data sets with increased time for analysis is hampering predictive modeling in drug discovery. Model building can be carried out on high-performance computer clusters, but these can be expensive to purchase and maintain. We have evaluated ligand-based modeling on cloud computing resources where computations are parallelized and run on the Amazon Elastic Cloud. We trained models on open data sets of varying sizes for the end points logP and Ames mutagenicity and compare with model building parallelized on a traditional high-performance computing cluster. We show that while high-performance computing results in faster model building, the use of cloud computing resources is feasible for large data sets and scales well within cloud instances. An additional advantage of cloud computing is that the costs of predictive models can be easily quantified, and a choice can be made between speed and economy. The easy access to computational resources with no up-front investments makes cloud computing an attractive alternative for scientists, especially for those without access to a supercomputer, and our study shows that it enables cost-efficient modeling of large data sets on demand within reasonable time.

  16. Parametric time-to-onset models were developed to improve causality assessment of adverse drug reactions from antidiabetic drugs

    NARCIS (Netherlands)

    Scholl, Joep H G; van de Ven, Peter M; van Puijenbroek, Eugène P

    2015-01-01

    OBJECTIVES: The aim of this study was to investigate whether the time to onset (TTO) of common adverse drug reactions (ADRs) of antidiabetic drugs could be modeled using parametric distributions and whether these TTO distributions were dependent on patient characteristics. Furthermore, information r

  17. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism

    DEFF Research Database (Denmark)

    Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik;

    2016-01-01

    The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R......)-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing a more detailed and realistic model. Multiple reaction barriers have been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers...... indicate that the direct N-oxidation mechanism is preferred and proceeds via the doublet spin state of Compound I. Molecular dynamics simulations indicate that the presence of an ordered water molecule in the active site assists in the binding of mexiletine in the active site...

  18. Drug discovery of antimicrobial photosensitizers using animal models.

    Science.gov (United States)

    Sharma, Sulbha K; Dai, Tianhong; Kharkwal, Gitika B; Huang, Ying-Ying; Huang, Liyi; De Arce, Vida J Bil; Tegos, George P; Hamblin, Michael R

    2011-01-01

    Antimicrobial photodynamic therapy (aPDT) is an emerging alternative to antibiotics motivated by growing problems with multi-drug resistant pathogens. aPDT uses non-toxic dyes or photosensitizers (PS) in combination with harmless visible of the correct wavelength to be absorbed by the PS. The excited state PS can form a long-lived triplet state that can interact with molecular oxygen to produce reactive oxygen species such as singlet oxygen and hydroxyl radical that kill the microbial cells. To obtain effective PS for treatment of infections it is necessary to use cationic PS with positive charges that are able to bind to and penetrate different classes of microbial cells. Other drug design criteria require PS with high absorption coefficients in the red/near infra-red regions of the spectrum where light penetration into tissue is maximum, high photostability to minimize photobleaching, and devising compounds that will selectively bind to microbial cells rather than host mammalian cells. Several molecular classes fulfill many of these requirements including phenothiazinium dyes, cationic tetrapyrroles such as porphyrins, phthalocyanines and bacteriochlorins, cationic fullerenes and cationic derivatives of other known PS. Larger structures such as conjugates between PS and cationic polymers, cationic nanoparticles and cationic liposomes that contain PS are also effective. In order to demonstrate in vivo efficacy it is necessary to use animal models of localized infections in which both PS and light can be effectively delivered into the infected area. This review will cover a range of mouse models we have developed using bioluminescent pathogens and a sensitive low light imaging system to non-invasively monitor the progress of the infection in real time. Effective aPDT has been demonstrated in acute lethal infections and chronic biofilm infections; in infections caused by Gram-positive, Gram-negative bacteria and fungi; in infections in wounds, third degree burns

  19. Rhodamine/Nanodiamond as a System Model for Drug Carrier.

    Science.gov (United States)

    Reina, G; Orlanducci, S; Cairone, C; Tamburri, E; Lenti, S; Cianchetta, I; Rossi, M; Terranova, M L

    2015-02-01

    In this paper we present some strategies that are being developed in our labs towards enabling nanodiamond-based applications for drug delivery. Rhodamine B (RhB) has been choosen as model molecule to study the loading of nanodiamonds with active moieties and the conditions for their controlled release. In order to test the chemical/physical interactions between functionalized detonation nanodiamond (DND) and complex molecules, we prepared and tested different RhB@DND systems, with RhB adsorbed or linked by ionic bonding to the DND surface. The chemical state of the DND surfaces before conjugation with the RhB molecules, and the chemical features of the DND-RhB interactions have been deeply analysed by coupling DND with Au nanoparticles and taking advantage of surface enhanced Raman spectroscopy SERS. The effects due to temperature and pH variations on the process of RhB release from the DND carrier have been also investigated. The amounts of released molecules are consistent with those required for effective drug action in conventional therapeutic applications, and this makes the DND promising nanostructured cargos for drug delivery applications.

  20. MR imaging of model drug distribution in simulated vitreous

    Directory of Open Access Journals (Sweden)

    Stein Sandra

    2015-09-01

    Full Text Available The in vitro and in vivo characterization of intravitreal injections plays an important role in developing innovative therapy approaches. Using the established vitreous model (VM and eye movement system (EyeMoS the distribution of contrast agents with different molecular weight was studied in vitro. The impact of the simulated age-related vitreal liquefaction (VL on drug distribution in VM was examined either with injection through the gel phase or through the liquid phase. For comparison the distribution was studied ex vivo in the porcine vitreous. The studies were performed in a magnetic resonance (MR scanner. As expected, with increasing molecular weight the diffusion velocity and the visual distribution of the injected substances decreased. Similar drug distribution was observed in VM and in porcine eye. VL causes enhanced convective flow and faster distribution in VM. Confirming the importance of the injection technique in progress of VL, injection through gelatinous phase caused faster distribution into peripheral regions of the VM than following injection through liquefied phase. VM and MR scanner in combination present a new approach for the in vitro characterization of drug release and distribution of intravitreal dosage forms.

  1. 21 CFR 201.319 - Water-soluble gums, hydrophilic gums, and hydrophilic mucilloids (including, but not limited to...

    Science.gov (United States)

    2010-04-01

    ... hydrophilic mucilloids (including, but not limited to agar, alginic acid, calcium polycarbophil... gum, kelp, methylcellulose, plantago seed (psyllium), polycarbophil tragacanth, and xanthan gum) as..., and hydrophilic mucilloids (including, but not limited to agar, alginic acid, calcium...

  2. Resurgence of alcohol seeking produced by discontinuing non-drug reinforcement as an animal model of drug relapse.

    Science.gov (United States)

    Podlesnik, Christopher A; Jimenez-Gomez, Corina; Shahan, Timothy A

    2006-06-01

    Findings from basic behavioral research suggest that simply discontinuing reinforcement for a recently reinforced operant response can cause the recurrence (i.e. resurgence) of a different previously reinforced response. The present experiment examined resurgence as an animal model of drug relapse. Initially, rats pressed levers to self-administer alcohol during baseline conditions. Next, alcohol self-administration was discontinued and non-drug reinforcers (food pellets) were presented contingent on an alternative response (chain pulling). Finally, when the non-drug reinforcer was discontinued, alcohol seeking recurred even though alcohol was still unavailable for lever pressing. These results suggest that simply discontinuing non-drug reinforcement for a behavior may be sufficient to produce relapse to drug seeking. The resurgence procedure could provide a method to examine environmental, pharmacological, and neurobiological factors that lead to relapse following the loss of a non-drug source of reinforcement.

  3. A Dual-Process Discrete-Time Survival Analysis Model: Application to the Gateway Drug Hypothesis

    Science.gov (United States)

    Malone, Patrick S.; Lamis, Dorian A.; Masyn, Katherine E.; Northrup, Thomas F.

    2010-01-01

    The gateway drug model is a popular conceptualization of a progression most substance users are hypothesized to follow as they try different legal and illegal drugs. Most forms of the gateway hypothesis are that "softer" drugs lead to "harder," illicit drugs. However, the gateway hypothesis has been notably difficult to directly test--that is, to…

  4. Condensing Heat Exchanger with Hydrophilic Antimicrobial Coating

    Science.gov (United States)

    Thomas, Christopher M. (Inventor); Ma, Yonghui (Inventor)

    2014-01-01

    A multi-layer antimicrobial hydrophilic coating is applied to a substrate of anodized aluminum, although other materials may form the substrate. A silver layer is sputtered onto a thoroughly clean anodized surface of the aluminum to about 400 nm thickness. A layer of crosslinked, silicon-based macromolecular structure about 10 nm thickness overlies the silver layer, and the outermost surface of the layer of crosslinked, silicon-based macromolecular structure is hydroxide terminated to produce a hydrophilic surface with a water drop contact angle of less than 10.degree.. The coated substrate may be one of multiple fins in a condensing heat exchanger for use in the microgravity of space, which has narrow channels defined between angled fins such that the surface tension of condensed water moves water by capillary flow to a central location where it is pumped to storage. The antimicrobial coating prevents obstruction of the capillary passages.

  5. Photocatalytic, highly hydrophilic porcelain stoneware slabs

    Science.gov (United States)

    Raimondo, M.; Guarini, G.; Zanelli, C.; Marani, F.; Fossa, L.; Dondi, M.

    2011-10-01

    Photocatalytic, highly hydrophilic industrial porcelain stoneware large slabs were realized by deposition of nanostructured TiO2 coatings. Different surface finishing and experimental conditions were considered in order to assess the industrial feasibility. Photocatalytic and wetting behaviour of functionalized slabs mainly depends on surface phase composition in terms of anatase/rutile ratio, this involving - as a key issue - the deposition of TiO2 on industrially sintered products with an additional annealing step to strengthen coatings' performances and durability.

  6. A hybrid Markov chain-von Mises density model for the drug-dosing interval and drug holiday distributions.

    Science.gov (United States)

    Fellows, Kelly; Rodriguez-Cruz, Vivian; Covelli, Jenna; Droopad, Alyssa; Alexander, Sheril; Ramanathan, Murali

    2015-03-01

    Lack of adherence is a frequent cause of hospitalizations, but its effects on dosing patterns have not been extensively investigated. The purpose of this work was to critically evaluate a novel pharmacometric model for deriving the relationships of adherence to dosing patterns and the dosing interval distribution. The hybrid, stochastic model combines a Markov chain process with the von Mises distribution. The model was challenged with electronic medication monitoring data from 207 hypertension patients and against 5-year persistence data. The model estimates distributions of dosing runs, drug holidays, and dosing intervals. Drug holidays, which can vary between individuals with the same adherence, were characterized by the patient cooperativity index parameter. The drug holiday and dosing run distributions deviate markedly from normality. The dosing interval distribution exhibits complex patterns of multimodality and can be long-tailed. Dosing patterns are an important but under recognized covariate for explaining within-individual variance in drug concentrations.

  7. Improving Detection of Arrhythmia Drug-Drug Interactions in Pharmacovigilance Data through the Implementation of Similarity-Based Modeling.

    Directory of Open Access Journals (Sweden)

    Santiago Vilar

    Full Text Available Identification of Drug-Drug Interactions (DDIs is a significant challenge during drug development and clinical practice. DDIs are responsible for many adverse drug effects (ADEs, decreasing patient quality of life and causing higher care expenses. DDIs are not systematically evaluated in pre-clinical or clinical trials and so the FDA U. S. Food and Drug Administration relies on post-marketing surveillance to monitor patient safety. However, existing pharmacovigilance algorithms show poor performance for detecting DDIs exhibiting prohibitively high false positive rates. Alternatively, methods based on chemical structure and pharmacological similarity have shown promise in adverse drug event detection. We hypothesize that the use of chemical biology data in a post hoc analysis of pharmacovigilance results will significantly improve the detection of dangerous interactions. Our model integrates a reference standard of DDIs known to cause arrhythmias with drug similarity data. To compare similarity between drugs we used chemical structure (both 2D and 3D molecular structure, adverse drug side effects, chemogenomic targets, drug indication classes, and known drug-drug interactions. We evaluated the method on external reference standards. Our results showed an enhancement of sensitivity, specificity and precision in different top positions with the use of similarity measures to rank the candidates extracted from pharmacovigilance data. For the top 100 DDI candidates, similarity-based modeling yielded close to twofold precision enhancement compared to the proportional reporting ratio (PRR. Moreover, the method helps in the DDI decision making through the identification of the DDI in the reference standard that generated the candidate.

  8. Animal models of skin disease for drug discovery

    Science.gov (United States)

    Avci, Pinar; Sadasivam, Magesh; Gupta, Asheesh; De Melo, Wanessa CMA; Huang, Ying-Ying; Yin, Rui; Rakkiyappan, Chandran; Kumar, Raj; Otufowora, Ayodeji; Nyame, Theodore; Hamblin, Michael R

    2013-01-01

    Introduction Discovery of novel drugs, treatments, and testing of consumer products in the field of dermatology is a multi-billion dollar business. Due to the distressing nature of many dermatological diseases, and the enormous consumer demand for products to reverse the effects of skin photodamage, aging, and hair loss, this is a very active field. Areas covered In this paper, we will cover the use of animal models that have been reported to recapitulate to a greater or lesser extent the features of human dermatological disease. There has been a remarkable increase in the number and variety of transgenic mouse models in recent years, and the basic strategy for constructing them is outlined. Expert opinion Inflammatory and autoimmune skin diseases are all represented by a range of mouse models both transgenic and normal. Skin cancer is mainly studied in mice and fish. Wound healing is studied in a wider range of animal species, and skin infections such as acne and leprosy also have been studied in animal models. Moving to the more consumer-oriented area of dermatology, there are models for studying the harmful effect of sunlight on the skin, and testing of sunscreens, and several different animal models of hair loss or alopecia. PMID:23293893

  9. Reconsidering GHB: orphan drug or new model antidepressant?

    Science.gov (United States)

    Bosch, Oliver G; Quednow, Boris B; Seifritz, Erich; Wetter, Thomas C

    2012-05-01

    For six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other efforts have been made to ameliorate the symptoms of depression by pharmacological means. The gamma-aminobutyric acid (GABA) system was and possibly still is one of the main alternative drug targets. Gammahydroxybutyrate (GHB) was developed as an orally active GABA analogue. It was tested in animal models of depression and human studies. The effects on sleep, agitation, anhedonia and depression were promising. However, the rise of benzodiazepines and tricyclic antidepressants brought GHB out of the scope of possible treatment alternatives. GHB is a GABA(B) and GHB receptor agonist with a unique spectrum of behavioural, neuroendocrine and sleep effects, and improves daytime sleepiness in various disorders such as narcolepsy, Parkinson's disease and fibromyalgia. Although it was banned from the US market at the end of the 1990s because of its abuse and overdose potential, it later was approved for the treatment of narcolepsy. New research methods and an extended view on other neurotransmitter systems as possible treatment targets of antidepressant treatment brought GHB back to the scene. This article discusses the unique neurobiological effects of GHB, its misuse potential and possible role as a model substance for the development of novel pharmacological treatment strategies in depressive disorders.

  10. Hydrophilic-oleophobic stimuli-responsive materials and surfaces

    Science.gov (United States)

    Howarter, John A.

    Due to their high surface energy, hydrophilic surfaces are susceptible to contamination which is difficult to remove and often ruins the surface. Hydrophilic-oleophobic coatings have a diverse engineering potential including applications as self-cleaning surfaces, extended life anti-fog coatings, and environmental remediation in the selective filtration of oil-in-water mixtures. A successful design model for hydrophilic-oleophobic behavior has been developed using perfluorinated surfactants covalently bound to a surface. Within this design model, a variety of materials have been explored which the surfactants are covalently bound to a substrate; similarly, the surfactants may also be incorporated as a monomer into bulk copolymers. Surfactant based surfaces exhibited simultaneous hydrophilicity, necessary for anti-fogging, and oleophobicity, necessary for contamination resistance. The combination of these features rendered the surface as self-cleaning. Surfactant based brushes, composed of polyethylene glycol and perfluorinated constituents were grafted on to silica surfaces. The relationship between brush density and stimuli-responsiveness was determined by varying grafting conditions. The resultant surfaces were characterized with respect to chemical composition, brush thickness, and wetting behavior of water and hexadecane. Optimized surfaces exhibited stimuli-responsive behavior such that the surfaces will be wetted by water but not by oil. Surfactants were incorporated into random copolymers to create self-cleaning polymers which could be easily coated on to surfaces post-synthesis. Acrylic acid, methyl methacrylate, and hydroxyethyl methacrylate were used as comonomers; feed ratio was varied to establish compositional limits of stimuli-responsive behavior. Polymer composition dictated coating durability and self-cleaning performance as determined by water and hexadecane contact angle. The ability of select coatings to mitigate fogging was assessed in two

  11. Development and validation of an alternative disturbed skin model by mechanical abrasion to study drug penetration.

    Science.gov (United States)

    Schlupp, P; Weber, M; Schmidts, T; Geiger, K; Runkel, F

    2014-01-01

    Pharmaceuticals and cosmetics for dermal application are usually tested on healthy skin, although the primary permeation barrier, the stratum corneum, is often impaired by skin diseases or small skin lesions, especially on the hands. These skin conditions can considerably influence the permeation of chemicals and drugs. Furthermore, risk assessment for example of nanoparticles should be performed under various skin conditions to reflect the true circumstances. Therefore, an alternative and reproducible method for a high throughput of skin samples with impaired skin barrier was developed and verified by skin permeation studies (25 h) of caffeine, sorbic acid and testosterone compared to healthy (untreated) and tape-stripped skin. Skin barrier disruption was controlled by TEWL measurement. Skin permeation of the three substances was increased in tape-stripped and abraded skin compared to untreated skin due to the reduced barrier integrity. Enhancement of drug uptake was highest for the most hydrophilic substance, caffeine, followed by sorbic acid and lipophilic testosterone. No significant difference in drug uptake studies was observed between the new abrasion method with an aluminum-coated sponge and the tape-stripping method. The obtained results demonstrate that this abrasion method is an alternative way to achieve a disturbed skin barrier for drug and chemical uptake studies.

  12. Old and new therapeutics for Rheumatoid Arthritis: in vivo models and drug development

    DEFF Research Database (Denmark)

    Sardar, Samra; Andersson, Åsa

    2016-01-01

    Development of novel drugs for treatment of chronic inflammatory diseases is to a large extent dependent on the availability of good experimental in vivo models in order to perform preclinical tests of new drugs and for the identification of novel drug targets. Here, we review a number of existing...... of in vivo models during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although one Rheumatoid Arthritis in vivo model cannot mirror...... the complexity of disease development, there exist a number of good animal models for Rheumatoid Arthritis, each defining some parts in disease development, which are useful for studies of drug response. We find that many of the established drugs were not tested in in vivo models before being used in the clinic...

  13. Skin models for the testing of transdermal drugs

    Science.gov (United States)

    Abd, Eman; Yousef, Shereen A; Pastore, Michael N; Telaprolu, Krishna; Mohammed, Yousuf H; Namjoshi, Sarika; Grice, Jeffrey E; Roberts, Michael S

    2016-01-01

    The assessment of percutaneous permeation of molecules is a key step in the evaluation of dermal or transdermal delivery systems. If the drugs are intended for delivery to humans, the most appropriate setting in which to do the assessment is the in vivo human. However, this may not be possible for ethical, practical, or economic reasons, particularly in the early phases of development. It is thus necessary to find alternative methods using accessible and reproducible surrogates for in vivo human skin. A range of models has been developed, including ex vivo human skin, usually obtained from cadavers or plastic surgery patients, ex vivo animal skin, and artificial or reconstructed skin models. Increasingly, largely driven by regulatory authorities and industry, there is a focus on developing standardized techniques and protocols. With this comes the need to demonstrate that the surrogate models produce results that correlate with those from in vivo human studies and that they can be used to show bioequivalence of different topical products. This review discusses the alternative skin models that have been developed as surrogates for normal and diseased skin and examines the concepts of using model systems for in vitro–in vivo correlation and the demonstration of bioequivalence. PMID:27799831

  14. [Classification models of structure - P-glycoprotein activity of drugs].

    Science.gov (United States)

    Grigorev, V Yu; Solodova, S L; Polianczyk, D E; Raevsky, O A

    2016-01-01

    Thirty three classification models of substrate specificity of 177 drugs to P-glycoprotein have been created using of the linear discriminant analysis, random forest and support vector machine methods. QSAR modeling was carried out using 2 strategies. The first strategy consisted in search of all possible combinations from 1÷5 descriptors on the basis of 7 most significant molecular descriptors with clear physico-chemical interpretation. In the second case forward selection procedure up to 5 descriptors, starting from the best single descriptor was used. This strategy was applied to a set of 387 DRAGON descriptors. It was found that only one of 33 models has necessary statistical parameters. This model was designed by means of the linear discriminant analysis on the basis of a single descriptor of H-bond (ΣC(ad)). The model has good statistical characteristics as evidenced by results to both internal cross-validation, and external validation with application of 44 new chemicals. This confirms an important role of hydrogen bond in the processes connected with penetration of chemical compounds through a blood-brain barrier.

  15. Fabrication of hydrophilic paclitaxel-loaded PLA-PEG-PLA microparticles via SEDS process

    Institute of Scientific and Technical Information of China (English)

    Ping OUYANG; Yun-qing KANG; Guang-fu YIN; Zhong-bing HUANG; Ya-dong YAO; Xiao-ming LIAO

    2009-01-01

    In this work, chemically bonded poly(D, L-lactide)-polyethylene glycol-poly(D, L-lactide) (PLA-PEG-PLA) triblock copolymers with various PEG contents and PLA homopolymer were synthesized via melt polymerization, and were confirmed by FTIR and 1 H-NMR results. The molecular weight and polydispersity of the synthesized PLA and PLA-PEG-PLA copolymers were investigated by gel permeation chromatography. Hydro-philicity of the copolymers was identified by contact angle measurement. PLA-PEG-PLA and PLA microparticles loaded with and without PTX were then produced via solution enhanced dispersion by supercritical CO2 (SEDS) process. The effect of the PEG content on the particle size distribution, morphology, drug load, and encapsulation efficiency of the fabricated microparticles was also studied. Results indicate that PLA and PLA-PEG-PLA micropar-ticles all exhibit sphere-like shape with smooth surface, when PEG content is relatively low. The produced microparticles have narrow particle size distributions and small particle sizes. The drug load and encapsulation efficiency of the produced microparticles decreases with higher PEG content in the copolymer matrix. Moreover, high hydrophilicity is found when PEG is chemically attached to originally hydrophobic PLA, providing the produced drug-loaded microparticles with high hydrophi-licity, biocompatibility, and prolonged circulation time, which are considered of vital importance for vessel-circulating drug delivery system.

  16. Dextran vesicular carriers for dual encapsulation of hydrophilic and hydrophobic molecules and delivery into cells.

    Science.gov (United States)

    Pramod, P S; Takamura, Kathryn; Chaphekar, Sonali; Balasubramanian, Nagaraj; Jayakannan, M

    2012-11-12

    Dextran vesicular nanoscaffolds were developed based on polysaccharide and renewable resource alkyl tail for dual encapsulation of hydrophilic and hydrophobic molecules (or drugs) and delivery into cells. The roles of the hydrophobic segments on the molecular self-organization of dextran backbone into vesicles or nanoparticles were investigated in detail. Dextran vesicles were found to be a unique dual carrier in which water-soluble molecules (like Rhodamine-B, Rh-B) and polyaromatic anticancer drug (camptothecin, CPT) were selectively encapsulated in the hydrophilic core and hydrophobic layer, respectively. The dextran vesicles were capable of protecting the plasma-sensitive CPT lactone pharmacophore against the hydrolysis by 10× better than the CPT alone in PBS. The aliphatic ester linkage connecting the hydrophobic tail with dextran was found to be cleaved by esterase under physiological conditions for fast releasing of CPT or Rh-B. Cytotoxicity of the dextran vesicle and its drug conjugate were tested on mouse embryonic fibroblast cells (MEFs) using MTT assay. The dextran vesicular scaffold was found to be nontoxic to living cells. CPT loaded vesicles were found to be 2.5-fold more effective in killing fibroblasts compared to that of CPT alone in PBS. Confocal microscopic images confirmed that both Rh-B and CPT loaded vesicles to be taken up by fibroblasts compared to CPT alone, showing a distinctly perinuclear localization in cells. The custom designed dextran vesicular provides new research opportunities for dual loading and delivering of hydrophilic and hydrophobic drug molecules.

  17. Effect of hydrophilic walls on the hydration of sodium cations in planar nanopores

    Science.gov (United States)

    Shevkunov, S. V.

    2016-09-01

    A computer simulation of the structure of Na+ ion hydration shells with sizes in the range of 1 to 100 molecules in a planar model nanopore 0.7 nm wide with structureless hydrophilic walls is performed using the Monte Carlo method at a temperature of 298 K. A detailed model of many-body intermolecular interactions, calibrated with reference to experimental data on the free energy and enthalpy of reactions after gaseous water molecules are added to a hydration shell, is used. It is found that perturbations produced by hydrophilic walls cause the hydration shell to decay into two components that differ in their spatial arrangement and molecular orientational order.

  18. Engineering and validation of a novel lipid thin film for biomembrane modeling in lipophilicity determination of drugs and xenobiotics

    Directory of Open Access Journals (Sweden)

    Ogbonna Udochi

    2009-09-01

    Full Text Available Abstract Background Determination of lipophilicity as a tool for predicting pharmacokinetic molecular behavior is limited by the predictive power of available experimental models of the biomembrane. There is current interest, therefore, in models that accurately simulate the biomembrane structure and function. A novel bio-device; a lipid thin film, was engineered as an alternative approach to the previous use of hydrocarbon thin films in biomembrane modeling. Results Retention behavior of four structurally diverse model compounds; 4-amino-3,5-dinitrobenzoic acid (ADBA, naproxen (NPX, nabumetone (NBT and halofantrine (HF, representing 4 broad classes of varying molecular polarities and aqueous solubility behavior, was investigated on the lipid film, liquid paraffin, and octadecylsilane layers. Computational, thermodynamic and image analysis confirms the peculiar amphiphilic configuration of the lipid film. Effect of solute-type, layer-type and variables interactions on retention behavior was delineated by 2-way analysis of variance (ANOVA and quantitative structure property relationships (QSPR. Validation of the lipid film was implemented by statistical correlation of a unique chromatographic metric with Log P (octanol/water and several calculated molecular descriptors of bulk and solubility properties. Conclusion The lipid film signifies a biomimetic artificial biological interface capable of both hydrophobic and specific electrostatic interactions. It captures the hydrophilic-lipophilic balance (HLB in the determination of lipophilicity of molecules unlike the pure hydrocarbon film of the prior art. The potentials and performance of the bio-device gives the promise of its utility as a predictive analytic tool for early-stage drug discovery science.

  19. Structured representation of drug indications: lexical and semantic analysis and object-oriented modeling.

    Science.gov (United States)

    Duclos, C; Venot, A

    2000-03-01

    No standardized representation of drug indications is currently available that could be used in drug knowledge bases. We describe an object-oriented representation of indications that should make it possible to develop new tools for selecting drugs and checking prescriptions in computerized drug prescription systems. The model was developed using the results of a lexical and semantic analysis of drug indications, collected into a single file and processed using natural language processing software. It distinguishes both the diseases for which the drug may be given and the efficiency of the drug for a given indication. Two aspects of the model were evaluated: the differences if two independent evaluators filled the attributes independently and the loss of information induced by the use of the model. A system based on this model, making it possible for the physician to select all the drugs satisfying various criteria, is also presented.

  20. SVM Based Descriptor Selection and Classification of Neurodegenerative Disease Drugs for Pharmacological Modeling.

    Science.gov (United States)

    Shahid, Mohammad; Shahzad Cheema, Muhammad; Klenner, Alexander; Younesi, Erfan; Hofmann-Apitius, Martin

    2013-03-01

    Systems pharmacological modeling of drug mode of action for the next generation of multitarget drugs may open new routes for drug design and discovery. Computational methods are widely used in this context amongst which support vector machines (SVM) have proven successful in addressing the challenge of classifying drugs with similar features. We have applied a variety of such SVM-based approaches, namely SVM-based recursive feature elimination (SVM-RFE). We use the approach to predict the pharmacological properties of drugs widely used against complex neurodegenerative disorders (NDD) and to build an in-silico computational model for the binary classification of NDD drugs from other drugs. Application of an SVM-RFE model to a set of drugs successfully classified NDD drugs from non-NDD drugs and resulted in overall accuracy of ∼80 % with 10 fold cross validation using 40 top ranked molecular descriptors selected out of total 314 descriptors. Moreover, SVM-RFE method outperformed linear discriminant analysis (LDA) based feature selection and classification. The model reduced the multidimensional descriptors space of drugs dramatically and predicted NDD drugs with high accuracy, while avoiding over fitting. Based on these results, NDD-specific focused libraries of drug-like compounds can be designed and existing NDD-specific drugs can be characterized by a well-characterized set of molecular descriptors.

  1. Design and Characterization of a Silk-Fibroin-Based Drug Delivery Platform Using Naproxen as a Model Drug

    Directory of Open Access Journals (Sweden)

    Tatyana Dyakonov

    2012-01-01

    Full Text Available The objective of this proof-of-concept study was to develop a platform for controlled drug delivery based on silk fibroin (SF and to explore the feasibility of using SF in oral drug delivery. The SF-containing matrixes were prepared via spray-drying and film casting, and the release profile of the model drug naproxen sodium was evaluated. Attenuated total reflectance Fourier transform infrared spectroscopy (FTIR has been used to observe conformational changes in SF- and drug-containing compositions. SF-based films, spray-dried microparticles, and matrixes loaded with naproxen were prepared. Both FTIR spectra and in vitro dissolution data demonstrated that SF β-sheet conformation regulates the release profile of naproxen. The controlled release characteristics of the SF-containing compositions were evaluated as a function of SF concentration, temperature, and exposure to dehydrating solvents. The results suggest that SF may be an attractive polymer for use in controlled drug delivery systems.

  2. Simulating the co-encapsulation of drugs in a "smart" core-shell-shell polymer nanoparticle.

    Science.gov (United States)

    Buxton, Gavin A

    2014-03-01

    A coarse-grained lattice Monte Carlo method is used to simulate co-encapsulation and delivery of both a hydrophilic and hydrophobic drug from polymer nanoparticles. In particular, core-shell-shell polymer nanoparticles with acid-labile bonds are simulated, and the preferential release of the encapsulated drugs near more acidic tumors is captured. While these simple models lack the molecular details of a real system, they can reveal interesting insights concerning the effects of entropy and enthalpy in these systems.

  3. Preparation of sustained release co-extrudates by hot-melt extrusion and mathematical modelling of in vitro/in vivo drug release profiles.

    Science.gov (United States)

    Quintavalle, U; Voinovich, D; Perissutti, B; Serdoz, F; Grassi, G; Dal Col, A; Grassi, M

    2008-03-01

    Aim of this work was to develop a cylindrical co-extrudate characterised by an in vivo sustained release profile by means of a hot-melt extrusion process. Co-extrudate was made up of two concentric extruded matrices: an inner one having a hydrophilic character, based on polyethylene glycol, and an outer one with lipophilic character, based on microcrystalline wax. Both segments contained theophylline as a model drug. A screening between several devices differing for dimensions (diameter and length) and relative proportions of the inner and outer part was carried out on the basis of their in vitro drug release and the release mechanism was studied by means of a mathematical model. The co-extrudate exhibiting the desired sustained release was selected for in vivo bioavailability studies. In vivo studies confirmed the achievement of the purpose of the research, demonstrating the desired release of theophylline on four healthy volunteers. Accordingly, hot-melt extrusion process is a viable method to produce in a single step co-extrudates showing a sustained release. In addition, the developed mathematical model proved to be a reliable descriptor of the both in vitro and in vivo experimental data.

  4. Skin models for the testing of transdermal drugs

    Directory of Open Access Journals (Sweden)

    Abd E

    2016-10-01

    Full Text Available Eman Abd,1 Shereen A Yousef,1 Michael N Pastore,2 Krishna Telaprolu,1 Yousuf H Mohammed,1 Sarika Namjoshi,1 Jeffrey E Grice,1 Michael S Roberts1,2 1Translational Research Institute, School of Medicine, University of Queensland, Brisbane, 2School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia Abstract: The assessment of percutaneous permeation of molecules is a key step in the evaluation of dermal or transdermal delivery systems. If the drugs are intended for delivery to humans, the most appropriate setting in which to do the assessment is the in vivo human. However, this may not be possible for ethical, practical, or economic reasons, particularly in the early phases of development. It is thus necessary to find alternative methods using accessible and reproducible surrogates for in vivo human skin. A range of models has been developed, including ex vivo human skin, usually obtained from cadavers or plastic surgery patients, ex vivo animal skin, and artificial or reconstructed skin models. Increasingly, largely driven by regulatory authorities and industry, there is a focus on developing standardized techniques and protocols. With this comes the need to demonstrate that the surrogate models produce results that correlate with those from in vivo human studies and that they can be used to show bioequivalence of different topical products. This review discusses the alternative skin models that have been developed as surrogates for normal and diseased skin and examines the concepts of using model systems for in vitro–in vivo correlation and the demonstration of bioequivalence. Keywords: percutaneous permeation, dermal delivery, transdermal, bioequivalence, ex vivo skin models, reconstructed skin

  5. Physiologically Based Pharmacokinetic Modeling to Predict Drug-Drug Interactions with Efavirenz Involving Simultaneous Inducing and Inhibitory Effects on Cytochromes.

