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Sample records for model hydrophilic drug

  1. MRI study of hydrophilic xanthan tablets with incorporated model drug

    OpenAIRE

    Mikac, Urša; Baumgartner, Saša; Sepe, Ana; Kristl, Julijana

    2015-01-01

    Magnetic resonance imaging was used to study swelling dynamics and hydrogel formation of xanthan tablets with or without Pentoxifylline drug in water and HCl pH 1.2 media at two different ionic strengths. Significant changes were observed only in the erosion front positions leading to different hydrogel thicknesses. The impact of the drug on the hydrogel thickness was found to be dependent on the medium conditions at high enough drug amount. The drug does not change the hydrogel thickness ...

  2. 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.

  3. Understanding the drug release mechanism from a montmorillonite matrix and its binary mixture with a hydrophilic polymer using a compartmental modelling approach

    Science.gov (United States)

    Choiri, S.; Ainurofiq, A.

    2018-03-01

    Drug release from a montmorillonite (MMT) matrix is a complex mechanism controlled by swelling mechanism of MMT and an interaction of drug and MMT. The aim of this research was to explain a suitable model of the drug release mechanism from MMT and its binary mixture with a hydrophilic polymer in the controlled release formulation based on a compartmental modelling approach. Theophylline was used as a drug model and incorporated into MMT and a binary mixture with hydroxyl propyl methyl cellulose (HPMC) as a hydrophilic polymer, by a kneading method. The dissolution test was performed and the modelling of drug release was assisted by a WinSAAM software. A 2 model was purposed based on the swelling capability and basal spacing of MMT compartments. The model evaluation was carried out to goodness of fit and statistical parameters and models were validated by a cross-validation technique. The drug release from MMT matrix regulated by a burst release mechanism of unloaded drug, swelling ability, basal spacing of MMT compartment, and equilibrium between basal spacing and swelling compartments. Furthermore, the addition of HPMC in MMT system altered the presence of swelling compartment and equilibrium between swelling and basal spacing compartment systems. In addition, a hydrophilic polymer reduced the burst release mechanism of unloaded drug.

  4. Circumvention of the tumor membrane barrier to WR-2721 absorption by reduction of drug hydrophilicity

    International Nuclear Information System (INIS)

    Yuhas, J.M.; Davis, M.E.; Glover, D.; Brown, D.Q.; Ritter, M.

    1982-01-01

    In attempting to account for the ability of most solid tumors to restrict the absorption of WR-2721, aminopropyl-aminoethylphosphorothioate, we examined a number of drug characteristics which might allow for this restriction, and observed that drug hypdrophilicity was a major contributing factor. When the highly hydrophilic WR-2721 was dephosphorylated, the drug became less hydrophilic and could readily cross tumor cell membranes. In addition, conventional radioprotectants, such as cysteine and mercaptoethylamine, were shown to be less hydrophilic than WR-2721 and also to cross tumor membranes readily. Therefore, drug hydrophilicity would appear to be the factor underlying the ability of WR-2721 to selectively protect normal tissues while most other protectors alter the radiation resistance of normal and tumor tissue alike. A red blood cell model for studying this problem in greater detail is described

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

    OpenAIRE

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

    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. Thiomers for oral delivery of hydrophilic macromolecular drugs.

    Science.gov (United States)

    Bernkop-Schnürch, Andreas; Hoffer, Martin H; Kafedjiiski, Krum

    2004-11-01

    In recent years thiolated polymers (thiomers) have appeared as a promising new tool in oral drug delivery. Thiomers are obtained by the immobilisation of thio-bearing ligands to mucoadhesive polymeric excipients. By the formation of disulfide bonds with mucus glycoproteins, the mucoadhesive properties of thiomers are up to 130-fold improved compared with the corresponding unmodified polymers. Owing to the formation of inter- and intramolecular disulfide bonds within the thiomer itself, matrix tablets and particulate delivery systems show strong cohesive properties, resulting in comparatively higher stability, prolonged disintegration times and a more controlled drug release. The permeation of hydrophilic macromolecular drugs through the gastrointestinal (GI) mucosa can be improved by the use of thiomers. Furthermore, some thiomers exhibit improved inhibitory properties towards GI peptidases. The efficacy of thiomers in oral drug delivery has been demonstrated by various in vivo studies. A pharmacological efficacy of 1%, for example, was achieved in rats by oral administration of calcitonin tablets comprising a thiomer. Furthermore, tablets comprising a thiomer and pegylated insulin resulted in a pharmacological efficacy of 7% after oral application to diabetic mice. Low-molecular-weight heparin embedded in thiolated polycarbophil led to an absolute bioavailability of > or = 20% after oral administration to rats. In these studies, formulations comprising the corresponding unmodified polymer had only a marginal or no effect. These results indicate drug carrier systems based on thiomers appear to be a promising tool for oral delivery of hydrophilic macromolecular drugs.

  7. Hydrophobic ampersand hydrophilic: Theoretical models of solvation for molecular biophysics

    International Nuclear Information System (INIS)

    Pratt, L.R.; Tawa, G.J.; Hummer, G.; Garcia, A.E.; Corcelli, S.A.

    1996-01-01

    Molecular statistical thermodynamic models of hydration for chemistry and biophysics have advanced abruptly in recent years. With liquid water as solvent, salvation phenomena are classified as either hydrophobic or hydrophilic effects. Recent progress in treatment of hydrophilic effects have been motivated by continuum dielectric models interpreted as a modelistic implementation of second order perturbation theory. New results testing that perturbation theory of hydrophilic effects are presented and discussed. Recent progress in treatment of hydrophobic effects has been achieved by applying information theory to discover models of packing effects in dense liquids. The simplest models to which those ideas lead are presented and discussed

  8. Labile conjugation of a hydrophilic drug to PLA oligomers to modify a drug delivery system: cephradin in a PLAGA matrix.

    Science.gov (United States)

    Ustariz-Peyret, C; Coudane, J; Vert, M; Kaltsatos, V; Boisramené, B

    2000-01-01

    The physical entrapment of a hydrophilic drug within degradable microspheres is generally difficult because of poor entrapment yield and/or fast release, depending on the microsphere fabrication method. In order to counter the effects of drug hydrophilicity, it is proposed to covalently attach the drug to lactic acid oligomers, with the aim of achieving temporary hydrophobization and slower release controlled by the separation of the drug from the degradable link within the polymer matrix. This strategy was tested on microspheres of the antibiotic cephradin. As the prodrug form, the entrapment of the drug was almost quantitative. The prodrug did degrade in an aqueous medium, modelling body fluids, but cleavage did not occur at the drug-oligomer junction and drug molecules bearing two lactyl residual units were released. When the prodrug is entrapped within a PLAGA matrix, no release was observed within the experimental time period. However, data suggest that conjugation via a bond more sensitive to hydrolysis than the main chain PLA ester bonds should make the system work as desired.

  9. Colon-specific pulsatile drug release provided by electrospun shellac nanocoating on hydrophilic amorphous composites.