    Science.gov (United States)

    Marzolini, Catia; Rajoli, Rajith; Battegay, Manuel; Elzi, Luigia; Back, David; Siccardi, Marco

    2017-04-01

    Antiretroviral drugs are among the therapeutic agents with the highest potential for drug-drug interactions (DDIs). In the absence of clinical data, DDIs are mainly predicted based on preclinical data and knowledge of the disposition of individual drugs. Predictions can be challenging, especially when antiretroviral drugs induce and inhibit multiple cytochrome P450 (CYP) isoenzymes simultaneously. This study predicted the magnitude of the DDI between efavirenz, an inducer of CYP3A4 and inhibitor of CYP2C8, and dual CYP3A4/CYP2C8 substrates (repaglinide, montelukast, pioglitazone, paclitaxel) using a physiologically based pharmacokinetic (PBPK) modeling approach integrating concurrent effects on CYPs. In vitro data describing the physicochemical properties, absorption, distribution, metabolism, and elimination of efavirenz and CYP3A4/CYP2C8 substrates as well as the CYP-inducing and -inhibitory potential of efavirenz were obtained from published literature. The data were integrated in a PBPK model developed using mathematical descriptions of molecular, physiological, and anatomical processes defining pharmacokinetics. Plasma drug-concentration profiles were simulated at steady state in virtual individuals for each drug given alone or in combination with efavirenz. The simulated pharmacokinetic parameters of drugs given alone were compared against existing clinical data. The effect of efavirenz on CYP was compared with published DDI data. The predictions indicate that the overall effect of efavirenz on dual CYP3A4/CYP2C8 substrates is induction of metabolism. The magnitude of induction tends to be less pronounced for dual CYP3A4/CYP2C8 substrates with predominant CYP2C8 metabolism. PBPK modeling constitutes a useful mechanistic approach for the quantitative prediction of DDI involving simultaneous inducing or inhibitory effects on multiple CYPs as often encountered with antiretroviral drugs.

  6. Old and new therapeutics for Rheumatoid Arthritis: in vivo models and drug development.

    Science.gov (United States)

    Sardar, Samra; Andersson, Åsa

    2016-01-01

    Development of novel drugs for treatment of chronic inflammatory diseases is to a large extent dependent on the availability of good experimental in vivo models in order to perform preclinical tests of new drugs and for the identification of novel drug targets. Here, we review a number of existing rodent models for Rheumatoid Arthritis in the context of how these models have been utilized for developing established therapy in Rheumatoid Arthritis and, furthermore, the present use of animal models for studies of novel drug candidates. We have studied the literature in the field for the use of in vivo models during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although a single Rheumatoid Arthritis in vivo model cannot mirror the complexity of disease development, there exist a number of good animal models for Rheumatoid Arthritis, each defining some parts in disease development, which are useful for studies of drug response. We find that many of the established drugs were not tested in in vivo models before being used in the clinic, but rather animal models have been subsequently used to find mechanisms for efficacy. Finally, we report a number of novel drugs, tested in preclinical in vivo models, presently in clinical trials.

  7. ENHANCED OIL RECOVERY BY FLOODING WITH HYDROPHILIC NANOPARTICLES

    Institute of Scientific and Technical Information of China (English)

    Binshan Ju; Tailiang Fan; Mingxue Ma

    2006-01-01

    In this paper, the mechanism of enhanced oil recovery using lipophobic and hydrophilic polysilicon (LHP)nanoparticles ranging in size from 10 to 500 nm for changing the wettability of porous media was analysed theoretically. A one-dimensional two-phase mathematical model considering the migration and adsorption of LHP and wettability change in reservoir rock was proposed, and a simulator was developed to quantitatively predict the changes in relative and effective permeability of the oil and water phases and the oil recovery in sandstone after water driving. Numerical simulations were conducted to study the distribution of the particle concentration, the reduction in porosity and absolute permeability, the LHP volume retention on pore walls and in pore throats along a dimensionless distance, and oil production performance. In conclusion, oil recovery can obviously be improved by flooding with hydrophilic nanometer powders though permeability declines for the retention of nanoparticles in porous media. It is suggested that an LHP concentration ranging from 0.02 to 0.03 is preferable to enhance oil recovery.

  8. Quantitative and qualitative evaluation of adsorption/desorption of bovine serum albumin on hydrophilic and hydrophobic surfaces.

    Science.gov (United States)

    Jeyachandran, Y L; Mielczarski, E; Rai, B; Mielczarski, J A

    2009-10-06

    We studied the adsorption of bovine serum albumin (BSA) from phosphate-buffered saline (pH 7.4) to hydrophilic and hydrophobic surfaces. Attenuated total reflection Fourier transform infrared spectroscopy, supported by spectral simulation, allowed us to determine with high precision the amount of BSA adsorbed (surface coverage) and its structural composition. The adsorbed BSA molecules had an alpha-helical structure on both hydrophobic and hydrophilic surfaces but had different molecular conformations and adsorption strengths on the two types of surface. Adsorption of BSA was saturated at around 50% surface coverage on the hydrophobic surface, whereas on the hydrophilic surface the adsorption reached 95%. The BSA molecules adsorbed to the hydrophilic surface with a higher interaction strength than to the hydrophobic surface. Very little adsorbed BSA could be desorbed from the hydrophilic surface, even using 0.1 M sodium dodecyl sulfate, a strong detergent solution. The formation of BSA-phosphate surface complexes was observed under different BSA adsorption conditions on hydrophobic and hydrophilic surfaces. The formation of these complexes correlated with the more efficient blocking of nonspecific interactions by the adsorbed BSA layer. Results from the molecular modeling of BSA interactions with hydrophobic and hydrophilic surfaces support the spectroscopic findings.

  9. Staphylococcus epidermidis adhesion on hydrophobic and hydrophilic textured biomaterial surfaces.

    Science.gov (United States)

    Xu, Li-Chong; Siedlecki, Christopher A

    2014-06-01

    It is of great interest to use nano- or micro-structured surfaces to inhibit microbial adhesion and biofilm formation and thereby to prevent biomaterial-associated infection, without modification of the surface chemistry or bulk properties of the materials and without use of the drugs. Our previous study showed that a submicron textured polyurethane surface can inhibit staphylococcal bacterial adhesion and biofilm formation. To further understand the effect of the geometry of textures on bacterial adhesion as well as the underlying mechanism, in this study, submicron and micron textured polyurethane surfaces featuring ordered arrays of pillars were fabricated and modified to have different wettabilities. All the textured surfaces were originally hydrophobic and showed significant reductions in Staphylococcus epidermidis RP62A adhesion in phosphate buffered saline or 25% platelet poor plasma solutions under shear, as compared to smooth surfaces. After being subjected to an air glow discharge plasma treatment, all polyurethane surfaces were modified to hydrophilic, and reductions in bacterial adhesion on surfaces were subsequently found to be dependent on the size of the patterns. The submicron patterned surfaces reduced bacterial adhesion, while the micron patterned surfaces led to increased bacterial adhesion. The extracellular polymeric substances (EPS) from the S. epidermidis cell surfaces were extracted and purified, and were coated on a glass colloidal surface so that the adhesion force and separation energy in interactions of the EPS and the surface could be measured by colloidal probe atomic force microscopy. These results were consistent with the bacterial adhesion observations. Overall, the data suggest that the increased surface hydrophobicity and the decreased availability of the contact area contributes to a reduction in bacterial adhesion to the hydrophobic textured surfaces, while the availability of the contact area is the primary determinant factor

  10. Modelling Formation of a Drug Reservoir in the Stratum Corneum and Its Impact on Drug Monitoring Using Reverse Iontophoresis

    Directory of Open Access Journals (Sweden)

    Yvonne Paulley

    2010-01-01

    Full Text Available Reverse iontophoresis is a relatively new technique for non-invasive drug monitoring in the body. It involves a small electrical current being passed through the skin to facilitate the movement of small charged ions and polar molecules on the skin's surface where the amount of drug can then be measured and hence an accurate estimate of the blood concentration can be made. In vivo studies for several molecules show that initially large amounts of drug are extracted from the body, which are unrelated to the magnitude of the blood concentration; over time the fluxes of extraction decrease to a level proportional to the steady state blood concentration. This suggests that, at first, the drug is being extracted from some source other than the blood; one such candidate for this source is the dead cells which form the stratum corneum. In this paper, we construct two related mathematical models; the first describes the formation of the drug reservoir in the stratum corneum as a consequence of repeated drug intake and natural death of skin cells in the body. The output from this model provides initial conditions for the model of reverse iontophoresis in which charged ions from both the blood and the stratum corneum reservoir compete for the electric current. Model parameters are estimated from data collected for lithium monitoring. Our models will improve interpretation of reverse iontophoretic data by discriminating the subdermal from the skin contribution to the fluxes of extraction. They also suggest that analysis of the skin reservoir might be a valuable tool to investigate patients' exposure to chemicals including therapeutic drugs.

  11. Wetting transitions on textured hydrophilic surfaces

    Science.gov (United States)

    Ishino, C.; Okumura, K.

    2008-04-01

    We consider the quasi-static energy of a drop on a textured hydrophilic surface, with taking the contact angle hysteresis (CAH) into account. We demonstrate how energy varies as the contact state changes from the Cassie state (in which air is trapped at the drop bottom) to the Wenzel state (in which liquid fills the texture at the drop bottom) assuming that the latter state nucleates from the center of the drop bottom. When the textured substrate is hydrophilic enough to allow spontaneous penetration of liquid film of the texture thickness, the present theory asserts that the drop develops into an experimentally observed state in which a drop looks like an egg fried without flipped over (sunny-side up) with a well-defined radius of “the egg yolk.” Otherwise, the final contact state of the drop becomes like a Wenzel state, but with the contact circle smaller than the original Wenzel state due to the CAH. We provide simple analytical estimations for the yolk radius of the “sunny-side-up” state and for the final radius of the contact circle of the pseudo-Wenzel state.

  12. Generalized Plasma Skimming Model for Cells and Drug Carriers in the Microvasculature

    CERN Document Server

    Lee, Tae-Rin; Yang, Jiho

    2016-01-01

    In microvascular transport, where both blood and drug carriers are involved, plasma skimming has a key role on changing hematocrit level and drug carrier concentration in capillary beds after continuous vessel bifurcation in the microvasculature. While there have been numerous studies on modeling the plasma skimming of blood, previous works lacked in consideration of its interaction with drug carriers. In this paper, a generalized plasma skimming model is suggested to predict the redistributions of both the cells and drug carriers at each bifurcation. In order to examine its applicability, this new model was applied on a single bifurcation system to predict the redistribution of red blood cells and drug carriers. Furthermore, this model was tested at microvascular network level under different plasma skimming conditions for predicting the concentration of drug carriers. Based on these results, the applicability of this generalized plasma skimming model is fully discussed and future works along with the model'...

  13. Multiscale modeling of drug-polymer nanoparticle assembly identifies parameters influencing drug encapsulation efficiency.

    Science.gov (United States)

    Mackenzie, R; Booth, J; Alexander, C; Garnett, M C; Laughton, C A

    2015-06-09

    Using a multiscale (dual resolution) approach combining an atomistic (GROMOS96) and coarse-grain (MARTINI) force field, we have been able to simulate the process of drug-polymer nanoparticle assembly by nanoprecipitation from mixed solvents. Here, we present the development and application of this method to the interaction of three poly(glycerol adipate) polymer variants with the anticancer drug dexamethasone phosphate. Differences in encapsulation efficiency and drug loading between the polymers are in agreement with the experimental trend. Reference atomistic simulations at key points along the predicted aggregation pathway support the accuracy of the much more computationally efficient multiscale methodology.

  14. A Physiologically-Based Flow Network Model for Hepatic Drug Elimination I: Regular Lattice Lobule Model

    CERN Document Server

    Rezania, Vahid; Coombe, Dennis; Tuszynski, Jack A

    2011-01-01

    We develop a physiologically-based lattice model for the transport and metabolism of drugs in the functional unit of the liver, called the lobule. In contrast to earlier studies, we have emphasized the dominant role of convection in well-vascularized tissue with a given structure. Estimates of convective, diffusive and reaction contributions are given. We have compared drug concentration levels observed exiting the lobule with their predicted detailed distribution inside the lobule, assuming that most often the former is accessible information while the latter is not.

  15. Model-based drug development: strengths, weaknesses, opportunities, and threats for broad application of pharmacometrics in drug development.

    Science.gov (United States)

    Wetherington, Jeffrey D; Pfister, Marc; Banfield, Christopher; Stone, Julie A; Krishna, Rajesh; Allerheiligen, Sandy; Grasela, Dennis M

    2010-09-01

    Systematic implementation of model-based drug development (MBDD) to drug discovery and development has the potential to significantly increase the rate of medical breakthroughs and make available new and better treatments to patients. An analysis of the strengths, weaknesses, opportunities, and threats (ie, SWOT) was conducted through focus group discussions that included 24 members representing 8 pharmaceutical companies to systematically assess the challenges to implementing MBDD into the drug development decision-making process. The application of the SWOT analysis to the successful implementation of MBDD yielded 19 strengths, 27 weaknesses, 34 opportunities, and 22 threats, which support the following conclusions. The shift from empirical drug development to MBDD requires a question-based mentality; early, proactive planning; dynamic access to multisource data; quantitative knowledge integration; multidisciplinary collaboration; effective communication and leadership skills; and innovative, impactful application of pharmacometrics focused on enhancing quantitative decision making. The ultimate goal of MBDD is to streamline discovery and development of innovative medicines to benefit patients.

  16. An explanatory model for state Medicaid per capita prescription drug expenditures.

    Science.gov (United States)

    Roy, Sanjoy; Madhavan, S Suresh

    2012-01-01

    Rising prescription drug expenditure is a growing concern for publicly funded drug benefit programs like Medicaid. To be able to contain drug expenditures in Medicaid, it is important that cause(s) for such increases are identified. This study attempts to establish an explanatory model for Medicaid prescription drugs expenditure based on the impacts of key influencers/predictors identified using a comprehensive framework of drug utilization. A modified Andersen's behavior model of health services utilization is employed to identify potential determinants of pharmaceutical expenditures in state Medicaid programs. Level of federal matching funds, access to primary care, severity of diseases, unemployment, and education levels were found to be key influencers of Medicaid prescription drug expenditure. Increases in all, except education levels, were found to result in increases in drug expenditures. Findings from this study could better inform intervention policies and cost-containment strategies for state Medicaid drug benefit programs.

  17. The drug-target residence time model: a 10-year retrospective.

    Science.gov (United States)

    Copeland, Robert A

    2016-02-01

    The drug-target residence time model was first introduced in 2006 and has been broadly adopted across the chemical biology, biotechnology and pharmaceutical communities. While traditional in vitro methods view drug-target interactions exclusively in terms of equilibrium affinity, the residence time model takes into account the conformational dynamics of target macromolecules that affect drug binding and dissociation. The key tenet of this model is that the lifetime (or residence time) of the binary drug-target complex, and not the binding affinity per se, dictates much of the in vivo pharmacological activity. Here, this model is revisited and key applications of it over the past 10 years are highlighted.

  18. A mathematical model to predict the release of water-soluble drugs from HPMC matrices.

    Science.gov (United States)

    Fu, X C; Wang, G P; Fu, C Y; Liang, W Q

    2004-09-01

    A mathematical model to predict the fraction of water-soluble drug released as a function of release time (t, h), HPMC concentration (CH, w/w), and volume of drug molecule (V, nm3) was derived with ranitidine hydrochloride, diltiazem hydrochloride, and ribavirin as model drugs. The model is log (M(t)/M(infinity)) = 0.5 log t-0.3322CH-0.2222V-0.2988 (n = 140, r = 0.9848), where M(t) is the amount of drug released at time t, M(infinity) is the amount of drug released over a very long time, which corresponds in principle to the initial loading, n is the number of samples, and r is the correlation coefficient. The model was validated using isoniazid and satisfactory results were obtained. The model can be used to predict the release fraction of various soluble drugs from HPMC matrices having different polymer levels.

  19. A Probabilistic Model of Illegal Drug Trafficking Operations in the Eastern Pacific and Caribbean Sea

    Science.gov (United States)

    2013-09-01

    Illicit drug - trafficking is a major concern of the United States and is a primary pillar of President Barack Obama’s Strategy to Combat Transnational...Organized Crime. In the eastern Pacific and Caribbean Sea, drug - trafficking organizations operate a variety of vessels to transit drugs from South...interdicts illegal drug - trafficking in this region. In this thesis, we develop a probability model based on intelligence inputs to generate a spatial

  20. Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models.

    Science.gov (United States)

    Peters, Sheila Annie; Jones, Christopher R; Ungell, Anna-Lena; Hatley, Oliver J D

    2016-06-01

    Intestinal metabolism can limit oral bioavailability of drugs and increase the risk of drug interactions. It is therefore important to be able to predict and quantify it in drug discovery and early development. In recent years, a plethora of models-in vivo, in situ and in vitro-have been discussed in the literature. The primary objective of this review is to summarize the current knowledge in the quantitative prediction of gut-wall metabolism. As well as discussing the successes of current models for intestinal metabolism, the challenges in the establishment of good preclinical models are highlighted, including species differences in the isoforms; regional abundances and activities of drug metabolizing enzymes; the interplay of enzyme-transporter proteins; and lack of knowledge on enzyme abundances and availability of empirical scaling factors. Due to its broad specificity and high abundance in the intestine, CYP3A is the enzyme that is frequently implicated in human gut metabolism and is therefore the major focus of this review. A strategy to assess the impact of gut wall metabolism on oral bioavailability during drug discovery and early development phases is presented. Current gaps in the mechanistic understanding and the prediction of gut metabolism are highlighted, with suggestions on how they can be overcome in the future.

  1. Mouse Models of Type 2 Diabetes Mellitus in Drug Discovery.

    Science.gov (United States)

    Baribault, Helene

    2016-01-01

    Type 2 diabetes is a fast-growing epidemic in industrialized countries, associated with obesity, lack of physical exercise, aging, family history, and ethnic background. Diagnostic criteria are elevated fasting or postprandial blood glucose levels, a consequence of insulin resistance. Early intervention can help patients to revert the progression of the disease together with lifestyle changes or monotherapy. Systemic glucose toxicity can have devastating effects leading to pancreatic beta cell failure, blindness, nephropathy, and neuropathy, progressing to limb ulceration or even amputation. Existing treatments have numerous side effects and demonstrate variability in individual patient responsiveness. However, several emerging areas of discovery research are showing promises with the development of novel classes of antidiabetic drugs.The mouse has proven to be a reliable model for discovering and validating new treatments for type 2 diabetes mellitus. We review here commonly used methods to measure endpoints relevant to glucose metabolism which show good translatability to the diagnostic of type 2 diabetes in humans: baseline fasting glucose and insulin, glucose tolerance test, insulin sensitivity index, and body type composition. Improvements on these clinical values are essential for the progression of a novel potential therapeutic molecule through a preclinical and clinical pipeline.

  2. Polypeptoids from N -Substituted Glycine N -Carboxyanhydrides: Hydrophilic, Hydrophobic, and Amphiphilic Polymers with Poisson Distribution

    KAUST Repository

    Fetsch, Corinna

    2011-09-13

    Preparation of defined and functional polymers has been one of the hottest topics in polymer science and drug delivery in the recent decade. Also, research on (bio)degradable polymers gains more and more interest, in particular at the interface of these two disciplines. However, in the majority of cases, combination of definition, functionality and degradability, is problematic. Here we present the preparation and characterization (MALDI-ToF MS, NMR, GPC) of nonionic hydrophilic, hydrophobic, and amphiphilic N-substituted polyglycines (polypeptoids), which are expected to be main-chain degradable and are able to disperse a hydrophobic model compound in aqueous media. Polymerization kinetics suggest that the polymerization is well controlled with strictly linear pseudo first-order kinetic plots to high monomer consumption. Moreover, molar mass distributions of products are Poisson-type and molar mass can be controlled by the monomer to initiator ratio. The presented polymer platform is nonionic, backbone degradable, and synthetically highly flexible and may therefore be valuable for a broad range of applications, in particular as a biomaterial. © 2011 American Chemical Society.

  3. Drug-target interaction prediction: databases, web servers and computational models.

    Science.gov (United States)

    Chen, Xing; Yan, Chenggang Clarence; Zhang, Xiaotian; Zhang, Xu; Dai, Feng; Yin, Jian; Zhang, Yongdong

    2016-07-01

    Identification of drug-target interactions is an important process in drug discovery. Although high-throughput screening and other biological assays are becoming available, experimental methods for drug-target interaction identification remain to be extremely costly, time-consuming and challenging even nowadays. Therefore, various computational models have been developed to predict potential drug-target associations on a large scale. In this review, databases and web servers involved in drug-target identification and drug discovery are summarized. In addition, we mainly introduced some state-of-the-art computational models for drug-target interactions prediction, including network-based method, machine learning-based method and so on. Specially, for the machine learning-based method, much attention was paid to supervised and semi-supervised models, which have essential difference in the adoption of negative samples. Although significant improvements for drug-target interaction prediction have been obtained by many effective computational models, both network-based and machine learning-based methods have their disadvantages, respectively. Furthermore, we discuss the future directions of the network-based drug discovery and network approach for personalized drug discovery based on personalized medicine, genome sequencing, tumor clone-based network and cancer hallmark-based network. Finally, we discussed the new evaluation validation framework and the formulation of drug-target interactions prediction problem by more realistic regression formulation based on quantitative bioactivity data.

  4. A graph theoretical perspective of a drug abuse epidemic model

    Science.gov (United States)

    Nyabadza, F.; Mukwembi, S.; Rodrigues, B. G.

    2011-05-01

    A drug use epidemic can be represented by a finite number of states and transition rules that govern the dynamics of drug use in each discrete time step. This paper investigates the spread of drug use in a community where some users are in treatment and others are not in treatment, citing South Africa as an example. In our analysis, we consider the neighbourhood prevalence of each individual, i.e., the proportion of the individual’s drug user contacts who are not in treatment amongst all of his or her contacts. We introduce parameters α∗, β∗ and γ∗, depending on the neighbourhood prevalence, which govern the spread of drug use. We examine how changes in α∗, β∗ and γ∗ affect the system dynamics. Simulations presented support the theoretical results.

  5. The application of antitumor drug-targeting models on liver cancer.

    Science.gov (United States)

    Yan, Yan; Chen, Ningbo; Wang, Yunbing; Wang, Ke

    2016-06-01

    Hepatocarcinoma animal models, such as the induced tumor model, transplanted tumor model, gene animal model, are significant experimental tools for the evaluation of targeting drug delivery system as well as the pre-clinical studies of liver cancer. The application of antitumor drug-targeting models not only furnishes similar biological characteristics to human liver cancer but also offers guarantee of pharmacokinetic indicators of the liver-targeting preparations. In this article, we have reviewed some kinds of antitumor drug-targeting models of hepatoma and speculated that the research on this field would be capable of attaining a deeper level and expecting a superior achievement in the future.

  6. Predicting Drug Combination Index and Simulating the Network-Regulation Dynamics by Mathematical Modeling of Drug-Targeted EGFR-ERK Signaling Pathway

    Science.gov (United States)

    Huang, Lu; Jiang, Yuyang; Chen, Yuzong

    2017-01-01

    Synergistic drug combinations enable enhanced therapeutics. Their discovery typically involves the measurement and assessment of drug combination index (CI), which can be facilitated by the development and applications of in-silico CI predictive tools. In this work, we developed and tested the ability of a mathematical model of drug-targeted EGFR-ERK pathway in predicting CIs and in analyzing multiple synergistic drug combinations against observations. Our mathematical model was validated against the literature reported signaling, drug response dynamics, and EGFR-MEK drug combination effect. The predicted CIs and combination therapeutic effects of the EGFR-BRaf, BRaf-MEK, FTI-MEK, and FTI-BRaf inhibitor combinations showed consistent synergism. Our results suggest that existing pathway models may be potentially extended for developing drug-targeted pathway models to predict drug combination CI values, isobolograms, and drug-response surfaces as well as to analyze the dynamics of individual and combinations of drugs. With our model, the efficacy of potential drug combinations can be predicted. Our method complements the developed in-silico methods (e.g. the chemogenomic profile and the statistically-inferenced network models) by predicting drug combination effects from the perspectives of pathway dynamics using experimental or validated molecular kinetic constants, thereby facilitating the collective prediction of drug combination effects in diverse ranges of disease systems.

  7. Sonochemical synthesis of versatile hydrophilic magnetite nanoparticles.

    Science.gov (United States)

    Marchegiani, G; Imperatori, P; Mari, A; Pilloni, L; Chiolerio, A; Allia, P; Tiberto, P; Suber, L

    2012-07-01

    Hydrophilic magnetite nanoparticles in the size range 30-10nm are easily and rapidly prepared under ultrasonic irradiation of Fe(OH)(2) in di- and tri-ethylene glycol/water solution with volume ratio varying between 7:3 and 3:7. Structural (XRD) and morphological (SEM) characterization reveal good crystalline and homogeneous particles whereas, when solvothermally prepared, the particles are inhomogeneous and aggregated. The sonochemically prepared particles are versatile, i.e. well suited to covalently bind molecules because of the free glycol hydroxylic groups on their surface or exchange the diethylene or triethylene glycol ligand. They can be easily transferred in hydrophobic solvents too. Room-temperature magnetic hysteresis properties measured by means of Vibrating Sample Magnetometer (VSM) display a nearly superparamagnetic character. The sonochemical preparation is easily scalable to meet industrial demand. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Capillary rise of water in hydrophilic nanopores

    CERN Document Server

    Gruener, Simon; Wallacher, Dirk; Kityk, Andriy V; Huber, Patrick; 10.1103/PhysRevE.79.067301

    2009-01-01

    We report on the capillary rise of water in three-dimensional networks of hydrophilic silica pores with 3.5nm and 5nm mean radii, respectively (porous Vycor monoliths). We find classical square root of time Lucas-Washburn laws for the imbibition dynamics over the entire capillary rise times of up to 16h investigated. Provided we assume two preadsorbed strongly bound layers of water molecules resting at the silica walls, which corresponds to a negative velocity slip length of -0.5nm for water flow in silica nanopores, we can describe the filling process by a retained fluidity and capillarity of water in the pore center. This anticipated partitioning in two dynamic components reflects the structural-thermodynamic partitioning in strongly silica bound water layers and capillary condensed water in the pore center which is documented by sorption isotherm measurements.

  9. Hydrophilic Polymer-associated Ischemic Enterocolitis.

    Science.gov (United States)

    Chavez, Jesus A; Chen, Wei; Frankel, Wendy L; Arnold, Christina A

    2017-02-01

    Hydrophilic polymer coating of medical devices serves to lubricate the device and prevent device-related complications. The coating can be mechanically disrupted and result in downstream injury via presumed thromboembolism. This process has been reported in the brain, heart, lung, and skin, and has been replicated through animal studies and in vitro histologic processing of the polymer coating. We report the first description of hydrophilic polymer-associated ischemic enterocolitis in a series of 7 specimens (small bowel=2, colon=4, aortic thrombus=1) from 3 patients. We report a 4% incidence among all patients with an ischemic bowel resection between April 29, 2014 and August 8, 2016. All patients developed bowel ischemia within 1 day of aortic repair, and all bowel resection specimens showed polymers, mainly in the submucosal vessels in areas of extensive ischemia. The polymers appeared as basophilic, intravascular, serpiginous structures. In a patient who developed acute paralysis after the aortic repair, identical polymers were identified in the aortic thrombus and the ischemic bowel segment. We demonstrate that the polymers display an altered morphology over time and with various graft types, and that the degrading polymers are associated with a foreign body giant cell reaction. Special stains can aid in diagnosis, with the polymers turquoise on a colloidal iron stain, pink on von Kossa and mucicarmine stains, and pale blue on trichrome. Clinical follow-up was available up to 115 weeks: 1 patient died, and 2 are alive and well. In summary, we report a new diagnostic entity to be considered in the differential diagnosis of iatrogenic ischemic injuries in the gastrointestinal tract. Awareness of this entity is important to elucidate the cause of ischemia and to prevent misdiagnosis of the polymers and their associated giant cell reaction as a parasitic infection, granulomatous vasculitis, sarcoidosis, and idiopathic inflammatory bowel disease.

  10. Reliability of a Novel Model for Drug Release from 2D HPMC-Matrices

    Directory of Open Access Journals (Sweden)

    Rumiana Blagoeva

    2010-04-01

    Full Text Available A novel model of drug release from 2D-HPMC matrices is considered. Detailed mathematical description of matrix swelling and the effect of the initial drug loading are introduced. A numerical approach to solution of the posed nonlinear 2D problem is used on the basis of finite element domain approximation and time difference method. The reliability of the model is investigated in two steps: numerical evaluation of the water uptake parameters; evaluation of drug release parameters under available experimental data. The proposed numerical procedure for fitting the model is validated performing different numerical examples of drug release in two cases (with and without taking into account initial drug loading. The goodness of fit evaluated by the coefficient of determination is presented to be very good with few exceptions. The obtained results show better model fitting when accounting the effect of initial drug loading (especially for larger values.

  11. The isolated perfused human skin flap model: A missing link in skin penetration studies?

    OpenAIRE

    Ternullo, Selenia; de Weerd, Louis; Flaten, Gøril Eide; Holsæter, Ann Mari; Skalko-Basnet, Natasa

    2016-01-01

    Development of effective (trans)dermal drug delivery systems requires reliable skinmodels to evaluate skin drug penetration. The isolated perfused human skin flap remainsmetabolically active tissue for up to 6 h during in vitro perfusion. We introduce the isolated perfused human skin flap as a close-to-in vivo skin penetration model. To validate the model's ability to evaluate skin drug penetration the solutions of a hydrophilic (calcein) and a lipophilic (rhodamine) fluorescence ...

  12. Effects of amphiphilic chitosan-g-poly(ε-caprolactone) polymer additives on paclitaxel release from drug eluting implants

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Weibin [Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092 (China); Gu, Chunhua [Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237 (China); Jiang, Han [Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092 (China); Zhang, Mengru [Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237 (China); Lang, Meidong, E-mail: mdlang@ecust.edu.cn [Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237 (China)

    2014-12-01

    Bioresorbable polymer stents have been proposed as promising medical implants to avoid long-term safety concerns and other potential issues caused by traditional materials. As an important member, poly(ε-caprolactone) (PCL) was used as the implant matrix with different drug loadings. To better regulate drug release rate, the hydrophilicity of PCL was adjusted by addition of amphiphilic graft copolymers, chitosan-g-poly(ε-caprolactone) (CP). The in vitro release results indicated that the improvement of bulk hydrophilicity could accelerate drug release better than that of surface coating. The optimum additive amount was 25% with CP9. Further study showed that the effect of aspirin molecules displayed no obvious difference to that of CP macromolecules on drug release rate. Moreover, these release profiles were fitted with mathematical models. The similarities were evaluated with similarity factors. Scanning electron microscopy (SEM) images displayed surface/cross-section morphologies of pure PCL and modified implants before and after release. - Highlights: • The improvement of bulk hydrophilicity better accelerated drug release. • The higher weight ratio of CP implants had, the faster the drug released. • The shorter PCL chain in CP graft coploymers, the faster the drug released. • The optimum additive amount was 25% with CP9. • Drug release profile conformed to controllable Fick diffusional release mechanism.

  13. Understanding the drop impact on moving hydrophilic and hydrophobic surfaces.

    Science.gov (United States)

    Almohammadi, H; Amirfazli, A

    2017-03-08

    In this paper, a systematic study was performed to understand the drop impact on hydrophilic and hydrophobic surfaces that were moving in the horizontal direction. Drops (D0 = 2.5 mm) of liquids with three different viscosities were used. Wide ranges of drop normal velocity (0.5 to 3.4 m s(-1)) and surface velocity (0 to 17 m s(-1)) were studied. High speed imaging from the top and side was used to capture the impact phenomena. It was found that drop impact behavior on a moving surface significantly differs from that on a stationary surface at both the lamella extension stage (i.e. t ≤ tmax) and the retraction stage (t > tmax). Starting with the lamella extension stage, it was observed that the drop spreads asymmetrically over a moving surface. It was also found that the splashing behavior of the drop upon impact on a moving surface, unlike the understanding in the literature, is azimuthally different along the lamella contact line. In the case of the drop spreading over a moving surface, the surface movement stretches the expanded lamella in the direction of the surface motion. For hydrophilic surfaces, the stretched lamella pins to the surface and moves with the surface velocity; however, for hydrophobic surfaces, the lamella recoils during such stretching. A new model was developed to determine the splashing threshold of the drop impact on a moving surface. The model is capable of describing the azimuthally different behavior of the splashing which is a function of normal capillary and Weber numbers, surface velocity, and surface wettability. It was also found that the increase of the viscosity decreases the splashing threshold. Finally, comprehensive regime maps of the drop impact outcome on a moving surface were provided for both t ≤ tmax and t > tmax stages.

  14. Hydrophilic block azidation of PCL-b-PEO block copolymers from epichlorohydrin.

    Science.gov (United States)

    Liu, Junjie; Gan, Zhihua

    2014-05-01

    Amphiphilic diblock copolymers poly(ϵ-caprolactone)-b-poly(ethylene oxide) (PCL-b-PEO) with well-controlled pendant azido groups along the hydrophilic PEO block, that is, poly(ϵ-caprolactone)-b-poly(ethylene oxide-co-glycidyl azide) (PCL-b-P(EO-co-GA)), are synthesized from poly(ϵ-caprolactone)-b-poly(ethylene oxide-co-epichlorohydrin) (PCL-b-P(EO-co-ECH)). The further conversion of those azido groups along the hydrophilic block of copolymers into amino or carboxyl groups via click chemistry is studied. The micelles self-assembled from PCL-b-P(EO-co-GA) with azido groups on the shell are crosslinked by the dialkynyl-PEO. The micelles with crosslinked shell show better stability, higher drug loading capacities, subsequent faster drug release rate, and higher cytotoxicity to cancer cells. The introduction of azido groups into PCL-b-PEO amphiphilic diblock copolymers from epichlorohydrin in PEO hydrophilic block in this work provides a new method for biofunctionalization of micelles via mild click chemistry.

  15. Molecular Modeling in Drug Design for the Development of Organophosphorous Antidotes/Prophylactics

    Science.gov (United States)

    1986-05-01

    5012 61102A 1102BS11 EB 025 11. TITLE (Include Security Classification) Molecular Modeling in Drug Design for the Development of Organophosphorous...t ....................................., ’ i.° AD MOLECULAR MODELING IN DRUG DESIGN FOR THE DEVELOPMENT OF ORGANOPHOSPHOROUS ANTIDOTES...Reed, W.J. Murray, E.B. Roche and L.N. Donelsmith, Gen. Pharmac., 12, 177-185 (1981). 5. L.B.Kier, "Molecular Orbital Theory in Drug Design ", Academic

  16. The Two Faces of Social Interaction Reward in Animal Models of Drug Dependence.

    Science.gov (United States)

    El Rawas, Rana; Saria, Alois

    2016-03-01

    Drug dependence is a serious health and social problem. Social factors can modify vulnerability to developing drug dependence, acting as risk factors or protective factors. Whereas stress and peer environment that encourage substance use may increase drug taking, strong attachments between family members and peer environment that do not experience drug use may protect against drug taking and, ultimately, drug dependence. The rewarding effects of drug abuse and social interaction can be evaluated using animal models. In this review we focus on evaluating social interaction reward in the conditioned place preference paradigm. We give an overview of how social interaction, if made available within the drug context, may facilitate, promote and interact with the drug's effects. However, social interaction, if offered alternatively outside the drug context, may have pronounced protective effects against drug abuse and relapse. We also address the importance of the weight difference parameter between the social partners in determining the positive or "agonistic" versus the hostile or "antagonistic" social interaction. We conclude that understanding social interaction reward and its subsequent effects on drug reward is sorely needed for therapeutic interventions against drug dependence.

  17. A Comparative Study of Successful Central Nervous System Drugs Using Molecular Modeling

    Science.gov (United States)

    Kim, Hyosub; Sulaimon, Segun; Menezes, Sandra; Son, Anne; Menezes, Warren J. C.

    2011-01-01

    Molecular modeling is a powerful tool used for three-dimensional visualization and for exploring electrostatic forces involved in drug transport. This tool enhances student understanding of structure-property relationships, as well as actively engaging them in class. Molecular modeling of several central nervous system (CNS) drugs is used to…

  18. A Comparative Study of Successful Central Nervous System Drugs Using Molecular Modeling

    Science.gov (United States)

    Kim, Hyosub; Sulaimon, Segun; Menezes, Sandra; Son, Anne; Menezes, Warren J. C.

    2011-01-01

    Molecular modeling is a powerful tool used for three-dimensional visualization and for exploring electrostatic forces involved in drug transport. This tool enhances student understanding of structure-property relationships, as well as actively engaging them in class. Molecular modeling of several central nervous system (CNS) drugs is used to…

  19. Computing characterizations of drugs for ion channels and receptors using Markov models

    CERN Document Server

    Tveito, Aslak

    2016-01-01

    Flow of ions through voltage gated channels can be represented theoretically using stochastic differential equations where the gating mechanism is represented by a Markov model. The flow through a channel can be manipulated using various drugs, and the effect of a given drug can be reflected by changing the Markov model. These lecture notes provide an accessible introduction to the mathematical methods needed to deal with these models. They emphasize the use of numerical methods and provide sufficient details for the reader to implement the models and thereby study the effect of various drugs. Examples in the text include stochastic calcium release from internal storage systems in cells, as well as stochastic models of the transmembrane potential. Well known Markov models are studied and a systematic approach to including the effect of mutations is presented. Lastly, the book shows how to derive the optimal properties of a theoretical model of a drug for a given mutation defined in terms of a Markov model.

  20. Species-specific activation time-lags can explain habitat restrictions in hydrophilic lichens.

    Science.gov (United States)

    Lidén, Marlene; Jonsson Cabrajić, Anna V; Ottosson-Löfvenius, Mikaell; Palmqvist, Kristin; Lundmark, Tomas

    2010-05-01

    Photosystem II (PSII) activation after hydration with water or humid air was measured in four hydrophilic and a generalist lichen to test the hypothesis that slow activation might explain habitat restriction in the former group. For the hydrophilic species, activation was after 4 h nearly completed in Lobaria amplissima and Platismatia norvegica, while only c. 50% for Bryoria bicolor and Usnea longissima. The generalist Platismatia glauca was activated instantaneously. The effect of this on lichen field performance was investigated using a dynamic model separating the two water sources rain and humid air. Model simulations were made using the species-specific characteristics and climate data from 12 stream microhabitats. For U. longissima, slow PSII activation could reduce realized photosynthesis by a factor of five. Bryoria bicolor was almost as severely affected, while P. norvegica displayed moderate reductions. Lobaria amplissima displayed longer realized activity periods even in unfavourable microclimates, possibly because of a higher water loss resistance. Both close proximity to streams and presence of turbulent water had a positive impact on realized activity among the slowly activated species, coinciding with observed distribution patterns of hydrophilic species. The results presented here may thus partly explain observed habitat restrictions of rare hydrophilic lichens.

  1. Polymerization- and solvent-induced phase separation in hydrophilic-rich dentin adhesive mimic.

    Science.gov (United States)

    Abedin, Farhana; Ye, Qiang; Good, Holly J; Parthasarathy, Ranganathan; Spencer, Paulette

    2014-07-01

    Current dental resin undergoes phase separation into hydrophobic-rich and hydrophilic-rich phases during infiltration of the over-wet demineralized collagen matrix. Such phase separation undermines the integrity and durability of the bond at the composite/tooth interface. This study marks the first time that the polymerization kinetics of model hydrophilic-rich phase of dental adhesive has been determined. Samples were prepared by adding varying water content to neat resins made from 95 and 99 wt.% hydroxyethylmethacrylate and 5 and 1 wt.% (2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl1]-propane prior to light curing. Viscosity of the formulations decreased with increased water content. The photopolymerization kinetics study was carried out with a time-resolved Fourier transform infrared spectrometer. All of the samples exhibited two-stage polymerization behavior which has not been reported previously for dental resin formulation. The lowest secondary rate maxima were observed for water contents of 10-30 wt.%. Differential scanning calorimetry (DSC) showed two glass transition temperatures for the hydrophilic-rich phase of dental adhesive. The DSC results indicate that the heterogeneity within the final polymer structure decreased with increasing water content. The results suggest a reaction mechanism involving both polymerization-induced phase separation and solvent-induced phase separation for the model hydrophilic-rich phase of dental resin.

  2. DrugOn: a fully integrated pharmacophore modeling and structure optimization toolkit

    Directory of Open Access Journals (Sweden)

    Dimitrios Vlachakis

    2015-01-01

    Full Text Available During the past few years, pharmacophore modeling has become one of the key components in computer-aided drug design and in modern drug discovery. DrugOn is a fully interactive pipeline designed to exploit the advantages of modern programming and overcome the command line barrier with two friendly environments for the user (either novice or experienced in the field of Computer Aided Drug Design to perform pharmacophore modeling through an efficient combination of the PharmACOphore, Gromacs, Ligbuilder and PDB2PQR suites. Our platform features a novel workflow that guides the user through each logical step of the iterative 3D structural optimization setup and drug design process. For the pharmacophore modeling we are focusing on either the characteristics of the receptor or the full molecular system, including a set of selected ligands. DrugOn can be freely downloaded from our dedicated server system at www.bioacademy.gr/bioinformatics/drugon/.

  3. Application of concave microwells to pancreatic tumor spheroids enabling anticancer drug evaluation in a clinically relevant drug resistance model.

    Directory of Open Access Journals (Sweden)

    Sang-Eun Yeon

    Full Text Available Intrinsic drug resistance of pancreatic ductal adenocarcinoma (PDAC warrants studies using models that are more clinically relevant for identifying novel resistance mechanisms as well as for drug development. Tumor spheroids (TS mimic in vivo tumor conditions associated with multicellular resistance and represent a promising model for efficient drug screening, however, pancreatic cancer cells often fail to form spheroids using conventional methods such as liquid overlay. This study describes the induction of TS of human pancreatic cancer cells (Panc-1, Aspc-1, Capan-2 in concave polydimethylsiloxane (PDMS microwell plates and evaluation of their usefulness as an anticancer efficacy test model. All three cell lines showed TS formation with varying degree of necrosis inside TS. Among these, Panc-1 spheroid with spherical morphology, a rather rough surface, and unique adhesion structures were successfully produced with no notable necrosis in concave microwell plates. Panc-1 TS contained growth factors or enzymes such as TGF-β1, CTGF, and MT1-MMP, and extracellular matrix proteins such as collagen type I, fibronectin, and laminin. Panc-1 cells grown as TS showed changes in stem cell populations and in expression levels of miRNAs that may play roles in chemoresistance. Visualization of drug penetration and detection of viability indicators, such as Ki-67 and MitoSOX, were optimized for TS for quantitative analysis. Water-soluble tetrazolium (MTS and acid phosphatase (APH assays were also successfully optimized. Overall, we demonstrated that concave PDMS microwell plates are a novel platform for preparation of TS of weakly aggregating cells and that Panc-1 spheroids may represent a novel three-dimensional model for anti-pancreatic cancer drug screening.

  4. Application of concave microwells to pancreatic tumor spheroids enabling anticancer drug evaluation in a clinically relevant drug resistance model.

    Science.gov (United States)

    Yeon, Sang-Eun; No, Da Yoon; Lee, Sang-Hoon; Nam, Suk Woo; Oh, Il-Hoan; Lee, Jaehwi; Kuh, Hyo-Jeong

    2013-01-01

    Intrinsic drug resistance of pancreatic ductal adenocarcinoma (PDAC) warrants studies using models that are more clinically relevant for identifying novel resistance mechanisms as well as for drug development. Tumor spheroids (TS) mimic in vivo tumor conditions associated with multicellular resistance and represent a promising model for efficient drug screening, however, pancreatic cancer cells often fail to form spheroids using conventional methods such as liquid overlay. This study describes the induction of TS of human pancreatic cancer cells (Panc-1, Aspc-1, Capan-2) in concave polydimethylsiloxane (PDMS) microwell plates and evaluation of their usefulness as an anticancer efficacy test model. All three cell lines showed TS formation with varying degree of necrosis inside TS. Among these, Panc-1 spheroid with spherical morphology, a rather rough surface, and unique adhesion structures were successfully produced with no notable necrosis in concave microwell plates. Panc-1 TS contained growth factors or enzymes such as TGF-β1, CTGF, and MT1-MMP, and extracellular matrix proteins such as collagen type I, fibronectin, and laminin. Panc-1 cells grown as TS showed changes in stem cell populations and in expression levels of miRNAs that may play roles in chemoresistance. Visualization of drug penetration and detection of viability indicators, such as Ki-67 and MitoSOX, were optimized for TS for quantitative analysis. Water-soluble tetrazolium (MTS) and acid phosphatase (APH) assays were also successfully optimized. Overall, we demonstrated that concave PDMS microwell plates are a novel platform for preparation of TS of weakly aggregating cells and that Panc-1 spheroids may represent a novel three-dimensional model for anti-pancreatic cancer drug screening.

  5. Hydrodynamic Effects on Drug Dissolution and Deaggregation in the Small Intestine-A Study with Felodipine as a Model Drug.

    Science.gov (United States)

    Lindfors, Lennart; Jonsson, Malin; Weibull, Emelie; Brasseur, James G; Abrahamsson, Bertil

    2015-09-01

    The aim of this study was to understand and predict the influence of hydrodynamic effects in the small intestine on dissolution of primary and aggregated drug particles. Dissolution tests of suspensions with a low-solubility drug, felodipine, were performed in a Couette cell under hydrodynamic test conditions corresponding to the fed small intestine. Dissolution was also performed in the USP II apparatus at two paddle speeds of 25 and 200 rpm and at different surfactant concentrations below critical micelle concentration. The experimental dissolution rates were compared with theoretical calculations. The different levels of shear stress in the in vitro tests did not influence the dissolution of primary or aggregated particles and experimental dissolution rates corresponded very well to calculations. The dissolution rate for the aggregated drug particles increased after addition of surfactant because of deaggregation, but there were still no effect of hydrodynamics. In conclusion, hydrodynamics do not influence dissolution and deaggregation of micronized drug particles in the small intestine of this model drug. Surface tension has a strong effect on the deaggregation and subsequent dissolution. Addition of surfactants at in vivo relevant surface tension levels is thus critical for in vivo predictive in vitro dissolution testing. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  6. The Two Faces of Social Interaction Reward in Animal Models of Drug Dependence

    Science.gov (United States)

    Rawas, Rana El

    2016-01-01

    Drug dependence is a serious health and social problem. Social factors can modify vulnerability to developing drug dependence, acting as risk factors or protective factors. Whereas stress and peer environment that encourage substance use may increase drug taking, strong attachments between family members and peer environment that do not experience drug use may protect against drug taking and, ultimately, drug dependence. The rewarding effects of drug abuse and social interaction can be evaluated using animal models. In this review we focus on evaluating social interaction reward in the conditioned place preference paradigm. We give an overview of how social interaction, if made available within the drug context, may facilitate, promote and interact with the drug’s effects. However, social interaction, if offered alternatively outside the drug context, may have pronounced protective effects against drug abuse and relapse. We also address the importance of the weight difference parameter between the social partners in determining the positive or “agonistic” versus the hostile or “antagonistic” social interaction. We conclude that understanding social interaction reward and its subsequent effects on drug reward is sorely needed for therapeutic interventions against drug dependence. PMID:26088685

  7. Emergence of the drug-resistant phenotype in tumor subpopulations: a hybrid model.

    Science.gov (United States)

    Michelson, S; Slate, D

    1989-09-20

    A mathematical model is proposed that describes the emergence of drug resistance in a tumor cell population. The model is termed a hybrid in the sense that the population-wide dynamics are described by a stochastic birth-death-migration model with transition probabilities dependent on the deterministic distribution of drug within the average cell. In the model, the probability that a cell dies is proportional to the concentration of drug within the target site in the cell. The micropharmacology describing the distribution of drug within the average cell is described by a standard well-mixed compartment model. Possible mechanisms that can confer drug resistance on a cell are described: decreased drug uptake, increased drug efflux, intracellular metabolism or inactivation, or both, of a drug, and a change in the level or sensitivity of a target. The biologic mechanisms underlying resistance and potential strategies for overcoming it are discussed within the context of our model. Results from a numerical simulation are presented as verification of the initial theory.

  8. Mathematical model for drug molecules encapsulated in lipid nanotube

    Science.gov (United States)

    Putthikorn, Sasipim; Baowan, Duangkamon

    2016-11-01

    Lipid nanotube is considered as a nanocontainer for drug and gene delivery. It is important to understand a basic idea of the encapsulation process. In this paper, we use the Lennard-Jones potential function and the continuous approximation to explain the energy behaviour of three hollow shapes of Doxorubicin (DOX) clusters that are a sphere, a cylinder, and an ellipsoid interacting with the lipid nanotube. On assuming that the surface areas of the three structures are equal, we can find the minimum size of the lipid nanotube that encapsulates DOX inside by determining the suction energy. Moreover, we find that a long cylindrical drug provides the largest suction energy among other structures studied here due to the perfect fit between the cylindrical drug and the cylindrical tube. This investigation is the first step to develop the design of nanocapsule for medical application.

  9. Effect of hydrophilic and hydrophobic polymers on release kinetics of metoprolol succinate extended release tablets

    Directory of Open Access Journals (Sweden)

    Ramani Gade

    2011-01-01

    Full Text Available The purpose of the present work is to design and evaluate extended release matrix tablets of metoprolol succinate to reduce the dosing frequency and to improve patient compliance. The matrix tablets were prepared by the combination of hydrophilic and hydrophobic polymers, using methocel 10000 Cps in combination with ethyl cellulose 7 Cps, Eudragit® RS100, Eudragit® S100, and Eudragit® L100.The tablets were prepared by direct compression technique. Prepared formulations were evaluated for various parameters like weight variation, thickness, hardness, friability, and % drug content. Tablets were subjected to in vitro drug release studies. The formulations containing methocel 10000 Cps, Eudragit® L100 showed good release retardation. All the prepared formulations showed first-order release kinetics with matrix diffusion mechanism of release. The formulation containing 52.06% w/w of methocel 10000 Cps, 8.75% Eudragit® L100 offered the required release rate according to USP Pharmacopoeial guidelines. The combination of hydrophilic and hydrophobic polymers can effectively control the drug release for freely water-soluble drugs in case of extended release formulations which are the upcoming dosage forms for patient compliance in all aspects.

  10. Hydrophilic interaction chromatographic analysis of anthocyanins.

    Science.gov (United States)

    Willemse, Chandré M; Stander, Maria A; de Villiers, André

    2013-12-06

    Hydrophilic interaction chromatography (HILIC) provides an alternative separation mode for the analysis of phenolic compounds, in which aqueous-organic mobile phases with polar stationary phases are used. This paper reports the evaluation of HILIC for the analysis of the natural pigments anthocyanins, which are of importance because of their chromophoric properties and a range of health benefits associated with their consumption. Several HILIC stationary phases (silica, diol, amine, cyanopropyl and amide) and mobile phase combinations were evaluated, with the latter proving particularly important due to the distinctive chromatographic behaviour of anthocyanins. Diode array detection was used for selective detection of anthocyanins, while high resolution quadrupole-time-of-flight mass spectrometry (Q-TOF-MS) was used for compound identification. The potential of HILIC separation is demonstrated for a range of anthocyanins varying in glycosylation and acylation patterns found in blueberries, grape skins, black beans, red cabbage and red radish. HILIC is shown to be a complementary separation method to reversed phase liquid chromatography (RP-LC) due to the alternative retention mechanism.

  11. Biopharmaceutical modeling of drug supersaturation during lipid-based formulation digestion considering an absorption sink.

    Science.gov (United States)

    Stillhart, Cordula; Imanidis, Georgios; Griffin, Brendan T; Kuentz, Martin

    2014-12-01

    In vitro lipolysis is widely utilized for predicting in vivo performance of oral lipid-based formulations (LBFs). However, evaluation of LBFs in the absence of an absorption sink may have limited in vivo relevance. This study aimed at employing biopharmaceutical modeling to simulate LBF digestion and drug supersaturation in a continuous absorptive environment. Three fenofibrate-loaded LBFs were characterized in vitro (dispersion and lipolysis) and drug precipitation was monitored using in-line Raman spectroscopy. In vitro data were combined with pharmacokinetic data derived from an in vivo study in pigs to simulate intestinal LBF transit. This biopharmaceutical model allowed calculation of lipolysis-triggered drug supersaturation while drug and lipolysis products are absorbed from the intestine. The biopharmaceutical model predicted that, in a continuous absorption environment, fenofibrate supersaturation was considerably lower compared to in vitro lipolysis (non-sink). Hence, the extensive drug precipitation observed in vitro was predicted to be unlikely in vivo. The absorption of lipolysis products increased drug supersaturation, but drug precipitation was unlikely for highly permeable drugs. Biopharmaceutical modeling is a valuable approach for predicting LBFs performance in vivo. In the absence of in vitro tools simulating absorptive conditions, modeling strategies should be further considered.

  12. Kinetic model of drug distribution in the urinary bladder wall following intravesical instillation.

    Science.gov (United States)

    Grabnar, I; Bogataj, M; Belic, A; Logar, V; Karba, R; Mrhar, A

    2006-09-28

    Intravesical administration of cytotoxic agents is commonly used in urological practice for treatment of superficial bladder cancer. The leading motive is optimisation of drug delivery near the site of action and reduction of systemic toxicity. Bladder pharmacokinetics is complicated by several mechanisms. The objectives of this work were to develop a kinetic model of drug distribution in the bladder wall following intravesical instillation and to study the effect of various parameters on tissue and systemic drug exposure and explore the potential benefits of permeability enhancing effects of chitosan (CH) and polycarbophil (PC) through simulation. Key elements of the model are variable urinary drug concentration due to urine formation and voiding, biphasic diffusion in the bladder tissue and systemic absorption. Model parameters were estimated from bladder-tissue concentration profiles obtained in previous in vitro experiments with pipemidic acid (PPA) as a model drug. The results support further investigations on application of CH and PC in intravesical drug delivery. Both polymers increase permeability of the bladder wall by diffusion enhancement in the urothelium and presumably by improving the contact with the bladder surface. The developed mathematical model could serve for optimisation of intravesical drug delivery and future development of intravesical drug delivery systems.

  13. The paradigm shift to an “open” model in drug development

    OpenAIRE

    Regina Au

    2014-01-01

    The rising cost of healthcare, the rising cost for drug development, the patent cliff for Big pharma, shorter patent protection, decrease reimbursement, and the recession have made it more difficult for the pharmaceutical and biotechnology industry to develop drugs. Due to the unsustainable amount of time and money in developing a drug that will have a significant return on investment (ROI) it has become hard to sustain a robust pipeline. The industry is transforming its business model to mee...

  14. Concepts and Challenges in Quantitative Pharmacology and Model-Based Drug Development

    OpenAIRE

    Zhang, Liping; Pfister, Marc; Meibohm, Bernd

    2008-01-01

    Model-based drug development (MBDD) has been recognized as a concept to improve the efficiency of drug development. The acceptance of MBDD from regulatory agencies, industry, and academia has been growing, yet today’s drug development practice is still distinctly distant from MBDD. This manuscript is aimed at clarifying the concept of MBDD and proposing practical approaches for implementing MBDD in the pharmaceutical industry. The following concepts are defined and distinguished: PK–PD modeli...

  15. The synergistic effect of nanotopography and sustained dual release of hydrophobic and hydrophilic neurotrophic factors on human mesenchymal stem cell neuronal lineage commitment.

    Science.gov (United States)

    Teo, Benjamin Kim Kiat; Tan, Guo-Dong Sean; Yim, Evelyn K F

    2014-08-01

    A combination of nanotopography and controlled release is a potential platform for neuronal tissue engineering applications. Previous studies showed that combining both physical and chemical guidance was more effective than individual cues in the directional promotion of neurite outgrowth. Nanotopography can direct human mesenchymal stem cells (hMSCs) into neuronal lineage, while controlled release of neurotrophic factors can deliver temporally controlled biochemical signals. Hypothesizing that the synergistic effect will enhance neuronal lineage commitment of hMSCs, a fabrication method for multiple neurotrophic factors delivery from a single nanopatterned (350 nm gratings), poly-ɛ-caprolactone (PCL) film was developed and evaluated. Our results showed a synergistic effect on hMSC differentiation cultured on substrates with both nanotopographical and biochemical cues. The protein/drug encapsulation into PCL nanopatterned films was first optimized using a hydrophilic model protein, bovine serum albumin. The hydrophobic retinoic acid (RA) molecule was directly incorporated into PCL films. To achieve sustained release, hydrophilic nerve growth factor (NGF) was first encapsulated within polyelectrolyte complexation fibers before they were embedded within the nanopatterned PCL film. Our results showed that nanotopography on the fabricated polymer films remained intact, while release of bioactive RA and NGF was sustained over a period of 3 weeks. Under the combinatorial effect of physical and biochemical cues, we observed an enhanced upregulation of neuronal genes such as microtubule-associated protein 2 (MAP2) and neurofilament light (NFL) as compared with sustained delivery of individual cues and bolus delivery. Quantitative polymerase chain reaction analysis showed that MAP2 and NFL gene upregulation in hMSCs was most pronounced on the nanogratings with sustained release of both RA and NGF. The fabricated platforms supported the sustained delivery of multiple

  16. Mechanistic modeling of ophthalmic drug delivery to the anterior chamber by eye drops and contact lenses.

    Science.gov (United States)

    Gause, Samuel; Hsu, Kuan-Hui; Shafor, Chancellor; Dixon, Phillip; Powell, Kristin Conrad; Chauhan, Anuj

    2016-07-01

    Ophthalmic drug for the anterior chamber diseases are delivered into tears by either eye drops or by extended release devices placed in the eyes. The instilled drug exits the eye through various routes including tear drainage into the nose through the canaliculi and transport across various ocular membranes. Understanding the mechanisms relevant to each route can be useful in predicting the dependency of ocular bioavailability on various formulation parameters, such as drug concentration, salinity, viscosity, etc. Mathematical modeling has been developed for each of the routes and validated by comparison with experiments. The individual models can be combined into a system model to predict the fraction of the instilled drug that reaches the target. This review summarizes the individual models for the transport of drugs across the cornea and conjunctiva and the canaliculi tear drainage. It also summarizes the combined tear dynamics model that can predict the ocular bioavailability of drugs instilled as eye drops. The predictions from the individual models and the combined model are in good agreement with experimental data. Both experiments and models predict that the corneal bioavailability for drugs delivered through eye drops is less than 5% due to the small area of the cornea in comparison to the conjunctiva, and the rapid clearance of the instilled solution by tear drainage. A contact lens is a natural choice for delivering drugs to the cornea due to the placement of the contact in the immediate vicinity of the cornea. The drug released by the contact towards the cornea surface is trapped in the post lens tear film for extended duration of at least 30min allowing transport of a large portion into the cornea. The model predictions backed by in vivo animal and clinical data show that the bioavailability increases to about 50% with contact lenses. This realization has encouraged considerable research towards delivering ocular drugs by contact lenses. Commercial

  17. THE MODELING OF DRUG ADDICTION PREVALENCE AND ITS CONSEQUENCES IN RUSSIAN REGIONS

    Directory of Open Access Journals (Sweden)

    V.P. Sirotin

    2009-12-01

    Full Text Available The narcotization prevalence in Russia as whole and its regions is described. In order to provide the adequate models the clusters of regions on the level of their economic development are defined. For every group the regression model of drug addiction social distress is constructed. Modeling results allow to find the features of regions and the most significant factors determining the drug addiction prevalence.

  18. Modeling Initiation into Drug Injection among Street Youth

    Science.gov (United States)

    Roy, Elise; Godin, Gaston; Boudreau, Jean-Francois; Cote, Philippe-Benoit; Denis, Veronique; Haley, Nancy; Leclerc, Pascale; Boivin, Jean-Francois

    2011-01-01

    This study aimed at examining the predictors of initiation into drug injection among street youth using social cognitive theory framework. A prospective cohort study based on semi-annual interviews was carried out. Psychosocial determinants referred to avoidance of initiation. Other potential predictors were: sociodemographic characteristics,…

  19. hiv prevention among drug and alcohol users: models of ...

    African Journals Online (AJOL)

    Administrator

    Few programs have been implemented in Africa to deal specifically ... INTRODUCTION. The abuse of ... Identification Test (AUDIT) (Shaffer et al. 2004). .... actual diagnosis meeting the DSM-IV-TR ..... effective entry point for screening clients ... also manage the HIV care of the drug and .... perspective, it is still an essential.

  20. Enhancement of intestinal absorption of poorly absorbed hydrophilic compounds by simultaneous use of mucolytic agent and non-ionic surfactant.

    Science.gov (United States)

    Takatsuka, Shinya; Kitazawa, Takeo; Morita, Takahiro; Horikiri, Yuji; Yoshino, Hiroyuki

    2006-01-01

    The effect of co-administration of a mucolytic agent with a penetration enhancer was assessed on the intestinal absorption of poorly absorbed hydrophilic compounds. Fluorescein isothiocyanate-labeled dextran with average molecular weight of ca. 4.4 kDa (FD-4) was used as a model compound, and N-acetylcysteine (NAC) was used as a mucolytic agent. Sodium caprate (C10), tartaric acid (TA), sodium taurodeoxycholate (TDC), sodium dodecyl sulfate (SDS), p-t-octyl phenol polyoxyethylene-9.5 (Triton X-100, TX-100) were selected as penetration enhancers with different mechanisms of action. Various dosing solutions containing a penetration enhancer in the absence or in the presence of NAC were directly administered into the exposed rat jejunum, and the bioavailability of FD-4 up to 2 h was determined. The extent of improvement by co-administration was highly dependent on the penetration enhancer species applied. The observed enhancement was thought to result from the mucolytic activity of NAC, which can reduce the mucus viscosity and facilitate the penetration of FD-4 to mucosal membrane. Among the combinations tested, the simultaneous administration of NAC and TX-100 provided the highest enhancement (22.5-fold) of intestinal FD-4 absorption compared to the control. Although the detailed mechanism for the observed drastic improvement is unclear, one possible reason was thought to be due to the improved diffusivity of TX-100 micellar system in the mucus layer. All these results suggest that the combination of a mucolytic agent and a non-ionic surfactant may have potential as an enhancing system for peroral delivery of poorly absorbed hydrophilic compounds like protein and peptide drugs.

  1. Mathematical Models for Controlled Drug Release Through pH-Responsive Polymeric Hydrogels.

    Science.gov (United States)

    Manga, Ramya D; Jha, Prateek K

    2017-02-01

    Hydrogels consisting of weakly charged acidic/basic groups are ideal candidates for carriers in oral delivery, as they swell in response to pH changes in the gastrointestinal tract, resulting in drug entrapment at low pH conditions of the stomach and drug release at high pH conditions of the intestine. We have developed 1-dimensional mathematical models to study the drug release behavior through pH-responsive hydrogels. Models are developed for 3 different cases that vary in the level of rigor, which together can be applied to predict both in vitro (drug release from carrier) and in vivo (drug concentration in the plasma) behavior of hydrogel-drug formulations. A detailed study of the effect of hydrogel and drug characteristics and physiological conditions is performed to gain a fundamental insight into the drug release behavior, which may be useful in the design of pH-responsive drug carriers. Finally, we describe a successful application of these models to predict both in vitro and in vivo behavior of docetaxel-loaded micelle in a pH-responsive hydrogel, as reported in a recent experimental study. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  2. Dosage and Dose Schedule Screening of Drug Combinations in Agent-Based Models Reveals Hidden Synergies.

    Science.gov (United States)

    Barros de Andrade E Sousa, Lisa C; Kühn, Clemens; Tyc, Katarzyna M; Klipp, Edda

    2015-01-01

    The fungus Candida albicans is the most common causative agent of human fungal infections and better drugs or drug combination strategies are urgently needed. Here, we present an agent-based model of the interplay of C. albicans with the host immune system and with the microflora of the host. We took into account the morphological change of C. albicans from the yeast to hyphae form and its dynamics during infection. The model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing situations. We specifically focused on the consequences of microflora reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely drugs that inhibit cell division and drugs that constrain the yeast-to-hyphae transition. Applied individually, the division drug turned out to successfully decrease hyphae while the transition drug leads to a burst in hyphae after the end of the treatment. To evaluate the effect of different drug combinations, doses, and schedules, we introduced a measure for the return to a healthy state, the infection score. Using this measure, we found that the addition of a transition drug to a division drug treatment can improve the treatment reliability while minimizing treatment duration and drug dosage. In this work we present a theoretical study. Although our model has not been calibrated to quantitative experimental data, the technique of computationally identifying synergistic treatment combinations in an agent based model exemplifies the importance of computational techniques in translational research.