    Science.gov (United States)

    Yang, Yao-Yao; Liu, Zhe-Peng; Yu, Deng-Guang; Wang, Ke; Liu, Ping; Chen, Xiaohong

    2018-01-01

    Colon-specific pulsatile drug release, as a combined drug controlled-release model, is a useful drug delivery manner for a series of diseases. New nanomedicines and related preparation methods are highly desired. With diclofenac sodium (DS) as a model drug, a new type of structural nanocomposite (SC), in which composite polyvinylpyrrolidone (PVP)-DS core was coated by shellac, was fabricated via modified coaxial electrospinning. For comparison, traditional PVP-DS monolithic hydrophilic nanocomposites (HCs) were generated using a traditional blending process. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), attenuated total reflectance-Fourier transform infrared (ATR-FTIR), water contact angle (WCA), and in vitro dissolution and ex vivo permeation tests were conducted to characterize the composites. SEM images demonstrated that both composites were linear nanofibers with smooth surface morphology and cross sections. TEM disclosed that the SCs had a thin shellac sheath layer of approximately 12 nm. XRD and ATR-FTIR results demonstrated that the crystalline DS was converted into amorphous composites with PVP because of favorable secondary interactions. WCA and in vitro dissolution tests demonstrated that the sheath shellac layers in SC could resist acid conditions and provide typical colon-specific pulsatile release, rather than a pulsatile release of HC under acid conditions. Ex vivo permeation results demonstrated that the SCs were able to furnish a tenfold drug permeation rate than the DS particles on the colon membrane. A new SC with a shellac coating on hydrophilic amorphous nanocomposites could furnish a colon-specific pulsatile drug release profile. The modified coaxial process can be exploited as a useful tool to create nanocoatings.

  10. Microencapsulation of a hydrophilic model molecule through vibration nozzle and emulsion phase inversion technologies.

    Science.gov (United States)

    Dorati, Rossella; Genta, Ida; Modena, Tiziana; Conti, Bice

    2013-01-01

    The goal of the present work was to evaluate and discuss vibration nozzle microencapsulation (VNM) technology combined to lyophilization, for the microencapsulation of a hydrophilic model molecule into a hydrophilic polymer. Fluorescein-loaded alginate microparticles prepared by VNM and emulsion phase inversion microencapsulation (EPIM) were lyophilized. Morphology, particle size distribution, lyophilized microspheres stability upon rehydration, drug loading and in vitro release were evaluated. Well-formed microspheres were obtained by the VNM technique, with higher yields of production (93.3-100%) and smaller particle size (d50138.10-158.00) than the EPIM microspheres. Rehydration upon lyophilization occurred in 30 min maintaining microsphere physical integrity. Fluorescein release was always faster from the microspheres obtained by VNM (364 h) than from those obtained by EPIM (504 h). The results suggest that VNM is a simple, easy to be scaled-up process suitable for the microencapsulation hydrophilic drugs.

  11. Thiolated nanocarriers for oral delivery of hydrophilic macromolecular drugs.

    Science.gov (United States)

    Dünnhaupt, S; Barthelmes, J; Köllner, S; Sakloetsakun, D; Shahnaz, G; Düregger, A; Bernkop-Schnürch, A

    2015-03-06

    It was the aim of this study to investigate the effect of unmodified as well as thiolated anionic poly(acrylic acid) (PAA) and cationic chitosan (CS) utilized in free-soluble form and as nanoparticulate system on the absorption of the hydrophilic compound FD4 across intestinal epithelial cell layer with and without a mucus layer. Modifications of these polymers were achieved by conjugation with cysteine to PAA (PAA-Cys) and thioglycolic acid to CS (CS-TGA). Particles were prepared via ionic gelation and characterized based on their amount of thiol groups, particle size and zeta potential. Effects on the cell layer concerning absorption enhancement, transepithelial electrical resistance (TEER) and cytotoxicity were investigated. Permeation enhancement was evaluated with respect to in vitro transport of FD4 across Caco-2 cells, while mucoadhesion was indirectly examined in terms of adsorption behaviour when cells were covered with a mucus layer. Lyophilized particles displayed around 1000 μmol/g of free thiol groups, particle sizes of less than 300 nm and a zeta potential of 18 mV (CS-TGA) and -14 mV (PAA-Cys). Cytotoxicity studies confirmed that all polymer samples were used at nontoxic concentrations (0.5% m/v). Permeation studies revealed that all thiolated formulations had pronounced effects on the paracellular permeability of mucus-free Caco-2 layers and enhanced the permeation of FD4 3.0- to 5.3-fold. Moreover, polymers administered as particles showed a higher permeation enhancement than their corresponding solutions. However, the absorption-enhancing effect of each thiolated formulation was significantly (pthiolated polymers as nanoparticulate delivery systems represent a promising tool for the oral administration of hydrophilic macromolecules. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Elastic vesicles for transdermal drug delivery of hydrophilic drugs: a comparison of important physicochemical characteristics of different vesicle types.

    Science.gov (United States)

    Ntimenou, Vassiliki; Fahr, Alfred; Antimisiaris, Sophia G

    2012-08-01

    The aim of this study is to evaluate the influence of different lipid vesicular systems on the skin permeation ability of hydrophilic molecules, and understand if and which vesicle physicochemical properties may be used as predictive tools. Calcein and carboxyfluorescein were used as hydrophilic drug models. All vesicles (conventional liposomes [CLs], transfersomes [TRs] and invasomes [INVs]), were characterized for particle size distribution, zeta-potential, vesicular shape and morphology, encapsulation efficiency, integrity, colloidal stability, elasticity and finally in vitro human skin permeation. Dynamic light scattering (DLS) and cryo-transmission electron microscopy (cryo-TEM) defined that almost all vesicles had spherical structure, low polydispersity (PI Elasticity values (measured by extrusion through membranes) were in the order INVs > TRs > CLs. Three vesicle types were selected (having different elasticity) and in vitro skin permeation experiments demonstrated that calcein permeation was minimal from an aqueous solution, slightly enhanced from CLs, and enhanced by 1.8 and 7.2 times from TRs and INVs, respectively. Permeation and elasticity values were correlated by rank order but not linearly, indicating that elasticity can be used as a crude predictive tool for enhancement of skin transport. Drug encapsulation efficiency was not found to be an important factor in the current study.

  13. Robust optimization of psychotropic drug mixture separation in hydrophilic interaction liquid chromatography.

    Science.gov (United States)

    Rakić, Tijana; Jovanović, Marko; Dumić, Aleksandra; Pekić, Marina; Ribić, Sanja; Stojanović, Biljana Jancić

    2013-01-01

    This paper presents multiobjective optimization of complex mixtures separation in hydrophilic interaction liquid chromatography (HILIC). The selected model mixture consisted of five psychotropic drugs: clozapine, thioridazine, sulpiride, pheniramine and lamotrigine. Three factors related to the mobile phase composition (acetonitrile content, pH of the water phase and concentration of ammonium acetate) were optimized in order to achieve the following goals: maximal separation quality, minimal total analysis duration and robustness of an optimum. The consideration of robustness in early phases of the method development provides reliable methods with low risk for failure in validation phase. The simultaneous optimization of all goals was achieved by multiple threshold approach combined with grid point search. The identified optimal separation conditions (acetonitrile content 83%, pH of the water phase 3.5 and ammonium acetate content in water phase 14 mM) were experimentally verified.

  14. Lipophilicity of basic drugs measured by hydrophilic interaction chromatography.

    Science.gov (United States)

    Bard, Bruno; Carrupt, Pierre-Alain; Martel, Sophie

    2009-05-28

    RPLC gains acceptance in pharmaceutical research for the rapid determination of lipophilicity but remains limited for the determination of partition coefficients of moderate to strong basic compounds under their neutral form because stationary phases are not compatible with high pH conditions. In this work, HILIC technique was used to accurately measure log P(oct) of the neutral form of basic drugs by measuring the difference between 2 isocratic log k values (Delta log k(0-95)) of their cationic form.