  3. Mathematical modeling of drug release from bioerodible microparticles: effect of gamma-irradiation.

    Science.gov (United States)

    Faisant, N; Siepmann, J; Richard, J; Benoit, J P

    2003-09-01

    Bioerodible polymers used in controlled drug delivery systems, such as poly(lactic-co-glycolic acid) (PLGA) undergo radiolytic degradation during gamma-irradiation. In spite of the considerable practical importance, yet only little knowledge is available on the consequences of this sterilization method on the resulting drug release patterns in a quantitative way. The major objectives of the present study were: (i) to monitor the effects of different gamma-irradiation doses on the physicochemical properties of drug-free and drug-loaded, PLGA-based microparticles; (ii) to analyze the obtained experimental results using adequate mathematical models; (iii) to get further insight into the occurring physical and chemical phenomena; and (iv) to relate the applied gamma-irradiation dose in a quantitative way to the resulting drug release rate. 5-Fluorouracil-loaded, PLGA-based microparticles were prepared with an oil-in-water solvent extraction method and exposed to gamma-irradiation doses ranging from 0 to 33 kGy. Size exclusion chromatography, differential scanning calorimetry, scanning electron microscopy, particle size analysis, determination of the actual drug loading and in vitro drug release kinetics were used to study the effects of the gamma-irradiation dose on the physicochemical properties of the microparticles. Two mathematical models-a simplified and a more comprehensive one-were used to analyze the experimental results. The simplified model considers drug diffusion based on Fick's second law for spherical geometry and a Higuchi-like pseudo-steady-state approach. The complex model combines Monte Carlo simulations (describing polymer erosion) with partial differential equations quantifying drug diffusion with time-, position- and direction-dependent diffusivities. Interestingly, exponential relationships between the gamma-irradiation dose and the initial drug diffusivity within the microparticles could be established. Based on this knowledge both models were

  4. Dosage and dose schedule screening of drug combinations in agent-based models reveals hidden synergies

    Directory of Open Access Journals (Sweden)

    Lisa Corina Barros de Andrade e Sousa1

    2016-01-01

    Full Text Available The fungus Candida albicans is the most common causative agent of human fungal infections and better drugs or drug combination strategies are urgently needed. Here, we present an agent-based model of the interplay of C. albicans with the host immune system and with the microflora of the host. We took into account the morphological change of C. albicans from the yeast to hyphae form and its dynamics during infection. The model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing situations. We specifically focused on the consequences of microflora reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely drugs that inhibit cell division and drugs that constrain the yeast-to-hyphae transition. Applied individually, the division drug turned out to successfully decrease hyphae while the transition drug leads to a burst in hyphae after the end of the treatment. To evaluate the effect of different drug combinations, doses, and schedules, we introduced a measure for the return to a healthy state, the infection score. Using this measure, we found that the addition of a transition drug to a division drug treatment can improve the treatment reliability while minimizing treatment duration and drug dosage. In this work we present a theoretical study. Although our model has not been calibrated to quantitative experimental data, the technique of computationally identifying synergistic treatment combinations in an agent based model exemplifies the importance of computational techniques in translational research.

  5. The paradigm shift to an “open” model in drug development

    Directory of Open Access Journals (Sweden)

    Regina Au

    2014-12-01

    Full Text Available The rising cost of healthcare, the rising cost for drug development, the patent cliff for Big pharma, shorter patent protection, decrease reimbursement, and the recession have made it more difficult for the pharmaceutical and biotechnology industry to develop drugs. Due to the unsustainable amount of time and money in developing a drug that will have a significant return on investment (ROI it has become hard to sustain a robust pipeline. The industry is transforming its business model to meet these challenges. In essence a paradigm shift is occurring; the old “closed” model is giving way to a new “open” business model.

  6. PREPARATION, CHARACTERIZATION AND IN VITRO EVALUATION OF REPAGLINIDE BINARY SOLID DISPERSIONS WITH HYDROPHILIC POLYMERS

    Directory of Open Access Journals (Sweden)

    Patel Manvi

    2010-09-01

    Full Text Available In the present study, the practically insoluble drug, repaglinide, employs formation of solid dispersions as a means to enhance the dissolution rate, thus enhancing bioavailability of repaglinide, typically employs hydrophilic polymer systems (Lutrol F127, PEG 6000 and Gelucire 44/14 with different ratios prepared using the melting, solvent and melting solvent methods. The formulations were evaluated for various in vitro parameters (Drug content, Drug release, FTIR, DSC, and XRD. Phase-solubility studies revealed AL type of curves for each carrier, indicating linear increase in drug solubility with carrier concentration. Good uniformity of drug content was observed with all formulations and ranged from 95.52 and 99.0%. All the solid dispersions showed dissolution improvement compare to pure drug. Solid state characterization of the drug?polymer binary systems using XRD, DSC and FTIR techniques revealed distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement in dissolution rate. The stability studies indicated, the best formulation LMS17 was stable for period of 6 months. The solid dispersion techniques provide a promising way to increase the solubility and dissolution rate of poorly soluble drugs.

  7. Monitoring model drug microencapsulation in PLGA scaffolds using X-ray powder diffraction

    OpenAIRE

    Adeyinka Aina; Manish Gupta; Yamina Boukari; Andrew Morris; Nashiru Billa; Stephen Doughty

    2015-01-01

    The microencapsulation of three model drugs; metronidazole, paracetamol and sulphapyridine into Poly (dl-Lactide-Co-Glycolide) (PLGA) scaffolds were probed using X-ray Powder Diffraction (XRPD). Changes in the diffraction patterns of the PLGA scaffolds after encapsulation was suggestive of a chemical interaction between the pure drugs and the scaffolds and not a physical intermixture.

  8. Monitoring model drug microencapsulation in PLGA scaffolds using X-ray powder d

    Directory of Open Access Journals (Sweden)

    Adeyinka Aina

    2016-03-01

    Full Text Available The microencapsulation of three model drugs; metronidazole, paracetamol and sulphapyridine into Poly (dl-Lactide-Co-Glycolide (PLGA scaffolds were probed using X-ray Powder Diffraction (XRPD. Changes in the diffraction patterns of the PLGA scaffolds after encapsulation was suggestive of a chemical interaction between the pure drugs and the scaffolds and not a physical intermixture.

  9. Monitoring model drug microencapsulation in PLGA scaffolds using X-ray powder diffraction.

    Science.gov (United States)

    Aina, Adeyinka; Gupta, Manish; Boukari, Yamina; Morris, Andrew; Billa, Nashiru; Doughty, Stephen

    2016-03-01

    The microencapsulation of three model drugs; metronidazole, paracetamol and sulphapyridine into Poly (dl-Lactide-Co-Glycolide) (PLGA) scaffolds were probed using X-ray Powder Diffraction (XRPD). Changes in the diffraction patterns of the PLGA scaffolds after encapsulation was suggestive of a chemical interaction between the pure drugs and the scaffolds and not a physical intermixture.

  10. A stochastic multicriteria model for evidence-based decision making in drug benefit-risk analysis

    NARCIS (Netherlands)

    Tervonen, Tommi; van Valkenhoef, Gert; Buskens, Erik; Hillege, Hans L.; Postmus, Douwe

    2011-01-01

    Drug benefit-risk (BR) analysis is based on firm clinical evidence regarding various safety and efficacy outcomes. In this paper, we propose a new and more formal approach for constructing a supporting multicriteria model that fully takes into account the evidence on efficacy and adverse drug reacti

  11. Why Do Adolescents Use Drugs? A Common Sense Explanatory Model from the Social Actor's Perspective

    Science.gov (United States)

    Nuno-Gutierrez, Bertha Lidia; Rodriguez-Cerda, Oscar; Alvarez-Nemegyei, Jose

    2006-01-01

    Analysis was made of the common sense explanations of 60 Mexican teenage illicit drug users in rehabilitation to determine their drug use debut. The explanatory model was separated into three blocks, two of which contained common sense aspects: interaction between subject's plane and the collectivity; and relationship between subject's interior…

  12. A Comprehensive Action Model to Combat Drug Abuse in High School

    Science.gov (United States)

    Petrillo, Robert F.

    1970-01-01

    Emphasized in the model are: creation and adoption of new Board policies and procedures to deal with the drug abuser, crash Emergency Room" program of drug education for grades 4 through 12, inservice education of staff, lowkey parent education, increased employment of paraprofessional supervisory personnel, and community acceptance of and…

  13. Boron nitride nanotubes coated with organic hydrophilic agents: Stability and cytocompatibility studies

    Energy Technology Data Exchange (ETDEWEB)

    Ferreira, Tiago Hilário; Soares, Daniel Crístian Ferreira; Moreira, Luciana Mara Costa; Ornelas da Silva, Paulo Roberto [Serviço de Nanotecnologia, Centro de Desenvolvimento da Tecnologia Nuclear CDTN/CNEN, Avenida Presidente Antônio Carlos, 6.627, Campus da UFMG, Pampulha, CEP 31270-901 Belo Horizonte, Minas Gerais (Brazil); Gouvêa dos Santos, Raquel [Laboratório de Radiobiologia, Centro de Desenvolvimento da Tecnologia Nuclear CNEN/CDTN, Av. Presidente Antônio Carlos 6.627, Campus da UFMG, Pampulha, 31270-901 Belo Horizonte, Minas Gerais (Brazil); Barros de Sousa, Edésia Martins, E-mail: sousaem@cdtn.br [Serviço de Nanotecnologia, Centro de Desenvolvimento da Tecnologia Nuclear CDTN/CNEN, Avenida Presidente Antônio Carlos, 6.627, Campus da UFMG, Pampulha, CEP 31270-901 Belo Horizonte, Minas Gerais (Brazil)

    2013-12-01

    In the present study, Boron Nitride Nanotubes (BNNTs) were synthesized and functionalized with organic hydrophilic agents constituted by glucosamine (GA), polyethylene glycol (PEG){sub 1000}, and chitosan (CH) forming new singular systems. Their size, distribution, and homogeneity were determined by photon correlation spectroscopy, while their surface charge was determined by laser Doppler anemometry. The morphology and structural organization were evaluated by Transmission Electron Microscopy. The functionalization was evaluated by Thermogravimetry analysis and Fourier Transformer Infrared Spectroscopy. The results showed that BNNTs were successfully obtained and functionalized, reaching a mean size and dispersity deemed adequate for in vitro studies. The in vitro stability tests also revealed a good adhesion of functionalized agents on BNNT surfaces. Finally, the in vitro cytocompatibility of functionalized BNNTs against MCR-5 cells was evaluated, and the results revealed that none of the different functionalization agents disturbed the propagation of normal cells up to the concentration of 50 μg/mL. Furthermore, in this concentration, no significantly chromosomal or morphologic alterations or increase in ROS (Reactive Oxygen Species) could be observed. Thus, findings from the present study reveal an important stability and cytocompatibility of functionalized BNNTs as new potential drugs or radioisotope nanocarriers to be applied in therapeutic procedures. - Highlights: • BNNTs were synthesized and functionalized with organic hydrophilic agents. • Hydrophilic molecules do not alter the biocompatibility profile of BNNTs. • No significantly chromosomal or morphologic alterations in ROS could be observed.

  14. Electroresponsive nanoparticles for drug delivery on demand

    Science.gov (United States)

    Samanta, Devleena; Hosseini-Nassab, Niloufar; Zare, Richard N.

    2016-04-01

    The potential of electroresponsive conducting polymer nanoparticles to be used as general drug delivery systems that allow electrically pulsed, linearly scalable, and on demand release of incorporated drugs is demonstrated. As examples, facile release from polypyrrole nanoparticles is shown for fluorescein, a highly water-soluble model compound, piroxicam, a lipophilic small molecule drug, and insulin, a large hydrophilic peptide hormone. The drug loading is about 13 wt% and release is accomplished in a few seconds by applying a weak constant current or voltage. To identify the parameters that should be finely tuned to tailor the carrier system for the release of the therapeutic molecule of interest, a systematic study of the factors that affect drug delivery is performed, using fluorescein as a model compound. The parameters studied include current, time, voltage, pH, temperature, particle concentration, and ionic strength. Results indicate that there are several degrees of freedom that can be optimized for efficient drug delivery. The ability to modulate linearly drug release from conducting polymers with the applied stimulus can be utilized to design programmable and minimally invasive drug delivery devices.

  15. Polymethacrylate microparticles gel for topical drug delivery.

    Science.gov (United States)

    Labouta, Hagar Ibrahim; El-Khordagui, Labiba K

    2010-10-01

    Evaluating the potentials of particulate delivery systems in topical drug delivery. Polymethacrylate microparticles (MPs) incorporating verapamil hydrochloride (VRP) as a model hydrophilic drug with potential topical clinical uses, using Eudragit RS100 and Eudragit L100 were prepared for the formulation of a composite topical gel. The effect of initial drug loading, polymer composition, particularly the proportion of Eudragit L100 as an interacting polymer component and the HLB of the dispersing agent on MPs characteristics was investigated. A test MPs formulation was incorporated in gel and evaluated for drug release and human skin permeation. MPs showed high % incorporation efficiency and % yield. Composition of the hybrid polymer matrix was a main determinant of MPs characteristics, particularly drug release. Factors known to influence drug release such as MPs size and high drug solubility were outweighed by strong VRP-Eudragit L100 interaction. The developed MPs gel showed controlled VRP release and reduced skin retention compared to a free drug gel. Topical drug delivery and skin retention could be modulated using particulate delivery systems. From a practical standpoint, the VRP gel developed may offer advantage in a range of dermatological conditions, in response to the growing off-label topical use of VRP.

  16. A hybrid cellular automaton model of solid tumor growth and bioreductive drug transport.

    Science.gov (United States)

    Kazmi, Nabila; Hossain, M A; Phillips, Roger M

    2012-01-01

    Bioreductive drugs are a class of hypoxia selective drugs that are designed to eradicate the hypoxic fraction of solid tumors. Their activity depends upon a number of biological and pharmacological factors and we used a mathematical modeling approach to explore the dynamics of tumor growth, infusion, and penetration of the bioreductive drug Tirapazamine (TPZ). An in-silico model is implemented to calculate the tumor mass considering oxygen and glucose as key microenvironmental parameters. The next stage of the model integrated extra cellular matrix (ECM), cell-cell adhesion, and cell movement parameters as growth constraints. The tumor microenvironments strongly influenced tumor morphology and growth rates. Once the growth model was established, a hybrid model was developed to study drug dynamics inside the hypoxic regions of tumors. The model used 10, 50 and 100 \\mu {\\rm M} as TPZ initial concentrations and determined TPZ pharmacokinetic (PK) (transport) and pharmacodynamics (cytotoxicity) properties inside hypoxic regions of solid tumor. The model results showed that diminished drug transport is a reason for TPZ failure and recommend the optimization of the drug transport properties in the emerging TPZ generations. The modeling approach used in this study is novel and can be a step to explore the behavioral dynamics of TPZ.

  17. Personalized drug administration for cancer treatment using Model Reference Adaptive Control.

    Science.gov (United States)

    Babaei, Naser; Salamci, Metin U

    2015-04-21

    A new Model Reference Adaptive Control (MRAC) approach is proposed for the nonlinear regulation problem of cancer treatment via chemotherapy. We suggest an approach for determining an optimal anticancer drug delivery scenario for cancer patients without prior knowledge of nonlinear model structure and parameters by compounding State Dependent Riccati Equation (SDRE) and MRAC which will lead to personalized drug administration. Several approaches have been proposed for eradicating cancerous cells in nonlinear tumor growth model. The main difficulty in these approaches is the requirement of nonlinear model parameters, which are unknown to physicians in reality. To cope with this shortage, we first determine the drug delivery scenario for a reference patient with known mathematical model and parameters via SDRE technique, and by using the proposed approach we adapt the drug administration scenario for another cancer patient despite unknown nonlinear model structure and model parameters. We propose an efficient approach to determine drug administration which will help physicians for prescribing a chemotherapy protocol for a cancer patient by regulating the drug delivery scenario of the reference patient. Stabilizing the tumor growth nonlinear model has been achieved via full state feedback techniques and yields a near optimal solution to cancer treatment problem. Numerical simulations show the effectiveness of the proposed algorithm for eradicating tumor lumps with different sizes in different patients.

  18. A drug cost model for injuries due to road traffic accidents.

    Directory of Open Access Journals (Sweden)

    Riewpaiboon A

    2008-03-01

    Full Text Available Objective: This study aimed to develop a drug cost model for injuries due to road traffic accidents for patients receiving treatment at a regional hospital in Thailand. Methods: The study was designed as a retrospective, descriptive analysis. The cases were all from road traffic accidents receiving treatment at a public regional hospital in the fiscal year 2004. Results: Three thousand seven hundred and twenty-three road accident patients were included in the study. The mean drug cost per case was USD18.20 (SD=73.49, median=2.36. The fitted drug cost model had an adjusted R2 of 0.449. The positive significant predictor variables of drug costs were prolonged length of stay, age over 30 years old, male, Universal Health Coverage Scheme, time of accident during 18:00-24:00 o’clock, and motorcycle comparing to bus. To forecast the drug budget for 2006, there were two approaches identified, the mean drug cost and the predicted average drug cost. The predicted average drug cost was calculated based on the forecasted values of statistically significant (p<0.05 predictor variables included in the fitted model; predicted total drug cost was USD44,334. Alternatively, based on the mean cost, predicted total drug cost in 2006 was USD63,408. This was 43% higher than the figure based on the predicted cost approach.Conclusions: The planned budget of drug cost based on the mean cost and predicted average cost were meaningfully different. The application of a predicted average cost model could result in a more accurate budget planning than that of a mean statistic approach.

  19. Assessment of anti-arrhythmic activity of antipsychotic drugs in an animal model

    DEFF Research Database (Denmark)

    Mow, Tomas; Frederiksen, Kristen; Thomsen, Morten B.

    2015-01-01

    Torsades de Pointes (TdP) is a potentially lethal cardiac arrhythmia and a known adverse effect of many drugs secondary to block of the rapidly activating delayed rectifier potassium current (IKr). In animal models antipsychotic drugs have shown reduced pro-arrhythmic potential compared to drugs...... of methoxamine induced increase in blood pressure. Further investigations are required to clarify the relative importance of α1-adrenergic receptor antagonism in conjunction with the additional effects of antipsychotic drugs on various receptors and ion channels....

  20. The runway model of drug self-administration

    OpenAIRE

    Ettenberg, Aaron

    2008-01-01

    Behavioral scientists have employed operant runways as a means of investigating the motivational impact of incentive stimuli for the better part of the past 100 years. In this task, the speed with which a trained animal traverses a long straight alley for positive incentive stimuli, like food or water, provides a reliable index of the subject’s motivation to seek those stimuli. The runway is therefore a particularly appropriate tool for investigating the drug-seeking behavior of animals worki...

  1. Reconsidering GHB: orphan drug or new model antidepressant?

    OpenAIRE

    Bosch, O G; Quednow, B. B.; Seifritz, E.; Wetter, T C

    2012-01-01

    For six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other efforts have been made to ameliorate the symptoms of depression by pharmacological means. The gamma-aminobutyric acid (GABA) syste...

  2. Pharmacological modeling and biostatistical analysis of a new drug

    OpenAIRE

    Revathi Ananthakrishnan; Philimon Gona

    2010-01-01

    Revathi Ananthakrishnan1, Philimon Gona21Cambridge, MA, USA; 2Boston University, Mathematics and Statistics Department, 111 Cummington St, Boston, MA-02215, USAAbstract: Clinical research and clinical trials of experimental drugs to treat human diseases have gained greater importance in recent years. Phase I–IV clinical trials offer patients the opportunity to gain access to a new, more efficacious and safer medication to alleviate or cure their disease. There are potential side eff...

  3. Molecular modeling study of chiral drug crystals: lattice energy calculations.

    Science.gov (United States)

    Li, Z J; Ojala, W H; Grant, D J

    2001-10-01

    The lattice energies of a number of chiral drugs with known crystal structures were calculated using Dreiding II force field. The lattice energies, including van der Waals, Coulombic, and hydrogen-bonding energies, of homochiral and racemic crystals of some ephedrine derivatives and of several other chiral drugs, are compared. The calculated energies are correlated with experimental data to probe the underlying intermolecular forces responsible for the formation of racemic species, racemic conglomerates, or racemic compounds, termed chiral discrimination. Comparison of the calculated energies among ephedrine derivatives reveals that a greater Coulombic energy corresponds to a higher melting temperature, while a greater van der Waals energy corresponds to a larger enthalpy of fusion. For seven pairs of homochiral and racemic compounds, correlation of the differences between the two forms in the calculated energies and experimental enthalpy of fusion suggests that the van der Waals interactions play a key role in the chiral discrimination in the crystalline state. For salts of the chiral drugs, the counter ions diminish chiral discrimination by increasing the Coulombic interactions. This result may explain why salt forms favor the formation of racemic conglomerates, thereby facilitating the resolution of racemates.

  4. NMR characterisation and transdermal drug delivery potential of microemulsion systems

    DEFF Research Database (Denmark)

    Kreilgaard, Mads; Pedersen, E J; Jaroszewski, J W

    2000-01-01

    The purpose of this study was to investigate the influence of structure and composition of microemulsions (Labrasol/Plurol Isostearique/isostearylic isostearate/water) on their transdermal delivery potential of a lipophilic (lidocaine) and a hydrophilic model drug (prilocaine hydrochloride......), and to compare the drug delivery potential of microemulsions to conventional vehicles. Self-diffusion coefficients determined by pulsed-gradient spin-echo NMR spectroscopy and T(1) relaxation times were used to characterise the microemulsions. Transdermal flux of lidocaine and prilocaine hydrochloride through...... and transdermal flux was indicated. The increased transdermal drug delivery from microemulsion formulations was found to be due mainly to the increased solubility of drugs and appeared to be dependent on the drug mobility in the individual vehicle. The microemulsions did not perturb the skin barrier, indicating...

  5. Predicting the oral uptake efficiency of chemicals in mammals: Combining the hydrophilic and lipophilic range

    Energy Technology Data Exchange (ETDEWEB)

    O' Connor, Isabel A., E-mail: i.oconnor@science.ru.nl [Radboud University Nijmegen, Institute for Water and Wetland Research, Department of Environmental Science, P.O. Box 9010, NL-6500 GL, Nijmegen (Netherlands); Huijbregts, Mark A.J., E-mail: m.huijbregts@science.ru.nl [Radboud University Nijmegen, Institute for Water and Wetland Research, Department of Environmental Science, P.O. Box 9010, NL-6500 GL, Nijmegen (Netherlands); Ragas, Ad M.J., E-mail: a.ragas@science.ru.nl [Radboud University Nijmegen, Institute for Water and Wetland Research, Department of Environmental Science, P.O. Box 9010, NL-6500 GL, Nijmegen (Netherlands); Open University, School of Science, P.O. Box 2960,6401 DL Heerlen (Netherlands); Hendriks, A. Jan, E-mail: a.j.hendriks@science.ru.nl [Radboud University Nijmegen, Institute for Water and Wetland Research, Department of Environmental Science, P.O. Box 9010, NL-6500 GL, Nijmegen (Netherlands)

    2013-01-01

    Environmental risk assessment requires models for estimating the bioaccumulation of untested compounds. So far, bioaccumulation models have focused on lipophilic compounds, and only a few have included hydrophilic compounds. Our aim was to extend an existing bioaccumulation model to estimate the oral uptake efficiency of pollutants in mammals for compounds over a wide K{sub ow} range with an emphasis on hydrophilic compounds, i.e. compounds in the lower K{sub ow} range. Usually, most models use octanol as a single surrogate for the membrane and thus neglect the bilayer structure of the membrane. However, compounds with polar groups can have different affinities for the different membrane regions. Therefore, an existing bioaccumulation model was extended by dividing the diffusion resistance through the membrane into an outer and inner membrane resistance, where the solvents octanol and heptane were used as surrogates for these membrane regions, respectively. The model was calibrated with uptake efficiencies of environmental pollutants measured in different mammals during feeding studies combined with human oral uptake efficiencies of pharmaceuticals. The new model estimated the uptake efficiency of neutral (RMSE = 14.6) and dissociating (RMSE = 19.5) compounds with logK{sub ow} ranging from − 10 to + 8. The inclusion of the K{sub hw} improved uptake estimation for 33% of the hydrophilic compounds (logK{sub ow} < 0) (r{sup 2} = 0.51, RMSE = 22.8) compared with the model based on K{sub ow} only (r{sup 2} = 0.05, RMSE = 34.9), while hydrophobic compounds (logK{sub ow} > 0) were estimated equally by both model versions with RMSE = 15.2 (K{sub ow} and K{sub hw}) and RMSE = 15.7 (K{sub ow} only). The model can be used to estimate the oral uptake efficiency for both hydrophilic and hydrophobic compounds. -- Highlights: ► A mechanistic model was developed to estimate oral uptake efficiency. ► Model covers wide logK{sub ow} range (- 10 to + 8) and several mammalian

  6. Recent advances in multiaxial electrospinning for drug delivery.

    Science.gov (United States)

    Khalf, Abdurizzagh; Madihally, Sundararajan V

    2017-03-01

    Electrospun fibers have seen an insurgence in biomedical applications due to their unique characteristics. Coaxial and triaxial electrospinning techniques have added new impetus via fabrication of multilayered nano and micro-size fibers. These techniques offer the possibility of forming fibers with features such as blending, reinforced core, porous and hollow structure. The unique fabrication process can be used to tailor the mechanical properties, biological properties and release of various factors, which can potentially be useful in various controlled drug delivery applications. Harvesting these advantages, various polymers and their combinations have been explored in a number of drug delivery and tissue regeneration applications. New advances have shown the requirement of drug-polymer compatibility in addition to drug-solvent compatibility. We summarize recent findings using both hydrophilic and hydrophobic (or lipophilic) drugs in hydrophobic or hydrophilic polymers on release behavior. We also describe the fundamental forces involved during the electrospinning process providing insight to the factors to be considered to form fibers. Also, various modeling efforts on the drug release profiles are summarized. In addition new developments in the immune response to the electrospun fibers, and advances in scale-up issues needed for industrial size manufacturing.

  7. 21 CFR 878.4018 - Hydrophilic wound dressing.

    Science.gov (United States)

    2010-04-01

    ... a wound and to absorb exudate. It consists of nonresorbable materials with hydrophilic properties that are capable of absorbing exudate (e.g., cotton, cotton derivatives, alginates, dextran, and...

  8. Treatment of ASP produced water with hydrophilic fibre ball filtration

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The conventional treatment process cannot meet the need for treatment of produced water from alkaline/surfactant/polymer flooding( ASP produced water) in Daqing oilfield. In this study, a new type of hydrophilic fibre ball medium was developed through surface modification method. The hydrophilic property of the surface modified fibre ball was tested with ASP produced liquid at laboratory. The results showed that this fibre ball had higher oil degreasing efficiency. The surface components were also observed by Scanning Electron Microscope and X-ray Photoelectron Spectroscopy, the result showed that the hydrophilic fibre' s surface was covered by sulfonic group. Using hydrophilic fibre ball as filter medium, a new type of filter was designed to treat ASP produced water in pilot-scale experiments. The obtained results indicated that this type of filter had high capability and efficiency for the treatment of ASP produced water. This filter should have a better application prospect in oilfield produced water treatment.

  9. Modeling the Release Kinetics of Poorly Water-Soluble Drug Molecules from Liposomal Nanocarriers

    Directory of Open Access Journals (Sweden)

    Stephan Loew

    2011-01-01

    Full Text Available Liposomes are frequently used as pharmaceutical nanocarriers to deliver poorly water-soluble drugs such as temoporfin, cyclosporine A, amphotericin B, and paclitaxel to their target site. Optimal drug delivery depends on understanding the release kinetics of the drug molecules from the host liposomes during the journey to the target site and at the target site. Transfer of drugs in model systems consisting of donor liposomes and acceptor liposomes is known from experimental work to typically exhibit a first-order kinetics with a simple exponential behavior. In some cases, a fast component in the initial transfer is present, in other cases the transfer is sigmoidal. We present and analyze a theoretical model for the transfer that accounts for two physical mechanisms, collisions between liposomes and diffusion of the drug molecules through the aqueous phase. Starting with the detailed distribution of drug molecules among the individual liposomes, we specify the conditions that lead to an apparent first-order kinetic behavior. We also discuss possible implications on the transfer kinetics of (1 high drug loading of donor liposomes, (2 attractive interactions between drug molecules within the liposomes, and (3 slow transfer of drugs between the inner and outer leaflets of the liposomes.

  10. Modeling the Release Kinetics of Poorly Water-Soluble Drug Molecules from Liposomal Nanocarriers

    Science.gov (United States)

    Loew, Stephan; Fahr, Alfred; May, Sylvio

    2011-01-01

    Liposomes are frequently used as pharmaceutical nanocarriers to deliver poorly water-soluble drugs such as temoporfin, cyclosporine A, amphotericin B, and paclitaxel to their target site. Optimal drug delivery depends on understanding the release kinetics of the drug molecules from the host liposomes during the journey to the target site and at the target site. Transfer of drugs in model systems consisting of donor liposomes and acceptor liposomes is known from experimental work to typically exhibit a first-order kinetics with a simple exponential behavior. In some cases, a fast component in the initial transfer is present, in other cases the transfer is sigmoidal. We present and analyze a theoretical model for the transfer that accounts for two physical mechanisms, collisions between liposomes and diffusion of the drug molecules through the aqueous phase. Starting with the detailed distribution of drug molecules among the individual liposomes, we specify the conditions that lead to an apparent first-order kinetic behavior. We also discuss possible implications on the transfer kinetics of (1) high drug loading of donor liposomes, (2) attractive interactions between drug molecules within the liposomes, and (3) slow transfer of drugs between the inner and outer leaflets of the liposomes. PMID:21773045

  11. Mathematical modeling analysis of intratumoral disposition of anticancer agents and drug delivery systems.

    Science.gov (United States)

    Popilski, Hen; Stepensky, David

    2015-05-01

    Solid tumors are characterized by complex morphology. Numerous factors relating to the composition of the cells and tumor stroma, vascularization and drainage of fluids affect the local microenvironment within a specific location inside the tumor. As a result, the intratumoral drug/drug delivery system (DDS) disposition following systemic or local administration is non-homogeneous and its complexity reflects the differences in the local microenvironment. Mathematical models can be used to analyze the intratumoral drug/DDS disposition and pharmacological effects and to assist in choice of optimal anticancer treatment strategies. The mathematical models that have been applied by different research groups to describe the intratumoral disposition of anticancer drugs/DDSs are summarized in this article. The properties of these models and of their suitability for prediction of the drug/DDS intratumoral disposition and pharmacological effects are reviewed. Currently available mathematical models appear to neglect some of the major factors that govern the drug/DDS intratumoral disposition, and apparently possess limited prediction capabilities. More sophisticated and detailed mathematical models and their extensive validation are needed for reliable prediction of different treatment scenarios and for optimization of drug treatment in the individual cancer patients.

  12. A predictive model for the release of slightly water-soluble drugs from HPMC matrices.

    Science.gov (United States)

    Fu, X C; Wang, G P; Wang, Y H; Liang, W Q

    2004-08-01

    A model to predict the fraction of slightly water-soluble drug released as a function of release time (t, h), HPMC concentration (C(H), w/w), drug solubility in distilled water at 37 degrees C (C(s), g/100 mL), and volume of drug molecule (V, nm3) was derived when theophyline, tinidazole, and propylthiouracil were selected as model drugs. The model is log (M(t)/M(infinity)) = 0.8683 logt-0.1930C(s) logt + 0.5406V logt-1.227C(H) + 0.1594C(s) + 0.4423C(H)C(s) - 0.8655 (n = 130, r = 0.9969), where Mt is the amount of drug released at time t, Minfinity is the amount of drug released over a very long time, which corresponds in principle to the initial loading, n is the number of samples, and r is the correlation coefficient. The model was validated using sulfamethoxazole and satisfactory results were obtained. The model can be used to predict the release fraction of variousslightly water-soluble drugs from HPMC matrices having different polymer levels.

  13. How Preclinical Models Evolved to Resemble the Diagnostic Criteria of Drug Addiction.

    Science.gov (United States)

    Belin-Rauscent, Aude; Fouyssac, Maxime; Bonci, Antonello; Belin, David

    2016-01-01

    Drug addiction is a complex neuropsychiatric disorder that affects a subset of the individuals who take drugs. It is characterized by maladaptive drug-seeking habits that are maintained despite adverse consequences and intense drug craving. The pathophysiology and etiology of addiction is only partially understood despite extensive research because of the gap between current preclinical models of addiction and the clinical criteria of the disorder. This review presents a brief overview, based on selected methodologies, of how behavioral models have evolved over the last 50 years to the development of recent preclinical models of addiction that more closely mimic diagnostic criteria of addiction. It is hoped that these new models will increase our understanding of the complex neurobiological mechanisms whereby some individuals switch from controlled drug use to compulsive drug-seeking habits and relapse to these maladaptive habits. Additionally, by paving the way to bridge the gap that exists between biobehavioral research on addiction and the human situation, these models may provide new perspectives for the development of novel and effective therapeutic strategies for drug addiction. Published by Elsevier Inc.

  14. Utility of population pharmacokinetic modeling in the assessment of therapeutic protein-drug interactions.

    Science.gov (United States)

    Chow, Andrew T; Earp, Justin C; Gupta, Manish; Hanley, William; Hu, Chuanpu; Wang, Diane D; Zajic, Stefan; Zhu, Min

    2014-05-01

    Assessment of pharmacokinetic (PK) based drug-drug interactions (DDI) is essential for ensuring patient safety and drug efficacy. With the substantial increase in therapeutic proteins (TP) entering the market and drug development, evaluation of TP-drug interaction (TPDI) has become increasingly important. Unlike for small molecule (e.g., chemical-based) drugs, conducting TPDI studies often presents logistical challenges, while the population PK (PPK) modeling may be a viable approach dealing with the issues. A working group was formed with members from the pharmaceutical industry and the FDA to assess the utility of PPK-based TPDI assessment including study designs, data analysis methods, and implementation strategy. This paper summarizes key issues for consideration as well as a proposed strategy with focuses on (1) PPK approach for exploratory assessment; (2) PPK approach for confirmatory assessment; (3) importance of data quality; (4) implementation strategy; and (5) potential regulatory implications. Advantages and limitations of the approach are also discussed.

  15. Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors

    Directory of Open Access Journals (Sweden)

    Lucianna Helene Santos

    2015-11-01

    Full Text Available Reverse transcriptase (RT is a multifunctional enzyme in the human immunodeficiency virus (HIV-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

  16. Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors.

    Science.gov (United States)

    Santos, Lucianna Helene; Ferreira, Rafaela Salgado; Caffarena, Ernesto Raúl

    2015-11-01

    Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

  17. Biodegradable Oxamide-Phenylene-Based Mesoporous Organosilica Nanoparticles with Unprecedented Drug Payloads for Delivery in Cells

    KAUST Repository

    Croissant, Jonas

    2016-06-03

    We describe biodegradable mesoporous hybrid NPs in the presence of proteins, and its application for drug delivery. We synthesized oxamide-phenylene-based mesoporous organosilica nanoparticles (MON) in the absence of silica source which had a remarkably high organic content with a high surface area. Oxamide functions provided biodegradability in the presence of trypsin model proteins. MON displayed exceptionally high payloads of hydrophilic and hydrophobic drugs (up to 84 wt%), and a unique zero premature leakage without the pore capping, unlike mesoporous silica. MON were biocompatible and internalized into cancer cells for drug delivery.

  18. Free surface entropic lattice Boltzmann simulations of film condensation on vertical hydrophilic plates

    DEFF Research Database (Denmark)

    Hygum, Morten Arnfeldt; Karlin, Iliya; Popok, Vladimir

    2015-01-01

    A model for vapor condensation on vertical hydrophilic surfaces is developed using the entropic lattice Boltzmann method extended with a free surface formulation of the evaporation–condensation problem. The model is validated with the steady liquid film formation on a flat vertical wall....... It is shown that the model is in a good agreement with the classical Nusselt equations for the laminar flow regime. Comparisons of the present model with other empirical models also demonstrate good agreement beyond the laminar regime. This allows the film condensation modeling at high film Reynolds numbers...

  19. The chemical modification of  -chymotrypsin with both hydrophobic and hydrophilic compounds stabilizes the enzyme against denaturation in water-organic media

    National Research Council Canada - National Science Library

    Vinogradov, A.A; Kudryashova, E.V; Grinberg, V.Ya; Grinberg, N.V; Burova, T.V; Levashov, A.V

    2001-01-01

    We considered [alpha]-chymotrypsin (CT) in homogeneous water-organic media as a model system to examine the influence of enzyme chemical modification with hydrophilic and hydrophobic substances on its stability, activity and structure...

  20. Discovery of Drug Synergies in Gastric Cancer Cells Predicted by Logical Modeling.

    Science.gov (United States)

    Flobak, Åsmund; Baudot, Anaïs; Remy, Elisabeth; Thommesen, Liv; Thieffry, Denis; Kuiper, Martin; Lægreid, Astrid

    2015-08-01

    Discovery of efficient anti-cancer drug combinations is a major challenge, since experimental testing of all possible combinations is clearly impossible. Recent efforts to computationally predict drug combination responses retain this experimental search space, as model definitions typically rely on extensive drug perturbation data. We developed a dynamical model representing a cell fate decision network in the AGS gastric cancer cell line, relying on background knowledge extracted from literature and databases. We defined a set of logical equations recapitulating AGS data observed in cells in their baseline proliferative state. Using the modeling software GINsim, model reduction and simulation compression techniques were applied to cope with the vast state space of large logical models and enable simulations of pairwise applications of specific signaling inhibitory chemical substances. Our simulations predicted synergistic growth inhibitory action of five combinations from a total of 21 possible pairs. Four of the predicted synergies were confirmed in AGS cell growth real-time assays, including known effects of combined MEK-AKT or MEK-PI3K inhibitions, along with novel synergistic effects of combined TAK1-AKT or TAK1-PI3K inhibitions. Our strategy reduces the dependence on a priori drug perturbation experimentation for well-characterized signaling networks, by demonstrating that a model predictive of combinatorial drug effects can be inferred from background knowledge on unperturbed and proliferating cancer cells. Our modeling approach can thus contribute to preclinical discovery of efficient anticancer drug combinations, and thereby to development of strategies to tailor treatment to individual cancer patients.

  1. Non steroidal antiinflammatory drugs may be harmful to normal kidneys: experimental surgery model*

    OpenAIRE

    Hur, E; E. Duman; Bozkurt, D; Sozmen, E; Sen, S; Taskin, H; Timur, O; Kaya, SO; Duman, S

    2012-01-01

    Background and aim: The exact effect of analgesics on normal kidneys is not known yet. We aimed to evaluate the impression of non steroidal antiinflammatory drugs (NSAID) used post-operatively on kidneys, in rat (tracheotomy) model.

  2. Prediction of drug-drug interactions between various antidepressants and ritonavir using a physiologically based pharmacokinetic model

    Directory of Open Access Journals (Sweden)

    M Siccardi

    2012-11-01

    Full Text Available Depression can impact on the treatment of HIV infection, and effective treatment of depressive conditions can have a beneficial effect improving adherence. However antidepressant treatment requires long-term maintenance, and is prone to pharmacokinetic drug-drug interactions (DDI with antiretrovirals. The aim of this study was to predict the magnitude of DDI between ritonavir (RTV and the most commonly prescribed antidepressants using a physiologically based pharmacokinetic (PBPK model simulating virtual clinical trials. In vitro data describing the physiochemical properties, absorption, metabolism, induction and inhibitory potential of RTV and five antidepressants were obtained from published literature. Interactions between RTV and antidepressants were evaluated using the full PBPK model implemented in the Simcyp Population-based Simulator (Version 11.1, Simcyp Limited, UK and virtual clinical studies were simulated on 50 Caucasian subjects receiving 100mg bid of RTV for 21 days plus sertraline (100mg qd, citalopram (40mg qd, fluoxetine (20mg qd, venlafaxine (25mg qd and then from day 14–21. Simulated pharmacokinetic parameters were compared with observed values available in the literature. The simulated PK parameters of RTV, sertraline, citalopram, fluoxetine, mirtazepine and venlafaxine given alone at standard dosage were similar to reference values obtain from published clinical studies. The effect of simulated RTV co-administration on sertaline, fluoxetine and venlaflaxine was an AUC decrease of 40%, 26% and 6%, respectively and on mirtazepine and citalopram, an AUC increase of 60% and 20% respectively. The magnitude of the simulated DDI between RTV and the antidepressants was overall weak to moderate according to the classification of the FDA. The modest magnitude of these drug-drug interactions could be explained by the fact that antidepressants are substrates of multiple isoforms thus metabolism can still occur through CYPs that are

  3. Mechanism of Hydrophilicity by Radiation-Induced Surface Activation

    Science.gov (United States)

    Honjo, Yoshio; Furuya, Masahiro; Takamasa, Tomoji; Okamoto, Koji

    When a metal oxide is irradiated by gamma rays, the irradiated surface becomes hydrophilic. This surface phenomenon is called as radiation-induced surface activation (RISA) hydrophilicity. In order to investigate gamma ray-induced and photoinduced hydrophilicity, the contact angles of water droplets on a titanium dioxide surface were measured in terms of irradiation intensity and time for gamma rays of cobalt-60 and for ultraviolet rays. Reciprocals of the contact angles increased in proportion to the irradiation time before the contact angles reached its super-hydrophilic state. The irradiation time dependency is equal to each other qualitatively. In addition, an effect of ambient gas was investigated. In pure argon gas, the contact angle remains the same against the irradiation time. This clearly indicates that certain humidity is required in ambient gas to take place of RISA hydrophilicity. A single crystal titanium dioxide (100) surface was analyzed by X-ray photoelectron spectrometry (XPS). After irradiation with gamma rays, a peak was found in the O1s spectrum, which indicates the adsorption of dissociative water to a surface 5-fold coordinate titanium site, and the formation of a surface hydroxyl group. We conclude that the RISA hydrophilicity is caused by chemisorption of the hydroxyl group on the surface.

  4. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance.

    Directory of Open Access Journals (Sweden)

    C Brandon Ogbunugafor

    2016-01-01

    regards to their basic contribution to the study of empirical adaptive landscapes, and in terms of how they inform new models for the evolution of drug resistance.

  5. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance.

    Science.gov (United States)

    Ogbunugafor, C Brandon; Wylie, C Scott; Diakite, Ibrahim; Weinreich, Daniel M; Hartl, Daniel L

    2016-01-01

    basic contribution to the study of empirical adaptive landscapes, and in terms of how they inform new models for the evolution of drug resistance.

  6. Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance

    Science.gov (United States)

    Ogbunugafor, C. Brandon; Wylie, C. Scott; Diakite, Ibrahim; Weinreich, Daniel M.; Hartl, Daniel L.

    2016-01-01

    regards to their basic contribution to the study of empirical adaptive landscapes, and in terms of how they inform new models for the evolution of drug resistance. PMID:26808374

  7. Drug Absorption Modeling as a Tool to Define the Strategy in Clinical Formulation Development

    OpenAIRE

    Kuentz, Martin

    2008-01-01

    The purpose of this mini review is to discuss the use of physiologically-based drug absorption modeling to guide the formulation development. Following an introduction to drug absorption modeling, this article focuses on the preclinical formulation development. Case studies are presented, where the emphasis is not only the prediction of absolute exposure values, but also their change with altered input values. Sensitivity analysis of technologically relevant parameters, like the drug’s partic...

  8. Controlled Release of Drugs FromHydrogel Based Matrices Systems: Experiments and Modeling

    OpenAIRE

    LAMBERTI, G.; Cascone, S.; Titomanlio, G.; Barba, A.A.

    2012-01-01

    Hydrogels are materials largely used in the formulation of pharmaceuticals since, in principle, they could produce a release system of zero-order kinetics, which is of great therapeutic interest. In this paper, a model was proposed for the description of the main transport phenomena involved in the drug release process from hydrogel matrices (water diffusion, polymer swelling, drug diffusion and polymer dissolution); the model predictions are successfully compared with a large set of exper...

  9. Calcium binding-mediated sustained release of minocycline from hydrophilic multilayer coatings targeting infection and inflammation.

    Directory of Open Access Journals (Sweden)

    Zhiling Zhang

    Full Text Available Infection and inflammation are common complications that seriously affect the functionality and longevity of implanted medical implants. Systemic administration of antibiotics and anti-inflammatory drugs often cannot achieve sufficient local concentration to be effective, and elicits serious side effects. Local delivery of therapeutics from drug-eluting coatings presents a promising solution. However, hydrophobic and thick coatings are commonly used to ensure sufficient drug loading and sustained release, which may limit tissue integration and tissue device communications. A calcium-mediated drug delivery mechanism was developed and characterized in this study. This novel mechanism allows controlled, sustained release of minocycline, an effective antibiotic and anti-inflammatory drug, from nanoscale thin hydrophilic polyelectrolyte multilayers for over 35 days at physiologically relevant concentrations. pH-responsive minocycline release was observed as the chelation between minocycline and Ca(2+ is less stable at acidic pH, enabling 'smart' drug delivery in response to infection and/or inflammation-induced tissue acidosis. The release kinetics of minocycline can be controlled by varying initial loading, Ca(2+ concentration, and Ca(2+ incorporation into different layers, enabling facile development of implant coatings with versatile release kinetics. This drug delivery platform can potentially be used for releasing any drug that has high Ca(2+ binding affinity, enabling its use in a variety of biomedical applications.

  10. Pluripotent Stem Cell-Based Platforms in Cardiac Disease Modeling and Drug Testing.

    Science.gov (United States)

    Shaheen, N; Shiti, A; Gepstein, L

    2017-08-01

    The ability to generate patient/disease-specific human pluripotent stem cell (hPSC)-derived cardiomyocytes (hPSC-CMs) brings a unique value to the fields of cardiac disease modeling, drug testing, drug discovery, and precision medicine. Further integration of emerging innovative technologies such as developmental-biology inspired differentiation into chamber-specific cardiomyocyte subtypes, genome-editing, tissue-engineering, and novel functional phenotyping methodologies should facilitate even more advanced investigations. Here, we review cornerstone concepts and recent highlights of hPSC-based cardiac disease modeling and drug testing. © 2017 American Society for Clinical Pharmacology and Therapeutics.

  11. Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women.

    Science.gov (United States)

    De Sousa Mendes, Maïlys; Hirt, Deborah; Urien, Saik; Valade, Elodie; Bouazza, Naïm; Foissac, Frantz; Blanche, Stephane; Treluyer, Jean-Marc; Benaboud, Sihem

    2015-11-01

    Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy. Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (Cmax ) and oral clearances (CL/F). PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%). Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy. © 2015 The British Pharmacological Society.

  12. In vivo models of cardiac diseases: application to drug development and screening.

    Science.gov (United States)

    Rokutan, Hirofumi; Anker, Stefan D; Springer, Jochen

    2010-01-01

    Cardiac disease is the top cause of human mortality in the Western world. Current drug therapy for cardiac disease has been established via experimental studies using a variety of in vivo animal models. The purpose of this review is to discuss the features (advantages and limitations) of the mainly used in vivo models of cardiac disease and provide the reader with an overview of how they can be utilized in the development and screening of cardiac drugs. A search for articles focusing on and including in vivo models for the main areas of cardiac diseases was performed on PubMed. We also searched the reference lists of identified articles for further original articles. Large and small animal models including genetically modified ones have made accomplishments in the process of cardiac drug development with different clinical relevance. However, there is still a clear need for lessening the gap between human and experimental models by improving in vivo models.

  13. Conservation of Hydrophobic and Hydrophilic Residues in Four-Helix Bundle

    Institute of Scientific and Technical Information of China (English)

    秦猛; 王骏; 王炜

    2003-01-01

    The conservation of the hydrophobic and the hydrophilic residue sites obtained from 1000 designed sequences with the Z-score method for a four-helix bundle has been studied. The folding dynamic and thermodynamic features of the designed sequences and their different mutations are also studied. It is found that this conservation is related to the stability and the fast folding of the model proteins. Our results are consistent with the experimental results.

  14. Atomic level insights into realistic molecular models of dendrimer-drug complexes through MD simulations

    Science.gov (United States)

    Jain, Vaibhav; Maiti, Prabal K.; Bharatam, Prasad V.

    2016-09-01

    Computational studies performed on dendrimer-drug complexes usually consider 1:1 stoichiometry, which is far from reality, since in experiments more number of drug molecules get encapsulated inside a dendrimer. In the present study, molecular dynamic (MD) simulations were implemented to characterize the more realistic molecular models of dendrimer-drug complexes (1:n stoichiometry) in order to understand the effect of high drug loading on the structural properties and also to unveil the atomistic level details. For this purpose, possible inclusion complexes of model drug Nateglinide (Ntg) (antidiabetic, belongs to Biopharmaceutics Classification System class II) with amine- and acetyl-terminated G4 poly(amidoamine) (G4 PAMAM(NH2) and G4 PAMAM(Ac)) dendrimers at neutral and low pH conditions are explored in this work. MD simulation analysis on dendrimer-drug complexes revealed that the drug encapsulation efficiency of G4 PAMAM(NH2) and G4 PAMAM(Ac) dendrimers at neutral pH was 6 and 5, respectively, while at low pH it was 12 and 13, respectively. Center-of-mass distance analysis showed that most of the drug molecules are located in the interior hydrophobic pockets of G4 PAMAM(NH2) at both the pH; while in the case of G4 PAMAM(Ac), most of them are distributed near to the surface at neutral pH and in the interior hydrophobic pockets at low pH. Structural properties such as radius of gyration, shape, radial density distribution, and solvent accessible surface area of dendrimer-drug complexes were also assessed and compared with that of the drug unloaded dendrimers. Further, binding energy calculations using molecular mechanics Poisson-Boltzmann surface area approach revealed that the location of drug molecules in the dendrimer is not the decisive factor for the higher and lower binding affinity of the complex, but the charged state of dendrimer and drug, intermolecular interactions, pH-induced conformational changes, and surface groups of dendrimer do play an

  15. Numerical modelling and experimental investigation of drug release from layered silicone matrix systems.

    Science.gov (United States)

    Snorradóttir, Bergthóra S; Jónsdóttir, Fjóla; Sigurdsson, Sven Th; Thorsteinsson, Freygardur; Másson, Már

    2013-07-16

    Medical devices and polymeric matrix systems that release drugs or other bioactive compounds are of interest for a variety of applications. The release of the drug can be dependent on a number of factors such as the solubility, diffusivity, dissolution rate and distribution of the solid drug in the matrix. Achieving the goal of an optimal release profile can be challenging when relying solely on traditional experimental work. Accurate modelling complementing experimentation is therefore desirable. Numerical modelling is increasingly becoming an integral part of research and development due to the significant advances in computer simulation technology. This work focuses on numerical modelling and investigation of multi-layered silicone matrix systems. A numerical model that can be used to model multi-layered systems was constructed and validated by comparison with experimental data. The model could account for the limited dissolution rate and effect of the drug distribution on the release profiles. Parametric study showed how different factors affect the characteristics of drug release. Multi-layered medical silicone matrices were prepared in special moulds, where the quantity of drug in each layer could be varied, and release was investigated with Franz-diffusion cell setup. Data for long-term release was fitted to the model and the full depletion of the system predicted. The numerical model constructed for this study, whose input parameters are the diffusion, effective dissolution rate and dimensional solubility coefficients, does not require any type of steady-state approximation. These results indicate that numerical model can be used as a design tool for development of controlled release systems such as drug-loaded medical devices.

  16. Comparing exponential and exponentiated models of drug demand in cocaine users.

    Science.gov (United States)

    Strickland, Justin C; Lile, Joshua A; Rush, Craig R; Stoops, William W

    2016-12-01

    Drug purchase tasks provide rapid and efficient measurement of drug demand. Zero values (i.e., prices with zero consumption) present a quantitative challenge when using exponential demand models that exponentiated models may resolve. We aimed to replicate and advance the utility of using an exponentiated model by demonstrating construct validity (i.e., association with real-world drug use) and generalizability across drug commodities. Participants (N = 40 cocaine-using adults) completed Cocaine, Alcohol, and Cigarette Purchase Tasks evaluating hypothetical consumption across changes in price. Exponentiated and exponential models were fit to these data using different treatments of zero consumption values, including retaining zeros or replacing them with 0.1, 0.01, or 0.001. Excellent model fits were observed with the exponentiated model. Means and precision fluctuated with different replacement values when using the exponential model but were consistent for the exponentiated model. The exponentiated model provided the strongest correlation between derived demand intensity (Q0) and self-reported free consumption in all instances (Cocaine r = .88; Alcohol r = .97; Cigarette r = .91). Cocaine demand elasticity was positively correlated with alcohol and cigarette elasticity. Exponentiated parameters were associated with real-world drug use (e.g., weekly cocaine use) whereas these correlations were less consistent for exponential parameters. Our findings show that selection of zero replacement values affects demand parameters and their association with drug-use outcomes when using the exponential model but not the exponentiated model. This work supports the adoption of the exponentiated demand model by replicating improved fit and consistency and demonstrating construct validity and generalizability. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  17. [In silico, in vitro, in omic experimental models and drug safety evaluation].

    Science.gov (United States)

    Claude, Nancy; Goldfain-Blanc, Françoise; Guillouzo, André

    2009-01-01

    Over the last few decades, toxicology has benefited from scientific, technical, and bioinformatic developments relating to patient safety assessment during clinical and drug marketing studies. Based on this knowledge, new in silico, in vitro, and "omic" experimental models are emerging. Although these models cannot currently replace classic safety evaluations performed on laboratory animals, they allow compounds with unacceptable toxicity to be rejected in the early stages of drug development, thereby reducing the number of laboratory animals needed. In addition, because these models are particularly adapted to mechanistic studies, they can help to improve the relevance of the data obtained, thus enabling better prevention and screening of the adverse effects that may occur in humans. Much progress remains to be done, especially in the field of validation. Nevertheless, current efforts by industrial, academic laboratories, and regulatory agencies should, in coming years, significantly improve preclinical drug safety evaluation thanks to the integration of these new methods into the drug research and development process.

  18. Vibrational spectroscopy modeling of a drug in molecular solvents and enzymes

    Science.gov (United States)

    Devereux, Christian J.; Fulfer, Kristen D.; Zhang, Xiaoliu; Kuroda, Daniel G.

    2017-09-01

    Modeling of drugs in enzymes is of immensurable value to many areas of science. We present a theoretical study on the vibrational spectroscopy of Rilpivirine, a HIV reverse transcriptase inhibitor, in conventional solvents and in clinically relevant enzymes. The study is based on vibrational spectroscopy modeling of the drug using molecular dynamics simulations, DFT frequency maps, and theory. The modeling of the infrared lineshape shows good agreement with experimental data for the drug in molecular solvents where the local environment motions define the vibrational band lineshape. On the other hand, the theoretical description of the drug in the different enzymes does not match previous experimental findings indicating that the utilized methodology might not apply to heterogeneous environments. Our findings show that the lack of reproducibility might be associated with the development of the frequency map which does not contain all of the possible interactions observed in such systems.

  19. The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis.

    Science.gov (United States)

    Ahidjo, Bintou A; Maiga, Mariama C; Ihms, Elizabeth A; Maiga, Mamoudou; Ordonez, Alvaro A; Cheung, Laurene S; Beck, Sarah; Andrade, Bruno B; Jain, Sanjay; Bishai, William R

    2016-09-08

    Pirfenidone is a recently approved antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). Because tuberculosis (TB) is characterized by granulomatous inflammation in conjunction with parenchymal destruction and replacement fibrosis, we sought to determine whether the addition of pirfenidone as an adjunctive, host-directed therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that pirfenidone's antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in granulomas to accelerate treatment response. The effectiveness of adjunctive pirfenidone during TB drug therapy was evaluated using a murine model of chronic TB. Mice treated with standard therapy 2HRZ/4HR (H, isoniazid; R, rifampin; and Z, pyrazinamide) were compared with 2 alternative regimens containing pirfenidone (Pf) (2HRZPf/4HRPf and 2HRZPf/4HR). Contrary to our hypothesis, adjunctive pirfenidone use leads to reduced bacterial clearance and increased relapse rates. This treatment failure is closely associated with the emergence of isoniazid monoresistant bacilli, increased cavitation, and significant lung pathology. While antifibrotic agents may eventually be used as part of adjunctive host-directed therapy of TB, this study clearly demonstrates that caution must be exercised. Moreover, as pirfenidone becomes more widely used in clinical practice, increased patient monitoring would be required in endemic TB settings.

  20. The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis

    Science.gov (United States)

    Ahidjo, Bintou A.; Maiga, Mariama C.; Ihms, Elizabeth A.; Maiga, Mamoudou; Ordonez, Alvaro A.; Cheung, Laurene S.; Beck, Sarah; Andrade, Bruno B.; Jain, Sanjay

    2016-01-01

    Pirfenidone is a recently approved antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). Because tuberculosis (TB) is characterized by granulomatous inflammation in conjunction with parenchymal destruction and replacement fibrosis, we sought to determine whether the addition of pirfenidone as an adjunctive, host-directed therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that pirfenidone’s antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in granulomas to accelerate treatment response. The effectiveness of adjunctive pirfenidone during TB drug therapy was evaluated using a murine model of chronic TB. Mice treated with standard therapy 2HRZ/4HR (H, isoniazid; R, rifampin; and Z, pyrazinamide) were compared with 2 alternative regimens containing pirfenidone (Pf) (2HRZPf/4HRPf and 2HRZPf/4HR). Contrary to our hypothesis, adjunctive pirfenidone use leads to reduced bacterial clearance and increased relapse rates. This treatment failure is closely associated with the emergence of isoniazid monoresistant bacilli, increased cavitation, and significant lung pathology. While antifibrotic agents may eventually be used as part of adjunctive host-directed therapy of TB, this study clearly demonstrates that caution must be exercised. Moreover, as pirfenidone becomes more widely used in clinical practice, increased patient monitoring would be required in endemic TB settings. PMID:27699232

  1. From bench to bedside: utilization of an in vitro model to predict potential drug-drug interactions in the kidney: the digoxin-mifepristone example.

    Science.gov (United States)

    Woodland, Cindy; Koren, Gideon; Ito, Shinya

    2003-07-01

    Drug interactions are a common source of drug-induced toxicity. For drugs with narrow therapeutic windows, such as digoxin, an understanding of the potential mechanisms by which drugs might interact is essential to clinical practice. This article describes the utility of a renal tubular cell culture model in the prediction of drug interactions involving P-glycoprotein. Digoxin is a cardiac glycoside that undergoes active secretion in the renal tubules by the MDR1 (P-glycoprotein) drug efflux pump. Mifepristone (RU486) is a recently introduced abortifacient that is largely unstudied in terms of drug-drug interactions. The authors used an in vitro model to study the effects of mifepristone on the renal tubular secretion and cellular uptake of digoxin by Madin-Darby canine kidney (MDCK) cells. Mifepristone significantly inhibited the renal tubular secretion of digoxin (p = 0.0005), without interfering with its ability to enter the renal tubular cell. Similar results were found with the P-glycoprotein substrate vinblastine. The findings suggest that drug interactions may result if mifepristone is administered with P-glycoprotein substrates, highlighting the usefulness of this model in the study of not only common but also rare combinations of drugs.

  2. A model ternary heparin conjugate by direct covalent bond strategy applied to drug delivery system.

    Science.gov (United States)

    Wang, Ying; Xin, Dingcheng; Hu, Jiawen; Liu, Kaijian; Pan, Jiangao; Xiang, Jiannan

    2009-01-01

    A model ternary heparin conjugate by direct covalent bond strategy has been developed, in which modified heparin using active mix anhydride as intermediate conjugates with model drug molecule and model specific ligand, respectively. Designed ester bonds between model drug and heparin facilitate hydrolysis kinetics research. The strategy can be extended to design and synthesize a targeted drug delivery system. The key point is to use mixed anhydride groups as activating intermediates to mediate the synthesis of the ternary heparin conjugate. Formation of mixed anhydride is detected by the conductimetry experiment. The ternary heparin conjugate is characterized by (13)C NMR, FT-IR and GPC, respectively. The decreased trend on degree of substitution (DS) is consistent with that of introduced anticancer drug and specific ligand in drug delivery system. Moreover, their anticoagulant activity is evaluated by measuring activated partial thromboplastin time (APTT) and anti-factor Xa activity. The results show that model ternary heparin conjugate with reduced anticoagulant activity may avoid the risk of severe hemorrhagic complication during the administration and is potential to develop a safe and effective drug delivery system on anticancer research.

  3. The Use of Animal Models for Cancer Chemoprevention Drug Development

    OpenAIRE

    2010-01-01

    Animal models currently are used to assess the efficacy of potential chemopreventive agents, including synthetic chemicals, chemical agents obtained from natural products and natural product mixtures. The observations made in these models as well as other data are then used to prioritize agents to determine which are qualified to progress to clinical chemoprevention trials. Organ specific animal models are employed to determine which agents or classes of agents are likely to be the most effec...

  4. Chromatographic analysis of olopatadine in hydrophilic interaction liquid chromatography.

    Science.gov (United States)

    Maksić, Jelena; Jovanović, Marko; Rakić, Tijana; Popović, Igor; Ivanović, Darko; Jančić-Stojanović, Biljana

    2015-01-01

    In this paper, chromatographic analysis of active substance olopatadine hydrochloride, which is used in eye drops as antihistaminic agent, and its impurity E isomer by hydrophilic interaction liquid chromatography (HILIC) and application of design of experiments (DoE) methodology are presented. In addition, benzalkonium chloride is very often used as a preservative in eye drops. Therefore, the evaluation of its chromatographic behavior in HILIC was carried out as well. In order to estimate chromatographic behavior and set optimal chromatographic conditions, DoE methodology was applied. After the selection of important chromatographic factors, Box-Behnken design was utilized, and on the basis of the obtained models factor effects were examined. Then, multi-objective robust optimization is performed aiming to obtain chromatographic conditions that comply with several quality criteria simultaneously: adequate and robust separation of critical peak pair and maximum retention of the first eluting peak. The optimal conditions are identified by using grid point search methodology. The experimental verification confirmed the adequacy of the defined optimal conditions. Finally, under optimal chromatographic conditions, the method was validated and applicability of the proposed method was confirmed.

  5. Modelling and enhanced molecular dynamics to steer structure-based drug discovery.

    Science.gov (United States)

    Kalyaanamoorthy, Subha; Chen, Yi-Ping Phoebe

    2014-05-01

    The ever-increasing gap between the availabilities of the genome sequences and the crystal structures of proteins remains one of the significant challenges to the modern drug discovery efforts. The knowledge of structure-dynamics-functionalities of proteins is important in order to understand several key aspects of structure-based drug discovery, such as drug-protein interactions, drug binding and unbinding mechanisms and protein-protein interactions. This review presents a brief overview on the different state of the art computational approaches that are applied for protein structure modelling and molecular dynamics simulations of biological systems. We give an essence of how different enhanced sampling molecular dynamics approaches, together with regular molecular dynamics methods, assist in steering the structure based drug discovery processes.

  6. Binary logistic regression modelling: Measuring the probability of relapse cases among drug addict

    Science.gov (United States)

    Ismail, Mohd Tahir; Alias, Siti Nor Shadila

    2014-07-01

    For many years Malaysia faced the drug addiction issues. The most serious case is relapse phenomenon among treated drug addict (drug addict who have under gone the rehabilitation programme at Narcotic Addiction Rehabilitation Centre, PUSPEN). Thus, the main objective of this study is to find the most significant factor that contributes to relapse to happen. The binary logistic regression analysis was employed to model the relationship between independent variables (predictors) and dependent variable. The dependent variable is the status of the drug addict either relapse, (Yes coded as 1) or not, (No coded as 0). Meanwhile the predictors involved are age, age at first taking drug, family history, education level, family crisis, community support and self motivation. The total of the sample is 200 which the data are provided by AADK (National Antidrug Agency). The finding of the study revealed that age and self motivation are statistically significant towards the relapse cases..