  15. Towards elucidation of the drug release mechanism from compressed hydrophilic matrices made of cellulose ethers. III. Critical use of thermodynamic parameters of activation for modeling the water penetration and drug release processes.

    Science.gov (United States)

    Ferrero, Carmen; Massuelle, Danielle; Jeannerat, Damien; Doelker, Eric

    2013-09-10

    The two main purposes of this work were: (i) to critically consider the use of thermodynamic parameters of activation for elucidating the drug release mechanism from hydroxypropyl methylcellulose (HPMC) matrices, and (ii) to examine the effect of neutral (pH 6) and acidic (pH 2) media on the release mechanism. For this, caffeine was chosen as model drug and various processes were investigated for the effect of temperature and pH: caffeine diffusion in solution and HPMC gels, and drug release from and water penetration into the HPMC tablets. Generally, the kinetics of the processes was not significantly affected by pH. As for the temperature dependence, the activation energy (E(a)) values calculated from caffeine diffusivities were in the range of Fickian transport (20-40 kJ mol⁻¹). Regarding caffeine release from HPMC matrices, fitting the profiles using the Korsmeyer-Peppas model would indicate anomalous transport. However, the low apparent E(a) values obtained were not compatible with a swelling-controlled mechanism and can be assigned to the dimensional change of the system during drug release. Unexpectedly, negative apparent E(a) values were calculated for the water uptake process, which can be ascribed to the exothermic dissolution of water into the initially dry HPMC, the expansion of the matrix and the polymer dissolution. Taking these contributions into account, the true E(a) would fall into the range valid for Fickian diffusion. Consequently, a relaxation-controlled release mechanism can be dismissed. The apparent anomalous drug release from HPMC matrices results from a coupled Fickian diffusion-erosion mechanism, both at pH 6 and 2. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. 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.

  17. Improvement of Tenofovir vaginal release from hydrophilic matrices through drug granulation with hydrophobic polymers.

    Science.gov (United States)

    Notario-Pérez, Fernando; Martín-Illana, Araceli; Cazorla-Luna, Raúl; Ruiz-Caro, Roberto; Peña, Juan; Veiga, María-Dolores

    2018-05-30

    Sustained-release vaginal microbicides hold out great hope for the prevention of sexual transmission of HIV from men to women. Tenofovir (TFV) -an antiretroviral drug- sustained-release vaginal compacts combining two release control systems (by drug-loading granules with hydrophobic polymers and incorporating them in a hydrophilic matrix) are proposed in this work as a possible microbicide. The polymers used for the drug granules are Eudragit® RS (ERS), an acrylic derivative, and Zein, a maize protein. The hydrophilic matrix is composed of a mixture of hydroxypropylmethyl cellulose (HPMC) and chitosan (CH). The thermal, microscopic, spectrophotometric and X-ray diffraction analysis showed that the drug was not altered during the granulation process. Studies of TFV release, swelling and ex vivo mucoadhesion were subsequently performed on simulated vaginal fluid. The formulation whereby TFV is granulated using twice its weight in ERS, and then including these granules in a matrix in which the CH predominates over HPMC, allows the sustained release of TFV for 144 h, mucoadhesion to the vaginal mucosa for 150 h and a moderate swelling, making it the most suitable formulation of all those studied. These compacts would therefore offer women protection against the sexual acquisition of HIV. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. 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.

  19. A New Application of Lipid Nanoemulsions as Coating Agent, Providing Zero-Order Hydrophilic Drug Release from Tablets

    Directory of Open Access Journals (Sweden)

    Nicolas Anton

    2012-01-01

    Full Text Available The objective of the present investigation was to evaluate potential of nanoemulsions as a coating material for the tablets. The nanoemulsion of size less than 100 nm was prepared using a simple and low-energy spontaneous emulsification method. Conventional tablets containing theophylline as a model hydrophilic drug were prepared. The theophylline tablets were coated with the nanoemulsion using a fluid bed coater. The effect of different levels of the nanoemulsion coating on the theophylline release was evaluated. The theophylline tablets containing different levels of the nanoemulsion coating could be successfully prepared. Interestingly, the coating of tablet with the nanoemulsion resulted in zero-order release of theophylline from the tablets. The noncoated theophylline tablets release the entire drug in less than 2 minutes, whereas nanoemulsion coating delayed the release of theophylline from tablets. This investigation establishes the proof of concept for the potential of nanoemulsions as a coating material for tablets.

  20. 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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  1. Improved design and characterization of PLGA/PLA-coated Chitosan based micro-implants for controlled release of hydrophilic drugs.

    Science.gov (United States)

    Manna, Soumyarwit; Donnell, Anna M; Kaval, Necati; Al-Rjoub, Marwan F; Augsburger, James J; Banerjee, Rupak K

    2018-05-29

    Repetitive intravitreal injections of Methotrexate (MTX), a hydrophilic chemotherapeutic drug, are currently used to treat selected vitreoretinal (VR) diseases, such as intraocular lymphoma. To avoid complications associated with the rapid release of MTX from the injections, a Polylactic acid (PLA) and Chitosan (CS)-based MTX micro-implant prototype was fabricated in an earlier study, which showed a sustained therapeutic release rate of 0.2-2.0 µg/day of MTX for a period ∼1 month in vitro and in vivo. In the current study, different combinations of Poly(lactic-co-glycolic) acid (PLGA)/PLA coatings were used for lipophilic surface modification of the CS-MTX micro-implant, such as PLGA 5050, PLGA 6535 and PLGA 7525 (PLA: PGA - 50:50, 65:35, 75:25, respectively; M.W: 54,400 - 103,000) and different PLA, such as PLA 100 and PLA 250 (MW: 102,000 and 257,000, respectively). This improved the duration of total MTX release from the coated CS-MTX micro-implants to ∼3-5 months. With an increase in PLA content in PLGA and molecular weight of PLA, a) the initial burst of MTX and the mean release rate of MTX can be reduced; and b) the swelling and biodegradation of the micro-implants can be delayed. The controlled drug release mechanism is caused by a combination of diffusion process and hydrolysis of the polymer coating, which can be modulated by a) PLA content in PLGA and b) molecular weight of PLA, as inferred from Korsmeyer Peppas model, Zero order, First order and Higuchi model fits. This improved micro-implant formulation has the potential to serve as a platform for controlled release of hydrophilic drugs to treat selected VR diseases. Copyright © 2018. Published by Elsevier B.V.

  2. Time-oriented experimental design method to optimize hydrophilic matrix formulations with gelation kinetics and drug release profiles.

    Science.gov (United States)

    Shin, Sangmun; Choi, Du Hyung; Truong, Nguyen Khoa Viet; Kim, Nam Ah; Chu, Kyung Rok; Jeong, Seong Hoon

    2011-04-04

    A new experimental design methodology was developed by integrating the response surface methodology and the time series modeling. The major purposes were to identify significant factors in determining swelling and release rate from matrix tablets and their relative factor levels for optimizing the experimental responses. Properties of tablet swelling and drug release were assessed with ten factors and two default factors, a hydrophilic model drug (terazosin) and magnesium stearate, and compared with target values. The selected input control factors were arranged in a mixture simplex lattice design with 21 experimental runs. The obtained optimal settings for gelation were PEO, LH-11, Syloid, and Pharmacoat with weight ratios of 215.33 (88.50%), 5.68 (2.33%), 19.27 (7.92%), and 3.04 (1.25%), respectively. The optimal settings for drug release were PEO and citric acid with weight ratios of 191.99 (78.91%) and 51.32 (21.09%), respectively. Based on the results of matrix swelling and drug release, the optimal solutions, target values, and validation experiment results over time were similar and showed consistent patterns with very small biases. The experimental design methodology could be a very promising experimental design method to obtain maximum information with limited time and resources. It could also be very useful in formulation studies by providing a systematic and reliable screening method to characterize significant factors in the sustained release matrix tablet. Copyright © 2011 Elsevier B.V. All rights reserved.