  7. THE MODEL IN PREVENTING AND SOLVING DRUGS IN THE THAI-LAO BORDER VILLAGES

    Directory of Open Access Journals (Sweden)

    Wattana Puttichart

    2014-01-01

    Full Text Available A drug issue is a problem at both national and international levels. The root causes of the problems lie inside and outside the humans. To solve the problems in a sustainable way, it is essential to get cooperation from many parties. The research aimed to study the situations and prevention and solution of drugs in the border villages, to construct the model to prevent and solve the drug issues and to evaluate the model for preventing and solving the drugs prevalent in the border villages. The work was a qualitative research. It analyzed documentary data and those from the field study gained by surveying, observing, interviewing, focus group and workshop. Twenty border villages in Khemarat district were used as the samples which derived by a specific random sampling. The research found that (1 as regards the drug situations, the drugs were prevalent in Khemarat. There were two guidelines to deal with the situation: Internal factor or participation from all; external factors or the cooperation between the state and the community residents. (2 Considering the guidelines for constructing the model for preventing drugs, there were four types of measures: (1 Integration from all sectors, (2 objectives in constructing the model which consisted of two items: 2.1 promotion and support for the state officials’ performance, 2.2 observation and protection of the community members from drugs. (3 The process of constructing the model was composed of the following: Finding a leader, communication to effect changes, multilateral communication in society, community participation in solving the problems, linking ideas from a variety of people, public forum to exchange the ideas, feedback on problems, turning burdens into energy, progress in people’s participation. (4 evaluation of the state officials’ and the community’s participation. (3 Given the suitability and practicality of the model, the model in question was found to be suitable and also found to

  8. Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM)

    Science.gov (United States)

    Lane, Andrew N.; Higashi, Richard M.; Fan, Teresa W-M.

    2016-01-01

    Aims In this review we compare the advantages and disadvantages of different model biological systems for determining the metabolic functions of cells in complex environments, how they may change in different disease states, and respond to therapeutic interventions. Background All preclinical drug-testing models have advantages and drawbacks. We compare and contrast established cell, organoid and animal models with ex vivo organ or tissue culture and in vivo human experiments in the context of metabolic readout of drug efficacy. As metabolism reports directly on the biochemical state of cells and tissues, it can be very sensitive to drugs and/or other environmental changes. This is especially so when metabolic activities are probed by stable isotope tracing methods, which can also provide detailed mechanistic information on drug action. We have developed and been applying Stable Isotope-Resolved Metabolomics (SIRM) to examine metabolic reprogramming of human lung cancer cells in monoculture, in mouse xenograft/explant models, and in lung cancer patients in situ (Lane et al. 2011; T. W. Fan et al. 2011; T. W-M. Fan et al. 2012; T. W. Fan et al. 2012; Xie et al. 2014b; Ren et al. 2014a; Sellers et al. 2015b). We are able to determine the influence of the tumor microenvironment using these models. We have now extended the range of models to fresh human tissue slices, similar to those originally described by O. Warburg (Warburg 1923), which retain the native tissue architecture and heterogeneity with a paired benign versus cancer design under defined cell culture conditions. This platform offers an unprecedented human tissue model for preclinical studies on metabolic reprogramming of human cancer cells in their tissue context, and response to drug treatment (Xie et al. 2014a). As the microenvironment of the target human tissue is retained and individual patient's response to drugs is obtained, this platform promises to transcend current limitations of drug selection

  9. Rodent models for Alzheimer’s disease drug discovery

    Science.gov (United States)

    Puzzo, Daniela; Gulisano, Walter; Palmeri, Agostino; Arancio, Ottavio

    2015-01-01

    Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, leading to dementia. Histophatological hallmarks are represented by aggregates of beta-amyloid peptide (Aβ) in senile plaques and deposition of hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Rare forms of early onset familial Alzheimer's disease are due to gene mutations. This has prompted researchers to develop genetically modified animals that could recapitulate the main features of the disease. The use of these models is complemented by non-genetically modified animals. Area covered This review summarizes the characteristics of the most used transgenic (Tg) and non-Tg models of AD. The authors have focused on models mainly used in their laboratories including: APP Tg2576, APP/PS1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of Aβ or tau, and models of physiological aging. Expert opinion Animal models of disease might be very useful for studying the pathophysiology of the disease and for testing new therapeutics in preclinical studies but they do not reproduce the entire clinical features of human AD. When selecting a model, researchers should consider the various factors that might influence the phenotype. They should also consider the timing of testing/treating animals since the age at which each model develops certain aspects of the AD pathology varies. PMID:25927677

  10. Microgels of silylated HPMC as a multimodal system for drug co-encapsulation.

    Science.gov (United States)

    Zayed, Mohamed; Tourne-Peteilh, Corine; Ramonda, Michel; Rethore, Gildas; Weiss, Pierre; Martinez, Jean; Subra, Gilles; Mehdi, Ahmad; Devoisselle, Jean-Marie; Legrand, Philippe

    2017-07-27

    Combined therapy is a global strategy developed to prevent drug resistance in cancer and infectious diseases. In this field, there is a need of multifunctional drug delivery systems able to co-encapsulate small drug molecules, peptides, proteins, associated to targeting functions, nanoparticles. Silylated hydrogels are alkoxysilane hybrid polymers that can be engaged in a sol-gel process, providing chemical cross linking in physiological conditions, and functionalized biocompatible hybrid materials. In the present work, microgels were prepared with silylated (hydroxypropyl)methyl cellulose (Si-HPMC) that was chemically cross linked in soft conditions of pH and temperature. They were prepared by an emulsion templating process, water in oil (W/O), as microreactors where the condensation reaction took place. The ability to functionalize the microgels, so-called FMGs, in a one-pot process, was evaluated by grafting a silylated hydrophilic model drug, fluorescein (Si-Fluor), using the same reaction of condensation. Biphasic microgels (BPMGs) were prepared to evaluate their potential to encapsulate lipophilic model drug (Nile red). They were composed of two separate compartments, one oily phase (sesame oil) trapped in the cross linked Si-HPMC hydrophilic phase. The FMGs and BPMGs were characterized by different microscopic techniques (optic, epi-fluorescence, Confocal Laser Scanning Microscopy and scanning electronic microscopy), the mechanical properties were monitored using nano indentation by Atomic Force Microscopy (AFM), and different preliminary tests were performed to evaluate their chemical and physical stability. Finally, it was demonstrated that it is possible to co-encapsulate both hydrophilic and hydrophobic drugs, in silylated microgels, that were physically and chemically stable. They were obtained by chemical cross linking in soft conditions, and without surfactant addition during the emulsification process. The amount of drug loaded was in favor of

  11. Current advances in mathematical modeling of anti-cancer drug penetration into tumor tissues

    Directory of Open Access Journals (Sweden)

    MunJu eKim

    2013-11-01

    Full Text Available Delivery of anti-cancer drugs to tumor tissues, including their interstitial transport and cellular uptake, is a complex process involving various biochemical, mechanical, and biophysical factors. Mathematical modeling provides a means through which to understand this complexity better, as well as to examine interactions between contributing components in a systematic way via computational simulations and quantitative analyses. In this review, we present the current state of mathematical modeling approaches that address phenomena related to drug delivery. We describe how various types of models were used to predict spatio-temporal distributions of drugs within the tumor tissue, to simulate different ways to overcome barriers to drug transport, or to optimize treatment schedules. Finally, we discuss how integration of mathematical modeling with experimental or clinical data can provide better tools to understand the drug delivery process, in particular to examine the specific tissue- or compound-related factors that limit drug penetration through tumors. Such tools will be important in designing new chemotherapy targets and optimal treatment strategies, as well as in developing non-invasive diagnosis to monitor treatment response and detect tumor recurrence.

  12. A systems-based mathematical modelling framework for investigating the effect of drugs on solid tumours

    Directory of Open Access Journals (Sweden)

    Liu Cong

    2011-12-01

    Full Text Available Abstract Background Elucidating the effects of drugs on solid tumours is a highly challenging multi-level problem, since this involves many complexities associated with transport and cellular response, which in turn is characterized by highly non-linear chemical signal transduction. Appropriate systems frameworks are needed to seriously address the sources of these complexities, especially from the cellular side. Results We develop a skeletal modelling framework incorporating interstitial drug transport, intracellular signal processing and cell population descriptions. The descriptions aim to appropriately capture the nature of information flow. The model is deliberately formulated to start with simple intracellular descriptions so that additional features can be incorporated in a modular fashion. Two kinds of intracellular signalling modules which describe the drug effect were considered, one a monostable switch and the other a bistable switch. Analysis of our model revealed how different drug stimuli can lead to cell killing in the tumour. Interestingly both modules considered exhibited similar trends. The effects of important parameters were also studied. Conclusions We have created a predictive systems platform integrating drug transport and cellular response which can be systematically augmented to include additional layers of cellular complexity. Our results indicate that intracellular signalling models which are qualitatively different can give rise to similar behaviour to simple (and typical stimuli, and that validating intracellular descriptions must be performed with care by considering a variety of drug stimuli.

  13. Animal models for predicting the efficacy and side effects of antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Pedro H. Gobira

    2013-01-01

    Full Text Available The use of antipsychotic drugs represents an important approach for the treatment of schizophrenia. However, their efficacy is limited to certain symptoms of this disorder, and they induce serious side effects. As a result, there is a strong demand for the development of new drugs, which depends on reliable animal models for pharmacological characterization. The present review discusses the face, construct, and predictive validity of classical animal models for studying the efficacy and side effects of compounds for the treatment of schizophrenia. These models are based on the properties of antipsychotics to impair the conditioned avoidance response and reverse certain behavioral changes induced by psychotomimetic drugs, such as stereotypies, hyperlocomotion, and deficit in prepulse inhibition of the startle response. Other tests, which are not specific to schizophrenia, may predict drug effects on negative and cognitive symptoms, such as deficits in social interaction and memory impairment. Regarding motor side effects, the catalepsy test predicts the liability of a drug to induce Parkinson-like syndrome, whereas vacuous chewing movements predict the liability to induce dyskinesia after chronic treatment. Despite certain limitations, these models may contribute to the development of more safe and efficacious antipsychotic drugs.

  14. Unusual ultra-hydrophilic, porous carbon cuboids for atmospheric-water capture.

    Science.gov (United States)

    Hao, Guang-Ping; Mondin, Giovanni; Zheng, Zhikun; Biemelt, Tim; Klosz, Stefan; Schubel, René; Eychmüller, Alexander; Kaskel, Stefan

    2015-02-02

    There is significant interest in high-performance materials that can directly and efficiently capture water vapor, particularly from air. Herein, we report a class of novel porous carbon cuboids with unusual ultra-hydrophilic properties, over which the synergistic effects between surface heterogeneity and micropore architecture is maximized, leading to the best atmospheric water-capture performance among porous carbons to date, with a water capacity of up to 9.82 mmol g(-1) at P/P0 =0.2 and 25 °C (20% relative humidity or 6000 ppm). Benefiting from properties, such as defined morphology, narrow pore size distribution, and high heterogeneity, this series of functional carbons may serve as model materials for fundamental research on carbon chemistry and the advance of new types of materials for water-vapor capture as well as other applications requiring combined highly hydrophilic surface chemistry, developed hierarchical porosity, and excellent stability.

  15. PLATINUM: a web tool for analysis of hydrophobic/hydrophilic organization of biomolecular complexes.

    Science.gov (United States)

    Pyrkov, Timothy V; Chugunov, Anton O; Krylov, Nikolay A; Nolde, Dmitry E; Efremov, Roman G

    2009-05-01

    The PLATINUM (Protein-Ligand ATtractions Investigation NUMerically) web service is designed for analysis and visualization of hydrophobic/hydrophilic properties of biomolecules supplied as 3D-structures. Furthermore, PLATINUM provides a number of tools for quantitative characterization of the hydrophobic/hydrophilic match in biomolecular complexes e.g. in docking poses. These complement standard scoring functions. The calculations are based on the concept of empirical Molecular Hydrophobicity Potential (MHP). The PLATINUM web tool as well as detailed documentation and tutorial are available free of charge for academic users at http://model.nmr.ru/platinum/. PLATINUM requires Java 5 or higher and Adobe Flash Player 9. Supplementary data are available at Bioinformatics online.

  16. Comprehensive analysis of pharmaceutical products using simultaneous mixed-mode (ion-exchange/reversed-phase) and hydrophilic interaction liquid chromatography.

    Science.gov (United States)

    Kazarian, Artaches A; Nesterenko, Pavel N; Soisungnoen, Phimpha; Burakham, Rodjana; Srijaranai, Supalax; Paull, Brett

    2014-08-01

    Liquid chromatographic assays were developed using a mixed-mode column coupled in sequence with a hydrophilic interaction liquid chromatography column to allow the simultaneous comprehensive analysis of inorganic/organic anions and cations, active pharmaceutical ingredients, and excipients (carbohydrates). The approach utilized dual sample injection and valve-mediated column switching and was based upon a single high-performance liquid chromatography gradient pump. The separation consisted of three distinct sequential separation mechanisms, namely, (i) ion-exchange, (ii) mixed-mode interactions under an applied dual gradient (reversed-phase/ion-exchange), and (iii) hydrophilic interaction chromatography. Upon first injection, the Scherzo SS C18 column (Imtakt) provided resolution of inorganic anions and cations under isocratic conditions, followed by a dual organic/salt gradient to elute active pharmaceutical ingredients and their respective organic counterions and potential degradants. At the top of the mixed-mode gradient (high acetonitrile content), the mobile phase flow was switched to a preconditioned hydrophilic interaction liquid chromatography column, and the standard/sample was reinjected for the separation of hydrophilic carbohydrates, some of which are commonly known excipients in drug formulations. The approach afforded reproducible separation and resolution of up to 23 chemically diverse solutes in a single run. The method was applied to investigate the composition of commercial cough syrups (Robitussin®), allowing resolution and determination of inorganic ions, active pharmaceutical ingredients, excipients, and numerous well-resolved unknown peaks.

  17. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, Sagnik, E-mail: Sagnik.Chatterjee@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Richert, Lysiane, E-mail: l.richert@kaly-cell.com [KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim (France); Augustijns, Patrick, E-mail: Patrick.Augustijns@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Annaert, Pieter, E-mail: Pieter.Annaert@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium)

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug

  18. Sealing ability of a novel hydrophilic vs. conventional hydrophobic obturation systems: A bacterial leakage study

    Science.gov (United States)

    Hegde, Vibha; Arora, Shashank

    2015-01-01

    Aim: Comparative assessment of apical sealing ability of a novel Smart-Seal System, Resilon, and conventional Gutta-Percha system using a bacterial leakage model. Materials and Methods: Seventy freshly extracted human single rooted teeth with fully formed apices were randomly divided into three groups (20 each) and two control groups (5 positive and 5 negative). Teeth were de-coronated, and roots were standardized to a working length of 16 mm. Root canal preparation was done with rotary pro-taper file system in all groups. Group A was obturated using Smart-Seal system (Hydrophilic), Group B using Resilon/Epiphany system (Hydrophilic), and Group C using Gutta-Percha (GP)/AH plus system (Hydrophobic) in a single cone technique. Using Enterococcus faecalis, a split chamber bacterial leakage model was developed to evaluate the sealing ability of three obturation systems. Samples will be monitored every 24 hours for 60 days. Results: All three groups have shown leakage. Novel Smart-Seal System and Resilon have shown similar results and relatively lesser samples leaked in comparison to GP obturations at the end of the observation period. There was no significant difference amongst Resilon and Smart-Seal System (P > 0.05) but there was a significant difference amongst them when compared to GP obturations (P < 0.05). Conclusion: Hydrophilic obturations of the root canal shows a better resistance to bacterial leakage as compared to hydrophobic obturations. PMID:25657530

  19. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

    NARCIS (Netherlands)

    Witte, W.E.; Wong, Y.C.; Nederpelt, I.; Heitman, L.H.; Danhof, M.; Graaf, van der P.H.; Gilissen, R.A.; de, Lange E.C.

    2016-01-01

    INTRODUCTION Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target

  20. Temperament and character model of personality profile of alcohol- and drug-dependent inpatients.

    Science.gov (United States)

    Evren, Cuneyt; Evren, Bilge; Yancar, Cenk; Erkiran, Murat

    2007-01-01

    The aims of this study were to evaluate the differences in dimensions of temperament and character in Turkish alcohol- and drug-dependent inpatients, and to examine which dimensions would predict drug dependency. The subjects consisted of 111 alcohol-dependent and 93 drug-dependent inpatients according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Subjects were tested using Cloninger's Temperament and Character Inventory (TCI). Among the temperament dimensions, novelty seeking score was higher and reward dependency score was lower in drug-dependent patients than in alcohol-dependent patients. Among the character dimensions, self-directedness and cooperativeness scores were lower in drug-dependent patients. Low age and novelty seeking predicted drug dependency in forward logistic regression model. Subscales that predicted drug dependency other than young age were lower scores on compassion vs revengefulness (C4) and helpfulness (C3), and higher score on spiritual acceptance vs rational materialism (ST3). As in previous studies, which indicate an association between personality and substance choice, in the present study, TCI was shown to be an efficient tool in discriminating alcohol and drug dependents; thus, it seems to be important to consider TCI dimensions in planning the treatment of substance dependency.

  1. Coupled gel spreading and diffusive transport models describing microbicidal drug delivery

    Science.gov (United States)

    Funke, Claire; MacMillan, Kelsey; Ham, Anthony S.; Szeri, Andrew J.; Katz, David F.

    2016-11-01

    Gels are a drug delivery platform being evaluated for application of active pharmaceutical ingredients, termed microbicides, that act topically against infection by sexually transmitted HIV. Despite success in one Phase IIb trial of a vaginal gel delivering tenofovir, problems of user adherence to designed gel application regimen compromised results in two other trials. The microbicide field is responding to this issue by simultaneously analyzing behavioral determinants of adherence and pharmacological determinants of drug delivery. Central to both user adherence and mucosal drug delivery are gel properties (e.g. rheology) and applied volume. The specific problem to be solved here is to develop a model for how gel rheology and volume, interacting with loaded drug concentration, govern the transport of the microbicide drug tenofovir into the vaginal mucosa to its stromal layer. The analysis here builds upon our current understanding of vaginal gel deployment and drug delivery, incorporating key features of the gel's environment, fluid production and subsequent gel dilution, and vaginal wall elasticity. We consider the microbicide drug tenofovir as it is the most completely studied drug, in both in vitroand in vivostudies, for use in vaginal gel application. Our goal is to contribute to improved pharmacological understanding of gel functionality, providing a computational tool that can be used in future vaginal microbicide gel design.

  2. Psychiatry's next top model: cause for a re-think on drug models of psychosis and other psychiatric disorders.

    Science.gov (United States)

    Carhart-Harris, R L; Brugger, S; Nutt, D J; Stone, J M

    2013-09-01

    Despite the widespread application of drug modelling in psychiatric research, the relative value of different models has never been formally compared in the same analysis. Here we compared the effects of five drugs (cannabis, psilocybin, amphetamine, ketamine and alcohol) in relation to psychiatric symptoms in a two-part subjective analysis. In the first part, mental health professionals associated statements referring to specific experiences, for example 'I don't bother to get out of bed', to one or more psychiatric symptom clusters, for example depression and negative psychotic symptoms. This measured the specificity of an experience for a particular disorder. In the second part, individuals with personal experience with each of the above-listed drugs were asked how reliably each drug produced the experiences listed in part 1, both acutely and sub-acutely. Part 1 failed to find any experiences that were specific for negative or cognitive psychotic symptoms over depression. The best model of positive symptoms was psilocybin and the best models overall were the acute alcohol and amphetamine models of mania. These results challenge current assumptions about drug models and motivate further research on this understudied area.

  3. A Novel Murine Model for the In Vivo Study of Transdermal Drug Penetration

    Directory of Open Access Journals (Sweden)

    Gábor Eros

    2012-01-01

    Full Text Available Enhancement of the transdermal penetration of different active agents is an important research goal. Our aim was to establish a novel in vivo experimental model which provides a possibility for exact measurement of the quantity of penetrated drug. The experiments were performed on SKH-1 hairless mice. A skin fold in the dorsal region was fixed with two fenestrated titanium plates. A circular wound was made on one side of the skin fold. A metal cylinder with phosphate buffer was fixed into the window of the titanium plate. The concentration of penetrated drug was measured in the buffer. The skin fold was morphologically intact and had a healthy microcirculation. The drug appeared in the acceptor buffer after 30 min, and its concentration exhibited a continuous increase. The presence of ibuprofen was also detected in the plasma. In conclusion, this model allows an exact in vivo study of drug penetration and absorption.

  4. Prediction of drug-like molecular properties: modeling cytochrome p450 interactions.

    Science.gov (United States)

    Jalaie, Mehran; Arimoto, Rieko; Gifford, Eric; Schefzick, Sabine; Waller, Chris L

    2004-01-01

    Preventing drug-drug interactions and reducing drug-related mortalities dictate cleaner and costlier medicines. The cost to bring a new drug to market has increased dramatically over the last 10 years, with post-discovery activities (preclinical and clinical) costs representing the majority of the spend. With the ever-increasing scrutiny that new drug candidates undergo in the post-discovery assessment phases, there is increasing pressure on discovery to deliver higher-quality drug candidates. Given that compound attrition in the early clinical stages can often be attributed to metabolic liabilities, it has been of great interest lately to implement predictive measures of metabolic stability/ liability in the drug design stage of discovery. The solution to this issue is wrapped in understanding the basic of the cytochrome P450 (CYP) enzymes functions and structures. Recently, experimental information on the structure of a variety of cytochrome P450 enzymes, major contributors to phase I metabolism, has become readily available. This, coupled with the availability of experimental information on substrate specificities, has lead to the development of numerous computational models (macromolecular, pharmacophore, and structure-activity) for the rationalization and prediction of CYP liabilities. A comprehensive review of these models is presented in this chapter.

  5. Hepatic Disposition of Drugs and the Utility of Mechanistic Modelling and Simulation

    OpenAIRE

    Sjögren, Erik

    2010-01-01

    The elimination of drugs from the body is in many cases performed by the liver. Much could be gained if an accurate prediction of this process could be made early in the development of new drugs. However, for the elimination to occur, the drug molecule needs first to get inside the liver cell. Disposition is the expression used to encapsulate both elimination and distribution. This thesis presents novel approaches and models based on simple in vitro systems for the investigation of processes...

  6. Stability Analysis of an HIV/AIDS Dynamics Model with Drug Resistance

    Directory of Open Access Journals (Sweden)

    Qianqian Li

    2012-01-01

    Full Text Available A mathematical model of HIV/AIDS transmission incorporating treatment and drug resistance was built in this study. We firstly calculated the threshold value of the basic reproductive number (R0 by the next generation matrix and then analyzed stability of two equilibriums by constructing Lyapunov function. When R0<1, the system was globally asymptotically stable and converged to the disease-free equilibrium. Otherwise, the system had a unique endemic equilibrium which was also globally asymptotically stable. While an antiretroviral drug tried to reduce the infection rate and prolong the patients’ survival, drug resistance was neutralizing the effects of treatment in fact.

  7. Nanoporous materials modified with biodegradable polymers as models for drug delivery applications

    DEFF Research Database (Denmark)

    Gruber, Mathias F; Schulte, Lars; Ndoni, Sokol

    2013-01-01

    Polymers play a central role in the development of carriers for diagnostic and therapeutic agents. Especially the use of either degradable polymers or porous materials to encapsulate drug compounds in order to obtain steady drug release profiles has received much attention. We present here a proof...... of principle for a system combining these two encapsulation methods and consisting of a nanoporous polymer (NP) with the pores filled with a degradable polymer mixed with a drug model. Rhodamine 6G (R6G) mixed with Poly(l-Lactic Acid) (PLLA) were confined within the 14nm pores of a NP with gyroid morphology...

  8. A corpus for mining drug-related knowledge from Twitter chatter: Language models and their utilities

    Directory of Open Access Journals (Sweden)

    Abeed Sarker

    2017-02-01

    Full Text Available In this data article, we present to the data science, natural language processing and public heath communities an unlabeled corpus and a set of language models. We collected the data from Twitter using drug names as keywords, including their common misspelled forms. Using this data, which is rich in drug-related chatter, we developed language models to aid the development of data mining tools and methods in this domain. We generated several models that capture (i distributed word representations and (ii probabilities of n-gram sequences. The data set we are releasing consists of 267,215 Twitter posts made during the four-month period—November, 2014 to February, 2015. The posts mention over 250 drug-related keywords. The language models encapsulate semantic and sequential properties of the texts.

  9. New drug candidates for liposomal delivery identified by computer modeling of liposomes' remote loading and leakage.

    Science.gov (United States)

    Cern, Ahuva; Marcus, David; Tropsha, Alexander; Barenholz, Yechezkel; Goldblum, Amiram

    2017-02-16

    Remote drug loading into nano-liposomes is in most cases the best method for achieving high concentrations of active pharmaceutical ingredients (API) per nano-liposome that enable therapeutically viable API-loaded nano-liposomes, referred to as nano-drugs. This approach also enables controlled drug release. Recently, we constructed computational models to identify APIs that can achieve the desired high concentrations in nano-liposomes by remote loading. While those previous models included a broad spectrum of experimental conditions and dealt only with loading, here we reduced the scope to the molecular characteristics alone. We model and predict API suitability for nano-liposomal delivery by fixing the main experimental conditions: liposome lipid composition and size to be similar to those of Doxil® liposomes. On that basis, we add a prediction of drug leakage from the nano-liposomes during storage. The latter is critical for having pharmaceutically viable nano-drugs. The "load and leak" models were used to screen two large molecular databases in search of candidate APIs for delivery by nano-liposomes. The distribution of positive instances in both loading and leakage models was similar in the two databases screened. The screening process identified 667 molecules that were positives by both loading and leakage models (i.e., both high-loading and stable). Among them, 318 molecules received a high score in both properties and of these, 67 are FDA-approved drugs. This group of molecules, having diverse pharmacological activities, may be the basis for future liposomal drug development.

  10. On the role of specific drug binding in modelling arterial eluting stents

    OpenAIRE

    McGinty, Sean; Pontrelli, Giuseppe

    2016-01-01

    In this paper we consider drug binding in the arterial wall following\\ud delivery by a drug-eluting stent. Whilst it is now generally accepted that a\\ud non-linear saturable reversible binding model is required to properly describe\\ud the binding process, the precise form of the binding model varies between authors.\\ud Our particular interest in this manuscript is in assessing to what extent\\ud modelling specific and non-specific binding in the arterial wall as separate\\ud phases is important...

  11. Surfactant-assisted water exposed electrospinning of novel super hydrophilic polycaprolactone based fibers.

    Science.gov (United States)

    Zargarian, S Sh; Haddadi-Asl, V

    2016-05-17

    Hybrid scaffolds prepared by blend electrospinning of Polycaprolactone and Pluronic solution benefit from enhanced fiber hydrophilicity and may offer satisfactory cell attachment and proliferation. To improve hybrid scaffold wettability and water swelling ratio, adequate amount of hydrophilic polymer is required; though this amount is limited by fiber surface enrichment of Pluronic and cannot be exceeded without affecting the scaffold mechanical properties. To overcome this problem, a routine blend electrospinning setup was modified by exposing the blend solution to water in order to attract Pluronic chains toward the surface of the charged jet. Morphology of scaffolds produced by the routine blend electrospinning and modified method was studied. A 50 nm thick Pluronic layer with linty appearance on the surface of the fibers fabricated by the modified method was detected. Drug-loaded fibers from modified method showed a moderate initial burst and then a prolonged release period while an abnormal two-stage phased release profile was observed for the routine blend method. The latter was associated to Pluronic/drug accumulations within the fibers fabricated by the routine method which resulted in fiber disintegration and a subsequent second burst release.

  12. A free-standing, sheet-shaped, "hydrophobic" biomaterial containing polymeric micelles formed from poly(ethylene glycol)-poly(lactic acid) block copolymer for possible incorporation/release of "hydrophilic" compounds.

    Science.gov (United States)

    Moroishi, Hitomi; Yoshida, Chikara; Murakami, Yoshihiko

    2013-02-01

    Sheet-shaped materials with a large contact area relative to the drug targeting site lead to advantages over conventional particle-shaped drug carriers and have several advantages for their biomedical applications. The present study proposes a methodology for preparing a novel sheet-shaped "hydrophobic" and biocompatible biomaterial in which polymeric micelles are uniformly dispersed for the incorporation of "hydrophilic" compounds into the sheet. The methoxy-terminated poly(ethylene glycol)-block-poly(lactic acid) block copolymer (CH(3)O-PEG-b-PLA) was successfully synthesized by means of the anionic ring-opening polymerization of both ethylene oxide and dl-lactide. CH(3)O-PEG-b-PLA was self-assembled and formed stable micelle-like w/o emulsion with a hydrophilic inner core in organic solvents. A sheet-shaped material containing a hydrophilic inner space for incorporating hydrophilic compounds was obtained by spin-coating both the micelle solution and a sheet-forming polymer. Fluorescent images of the sheet proved that polymeric micelles providing hydrophilic spaces were uniformly dispersed in the hydrophobic sheet. The facile technique presented in this paper can be a tool for fabricating sheet-shaped biomaterials that have a hydrophilic inner core and, consequently, that are suitable for the sustained release of hydrophilic compounds.

  13. Glutathione metabolism modeling: a mechanism for liver drug-robustness and a new biomarker strategy.

    NARCIS (Netherlands)

    Geenen, S.; du Preez, F.B.; Snoep, J.L.; Foster, A.J.; Sarda, S.; Kenna, J.G.; Wilson, I.D.; Westerhoff, H.V.

    2013-01-01

    BACKGROUND: Glutathione metabolism can determine an individual's ability to detoxify drugs. To increase understanding of the dynamics of cellular glutathione homeostasis, we have developed an experiment-based mathematical model of the kinetics of the glutathione network. This model was used to simul

  14. Thermoresponsive polymeric gel as an on-demand transdermal drug delivery system for pain management.

    Science.gov (United States)

    Indulekha, S; Arunkumar, P; Bahadur, D; Srivastava, R

    2016-05-01

    The main aim of this work is to design a heat triggered transdermal drug delivery system (TDDS) using a thermoresponsive polymer, poly (N-vinyl caprolactam) [PNVCL] based gel, where in patients can themselves administer a pulse of drug on mere application of heat pad over the TDDS, whenever pain is experienced. The phase transition temperature of PNVCL was tuned to 35 °C by grafting it onto a pH sensitive biopolymer, Chitosan, to synthesize Chitosan-g-PNVCL (CP) co-polymer which render the gel both thermo- and pH-responsive property. The application of triggered delivery was explored by loading acetamidophenol (a model hydrophilic drug) and etoricoxib (a model hydrophobic drug). In vitro drug release experiments were performed at three different temperatures (25, 32 and 39 °C) at two different pH (5.5 and 7) to study its drug release with response to temperature and pH. Drug release profiles obtained were found to have enhanced release for both the drugs respectively at 39 °C (above LCST) and pH5.5 when compared to other release conditions. In vitro skin permeation of both the drugs performed in rat abdominal skin using Franz diffusion cell showed enhanced drug release when the skin was subjected to higher temperature (39 °C). Moreover, it was also found that skin permeation for hydrophobic drug was better than that of hydrophilic drug. The in vivo biocompatibility studies of the CP gel in rat skin proved that the gel is biocompatible. The results obtained demonstrated the potential use of the thermoresponsive CP gel as an on-demand localized drug delivery system.

  15. Drug perfusion enhancement in tissue model by steady streaming induced by oscillating microbubbles.

    Science.gov (United States)

    Oh, Jin Sun; Kwon, Yong Seok; Lee, Kyung Ho; Jeong, Woowon; Chung, Sang Kug; Rhee, Kyehan

    2014-01-01

    Drug delivery into neurological tissue is challenging because of the low tissue permeability. Ultrasound incorporating microbubbles has been applied to enhance drug delivery into these tissues, but the effects of a streaming flow by microbubble oscillation on drug perfusion have not been elucidated. In order to clarify the physical effects of steady streaming on drug delivery, an experimental study on dye perfusion into a tissue model was performed using microbubbles excited by acoustic waves. The surface concentration and penetration length of the drug were increased by 12% and 13%, respectively, with streaming flow. The mass of dye perfused into a tissue phantom for 30s was increased by about 20% in the phantom with oscillating bubbles. A computational model that considers fluid structure interaction for streaming flow fields induced by oscillating bubbles was developed, and mass transfer of the drug into the porous tissue model was analyzed. The computed flow fields agreed with the theoretical solutions, and the dye concentration distribution in the tissue agreed well with the experimental data. The computational results showed that steady streaming with a streaming velocity of a few millimeters per second promotes mass transfer into a tissue.

  16. Hybrid imbalanced data classifier models for computational discovery of antibiotic drug targets.

    Science.gov (United States)

    Kocyigit, Yucel; Seker, Huseyin

    2014-01-01

    Identification of drug candidates is an important but also difficult process. Given drug resistance bacteria that we face, this process has become more important to identify protein candidates that demonstrate antibacterial activity. The aim of this study is therefore to develop a bioinformatics approach that is more capable of identifying a small but effective set of proteins that are expected to show antibacterial activity, subsequently to be used as antibiotic drug targets. As this is regarded as an imbalanced data classification problem due to smaller number of antibiotic drugs available, a hybrid classification model was developed and applied to the identification of antibiotic drugs. The model was developed by taking into account of various statistical models leading to the development of six different hybrid models. The best model has reached the accuracy of as high as 50% compared to earlier study with the accuracy of less than 1% as far as the proportion of the candidates identified and actual antibiotics in the candidate list is concerned.