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

    Czech Academy of Sciences Publication Activity Database

    Severino, P.; Andreani, T.; Jäger, Alessandro; Chaud, M. V.; Santana, M. H. A.; Silva, A. M.; Souto, E. B.

    2014-01-01

    Roč. 81, 23 June (2014), s. 28-34 ISSN 0223-5234 R&D Projects: GA ČR GAP208/10/1600 Institutional support: RVO:61389013 Keywords : lipid nanoparticles * double emulsion * hydrophilic biotech drugs Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.447, year: 2014

  4. 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.

  5. The effects of disordered structure on the solubility and dissolution rates of some hydrophilic, sparingly soluble drugs.

    Science.gov (United States)

    Mosharraf, M; Sebhatu, T; Nyström, C

    1999-01-15

    The effects of experimental design on the apparent solubility of two sparingly soluble hydrophilic compounds (barium sulphate and calcium carbonate) were studied in this paper. The apparent solubility appeared to be primarily dependent on the amount of solute added to the solvent in each experiment, increasing with increased amounts. This effect seems to be due to the existence of a peripheral disordered layer. However physico-chemical methods used in the present study were not able to unambiguously verify the existence of any disorder in the solid state structure of the drugs. At higher proportions of solute to solvent, the solubility reached a plateau corresponding to the solubility of the disordered or amorphous molecular form of the material. Milling the powders caused the plateau to be reached at lower proportions of solute to solvent, since this further disordered the surface of the drug particles. It was also found that the apparent solubility of the drugs tested decreased after storage at high relative humidities. A model for describing the effects of a disordered surface layer of varying thickness and continuity on the solubility of a substance is presented. This model may be used as a method for detection of minute amount of disorder, where no other technique is capable of detecting the disordered structure. It is suggested that recrystallisation of the material occurs via slow solid-state transition at the surface of the drug particle; this would slowly reduce the apparent solubility of the substance at the plateau level to the thermodynamically stable value. A biphasic dissolution rate profile was obtained. The solubility of the disordered surface of the particles appeared to be the rate-determining factor during the initial dissolution phase, while the solubility of the crystalline core was the rate-determining factor during the final slower phase.

  6. Hydrophilic Interaction Liquid Chromatography/Mass Spectrometry: An Attractive and Prospective Method for the Quantitative Bioanalysis in Drug Metabolism.

    Science.gov (United States)

    Li, Zheng; Han, Jie; Sun, Shi-an; Chen, Kai; Tang, Dao-quan

    2016-01-01

    During the development, dosage optimization and safety evaluation of a drug, rapid and precise monitoring of administered drug and/or its metabolites in biological samples including blood, plasma, serum, tissues and saliva are vital. As drug biotransformation produces more hydrophilic metabolites for the enhancement of drug elimination, which is often a challenge for traditional reversed-phase liquid chromatography (RPLC) separation. Because hydrophilic interaction liquid chromatography (HILIC) is capable of retaining polar compounds and readily compatible with mass spectrometry (MS), HILIC has been used as a complementary separation technique to RPLC for analysis of polar metabolites, especially polar drugs and their metabolites. This review covers core aspects of HILIC-MS/MS method and overall profile of its application in analysis of drug and/or its metabolites. The emphasis of this paper has been placed on the applications of HILIC-MS/MS method in quantitative bioanalysis of drugs alone or along with their metabolites in drug metabolism studies in recent years. As a fundamental and critical step of bioanalytical method, conventional sample preparation techniques of biological matrices for the HILIC-MS/MS analysis of drugs and/or their metabolites are also briefly featured.

  7. Formulation and characterization of hydrophilic drug diclofenac sodium-loaded solid lipid nanoparticles based on phospholipid complexes technology.

    Science.gov (United States)

    Liu, Dongfei; Chen, Li; Jiang, Sunmin; Zhu, Shuning; Qian, Yong; Wang, Fengzhen; Li, Rui; Xu, Qunwei

    2014-03-01

    To successfully prepare the diclofenac sodium (DS)-loaded solid lipid nanoparticles (SLNs), phospholipid complexes (PCs) technology was applied here to improve the liposolubility of DS. Solid lipid nanoparticles (SLNs) loaded with phospholipid complexes (PCs) were prepared by the modified emulsion/solvent evaporation method. DS could be solubilized effectively in the organic solvents with the existence of phospholipid and apparent partition coefficient of DS in PCs increased significantly. X-ray diffraction analysis suggested that DS in PCs was either molecularly dispersed or in an amorphous form. However, no significant difference was observed between the Fourier transform infrared spectroscopy (FT-IR) spectra of physical mixture and that of PCs. Particles with small sizes, narrow polydispersity indexes and high entrapment efficiencies could be obtained with the addition of PCs. Furthermore, according to the transmission electron microscopy, a core-shell structure was likely to be formed. The presence of PCs caused the change of zeta potential and retarded the drug release of SLNs, which indicated that phospholipid formed multilayers around the solid lipid core of SLNs. Both FT-IR and differential scanning calorimetry analysis also illustrated that some weak interactions between DS and lipid materials might take place during the preparation of SLNs. In conclusion, the model hydrophilic drug-DS can be formulated into the SLNs with the help of PCs.

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

    International Nuclear Information System (INIS)

    Mandal, Biman B; Kundu, S C

    2009-01-01

    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.

  9. 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.

  10. Ultra-hydrophilic stent platforms promote early vascular healing and minimise late tissue response: a potential alternative to second-generation drug-eluting stents.

    Science.gov (United States)

    Kolandaivelu, Kumaran; Bailey, Lynn; Buzzi, Stefano; Zucker, Arik; Milleret, Vincent; Ziogas, Algirdas; Ehrbar, Martin; Khattab, Ahmed A; Stanley, James R L; Wong, Gee K; Zani, Brett; Markham, Peter M; Tzafriri, Abraham R; Bhatt, Deepak L; Edelman, Elazer R

    2017-04-20

    Simple surface modifications can enhance coronary stent performance. Ultra-hydrophilic surface (UHS) treatment of contemporary bare metal stents (BMS) was assessed in vivo to verify whether such stents can provide long-term efficacy comparable to second-generation drug-eluting stents (DES) while promoting healing comparably to BMS. UHS-treated BMS, untreated BMS and corresponding DES were tested for three commercial platforms. A thirty-day and a 90-day porcine coronary model were used to characterise late tissue response. Three-day porcine coronary and seven-day rabbit iliac models were used for early healing assessment. In porcine coronary arteries, hydrophilic treatment reduced intimal hyperplasia relative to the BMS and corresponding DES platforms (1.5-fold to threefold reduction in 30-day angiographic and histological stenosis; p<0.04). Endothelialisation was similar on UHS-treated BMS and untreated BMS, both in swine and rabbit models, and lower on DES. Elevation in thrombotic indices was infrequent (never observed with UHS, rare with BMS, most often with DES), but, when present, correlated with reduced endothelialisation (p<0.01). Ultra-hydrophilic surface treatment of contemporary stents conferred good healing while moderating neointimal and thrombotic responses. Such surfaces may offer safe alternatives to DES, particularly when rapid healing and short dual antiplatelet therapy (DAPT) are crucial.

  11. Morphologic characterization and properties of a nanocomposite matrix of polyvinylpyrrolidone and sodium bentonite for hydrophilic drug controlled release

    International Nuclear Information System (INIS)

    Almeida, Dario B.R. de; Tavares, Maria I.B.; Iulianelli, Gisele C.V.

    2015-01-01

    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)

  12. Effects of membrane composition on release of model hydrophilic compound from osmotic delivery systems.

    Science.gov (United States)

    Ozdemir, N; Ozalp, Y; Ozkan, Y

    2000-01-01

    In this study, the effects of surface-active agents in different types and concentrations, added into the coating solution, on release of model hydrophilic compound have been examined. For this purpose, the tablets, prepared with the use of methylene blue as a model substance, were coated by spray coating technique with cellulose acetate solution containing polyethylene glycol 400 as a plasticizer. In addition, cetylpyridinium chloride as cationic surface-active agent and sodium lauryl sulphate as anionic surface-active agent were added into coating solution in different concentrations. After creating a delivery orifice by a microdrill on the tablets, release of model hydrophilic compound was tested by the USP paddle method. The data obtained were evaluated according to the different kinetics and the mechanism of release from the preparations was examined. The surface properties of the coating material were investigated by scanning electron microscope taken before and after the contact with medium fluid, as well as the mechanical properties by tensile tests. In conclusion, it has been found that the cationic surface active agent, cetylpyridinium chloride reduced the lag time, observed during the release of model hydrophilic compound, as a result of its enhancing effect on wettability of tablets by reducing the contact angle between the medium fluid and the coating material. On the other hand, the anionic surface active agent, sodium lauryl sulphate has been inactivated possibly due to the interaction with model hydrophilic compound that has cationic properties and/or substances contained in membrane composition; thus, the lag time has not decreased and furthermore, a significant decrease in the delivery rate of model hydrophilic compound has been observed.

  13. The effect of solvents and hydrophilic additive on stable coating and controllable sirolimus release system for drug-eluting stent.

    Science.gov (United States)

    Kim, Seong Min; Park, Sung-Bin; Bedair, Tarek M; Kim, Man-Ho; Park, Bang Ju; Joung, Yoon Ki; Han, Dong Keun

    2017-09-01

    Various drug-eluting stents (DESs) have been developed to prevent restenosis after stent implantation. However, DES still needs to improve the drug-in-polymer coating stability and control of drug release for effective clinical treatment. In this study, the cobalt-chromium (CoCr) alloy surface was coated with biodegradable poly(D,L-lactide) (PDLLA) and sirolimus (SRL) mixed with hydrophilic Pluronic F127 additive by using ultrasonic spray coating system in order to achieve a stable coating surface and control SRL release. The degradation of PDLLA/SRL coating was studied under physiological solution. It was found that adding F127 reduced the degradation of PDLLA and improved the coating stability during 60days. The effects of organic solvent such as chloroform and tetrahydrofuran (THF) on the coating uniformity were also examined. It was revealed that THF produced a very smooth and uniform coating compared to chloroform. The patterns of in vitro drug release according to the type of organic solvent and hydrophilic additive proposed the possibility of controllable drug release design in DES. It was found that using F127 the drug release was sustained regardless of the organic solvent used. In addition, THF was able to get faster and controlled release profile when compared to chloroform. The structure of SRL molecules in different organic solvents was investigated using ultra-small angle neutron scattering. Furthermore, the structure of SRL is concentration-dependent in chloroform with tight nature under high concentration, but concentration-independent in THF. These results strongly demonstrated that coating stability and drug release patterns can be changed by physicochemical properties of various parameters such as organic solvents, additive, and coating strategy. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    International Nuclear Information System (INIS)

    Meerod, Siraprapa; Rutnakornpituk, Boonjira; Wichai, Uthai; Rutnakornpituk, Metha

    2015-01-01

    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

  15. Hydrophilic interaction chromatography with a focus on the drug-phosphate interaction in drug screening to determine the phospholipidosis induction risk.

    Science.gov (United States)

    Okamoto, Haruka; Hamaguchi, Ryohei; Kuroda, Yukihiro

    2017-04-15

    Cationic amphiphilic drugs (CADs) can induce the hyperaccumulation of phospholipids in cells and tissues. This side effect, which is known as drug-induced phospholipidosis, is sometimes problematic in the development and clinical use of CADs. It is known that CADs generally interact with phospholipids via both hydrophobic and acid-base interactions, and CADs with the larger affinity to phospholipid exhibit the larger induction risk. To develop a chromatographic assay system to predict the phospholipidosis-inducing potential with considering the acid-base interaction between CAD and phosphate group of phospholipid, hydrophilic interaction chromatographic (HILIC) methods were tested in this study. First, a PC HILIC column with phosphocholine groups on a packed material was used. The acid-base or other hydrophilic interactions to the stationary phase differed among basic drugs, and retention to the PC HILIC column did not accurately reflect the induction potential of phospholipidosis. As an alternative HILIC approach, the elution of CADs with the phosphate buffer from an amide column was tested. The elution effect, which is expressed as ratio of retention factors between different phosphate content in the mobile phase, closely correlated with the induction potential. Using the elution effect and retention factor to a reversed-phase HPLC column, the phospholipidosis-inducing drugs were clearly discriminated from the non-inducers. These results suggest that the proposed chromatographic approach can screen phospholipidosis-inducing drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Polylactic acid nano- and microchamber arrays for encapsulation of small hydrophilic molecules featuring drug release via high intensity focused ultrasound.

    Science.gov (United States)

    Gai, Meiyu; Frueh, Johannes; Tao, Tianyi; Petrov, Arseniy V; Petrov, Vladimir V; Shesterikov, Evgeniy V; Tverdokhlebov, Sergei I; Sukhorukov, Gleb B

    2017-06-01

    Long term encapsulation combined with spatiotemporal release for a precisely defined quantity of small hydrophilic molecules on demand remains a challenge in various fields ranging from medical drug delivery, controlled release of catalysts to industrial anti-corrosion systems. Free-standing individually sealed polylactic acid (PLA) nano- and microchamber arrays were produced by one-step dip-coating a PDMS stamp into PLA solution for 5 s followed by drying under ambient conditions. The wall thickness of these hydrophobic nano-microchambers is tunable from 150 nm to 7 μm by varying the PLA solution concentration. Furthermore, small hydrophilic molecules were successfully in situ precipitated within individual microchambers in the course of solvent evaporation after sonicating the PLA@PDMS stamp to remove air-bubbles and to load the active substance containing solvent. The cargo capacity of single chambers was determined to be in the range of several picograms, while it amounts to several micrograms per cm 2 . Two different methods for sealing chambers were compared: microcontact printing versus dip-coating whereby microcontact printing onto a flat PLA sheet allows for entrapment of micro-air-bubbles enabling microchambers with both ultrasound responsiveness and reduced permeability. Cargo release triggered by external high intensity focused ultrasound (HIFU) stimuli is demonstrated by experiment and compared with numerical simulations.

  17. Tailoring the properties of mPEG-PLLA nanoparticles for better encapsulation and tuned release of the hydrophilic anticancer drug.