  17. Advances in Engineered Liver Models for Investigating Drug-Induced Liver Injury

    Science.gov (United States)

    Lin, Christine

    2016-01-01

    Drug-induced liver injury (DILI) is a major cause of drug attrition. Testing drugs on human liver models is essential to mitigate the risk of clinical DILI since animal studies do not always suffice due to species-specific differences in liver pathways. While primary human hepatocytes (PHHs) can be cultured on extracellular matrix proteins, a rapid decline in functions leads to low sensitivity (<50%) in DILI prediction. Semiconductor-driven engineering tools now allow precise control over the hepatocyte microenvironment to enhance and stabilize phenotypic functions. The latest platforms coculture PHHs with stromal cells to achieve hepatic stability and enable crosstalk between the various liver cell types towards capturing complex cellular mechanisms in DILI. The recent introduction of induced pluripotent stem cell-derived human hepatocyte-like cells can potentially allow a better understanding of interindividual differences in idiosyncratic DILI. Liver models are also being coupled to other tissue models via microfluidic perfusion to study the intertissue crosstalk upon drug exposure as in a live organism. Here, we review the major advances being made in the engineering of liver models and readouts as they pertain to DILI investigations. We anticipate that engineered human liver models will reduce drug attrition, animal usage, and cases of DILI in humans. PMID:27725933

  18. Molecular Communication Model for Targeted Drug Delivery in Multiple Disease Sites With Diversely Expressed Enzymes.

    Science.gov (United States)

    Chude-Okonkwo, Uche A K; Malekian, Reza; Maharaj, B T Sunil

    2016-04-01

    Targeted drug delivery (TDD) for disease therapy using liposomes as nanocarriers has received extensive attention in the literature. The liposome's ability to incorporate capabilities such as long circulation, stimuli responsiveness, and targeting characteristics, makes it a versatile nanocarrier. Timely drug release at the targeted site requires that trigger stimuli such as pH, light, and enzymes be uniquely overexpressed at the targeted site. However, in some cases, the targeted sites may not express trigger stimuli significantly, hence, achieving effective TDD at those sites is challenging. In this paper, we present a molecular communication-based TDD model for the delivery of therapeutic drugs to multiple sites that may or may not express trigger stimuli. The nanotransmitter and nanoreceiver models for the molecular communication system are presented. Here, the nanotransmitter and nanoreceiver are injected into the targeted body system's blood network. The compartmental pharmacokinetics model is employed to model the transportation of these therapeutic nanocarriers to the targeted sites where they are meant to anchor before the delivery process commences. We also provide analytical expressions for the delivered drug concentration. The effectiveness of the proposed model is investigated for drug delivery on tissue surfaces. Results show that the effectiveness of the proposed molecular communication-based TDD depends on parameters such as the total transmitter volume capacity, the receiver radius, the diffusion characteristic of the microenvironment of the targeted sites, and the concentration of the enzymes associated with the nanotransmitter and the nanoreceiver designs.

  19. A mimetic tissue model for the quantification of drug distributions by MALDI imaging mass spectrometry.

    Science.gov (United States)

    Groseclose, M Reid; Castellino, Stephen

    2013-11-05

    The full potential of imaging mass spectrometry (IMS) as a tool in drug development will not be realized until reliable quantitative information can be integrated with the molecular distributions. Here we report a novel method for the quantification of drugs in tissue sections using matrix-assisted laser desorption/ionization (MALDI) IMS. This method uses a mimetic tissue model consisting of a set of tissue homogenates spiked with a range of different drug concentrations that have been frozen into a polymer support mold. The goal of this model is to mimic a dosed tissue in its effects on analyte extraction and ion suppression. Parallel preparation and analysis of sections from the tissue model and the dosed tissues allow for the quantification of a drug's distribution. Here we detail the steps involved in constructing the model and provide proof of concept data to highlight the potential of this approach. Several figures of merit are evaluated including linearity of response, variability, and section-to-section reproducibility. Finally, the tissue model is used to quantify two different drugs, lapatinib and nevirapine, in dosed tissues from nonclinical species and the results are compared with those generated by LC-MS quantification.

  20. Modelling Drug Administration Regimes for Asthma: A Romanian Experience

    Science.gov (United States)

    Andras, Szilard; Szilagyi, Judit

    2010-01-01

    In this article, we present a modelling activity, which was a part of the project DQME II (Developing Quality in Mathematics Education, for more details see http://www.dqime.uni-dortmund.de) and some general observations regarding the maladjustments and rational errors arising in such type of activities.

  1. Mathematical Model for TSPP Drug-delivery in Nanomedicine

    Directory of Open Access Journals (Sweden)

    Simona Clichici

    2011-01-01

    Full Text Available Helping improve humanity is one of the promises of nanotechnology and nanomedicine. This paper will highlight some of the research findings in the nanomedicine area by creating a pharmacokinetic model of 5,10,15,20-tetra-(4-sulfonatophenylporphyrin (TSPP used as sensitizer in
    photodynamic therapy.

  2. Coupled gel spreading and diffusive transport models describing microbicidal drug delivery.

    Science.gov (United States)

    Funke, Claire; MacMillan, Kelsey; Ham, Anthony; Szeri, Andrew J; Katz, David F

    2016-10-02

    Gels are a drug delivery platform that is being evaluated for application of active pharmaceutical ingredients, termed microbicides, that act topically against vaginal and rectal mucosal infection by sexually transmitted HIV. Despite success in one Phase IIb trial of a vaginal gel delivering tenofovir, problems of user adherence to designed gel application scheduling have compromised results in two other trials. The microbicides field is responding to this dilemma by expanding behavioral analysis of the determinants of adherence while simultaneously improving the pharmacological, biochemical, and biophysical analyses of the determinants of microbicide drug delivery. The intent is to combine results of these two complementary perspectives on microbicide performance and epidemiological success to create an improved product design paradigm. Central to both user sensory perceptions and preferences, key factors that underlie adherence, and to vaginal gel mucosal drug delivery, that underlies anti-HIV efficacy, are gel properties (e.g. rheology) and volume. The specific engineering problem to be solved here is to develop a model for how gel rheology and volume, interacting with loaded drug concentration, govern the transport of the microbicide drug tenofovir into the vaginal mucosa to its stromal layer. These are factors that can be controlled in microbicide gel design. The analysis here builds upon our current understanding of vaginal gel deployment and drug delivery, incorporating key features of the gel's environment, the vaginal canal, fluid production and subsequent gel dilution, and vaginal wall elasticity. These have not previously been included in the modeling of drug delivery. We consider the microbicide drug tenofovir, which is the drug most completely studied for gels: in vitro, in animal studies in vivo, and in human clinical trials with both vaginal or rectal gel application. Our goal is to contribute to improved biophysical and pharmacological understanding

  3. How modeling and simulation have enhanced decision making in new drug development.

    Science.gov (United States)

    Miller, Raymond; Ewy, Wayne; Corrigan, Brian W; Ouellet, Daniele; Hermann, David; Kowalski, Kenneth G; Lockwood, Peter; Koup, Jeffrey R; Donevan, Sean; El-Kattan, Ayman; Li, Cheryl S W; Werth, John L; Feltner, Douglas E; Lalonde, Richard L

    2005-04-01

    The idea of model-based drug development championed by Lewis Sheiner, in which pharmacostatistical models of drug efficacy and safety are developed from preclinical and available clinical data, offers a quantitative approach to improving drug development and development decision-making. Examples are presented that support this paradigm. The first example describes a preclinical model of behavioral activity to predict potency and time-course of response in humans and assess the potential for differentiation between compounds. This example illustrates how modeling procedures expounded by Lewis Sheiner provided the means to differentiate potency and the lag time between drug exposure and response and allow for rapid decision making and dose selection. The second example involves planning a Phase 2a dose-ranging and proof of concept trial in Alzheimer's disease (AD). The issue was how to proceed with the study and what criteria to use for a go/no go decision. The combined knowledge of AD disease progression, and preclinical and clinical information about the drug were used to simulate various clinical trial scenarios to identify an efficient and effective Phase 2 study. A design was selected and carried out resulting in a number of important learning experiences as well as extensive financial savings. The motivation for this case in point was the "Learn-Confirm" paradigm described by Lewis Sheiner. The final example describes the use of Pharmacokinetic and Pharmacodynamic (PK/PD) modeling and simulation to confirm efficacy across doses. In the New Drug Application for gabapentin, data from two adequate and well-controlled clinical trials was submitted to the Food and Drug Administration (FDA) in support of the approval of the indication for the treatment of post-herpetic neuralgia. The clinical trial data was not replicated for each of the sought dose levels in the drug application presenting a regulatory dilemma. Exposure response analysis submitted in the New Drug

  4. Optimal drug cocktail design: methods for targeting molecular ensembles and insights from theoretical model systems.

    Science.gov (United States)

    Radhakrishnan, Mala L; Tidor, Bruce

    2008-05-01

    Drug resistance is a significant obstacle in the effective treatment of diseases with rapidly mutating targets, such as AIDS, malaria, and certain forms of cancer. Such targets are remarkably efficient at exploring the space of functional mutants and at evolving to evade drug binding while still maintaining their biological role. To overcome this challenge, drug regimens must be active against potential target variants. Such a goal may be accomplished by one drug molecule that recognizes multiple variants or by a drug "cocktail"--a small collection of drug molecules that collectively binds all desired variants. Ideally, one wants the smallest cocktail possible due to the potential for increased toxicity with each additional drug. Therefore, the task of designing a regimen for multiple target variants can be framed as an optimization problem--find the smallest collection of molecules that together "covers" the relevant target variants. In this work, we formulate and apply this optimization framework to theoretical model target ensembles. These results are analyzed to develop an understanding of how the physical properties of a target ensemble relate to the properties of the optimal cocktail. We focus on electrostatic variation within target ensembles, as it is one important mechanism by which drug resistance is achieved. Using integer programming, we systematically designed optimal cocktails to cover model target ensembles. We found that certain drug molecules covered much larger regions of target space than others, a phenomenon explained by theory grounded in continuum electrostatics. Molecules within optimal cocktails were often dissimilar, such that each drug was responsible for binding variants with a certain electrostatic property in common. On average, the number of molecules in the optimal cocktails correlated with the number of variants, the differences in the variants' electrostatic properties at the binding interface, and the level of binding affinity

  5. Enchanced methods of hydrophilized CdSe quantum dots synthesis

    Science.gov (United States)

    Potapkin, D. V.; Zharkova, I. S.; Goryacheva, I. Y.

    2015-03-01

    Quantum dots are bright and stable fluorescence signal sources, but for most of applications they need an additional hydrophilization step. Unfortunately, most of existing approaches lead to QD's fluorescence quenching, so there is a need for additional enhancing of hydrophilized QD's brightness like UV irradiation, which can be used both on water insoluble QD's with oleic acid ligands (in toluene) and on hydrophilized QD's covered with UV-stable polymer (in aqueous solution). For synthesis of bright water-soluble fluorescent labels CdSe/CdS/ZnS colloidal quantum dots were covered with PAMAM dendrimer and irradiated with UV lamp in quartz cuvettes for 3 hours at the room temperature and then compared with control sample.

  6. Study on hydrophilicity of polymer surfaces improved by plasma treatment

    Science.gov (United States)

    Lai, Jiangnan; Sunderland, Bob; Xue, Jianming; Yan, Sha; Zhao, Weijiang; Folkard, Melvyn; Michael, Barry D.; Wang, Yugang

    2006-03-01

    Surface properties of polycarbonate (PC), polypropylene (PP), polyethylene terephthalate (PET) samples treated by microwave-induced argon plasma have been studied with contact angle measurement, X-ray photoelectron spectroscopy (XPS) and scanned electron microscopy (SEM). It is found that plasma treatment modified the surfaces both in composition and roughness. Modification of composition makes polymer surfaces tend to be highly hydrophilic, which mainly depended on the increase of ratio of oxygen-containing group as same as other papers reported. And this experiment further revealed that C dbnd O bond is the key factor to the improvement of the hydrophilicity of polymer surfaces. Our SEM observation on PET shown that the roughness of the surface has also been improved in micron scale and it has influence on the surface hydrophilicity.

  7. Study on hydrophilicity of polymer surfaces improved by plasma treatment

    Energy Technology Data Exchange (ETDEWEB)

    Lai Jiangnan [Key Laboratory of Heavy Ion Physics, Peking University, MOE, Beijing (China); Sunderland, Bob [Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex (United Kingdom); Xue Jianming [Key Laboratory of Heavy Ion Physics, Peking University, MOE, Beijing (China); Yan, Sha [Key Laboratory of Heavy Ion Physics, Peking University, MOE, Beijing (China); Zhao Weijiang [Key Laboratory of Heavy Ion Physics, Peking University, MOE, Beijing (China); Folkard, Melvyn [Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex (United Kingdom); Michael, Barry D. [Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex (United Kingdom); Wang Yugang [Key Laboratory of Heavy Ion Physics, Peking University, MOE, Beijing (China)]. E-mail: ygwang@pku.edu.cn

    2006-03-15

    Surface properties of polycarbonate (PC), polypropylene (PP), polyethylene terephthalate (PET) samples treated by microwave-induced argon plasma have been studied with contact angle measurement, X-ray photoelectron spectroscopy (XPS) and scanned electron microscopy (SEM). It is found that plasma treatment modified the surfaces both in composition and roughness. Modification of composition makes polymer surfaces tend to be highly hydrophilic, which mainly depended on the increase of ratio of oxygen-containing group as same as other papers reported. And this experiment further revealed that C=O bond is Key factor to the improvement of the hydrophilicity of polymer surfaces. Our SEM observation on PET shown that the roughness of the surface has also been improved in micron scale and it has influence on the surface hydrophilicity.

  8. Frictional forces between hydrophilic and hydrophobic particle coated nanostructured surfaces

    DEFF Research Database (Denmark)

    Hansson, Petra M; Claesson, Per M.; Swerin, Agne;

    2013-01-01

    by utilizing the atomic force microscope (AFM). The chemistry of the surfaces and the probe was varied between hydrophilic silica and hydrophobized silica. For hydrophilic silica surfaces, the friction coefficient was significantly higher for the particle coated surfaces than on the flat reference surface. All...... the particle coated surfaces exhibited similar friction coefficients, from which it may be concluded that the surface geometry, and not the roughness amplitude per se, influenced the measured friction. During measurements with hydrophobic surfaces, strong adhesive forces related to the formation of a bridging...... air cavity were evident from both normal force and friction force measurements. In contrast to the frictional forces between the hydrophilic surfaces, the friction coefficient for hydrophobic surfaces was found to depend on the surface structure and we believe that this dependence is related...

  9. Identifying co-targets to fight drug resistance based on a random walk model

    Directory of Open Access Journals (Sweden)

    Chen Liang-Chun

    2012-01-01

    Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.

  10. Computational modeling of drug-resistant bacteria. Final report

    Energy Technology Data Exchange (ETDEWEB)

    MacDougall, Preston [Middle Tennessee State Univ., Murfreesboro, TN (United States)

    2015-03-12

    Initial proposal summary: The evolution of antibiotic-resistant mutants among bacteria (superbugs) is a persistent and growing threat to public health. In many ways, we are engaged in a war with these microorganisms, where the corresponding arms race involves chemical weapons and biological targets. Just as advances in microelectronics, imaging technology and feature recognition software have turned conventional munitions into smart bombs, the long-term objectives of this proposal are to develop highly effective antibiotics using next-generation biomolecular modeling capabilities in tandem with novel subatomic feature detection software. Using model compounds and targets, our design methodology will be validated with correspondingly ultra-high resolution structure-determination methods at premier DOE facilities (single-crystal X-ray diffraction at Argonne National Laboratory, and neutron diffraction at Oak Ridge National Laboratory). The objectives and accomplishments are summarized.

  11. Mining adverse drug reactions from online healthcare forums using hidden Markov model.

    Science.gov (United States)

    Sampathkumar, Hariprasad; Chen, Xue-wen; Luo, Bo

    2014-10-23

    Adverse Drug Reactions are one of the leading causes of injury or death among patients undergoing medical treatments. Not all Adverse Drug Reactions are identified before a drug is made available in the market. Current post-marketing drug surveillance methods, which are based purely on voluntary spontaneous reports, are unable to provide the early indications necessary to prevent the occurrence of such injuries or fatalities. The objective of this research is to extract reports of adverse drug side-effects from messages in online healthcare forums and use them as early indicators to assist in post-marketing drug surveillance. We treat the task of extracting adverse side-effects of drugs from healthcare forum messages as a sequence labeling problem and present a Hidden Markov Model(HMM) based Text Mining system that can be used to classify a message as containing drug side-effect information and then extract the adverse side-effect mentions from it. A manually annotated dataset from http://www.medications.com is used in the training and validation of the HMM based Text Mining system. A 10-fold cross-validation on the manually annotated dataset yielded on average an F-Score of 0.76 from the HMM Classifier, in comparison to 0.575 from the Baseline classifier. Without the Plain Text Filter component as a part of the Text Processing module, the F-Score of the HMM Classifier was reduced to 0.378 on average, while absence of the HTML Filter component was found to have no impact. Reducing the Drug names dictionary size by half, on average reduced the F-Score of the HMM Classifier to 0.359, while a similar reduction to the side-effects dictionary yielded an F-Score of 0.651 on average. Adverse side-effects mined from http://www.medications.com and http://www.steadyhealth.com were found to match the Adverse Drug Reactions on the Drug Package Labels of several drugs. In addition, some novel adverse side-effects, which can be potential Adverse Drug Reactions, were also

  12. Neutral hydrophilic cathode catalyst binders for microbial fuel cells

    KAUST Repository

    Saito, Tomonori

    2011-01-01

    Improving oxygen reduction in microbial fuel cell (MFC) cathodes requires a better understanding of the effects of the catalyst binder chemistry and properties on performance. A series of polystyrene-b-poly(ethylene oxide) (PS-b-PEO) polymers with systematically varying hydrophilicity were designed to determine the effect of the hydrophilic character of the binder on cathode performance. Increasing the hydrophilicity of the PS-b-PEO binders enhanced the electrochemical response of the cathode and MFC power density by ∼15%, compared to the hydrophobic PS-OH binder. Increased cathode performance was likely a result of greater water uptake by the hydrophilic binder, which would increase the accessible surface area for oxygen reduction. Based on these results and due to the high cost of PS-b-PEO, the performance of an inexpensive hydrophilic neutral polymer, poly(bisphenol A-co-epichlorohydrin) (BAEH), was examined in MFCs and compared to a hydrophilic sulfonated binder (Nafion). MFCs with BAEH-based cathodes with two different Pt loadings initially (after 2 cycles) had lower MFC performance (1360 and 630 mW m-2 for 0.5 and 0.05 mg Pt cm-2) than Nafion cathodes (1980 and 1080 mW m -2 for 0.5 and 0.05 mg Pt cm-2). However, after long-term operation (22 cycles, 40 days), power production of each cell was similar (∼1200 and 700-800 mW m-2 for 0.5 and 0.05 mg Pt cm-2) likely due to cathode biofouling that could not be completely reversed through physical cleaning. While binder chemistry could improve initial electrochemical cathode performance, binder materials had less impact on overall long-term MFC performance. This observation suggests that long-term operation of MFCs will require better methods to avoid cathode biofouling. © 2011 The Royal Society of Chemistry.

  13. Novel preparation method for sustained-release PLGA microspheres using water-in-oil-in-hydrophilic-oil-in-water emulsion

    Directory of Open Access Journals (Sweden)

    Hong X

    2013-07-01

    Full Text Available Xiaoyun Hong,1,2,* Liangming Wei,3,* Liuqing Ma,2 Yinghui Chen,4 Zhenguo Liu,1 Weien Yuan2,* 1Department of Neurology, Xinhua Hospital affiliated to Shanghai JiaoTong University, School of Medicine, Shanghai, People's Republic of China; 2School of Pharmacy, Shanghai JiaoTong University, 3Key Laboratory for Thin Film and Microfabrication Technology, Ministry of Education, Research Institute of Micro/Nanometer Science and Technology, Shanghai JiaoTong University, Shanghai, People's Republic of China; 4Department of Neurology, Jinshan Hospital, Fudan University, Shanghai, People's Republic of China *These authors contributed equally to this work Abstract: An increasing number of drugs are needing improved formulations to optimize patient compliance because of their short half-lives in blood. Sustained-release formulations of drugs are often required for long-term efficacy, and microspheres are among the most popular ones. When drugs are encapsulated into microsphere formulations, different methods of preparation need to be used according to specific clinical requirements and the differing physicochemical characteristics of individual drugs. In this work, we developed a novel method for sustained-release drug delivery using a water-in-oil-in-hydrophilic oil-in-water (w/o/oh/w emulsion to encapsulate a drug into poly(lactic-co-glycolic acid (PLGA microspheres. Different effects were achieved by varying the proportions and concentrations of hydrophilic oil and PLGA. Scanning electron and optical microscopic images showed the surfaces of the microspheres to be smooth and that their morphology was spherical. Microspheres prepared using the w/o/oh/w emulsion were able to load protein efficiently and had sustained-release properties. These results indicate that the above-mentioned method might be useful for developing sustained-release microsphere formulations in the future. Keywords: protein, microspheres, water-in-oil-in-hydrophilic oil

  14. Antibiotic-eluting hydrophilized PMMA bone cement with prolonged bactericidal effect for the treatment of osteomyelitis.

    Science.gov (United States)

    Oh, Eun Jo; Oh, Se Heang; Lee, In Soo; Kwon, Oh Soo; Lee, Jin Ho

    2016-05-01

    Osteomyelitis is still considered to be one of the major challenges for orthopedic surgeons despite advanced antiseptic surgical procedures and pharmaceutical therapeutics. In this study, hydrophilized poly(methyl methacrylate) (PMMA) bone cements containing Pluronic F68 (EG79PG28EG79) as a hydrophilic additive and vancomycin (F68-VAcements) were prepared to allow the sustained release of the antibiotic for adequate periods of time without any significant loss of mechanical properties. The compressive strengths of the bone cements with Pluronic F68 compositions less than 7 wt% were not significantly different compared with the control vancomycin-loaded bone cement (VAcement). TheF68 (7 wt%)-VAcement showed sustained release of the antibiotic for up to 11 weeks and almost 100% release from the bone cement. It also prohibited the growth ofS. aureus(zone of inhibition) over six weeks (the required period to treat osteomyelitis), and it did not show any notable cytotoxicity. From an animal study using a femoral osteomyelitis rat model, it was observed that theF68 (7 wt%)-VAcement was effective for the treatment of osteomyelitis, probably as a result of the prolonged release of antibiotic from the PMMA bone cement. On the basis of these findings, it can be suggested that the use of Pluronic F68 as a hydrophilic additive for antibiotic-eluting PMMA bone cement can be a promising strategy for the treatment of osteomyelitis.

  15. Analysis of plant nucleotide sugars by hydrophilic interaction liquid chromatography and tandem mass spectrometry.

    Science.gov (United States)

    Ito, Jun; Herter, Thomas; Baidoo, Edward E K; Lao, Jeemeng; Vega-Sánchez, Miguel E; Michelle Smith-Moritz, A; Adams, Paul D; Keasling, Jay D; Usadel, Björn; Petzold, Christopher J; Heazlewood, Joshua L

    2014-03-01

    Understanding the intricate metabolic processes involved in plant cell wall biosynthesis is limited by difficulties in performing sensitive quantification of many involved compounds. Hydrophilic interaction liquid chromatography is a useful technique for the analysis of hydrophilic metabolites from complex biological extracts and forms the basis of this method to quantify plant cell wall precursors. A zwitterionic silica-based stationary phase has been used to separate hydrophilic nucleotide sugars involved in cell wall biosynthesis from milligram amounts of leaf tissue. A tandem mass spectrometry operating in selected reaction monitoring mode was used to quantify nucleotide sugars. This method was highly repeatable and quantified 12 nucleotide sugars at low femtomole quantities, with linear responses up to four orders of magnitude to several 100pmol. The method was also successfully applied to the analysis of purified leaf extracts from two model plant species with variations in their cell wall sugar compositions and indicated significant differences in the levels of 6 out of 12 nucleotide sugars. The plant nucleotide sugar extraction procedure was demonstrated to have good recovery rates with minimal matrix effects. The approach results in a significant improvement in sensitivity when applied to plant samples over currently employed techniques.

  16. Impacts of hydrophilic colanic acid on bacterial attachment to microfiltration membranes and subsequent membrane biofouling.

    Science.gov (United States)

    Yoshida, Keitaro; Tashiro, Yosuke; May, Thithiwat; Okabe, Satoshi

    2015-06-01

    In order to examine the interactions between physicochemical properties of specific extracellular polymeric substances (EPS) and membrane biofouling, we investigated the impacts of hydrophilic colanic acid, as a model extracellular polysaccharide component, on initial bacterial attachment to different microfiltration (MF) membranes and membrane biofouling by using Escherichia coli strains producing different amounts of colanic acid. In a newly designed microtiter plate assay, the bacterial attachment by an E. coli strain RcsF(+), which produces massive amounts of colanic acid, decreased only to a hydrophobic membrane because the colanic acid made cell surfaces more hydrophilic, resulting in low cell attachment to hydrophobic membranes. The bench-scale cross-flow filtration tests followed by filtration resistance measurement revealed that RcsF(+) caused severe irreversible membrane fouling (i.e., pore-clogging), whereas less extracellular polysaccharide-producing strains caused moderate but reversible fouling to all membranes used in this study. Further cross-flow filtration tests indicated that colanic acid liberated in the bulk phase could rapidly penetrate pre-accumulated biomass layers (i.e., biofilms) and then directly clogged membrane pores. These results indicate that colanic acid, a hydrophilic extracellular polysaccharide, and possible polysaccharides with similar characteristics with colanic acid are considered as a major cause of severe irreversible membrane fouling (i.e., pore-clogging) regardless of biofilm formation (dynamic membrane).

  17. Evaporation Flux Distribution of Drops on a Hydrophilic or Hydrophobic Flat Surface by Molecular Simulations.

    Science.gov (United States)

    Xie, Chiyu; Liu, Guangzhi; Wang, Moran

    2016-08-16

    The evaporation flux distribution of sessile drops is investigated by molecular dynamic simulations. Three evaporating modes are classified, including the diffusion dominant mode, the substrate heating mode, and the environment heating mode. Both hydrophilic and hydrophobic drop-substrate interactions are considered. To count the evaporation flux distribution, which is position dependent, we proposed an azimuthal-angle-based division method under the assumption of spherical crown shape of drops. The modeling results show that the edge evaporation, i.e., near the contact line, is enhanced for hydrophilic drops in all the three modes. The surface diffusion of liquid molecular absorbed on solid substrate for hydrophilic cases plays an important role as well as the space diffusion on the enhanced evaporation rate at the edge. For hydrophobic drops, the edge evaporation flux is higher for the substrate heating mode, but lower than elsewhere of the drop for the diffusion dominant mode; however, a nearly uniform distribution is found for the environment heating mode. The evidence shows that the temperature distribution inside drops plays a key role in the position-dependent evaporation flux.

  18. Different assembly of type IV collagen on hydrophilic and hydrophobic substrata alters endothelial cells interaction.

    Science.gov (United States)

    Coelho, N Miranda; González-García, C; Planell, J A; Salmerón-Sánchez, M; Altankov, G

    2010-06-09

    Considering the structural role of type IV collagen (Col IV) in the assembly of the basement membrane (BM) and the perspective of mimicking its organization for vascular tissue engineering purposes, we studied the adsorption pattern of this protein on model hydrophilic (clean glass) and hydrophobic trichloro(octadecyl)silane (ODS) surfaces known to strongly affect the behavior of other matrix proteins. The amount of fluorescently labeled Col IV was quantified showing saturation of the surface for concentration of the adsorbing solution of about 50microg/ml, but with approximately twice more adsorbed protein on ODS. AFM studies revealed a fine - nearly single molecular size - network arrangement of Col IV on hydrophilic glass, which turns into a prominent and growing polygonal network consisting of molecular aggregates on hydrophobic ODS. The protein layer forms within minutes in a concentration-dependent manner. We further found that human umbilical vein endothelial cells (HUVEC) attach less efficiently to the aggregated Col IV (on ODS), as judged by the significantly altered cell spreading, focal adhesions formation and the development of actin cytoskeleton. Conversely, the immunofluorescence studies for integrins revealed that the fine Col IV network formed on hydrophilic substrata is better recognized by the cells via both alpha1 and alpha2 heterodimers which support cellular interaction, apart from these on hydrophobic ODS where almost no clustering of integrins was observed.

  19. Structure and Hydrogen Bonding of Water in Polyacrylate Gels: Effects of Polymer Hydrophilicity and Water Concentration.

    Science.gov (United States)

    Mani, Sriramvignesh; Khabaz, Fardin; Godbole, Rutvik V; Hedden, Ronald C; Khare, Rajesh

    2015-12-10

    The ability to tune the hydrophilicity of polyacrylate copolymers by altering their composition makes these materials attractive candidates for membranes used to separate alcohol-water mixtures. The separation behavior of these polyacrylate membranes is governed by a complex interplay of factors such as water and alcohol concentrations, water structure in the membrane, polymer hydrophilicity, and temperature. We use molecular dynamics simulations to investigate the effect of polymer hydrophilicity and water concentration on the structure and dynamics of water molecules in the polymer matrix. Samples of poly(n-butyl acrylate) (PBA), poly(2-hydroxyethyl acrylate) (PHEA), and a 50/50 copolymer of BA and HEA were synthesized in laboratory, and their properties were measured. Model structures of these systems were validated by comparing the simulated values of their volumetric properties with the experimental values. Molecular simulations of polyacrylate gels swollen in water and ethanol mixtures showed that water exhibits very different affinities toward the different (carbonyl, alkoxy, and hydroxyl) functional groups of the polymers. Water molecules are well dispersed in the system at low concentrations and predominantly form hydrogen bonds with the polymer. However, water forms large clusters at high concentrations along with the predominant formation of water-water hydrogen bonds and the acceleration of hydrogen bond dynamics.

  20. Different assembly of type IV collagen on hydrophilic and hydrophobic substrata alters endothelial cells interaction

    Directory of Open Access Journals (Sweden)

    NM Coelho

    2010-06-01

    Full Text Available Considering the structural role of type IV collagen (Col IV in the assembly of the basement membrane (BM and the perspective of mimicking its organization for vascular tissue engineering purposes, we studied the adsorption pattern of this protein on model hydrophilic (clean glass and hydrophobic trichloro(octadecylsilane (ODS surfaces known to strongly affect the behavior of other matrix proteins. The amount of fluorescently labeled Col IV was quantified showing saturation of the surface for concentration of the adsorbing solution of about 50μg/ml, but with approximately twice more adsorbed protein on ODS. AFM studies revealed a fine – nearly single molecular size – network arrangement of Col IV on hydrophilic glass, which turns into a prominent and growing polygonal network consisting of molecular aggregates on hydrophobic ODS. The protein layer forms within minutes in a concentration-dependent manner. We further found that human umbilical vein endothelial cells (HUVEC attach less efficiently to the aggregated Col IV (on ODS, as judged by the significantly altered cell spreading, focal adhesions formation and the development of actin cytoskeleton. Conversely, the immunofluorescence studies for integrins revealed that the fine Col IV network formed on hydrophilic substrata is better recognized by the cells via both α1 and α2 heterodimers which support cellular interaction, apart from these on hydrophobic ODS where almost no clustering of integrins was observed.