    Science.gov (United States)

    Surwase, Sachin S; Munot, Neha M; Idage, Bhaskar B; Idage, Susheela B

    2017-06-01

    Gemcitabine is used as a first-line drug for treating many solid tumours. However, it suffers from a major drawback of strong side effects and short plasma half-life because of degradation by enzyme when administered intravenously. Polyesters and copolyesters are the most widely used and preferred class of biodegradable polymer. In the present work, efforts have been made to prepare poly(ethylene glycol) monomethoxy ether-poly(L-lactide) (mPEG-PLLA), a biodegradable amphiphilic copolymer with a view to improve the entrapment and tuned release of hydrophilic drug gemcitabine. The different mPEG-PLLA copolymers were synthesized with the varying ratios of mPEG and characterized by different techniques namely FTIR and 1 H NMR spectroscopy, solution viscosity, differential scanning calorimetry (DSC) and gel permeation chromatography (GPC). Gemcitabine-loaded nanoparticles were prepared using mPEG-PLLA copolymers by two methods i.e. nanoprecipitation and double emulsion solvent evaporation. The nanoprecipitation method showed very less entrapment and polymer solubility in the acetone-water mixture leading to uncontrolled polymer precipitation. The difficulties encountered in the nanoprecipitation method were overcome with the help of the double emulsion (w/o/w) solvent evaporation technique. It has been observed from the results that biodegradable copolymer nanoparticles protect the drug from degradation and also help in controlling the release of encapsulated drug. The properties of nanoparticles can be tailored by varying the composition of mPEG in order to get improved entrapment efficiency and desired drug release. The nanoparticles were assessed for their in vitro cytotoxicity (MTT and FACS) and cellular uptake (fluorescence microscopy) study which showed very promising results. Nanoparticles were also studied for their in vivo release after intravenous administration to Wistar albino rats, which successfully showed controlled drug release for more than 14 days.

  18. Impact of cathepsin B-sensitive triggers and hydrophilic linkers on in vitro efficacy of novel site-specific antibody-drug conjugates.

    Science.gov (United States)

    Bryden, Francesca; Martin, Camille; Letast, Stéphanie; Lles, Eva; Viéitez-Villemin, Inmaculada; Rousseau, Anaïs; Colas, Cyril; Brachet-Botineau, Marie; Allard-Vannier, Emilie; Larbouret, Christel; Viaud-Massuard, Marie-Claude; Joubert, Nicolas

    2018-03-14

    Herein we describe the synthesis and evaluation of four novel HER2-targeting, cathepsin B-sensitive antibody-drug conjugates bearing a monomethylauristatin E (MMAE) cytotoxic payload, constructed via the conjugation of cleavable linkers to trastuzumab using a site-specific bioconjugation methodology. These linkers vary by both cleavable trigger motif and hydrophilicity, containing one of two cathepsin B sensitive dipeptides (Val-Cit and Val-Ala), and engendered with either hydrophilic or hydrophobic character via application of a PEG 12 spacer. Through evaluation of physical properties, in vitro cytotoxicity, and receptor affinity of the resulting antibody-drug conjugates (ADCs), we have demonstrated that while both dipeptide triggers are effective, the increased hydrophobicity of the Val-Ala pair limits its utility within this type of linker. In addition, while PEGylation augments linker hydrophilicity, this change does not translate to more favourable ADC hydrophilicity or potency. While all described structures demonstrated excellent and similar in vitro cytotoxicity, the ADC with the ValCitPABMMAE linker shows the most promising combination of in vitro potency, structural homogeneity, and hydrophilicity, warranting further evaluation into its therapeutic potential.

  19. Multivariate analysis for the optimization of microfluidics-assisted nanoprecipitation method intended for the loading of small hydrophilic drugs into PLGA nanoparticles.

    Science.gov (United States)

    Chiesa, E; Dorati, R; Modena, T; Conti, B; Genta, I

    2018-01-30

    Design of Experiment-assisted evaluation of critical process (total flow rate, TFR, flow rate ratio, FRR) and formulation (polymer concentration and structure, drug:polymer ratio) variables in a novel microfluidics-based device, a staggered herringbone micromixer (SHM), for poly(lactic-co-glycolic acid) copolymer (PLGA) nanoparticles (NPs) manufacturing was performed in order to systematically evaluate and mathematically describe their effects on NPs sizes and drug encapsulation; a small hydrophilic moiety, N-acetylcysteine, was chosen as challenging model drug. SHM-assisted nanoprecipitation method consistently yielded NPs with tailor made sizes (in the range of 100-900 nm) and polydispersity index range from 0.061 to 0.286. Significant effects on NPs sizes were highlighted for TFR and FRR: increasing TFR (from 5 to 15 mL/min) and decreasing FRR (from 1:1 to 1:5 v/v, acetonitrile: buffer) NPs with mean diameter <200 nm were obtained. SHM technique allowed for flexible, application-specific tuning of PLGA NPs size using organic solvents with relatively low toxicity (acetone, acetonitrile), varying aqueous phase composition (Tris buffer vs PVA aqueous solution) and PLGA characteristics (Mw ranging from 25-90 kDa, capped or un-capped PLGA, different lactide:glycolide molar ratio). A very satisfactory N-Ac encapsulation efficiency (more than 67%) and a prolonged release (by 168 h) were achieved. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. 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.

  1. Vaginal drug distribution modeling.

    Science.gov (United States)

    Katz, David F; Yuan, Andrew; Gao, Yajing

    2015-09-15

    This review presents and applies fundamental mass transport theory describing the diffusion and convection driven mass transport of drugs to the vaginal environment. It considers sources of variability in the predictions of the models. It illustrates use of model predictions of microbicide drug concentration distribution (pharmacokinetics) to gain insights about drug effectiveness in preventing HIV infection (pharmacodynamics). The modeling compares vaginal drug distributions after different gel dosage regimens, and it evaluates consequences of changes in gel viscosity due to aging. It compares vaginal mucosal concentration distributions of drugs delivered by gels vs. intravaginal rings. Finally, the modeling approach is used to compare vaginal drug distributions across species with differing vaginal dimensions. Deterministic models of drug mass transport into and throughout the vaginal environment can provide critical insights about the mechanisms and determinants of such transport. This knowledge, and the methodology that obtains it, can be applied and translated to multiple applications, involving the scientific underpinnings of vaginal drug distribution and the performance evaluation and design of products, and their dosage regimens, that achieve it. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Drug-conjugated PLA-PEG-PLA copolymers: a novel approach for controlled delivery of hydrophilic drugs by micelle formation.

    Science.gov (United States)

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

    2017-12-01

    A conjugate of the antihypertensive drug, lisinopril, with triblock poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA) copolymer was synthesized by the reaction of PLA-PEG-PLA copolymer with lisinopril in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The conjugated copolymer was characterized in vitro by hydrogen nuclear magnetic resonance (HNMR), Fourier transform infrared (FTIR), differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) techniques. Then, the lisinopril conjugated PLA-PEG-PLA were self-assembled into micelles in aqueous solution. The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM). The results revealed that the micelles formed by the lisinopril-conjugated PLA-PEG-PLA have spherical structure with the average size of 162 nm. The release behavior of conjugated copolymer, micelles and micelles physically loaded by lisinopril were compared in different media. In vitro release study showed that in contrast to physically loaded micelles, the release rate of micelles consisted of the conjugated copolymer was dependent on pH of media where it was higher at lower pH compared to the neutral medium. Another feature of the conjugated micelles was their more sustained release profile compared to the lisinopril-conjugated copolymer and physically loaded micelles.

  3. Modeling the drug transport in the anterior segment of the eye.

    Science.gov (United States)

    Avtar, Ram; Tandon, Deepti

    2008-10-02

    The aim of the present work is the development of a simple mathematical model for the time course concentration profile of topically administered drugs in the anterior chamber aqueous humor and investigation of the effects of various model parameters on the aqueous humor concentration of lipophilic and hydrophilic drugs. A simple pharmacokinetic model for the transient drug transport in the anterior segment has been developed by using the conservation of mass in the precorneal tear film, Fick's law of diffusion and Michaelis-Menten kinetics of drug metabolism in cornea, and the conservation of mass in the anterior chamber. An analytical solution describing the drug concentration in the anterior chamber has been obtained. The model predicts that an increase in the drug metabolic (consumption) rate in the corneal epithelium reduces the drug concentration in the anterior chamber for both lipophilic and hydrophilic molecules. A decrease in the clearance rate and distribution volume of the drug in the anterior chamber raises the aqueous humor concentration significantly. It is also observed that decay rate of drug concentration in the anterior chamber is higher for lipophilic molecules than that for hydrophilic molecules. The bioavailability of drugs applied topically to the eye may be improved by a rise in the precorneal tear volume, diffusion coefficient in corneal epithelium and distribution coefficient across the endothelium anterior chamber interface, and by reducing the drug metabolism, drug clearance rate and distribution volume in anterior chamber.

  4. Computational modeling of drug transport across the in vitro cornea.

    Science.gov (United States)

    Pak, Joseph; Chen, Z J; Sun, Kay; Przekwas, Andrzej; Walenga, Ross; Fan, Jianghong

    2018-01-01

    A novel quasi-3D (Q3D) modeling approach was developed to model networks of one dimensional structures like tubes and vessels common in human anatomy such as vascular and lymphatic systems, neural networks, and respiratory airways. Instead of a branching network of the same tissue type, this approach was extended to model an interconnected stack of different corneal tissue layers with membrane junction conditions assigned between the tissues. The multi-laminate structure of the cornea presents a unique barrier design and opportunity for investigation using Q3D modeling. A Q3D model of an in vitro rabbit cornea was created to simulate the drug transport across the cornea, accounting for transcellular and paracellular pathways of passive and convective drug transport as well as physicochemistry of lipophilic partitioning and protein binding. Lipophilic Rhodamine B and hydrophilic fluorescein were used as drug analogs. The model predictions for both hydrophilic and lipophilic tracers were able to match the experimental measurements along with the sharp discontinuities at the epithelium-stroma and stroma-endothelium interfaces. This new modeling approach was successfully applied towards pharmacokinetic modeling for use in topical ophthalmic drug design. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Formas farmacêuticas de liberação modificada: polímeros hidrifílicos Modified release of drug delivery systems: hydrophilic polymers

    Directory of Open Access Journals (Sweden)

    Carla Martins Lopes

    2005-06-01

    Full Text Available Os sistemas de liberação de fármacos são parte integrante da investigação farmacêutica. A maioria dos sistemas de liberação oral de fármacos é baseada em matrizes poliméricas. Nas duas décadas passadas, as matrizes hidrofílicas tornaram-se muito populares na formulação de formas farmacêuticas de liberação modificada. A escolha do polímero hidrofílico na formulação da matriz pode fornecer uma combinação apropriada dos mecanismos de intumescimento, de dissolução ou de erosão e determinam a cinética de liberação in vitro. As matrizes de intumescimento são sistemas monolíticos preparados pela compressão de mistura de um polímero hidrofílico e de um fármaco. Elas representam sistemas da liberação em que os vários mecanismos podem ser adaptados ao programa de liberação. O sucesso desses sistemas está relacionado com a tecnologia de fabricação e com as características físicas e físico-químicas do polímero, responsáveis pelo mecanismo de liberação.Drug delivery systems (DDS became an integral part of pharmaceutical research. The majority of oral DDS are matrix-based systems. Hydrophilic matrices for the past two decades have been popular in the formulation of controlled release solid dosage forms. Swellable matrices are monolithic systems prepared by compression of a powdered mixture of a hydrophilic polymer and a drug. They represent a delivery system in which various mechanisms can be adapted to the delivery program. Their success is linked to the established tabletting technology of manufacture. The choice of the hydrophilic polymer in the matrix formulation can provide an appropriate combination of swelling, dissolution or erosion mechanisms to evaluate in vitro release kinetics.

  6. SC lipid model membranes designed for studying impact of ceramide species on drug diffusion and permeation--part II: diffusion and permeation of model drugs.

    Science.gov (United States)

    Ochalek, M; Podhaisky, H; Ruettinger, H-H; Wohlrab, J; Neubert, R H H

    2012-10-01

    The barrier function of two quaternary stratum corneum (SC) lipid model membranes, which were previously characterized with regard to the lipid organization, was investigated based on diffusion studies of model drugs with varying lipophilicities. Diffusion experiments of a hydrophilic drug, urea, and more lipophilic drugs than urea (i.e. caffeine, diclofenac sodium) were conducted using Franz-type diffusion cells. The amount of permeated drug was analyzed using either HPLC or CE technique. The subjects of interest in the present study were the investigation of the influence of physicochemical properties of model drugs on their diffusion and permeation through SC lipid model membranes, as well as the study of the impact of the constituents of these artificial systems (particularly ceramide species) on their barrier properties. The diffusion through both SC lipid model membranes and the human SC of the most hydrophilic model drug, urea, was faster than the permeation of the more lipophilic drugs. The slowest rate of permeation through SC lipid systems occurred in the case of caffeine. The composition of SC lipid model membranes has a significant impact on their barrier function. Model drugs diffused and permeated faster through Membrane II (presence of Cer [EOS]). In terms of the barrier properties, Membrane II is much more similar to the human SC than Membrane I. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Modelling of Hydrophilic Interaction Liquid Chromatography Stationary Phases Using Chemometric Approaches

    Science.gov (United States)

    Ortiz-Villanueva, Elena; Tauler, Romà

    2017-01-01

    Metabolomics is a powerful and widely used approach that aims to screen endogenous small molecules (metabolites) of different families present in biological samples. The large variety of compounds to be determined and their wide diversity of physical and chemical properties have promoted the development of different types of hydrophilic interaction liquid chromatography (HILIC) stationary phases. However, the selection of the most suitable HILIC stationary phase is not straightforward. In this work, four different HILIC stationary phases have been compared to evaluate their potential application for the analysis of a complex mixture of metabolites, a situation similar to that found in non-targeted metabolomics studies. The obtained chromatographic data were analyzed by different chemometric methods to explore the behavior of the considered stationary phases. ANOVA-simultaneous component analysis (ASCA), principal component analysis (PCA) and partial least squares regression (PLS) were used to explore the experimental factors affecting the stationary phase performance, the main similarities and differences among chromatographic conditions used (stationary phase and pH) and the molecular descriptors most useful to understand the behavior of each stationary phase. PMID:29064436

  8. Strategies for encapsulation of small hydrophilic and amphiphilic drugs in PLGA microspheres: State-of-the-art and challenges

    NARCIS (Netherlands)

    Ramazani, F.; Chen, Weiluan; van Nostrum, C.F.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria; Hennink, W.E.; Kok, R.J.