  1. Design and Fabrication of a Hybrid Superhydrophobic-Hydrophilic Surface That Exhibits Stable Dropwise Condensation.

    Science.gov (United States)

    Mondal, Bikash; Mac Giolla Eain, Marc; Xu, QianFeng; Egan, Vanessa M; Punch, Jeff; Lyons, Alan M

    2015-10-28

    Condensation of water vapor is an essential process in power generation, water collection, and thermal management. Dropwise condensation, where condensed droplets are removed from the surface before coalescing into a film, has been shown to increase the heat transfer efficiency and water collection ability of many surfaces. Numerous efforts have been made to create surfaces which can promote dropwise condensation, including superhydrophobic surfaces on which water droplets are highly mobile. However, the challenge with using such surfaces in condensing environments is that hydrophobic coatings can degrade and/or water droplets on superhydrophobic surfaces transition from the mobile Cassie to the wetted Wenzel state over time and condensation shifts to a less-effective filmwise mechanism. To meet the need for a heat-transfer surface that can maintain stable dropwise condensation, we designed and fabricated a hybrid superhydrophobic-hydrophilic surface. An array of hydrophilic needles, thermally connected to a heat sink, was forced through a robust superhydrophobic polymer film. Condensation occurs preferentially on the needle surface due to differences in wettability and temperature. As the droplet grows, the liquid drop on the needle remains in the Cassie state and does not wet the underlying superhydrophobic surface. The water collection rate on this surface was studied using different surface tilt angles, needle array pitch values, and needle heights. Water condensation rates on the hybrid surface were shown to be 4 times greater than for a planar copper surface and twice as large for silanized silicon or superhydrophobic surfaces without hydrophilic features. A convection-conduction heat transfer model was developed; predicted water condensation rates were in good agreement with experimental observations. This type of hybrid superhydrophobic-hydrophilic surface with a larger array of needles is low-cost, robust, and scalable and so could be used for heat

  2. STUDY ON A HYDROPHOBIC-HYDROPHILIC GRADIENT ROD

    Institute of Scientific and Technical Information of China (English)

    Jun Ma; Bai-yu Li; Hai-yun Liu; Zhi-min Zheng; Jian Xu

    2004-01-01

    A hydrophobic-hydrophilic gradient rod with a length of 40 mm and a diameter of 3 mm was prepared by heating a polymethylsilsesquioxane rod in a cylindrical stove with temperature gradient. The rod was thus pyrolyzed under a temperature gradient condition. The organic end of the gradient rod appears hydrophobic with a contact angle of 109.9° while the other end is hydrophilic with a contact angle of 62.4°. The gradient chemical structure and the gradient microstructure along the rod were characterized by FTIR and SEM, respectively.

  3. Life in 3D is never flat: 3D models to optimise drug delivery.

    Science.gov (United States)

    Fitzgerald, Kathleen A; Malhotra, Meenakshi; Curtin, Caroline M; O' Brien, Fergal J; O' Driscoll, Caitriona M

    2015-10-10

    The development of safe, effective and patient-acceptable drug products is an expensive and lengthy process and the risk of failure at different stages of the development life-cycle is high. Improved biopharmaceutical tools which are robust, easy to use and accurately predict the in vivo response are urgently required to help address these issues. In this review the advantages and challenges of in vitro 3D versus 2D cell culture models will be discussed in terms of evaluating new drug products at the pre-clinical development stage. Examples of models with a 3D architecture including scaffolds, cell-derived matrices, multicellular spheroids and biochips will be described. The ability to simulate the microenvironment of tumours and vital organs including the liver, kidney, heart and intestine which have major impact on drug absorption, distribution, metabolism and toxicity will be evaluated. Examples of the application of 3D models including a role in formulation development, pharmacokinetic profiling and toxicity testing will be critically assessed. Although utilisation of 3D cell culture models in the field of drug delivery is still in its infancy, the area is attracting high levels of interest and is likely to become a significant in vitro tool to assist in drug product development thus reducing the requirement for unnecessary animal studies. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. A Model of Consumer Response to Over-the-Counter Drug Advertising: Antecedents and Influencing Factors.

    Science.gov (United States)

    Huh, Jisu; Delorme, Denise E; Reid, Leonard N

    2016-01-01

    Given the importance of over-the-counter (OTC) drugs in the health care marketplace and lack of systematic research on OTC drug advertising (OTCA) effects, this study tested a theory-based, product category-specific OTCA effects model. Structural equation modeling analysis of data for 1 OTC drug category, analgesics, supported the proposed model, explaining the OTCA effect process from key consumer antecedents to ad involvement, from ad involvement to ad attention, from ad attention to cognitive responses, then to affective/evaluative responses, leading to the final behavioral outcome. Several noteworthy patterns also emerged: (a) Product involvement was directly linked to ad attention, rather than exerting an indirect influence through ad involvement; (b) ad attention was significantly related to both cognitive and affective/evaluative responses to different degrees, with stronger links to cognitive responses; and

  5. An analytical solution for the model of drug distribution and absorption in small intestine

    Science.gov (United States)

    Mingyu, Xu

    1990-11-01

    According to the physiological and anatomical characteristics of small intestine, neglecting the effect of its motility on the distribution and absorption of drug and nutrient, Y. Miyamoto et al.[1] proposed a model of two-dimensional laminar flow in a circular porous tube with permeable wall and calculated the concentration profile of drug by numerical analysis. In this paper, we give a steady state analytical solution of the above model including deactivation term. The obtained results are in agreement with the results of their numerical analysis. Moreover the analytical solution presented in this paper reveals the relation among the physiological parameters of the model and describes the basic absorption rule of drug and nutrient through the intestinal wall and hence provides a theoretical basis for determining the permeability and reflection coefficient through in situ experiments.

  6. Development of a blood-brain barrier model in a membrane-based microchip for characterization of drug permeability and cytotoxicity for drug screening.

    Science.gov (United States)

    Shao, Xiaojian; Gao, Dan; Chen, Yongli; Jin, Feng; Hu, Guangnan; Jiang, Yuyang; Liu, Hongxia

    2016-08-31

    Since most of the central nervous system (CNS) drug candidates show poor permeability across the blood-brain barrier (BBB), development of a reliable platform for permeability assay will greatly accelerate drug discovery. Herein, we constructed a microfluidic BBB model to mimic drug delivery into the brain to induce cytotoxicity at target cells. To reconstitute the in vivo BBB properties, human cerebral microvessel endothelial cells (hCMEC/D3) were dynamically cultured in a membrane-based microchannel. Sunitinib, a model drug, was then delivered into the microchannel and forced to permeate through the BBB model. The permeated amount was directly quantified by an electrospray ionization quadrupole time-of-flight mass spectrometer (ESI-Q-TOF MS) after on-chip SPE (μSPE) pretreatment. Moreover, the permeated drug was incubated with glioma cells (U251) cultured inside agarose gel in the downstream to investigate drug-induced cytotoxicity. The resultant permeability of sunitinib was highly correlated with literature reported value, and it only required 30 min and 5 μL of sample solution for each permeation experiment. Moreover, after 48 h of treatment, the survival rate of U251 cells cultured in 3D scaffolds was nearly 6% higher than that in 2D, which was in accordance with the previously reported results. These results demonstrate that this platform provides a valid tool for drug permeability and cytotoxicity assays which have great value for the research and development of CNS drugs.

  7. Healthcare resource consumption for intermittent urinary catheterisation: cost-effectiveness of hydrophilic catheters and budget impact analyses.

    Science.gov (United States)

    Rognoni, Carla; Tarricone, Rosanna

    2017-01-17

    This study presents a cost-effectiveness analysis comparing hydrophilic coated to uncoated catheters for patients performing urinary intermittent catheterisation. A national budget impact analysis is also included to evaluate the impact of intermittent catheterisation for management of bladder dysfunctions over a period of 5 years. A Markov model (lifetime horizon, 1 year cycle length) was developed to project health outcomes (life years and quality-adjusted life years) and economic consequences related to patients using hydrophilic coated or uncoated catheters. The model was populated with catheter-related clinical efficacy data retrieved from randomised controlled trials and quality-of-life data (utility weights) from the literature. Cost data (EUR, 2015) were estimated on the basis of healthcare resource consumption derived from an e-survey addressed to key opinion leaders in the field. Italian Healthcare Service perspective. Patients with spinal cord injury performing intermittent urinary catheterisation in the home setting. Incremental cost-effectiveness and cost-utility ratios (ICER and ICUR) of hydrophilic coated versus uncoated catheters and associated healthcare budget impact. The base-case ICER and ICUR associated with hydrophilic coated catheters were €20 761 and €24 405, respectively. This implies that hydrophilic coated catheters are likely to be cost-effective in comparison to uncoated ones, as proposed Italian threshold values range between €25 000 and €66 400. Considering a market share at year 5 of 89% hydrophilic catheters and 11% uncoated catheters, the additional cost for Italy is approximately €12 million in the next 5 years (current market share scenario for year 0: 80% hydrophilic catheters and 20% uncoated catheters). Considered over a lifetime, hydrophilic coated catheters are potentially a cost-effective choice in comparison to uncoated ones. These findings can assist policymakers in evaluating intermittent

  8. Modeling structure-function relationships for diffusive drug transport in inert porous geopolymer matrices.

    Science.gov (United States)

    Jämstorp, Erik; Strømme, Maria; Frenning, Göran

    2011-10-01

    A unique structure-function relationship investigation of mechanically strong geopolymer drug delivery vehicles for sustained release of potent substances is presented. The effect of in-synthesis water content on geopolymer pore structure and diffusive drug transport is investigated. Scanning electron microscopy, N2 gas adsorption, mercury intrusion porosimetry, compression strength test, drug permeation, and release experiments are performed. Effective diffusion coefficients are measured and compared with corresponding theoretical values as derived from pore size distribution and connectivity via pore-network modeling. By solely varying the in-synthesis water content, mesoporous and mechanically strong geopolymers with porosities of 8%-45% are obtained. Effective diffusion coefficients of the model drugs Saccharin and Zolpidem are observed to span two orders of magnitude (∼1.6-120 × 10(-8) cm(2) /s), comparing very well to theoretical estimations. The ability to predict drug permeation and release from geopolymers, and materials alike, allows future formulations to be tailored on a structural and chemical level for specific applications such as controlled drug delivery of highly potent substances.

  9. Drugs for Neglected Diseases initiative model of drug development for neglected diseases: current status and future challenges.

    Science.gov (United States)

    Ioset, Jean-Robert; Chang, Shing

    2011-09-01

    The Drugs for Neglected Diseases initiative (DNDi) is a patients' needs-driven organization committed to the development of new treatments for neglected diseases. Created in 2003, DNDi has delivered four improved treatments for malaria, sleeping sickness and visceral leishmaniasis. A main DNDi challenge is to build a solid R&D portfolio for neglected diseases and to deliver preclinical candidates in a timely manner using an original model based on partnership. To address this challenge DNDi has remodeled its discovery activities from a project-based academic-bound network to a fully integrated process-oriented platform in close collaboration with pharmaceutical companies. This discovery platform relies on dedicated screening capacity and lead-optimization consortia supported by a pragmatic, structured and pharmaceutical-focused compound sourcing strategy.

  10. The skill and style to model the evolution of resistance to pesticides and drugs.

    Science.gov (United States)

    2010-07-01

    Resistance to pesticides and drugs led to the development of theoretical models aimed at identifying the main factors of resistance evolution and predicting the efficiency of resistance management strategies. We investigated the various ways in which the evolution of resistance has been modelled over the last three decades, by reviewing 187 articles published on models of the evolution of resistance to all major classes of pesticides and drugs. We found that (i) the technical properties of the model were most strongly influenced by the class of pesticide or drug and the target organism, (ii) the resistance management strategies studied were quite similar for the different classes of pesticides or drugs, except that the refuge strategy was mostly used in models of the evolution of resistance to insecticidal proteins, (iii) economic criteria were rarely used to evaluate the evolution of resistance and (iv) the influence of mutation, migration and drift on the speed of resistance development has been poorly investigated. We propose guidelines for the future development of theoretical models of the evolution of resistance. For instance, we stress the potential need to give more emphasis to the three evolutionary forces migration, mutation and genetic drift rather than simply selection.

  11. Zebrafish as a Model Organism for the Development of Drugs for Skin Cancer

    Directory of Open Access Journals (Sweden)

    Fatemeh Bootorabi

    2017-07-01

    Full Text Available Skin cancer, which includes melanoma and squamous cell carcinoma, represents the most common type of cutaneous malignancy worldwide, and its incidence is expected to rise in the near future. This condition derives from acquired genetic dysregulation of signaling pathways involved in the proliferation and apoptosis of skin cells. The development of animal models has allowed a better understanding of these pathomechanisms, with the possibility of carrying out toxicological screening and drug development. In particular, the zebrafish (Danio rerio has been established as one of the most important model organisms for cancer research. This model is particularly suitable for live cell imaging and high-throughput drug screening in a large-scale fashion. Thanks to the recent advances in genome editing, such as the clustered regularly-interspaced short palindromic repeats (CRISPR/CRISPR-associated protein 9 (Cas9 methodologies, the mechanisms associated with cancer development and progression, as well as drug resistance can be investigated and comprehended. With these unique tools, the zebrafish represents a powerful platform for skin cancer research in the development of target therapies. Here, we will review the advantages of using the zebrafish model for drug discovery and toxicological and phenotypical screening. We will focus in detail on the most recent progress in the field of zebrafish model generation for the study of melanoma and squamous cell carcinoma (SCC, including cancer cell injection and transgenic animal development. Moreover, we will report the latest compounds and small molecules under investigation in melanoma zebrafish models.

  12. Recent advances using zebrafish animal models for muscle disease drug discovery

    Science.gov (United States)

    Maves, Lisa

    2015-01-01

    Introduction Animal models have enabled great progress in the discovery and understanding of pharmacological approaches for treating muscle diseases like Duchenne muscular dystrophy. Areas covered With this article, the author provides the reader with a description of the zebrafish animal model, which has been employed to identify and study pharmacological approaches to muscle disease. In particular, the author focuses on how both large-scale chemical screens and targeted drug treatment studies have established zebrafish as an important model for muscle disease drug discovery. Expert opinion There are a number of opportunities arising for the use of zebrafish models for further developing pharmacological approaches to muscle diseases, including studying drug combination therapies and utilizing genome editing to engineer zebrafish muscle disease models. It is the author’s particular belief that the availability of a wide range of zebrafish transgenic strains for labeling immune cell types, combined with live imaging and drug treatment of muscle disease models, should allow for new elegant studies demonstrating how pharmacological approaches might influence inflammation and the immune response in muscle disease. PMID:24931439

  13. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

  14. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

  15. The effect of hydrophilic and hydrophobic structure of amphiphilic polymeric micelles on their transport in epithelial MDCK cells.

    Science.gov (United States)

    Yu, Chao; He, Bing; Xiong, Meng-Hua; Zhang, Hua; Yuan, Lan; Ma, Ling; Dai, Wen-Bing; Wang, Jun; Wang, Xing-Lin; Wang, Xue-Qing; Zhang, Qiang

    2013-08-01

    The interaction of nanocarriers with cells including their transcellular behavior is vital not only for a drug delivery system, but also for the safety of nanomaterials. In an attempt to clarify how the structures of polymers impact the transport mechanisms of their nanocarriers in epithelial cells, three amphiphilic polymers (PEEP-PCL, PEG-PCL and PEG-DSPE) with different hydrophilic or hydrophobic blocks were synthesized or chosen to form different micelle systems here. The endocytosis, exocytosis, intracellular colocalization, paracellular permeability and transcytosis of these micelle systems were compared using Förster resonance energy transfer analysis, real-time confocal images, colocalization assay, transepithelial electrical resistance study, and so on. All micelle systems were found intact during the studies with cells. The endocytosis and exocytosis studies with undifferentiated MDCK cells and the transcytosis study with differentiated MDCK monolayers all indicated the fact that PEG-DSPE micelles achieved the most and fastest transport, followed by PEG-PCL and PEEP-PCL in order. These might be because DSPE has higher hydrophobicity than PCL while PEG has lower hydrophilicity than PEEP. Different in hydrophilic or hydrophobic structures, all kinds of micelles demonstrated similar pathways during endocytosis and exocytosis, both caveolae- and clathrin-mediated but with difference in degree. The colocalization studies revealed different behaviors in intracellular trafficking among the three polymer micelles, suggesting the decisive role of hydrophilic shells on this process. Finally, all micelle systems did not impact the paracellular permeability of test cell monolayer. In conclusion, the hydrophilic and hydrophobic structures of test micelles could influence their transport ability, intracellular trafficking and the transport level under each pathway in MDCK cells.

  16. Spatio-temporal tumour model for analysis and mechanism of action of intracellular drug accumulation

    Indian Academy of Sciences (India)

    Somna Mishra; V K Katiyar

    2008-09-01

    We have developed a one-dimensional tumour simulator to describe the biodistribution of chemotherapeutic drugs to a tumoral lesion and the tumour cell’s response to therapy. A three-compartment model is used for drug dynamics within the tumour. The first compartment represents the extracellular space in which cells move, the second corresponds to the intracellular fluid space (including cell membrane) which is in direct equilibrium with the extracellular space, and the third is a non-exchangeable compartment that represents sequestered drug which is trapped in the nucleus to damage the cellular DNA, directly triggering cell death. Analytical and numerical techniques (Finite Element Method) are used to describe the tumour’s response to therapy and the effect of parameter variation on the drug concentration profiles in the three compartments.

  17. Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.

    Directory of Open Access Journals (Sweden)

    Richard de Boer

    Full Text Available Today HIV-1 infection is recognized as a chronic disease with obligatory lifelong treatment to keep viral titers below detectable levels. The continuous intake of antiretroviral drugs however, leads to severe and even life-threatening side effects, supposedly by the deleterious impact of nucleoside-analogue type compounds on the functioning of the mitochondrial DNA polymerase. For detailed investigation of the yet partially understood underlying mechanisms, the availability of a versatile model system is crucial. We therefore set out to develop the use of Caenorhabditis elegans to study drug induced mitochondrial toxicity. Using a combination of molecular-biological and functional assays, combined with a quantitative analysis of mitochondrial network morphology, we conclude that anti-retroviral drugs with similar working mechanisms can be classified into distinct groups based on their effects on mitochondrial morphology and biochemistry. Additionally we show that mitochondrial toxicity of antiretroviral drugs cannot be exclusively attributed to interference with the mitochondrial DNA polymerase.

  18. Application of Fused Deposition Modelling (FDM) Method of 3D Printing in Drug Delivery.

    Science.gov (United States)

    Long, Jingjunjiao; Gholizadeh, Hamideh; Lu, Jun; Bunt, Craig; Seyfoddin, Ali

    2017-01-01

    Three-dimensional (3D) printing is an emerging manufacturing technology for biomedical and pharmaceutical applications. Fused deposition modelling (FDM) is a low cost extrusion-based 3D printing technique that can deposit materials layer-by-layer to create solid geometries. This review article aims to provide an overview of FDM based 3D printing application in developing new drug delivery systems. The principle methodology, suitable polymers and important parameters in FDM technology and its applications in fabrication of personalised tablets and drug delivery devices are discussed in this review. FDM based 3D printing is a novel and versatile manufacturing technique for creating customised drug delivery devices that contain accurate dose of medicine( s) and provide controlled drug released profiles. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Modeling of drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls to treat vulnerable plaques

    KAUST Repository

    Hossain, Shaolie S.

    2010-01-01

    The main objective of this work is to develop computational tools to support the design of a catheter-based local drug delivery system that uses nanoparticles as drug carriers in order to treat vulnerable plaques and diffuse atherosclerotic disease.

  20. Effect of drugs of abuse on social behaviour: a review of animal models.

    Science.gov (United States)

    Blanco-Gandía, Maria C; Mateos-García, Ana; García-Pardo, Maria P; Montagud-Romero, Sandra; Rodríguez-Arias, Marta; Miñarro, José; Aguilar, María A

    2015-09-01

    Social behaviour is disturbed in many substance abuse and psychiatric disorders. Given the consensus that social behaviours of lower mammals may help to understand some human emotional reactions, the aim of the present work was to provide an up-to-date review of studies on the changes in social behaviour induced by drugs of abuse. Various animal models have been used to study the relationship between drugs of abuse and social behaviour. Herein, we describe the effects of different substances of abuse on the three most commonly used animal models of social behaviour: the social play test, the social interaction test and the resident-intruder paradigm. The first is the most widely used test to assess adolescent behaviour in rodents, the second is generally used to evaluate a wide repertoire of behaviours in adulthood and the latter is specific to aggressive behaviour. Throughout the review we will explore the most relevant studies carried out to date to evaluate the effects of alcohol, cocaine, opioids, 3,4-methylenedioxymethamphetamine (MDMA), cannabinoids, nicotine and other drugs of abuse on these three paradigms, taking into account the influence of different variables, such as social history, age and type of exposure. Drugs of diverse pharmacological classes induce alterations in social behaviour, although they can be contrasting depending on several factors (drug, individual differences and environmental conditions). Ethanol and nicotine increase social interaction at low doses but reduce it at high doses. Psychostimulants, MDMA and cannabinoids reduce social interaction, whereas opiates increase it. Ethanol and psychostimulants enhance aggression, whereas MDMA, opiates, cannabinoids and nicotine reduce it. Prenatal drug exposure alters social behaviour, whereas drug withdrawal decreases sociability and enhances aggression. As a whole, this evidence has improved our understanding of the social dimension of drug addiction.

  1. Caenorhabditis elegans: A Model System for Anti-Cancer Drug Discovery and Therapeutic Target Identification

    Science.gov (United States)

    Kobet, Robert A.; Pan, Xiaoping; Zhang, Baohong; Pak, Stephen C.; Asch, Adam S.; Lee, Myon-Hee

    2014-01-01

    The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the

  2. Evaluation of drug combination for glioblastoma based on an intestine-liver metabolic model on microchip.

    Science.gov (United States)

    Jie, Mingsha; Mao, Sifeng; Liu, Hanyang; He, Ziyi; Li, Hai-Fang; Lin, Jin-Ming

    2017-08-30

    An intestine-liver-glioblastoma biomimetic system was developed to evaluate the drug combination therapy for glioblastoma. A hollow fiber (HF) was embedded into the upper layer of the microfluidic chip for culturing Caco-2 cells to mimic drug delivery as an artificial intestine. HepG2 cells cultured in the bottom chamber of the chip acted as an artificial liver for metabolizing the drugs. The dual-drug combination to glioblastoma U251 cells was evaluated based on the intestine-liver metabolic model. The drugs, irinotecan (CPT-11), temozolomide (TMZ) and cyclophosphamide (CP), were used to dynamically stimulate the cells by continuous infusion into the intestine unit. After intestine absorption and liver metabolism, the prodrugs were transformed to active metabolites, which induced glioblastoma cells apoptosis. The anticancer activity of the CPT-11 and TMZ combination is significantly enhanced compared to that of the single drug treatments. Combination index (CI) values of the combination groups, CPT-11 and TMZ, CPT-11 and CP, and TMZ and CP, at half maximal inhibitory concentration were 0.137, 0.288, and 0.482, respectively. The results indicated that the CPT-11 and TMZ combination was superior to the CPT-11 and CP group as well as the TMZ and CP group towards the U251 cells. The metabolism mechanism of CPT-11 and TMZ was further studied by coupling with mass spectrometric analysis. The biomimetic model enables the performance of long-term cell co-culture, drug delivery, metabolism and real-time analysis of drug effects, promising systematic in vitro mimicking of physiological and pharmacological processes.

  3. Permeability analysis of neuroactive drugs through a dynamic microfluidic in vitro blood-brain barrier model.

    Science.gov (United States)

    Booth, R; Kim, H

    2014-12-01

    This paper presents the permeability analysis of neuroactive drugs and correlation with in vivo brain/plasma ratios in a dynamic microfluidic blood-brain barrier (BBB) model. Permeability of seven neuroactive drugs (Ethosuximide, Gabapentin, Sertraline, Sunitinib, Traxoprodil, Varenicline, PF-304014) and trans-endothelial electrical resistance (TEER) were quantified in both dynamic (microfluidic) and static (transwell) BBB models, either with brain endothelial cells (bEnd.3) in monoculture, or in co-culture with glial cells (C6). Dynamic cultures were exposed to 15 dyn/cm(2) shear stress to mimic the in vivo environment. Dynamic models resulted in significantly higher average TEER (respective 5.9-fold and 8.9-fold increase for co-culture and monoculture models) and lower drug permeabilities (average respective decrease of 0.050 and 0.052 log(cm/s) for co-culture and monoculture) than static models; and co-culture models demonstrated higher average TEER (respective 90 and 25% increase for static and dynamic models) and lower drug permeability (average respective decrease of 0.063 and 0.061 log(cm/s) for static and dynamic models) than monoculture models. Correlation of the resultant logP e values [ranging from -4.06 to -3.63 log(cm/s)] with in vivo brain/plasma ratios (ranging from 0.42 to 26.8) showed highly linear correlation (R (2) > 0.85) for all model conditions, indicating the feasibility of the dynamic microfluidic BBB model for prediction of BBB clearance of pharmaceuticals.

  4. 3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs

    Science.gov (United States)

    Surolia, Ranu; Li, Fu Jun; Wang, Zheng; Li, Huashi; Liu, Gang; Zhou, Yong; Luckhardt, Tracy; Bae, Sejong; Liu, Rui-ming; de Andrade, Joao; Thannickal, Victor J.; Antony, Veena B.

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrotic lung disease characterized by the presence of invasive myofibroblasts in the lung. Currently, there are only two FDA-approved drugs (pirfenidone and nintedanib) for the treatment of IPF. There are no defined criteria to guide specific drug therapy. New methodologies are needed not only to predict personalized drug therapy, but also to screen novel molecules that are on the horizon for treatment of IPF. We have developed a model system that exploits the invasive phenotype of IPF lung tissue. This ex vivo 3D model uses lung tissue from patients to develop pulmospheres. Pulmospheres are 3D spheroids composed of cells derived exclusively from primary lung biopsies and inclusive of lung cell types reflective of those in situ, in the patient. We tested the pulmospheres of 20 subjects with IPF and 9 control subjects to evaluate the responsiveness of individual patients to antifibrotic drugs. Clinical parameters and outcomes were also followed in the same patients. Our results suggest that pulmospheres simulate the microenvironment in the lung and serve as a personalized and predictive model for assessing responsiveness to antifibrotic drugs in patients with IPF. PMID:28138565

  5. Near-infrared labeled, ovalbumin loaded polymeric nanoparticles based on a hydrophilic polyester as model vaccine : In vivo tracking and evaluation of antigen-specific CD8+ T cell immune response

    NARCIS (Netherlands)

    Rahimian, Sima; Kleinovink, Jan Willem; Fransen, Marieke F.; Mezzanotte, Laura; Gold, Henrik; Wisse, Patrick; Overkleeft, Hermen; Amidi, Maryam; Jiskoot, Wim; Lo¨wik, Clemens W.; Ossendorp, Ferry; Hennink, Wim E.

    2015-01-01

    Particulate antigen delivery systems aimed at the induction of antigen-specific T cells form a promising approach in immunotherapy to replace pharmacokinetically unfavorable soluble antigen formulations. In this study, we developed a delivery system using the model protein antigen ovalbumin (OVA) en

  6. A new stochastic model for subgenomic hepatitis C virus replication considers drug resistant mutants.

    Directory of Open Access Journals (Sweden)

    Nikita V Ivanisenko

    Full Text Available As an RNA virus, hepatitis C virus (HCV is able to rapidly acquire drug resistance, and for this reason the design of effective anti-HCV drugs is a real challenge. The HCV subgenomic replicon-containing cells are widely used for experimental studies of the HCV genome replication mechanisms, for drug testing in vitro and in studies of HCV drug resistance. The NS3/4A protease is essential for virus replication and, therefore, it is one of the most attractive targets for developing specific antiviral agents against HCV. We have developed a stochastic model of subgenomic HCV replicon replication, in which the emergence and selection of drug resistant mutant viral RNAs in replicon cells is taken into account. Incorporation into the model of key NS3 protease mutations leading to resistance to BILN-2061 (A156T, D168V, R155Q, VX-950 (A156S, A156T, T54A and SCH 503034 (A156T, A156S, T54A inhibitors allows us to describe the long term dynamics of the viral RNA suppression for various inhibitor concentrations. We theoretically showed that the observable difference between the viral RNA kinetics for different inhibitor concentrations can be explained by differences in the replication rate and inhibitor sensitivity of the mutant RNAs. The pre-existing mutants of the NS3 protease contribute more significantly to appearance of new resistant mutants during treatment with inhibitors than wild-type replicon. The model can be used to interpret the results of anti-HCV drug testing on replicon systems, as well as to estimate the efficacy of potential drugs and predict optimal schemes of their usage.

  7. Assembly of citrate gold nanoparticles on hydrophilic monolayers

    Energy Technology Data Exchange (ETDEWEB)

    Vikholm-Lundin, Inger, E-mail: inger.vikholm-lundin@uta.fi [University of Tampere, BioMediTech, Tampere (Finland); Fimlab Laboratories Ltd., Tampere (Finland); Rosqvist, Emil; Ihalainen, Petri [Abo Akademi University, Center for Functional Materials, Laboratory of Physical Chemistry (Finland); Munter, Tony [VTT Technical Research Centre of Finland, Process Chemistry end Environmental Engineering, Tampere (Finland); Honkimaa, Anni [University of Tampere, Department of Virology, School of Medicine, Tampere (Finland); Marjomäki, Varpu [University of Jyväskylä, Department of Biological and Environmental Science, Nanoscience Center, Jyväskylä (Finland); Albers, Willem M. [BioNavis Oy Ltd., Ylöjärvi, Tampere (Finland); Peltonen, Jouko [Abo Akademi University, Center for Functional Materials, Laboratory of Physical Chemistry (Finland)

    2016-08-15

    Highlights: • The self-assembled layers were all hydrophilic with Lipa-pTHMMAA exhibiting close to full wetting. • The polyacrylamide layers smoothen the gold surface to a higher extent than the polyethylene glycol and lipoic acid terminated with an amino group. • SPR resonance curves shift to higher angles and become increasingly damped when large nanoparticles assembled on the surface. • Topographical images confirmed that the highest number of particles were assembled on the polyethylene glycol monolayer. • By increasing the interaction time more particles could be assembled on the surface. - Abstract: Self-assembled monolayers (SAMs) as model surfaces were linked onto planar gold films thorough lipoic acid or disulfide groups. The molecules used were polyethylene glycol (EG-S-S), N-[tris-(hydroxymethyl)methyl]acrylamide polymers with and without lipoic acid (Lipa-pTHMMAA and pTHMMAA) and a lipoic acid triazine derivative (Lipa-MF). All the layers, but Lipa-MF with a primary amino group were hydroxyl terminated. The layers were characterized by contact angle measurements and atomic force microscopy, AFM. Citrate stabilized nanoparticles, AuNPs in water and phosphate buffer were allowed to assemble on the layers for 10 min and the binding was followed in real-time with surface plasmon resonance, SPR. The SPR resonance curves were observed to shift to higher angles and become increasingly damped, while also the peaks strongly broaden when large nanoparticles assembled on the surface. Both the angular shift and the damping of the curve was largest for nanoparticles assembling on the EG-S-S monolayer. High amounts of particles were also assembled on the pTHMMAA layer without the lipoic acid group, but the damping of the curve was considerably lower with a more even distribution of the particles. Topographical images confirmed that the highest number of particles were assembled on the polyethylene glycol monolayer. By increasing the interaction time more

  8. Zebrafish as a potential model organism for drug test against hepatitis C virus.

    Directory of Open Access Journals (Sweden)

    Cun-Bao Ding

    Full Text Available Screening and evaluating anti- hepatitis C virus (HCV drugs in vivo is difficult worldwide, mainly because of the lack of suitable small animal models. We investigate whether zebrafish could be a model organism for HCV replication. To achieve NS5B-dependent replication an HCV sub-replicon was designed and created with two vectors, one with HCV ns5b and fluorescent rfp genes, and the other containing HCV's 5'UTR, core, 3'UTR and fluorescent gfp genes. The vectors containing sub-replicons were co-injected into zebrafish zygotes. The sub-replicon amplified in liver showing a significant expression of HCV core RNA and protein. The sub-replicon amplification caused no abnormality in development and growth of zebrafish larvae, but induced gene expression change similar to that in human hepatocytes. As the amplified core fluorescence in live zebrafish was detectable microscopically, it rendered us an advantage to select those with replicating sub-replicon for drug experiments. Ribavirin and oxymatrine, two known anti-HCV drugs, inhibited sub-replicon amplification in this model showing reduced levels of HCV core RNA and protein. Technically, this method had a good reproducibility and is easy to operate. Thus, zebrafish might be a model organism to host HCV, and this zebrafish/HCV (sub-replicon system could be an animal model for anti-HCV drug screening and evaluation.

  9. In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs

    Directory of Open Access Journals (Sweden)

    Ricardo Rojas Gómez

    2015-10-01

    Full Text Available Introduction: The in vitro-in vivo pharmacokinetic correlation models (IVIVC are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance. 

  10. Comparison of in vitro cell models in predicting in vivo brain entry of drugs.

    Science.gov (United States)

    Hakkarainen, Jenni J; Jalkanen, Aaro J; Kääriäinen, Tiina M; Keski-Rahkonen, Pekka; Venäläinen, Tetta; Hokkanen, Juho; Mönkkönen, Jukka; Suhonen, Marjukka; Forsberg, Markus M

    2010-12-15

    Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood-brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient (P(app)) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a