    2016-01-01

    Poly(lactide-co-glycolide) (PLGA) microspheres are efficient delivery systems for controlled release of low molecular weight drugs as well as therapeutic macromolecules. The most common microencapsulation methods are based on emulsification procedures, in which emulsified droplets of polymer and

  9. On-line solid-phase extraction coupled to hydrophilic interaction chromatography-mass spectrometry for the determination of polar drugs.

    Science.gov (United States)

    Fontanals, Núria; Marcé, Rosa M; Borrull, Francesc

    2011-09-02

    The present study describes the first fully automated method based on on-line solid-phase extraction (SPE) coupled to hydrophilic interaction chromatography-electrospray-mass spectrometry (HILIC-(ESI)MS) to determine a group of polar drugs that includes illicit drugs (such as cocaine, morphine, codeine and metabolites) and pharmaceuticals in environmental water samples. The SPE was performed using a highly retentive polymeric sorbent. The HILIC separation was optimised and the initial high organic content of the chromatographic mobile phase, was also suitable for the proper on-line elution of the analytes retained in the SPE column and for enhancing the ESI ionisation efficiency. This method allows the loading of samples of up to 250ml of ultrapure water or 10ml of environmental water samples spiked at low ngl(-1) levels of the analytes. The method yields near 100% recoveries for all the analytes. The method was also validated with environmental water samples with linear ranges from 5 to 1000ngl(-1) and limits of detection ≤2ngl(-1) for most of the compounds. Copyright © 2010 Elsevier B.V. All rights reserved.

  10. Comparison of isocratic retention models for hydrophilic interaction liquid chromatographic separation of native and fluorescently labeled oligosaccharides.

    Science.gov (United States)

    Česla, Petr; Vaňková, Nikola; Křenková, Jana; Fischer, Jan

    2016-03-18

    In this work, we have investigated retention of maltooligosaccharides and their fluorescent derivatives in hydrophilic interaction liquid chromatography using four different stationary phases. The non-derivatized maltooligosaccharides (maltose to maltoheptaose) and their derivatives with 2-aminobenzoic acid, 2-aminobenzamide, 2-aminopyridine and 8-aminonaphthalene-1,3,6-trisulfonic acid were analyzed on silica gel, aminopropyl silica, amide (carbamoyl-bonded silica) and ZIC-HILIC zwitterionic sulfobetain bonded phase. The partitioning of the analytes between the bulk mobile phase and adsorbed water-rich layer, polar and ionic interactions of analytes with stationary phase have been evaluated and compared. The effects of the mobile phase additives (0.1% (v/v) of acetic acid and ammonium acetate in concentration range 5-30 mmol L(-1)) on retention were described. The suitability of different models for prediction of retention was tested including linear solvent strength model, quadratic model, mixed-mode model, and empirical Neue-Kuss model. The mixed-mode model was extended to the parameter describing the contribution of monomeric glucose unit to the retention of non-derivatized and derivatized maltooligosaccharides, which was used for evaluation of contribution of both, oligosaccharide backbone and end-group to retention. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. 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 water...

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

    Science.gov (United States)

    Tredenick, Eloise C; Farrell, Troy W; Forster, W Alison; Psaltis, Steven T P

    2017-01-01

    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.

  13. 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.

  14. INFLUENCE OF LIPOPHILIC AND HYDROPHILIC CO-MONOMERS ON THE HYDRODYNAMIC DIAMETER OF THERMOSENSITIVE NIPA DERIVATIVES FOR THERMALLY CONTROLLED DRUG DELIVERY.

    Science.gov (United States)

    Musial, Witold; Gasztych, Monika; Kokol, Vanja; Mucha, Igor; Makanis, Aleksandra; Kolodziejczyk, Woiciech; Gola, Agnieszka

    2017-01-01

    For modem drug delivery, new drug carriers sensitive to various factors and with size in the range of micro- and nanometers are required. The aim of this work was to evaluate the influence of hydrophilic and hydrophobic co-monomers on the hydrodynamic diameter of three co-polymers of N-isopropylacrylamide (NIPA) nanogels synthesized at 70*C in the presence of potassium persulfate (KPS) as the initiator and N.N'-methylene bis-acrylamide (MBA) as the cross-linker. The first batch of nanoparticles was synthesized without co-monomer, whereas poly(ethylene glycol) methyl ether acrylate (PEG-MEA), and N-teii-butylacrylamide (NTB), were implemented as co-monomers for the second and third batch. Hydrodynamic diameter of nanoparticles was in the range 550-800 rn. The compositions of the synthesized co-polymer nanoparticles were con- firmed via IR and NMR analyses. The SFPP conditions resulted in hydrodynamic diameters ranging from approximately 550 to 800 nm at temperatures lower than the volume phase transition temperature (VPTT) and diameters ranging from 250 to 600 nm at temperatures above the VPTT, where the VPTT was between 26 and 41'C. The polydispersity index (PDI) showed a maximum or a minimum value at the VPTT, which was an important indicator of the volume phase transition. According to the PDI observation during thermal cycling, the addition of NTB into the polymeric chain resulted in maximal values of the PDI at the VPIT, similar to the case of nanoparticles without any additional co-monomers. In contrast, in the case of PEG-MEA, the PDI presented a minimal value. Dynamic light scattering (DLS) volume measurements, performed simultaneously with spectral methods, may lead to a fast evaluation of nanoparticles prepared by SFPP.

  15. 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.

  16. Drug-model membrane interactions

    International Nuclear Information System (INIS)

    Deniz, Usha K.

    1994-01-01

    In the present day world, drugs play a very important role in medicine and it is necessary to understand their mode of action at the molecular level, in order to optimise their use. Studies of drug-biomembrane interactions are essential for gaining such as understanding. However, it would be prohibitively difficult to carry out such studies, since biomembranes are highly complex systems. Hence, model membranes (made up of these lipids which are important components of biomembranes) of varying degrees of complexity are used to investigate drug-membrane interactions. Bio- as well as model-membranes undergo a chain melting transition when heated, the chains being in a disordered state above the transition point, T CM . This transition is of physiological importance since biomembranes select their components such that T CM is less than the ambient temperature but not very much so, so that membrane flexibility is ensured and porosity, avoided. The influence of drugs on the transition gives valuable clues about various parameters such as the location of the drug in the membrane. Deep insights into drug-membrane interactions are obtained by observing the effect of drugs on membrane structure and the mobilities of the various groups in lipids, near T CM . Investigation of such changes have been carried out with several drugs, using techniques such as DSC, XRD and NMR. The results indicate that the drug-membrane interaction not only depends on the nature of drug and lipids but also on the form of the model membrane - stacked bilayer or vesicles. The light that these results shed on the nature of drug-membrane interactions is discussed. (author). 13 refs., 13 figs., 1 tab

  17. Continuum-Scale Modeling of Liquid Redistribution in a Stack of Thin Hydrophilic Fibrous Layers

    NARCIS (Netherlands)

    Tavangarrad, A.H.; Mohebbi, Behzad; Hassanizadeh, S.M.|info:eu-repo/dai/nl/074974424; Rosati, Rodrigo; Claussen, Jan; Blümich, Bernhard

    Macroscale three-dimensional modeling of fluid flow in a thin porous layer under unsaturated conditions is a challenging task. One major issue is that such layers do not satisfy the representative elementary volume length-scale requirement. Recently, a new approach, called reduced continua model

  18. Mathematical modeling of drug dissolution.

    Science.gov (United States)

    Siepmann, J; Siepmann, F

    2013-08-30

    The dissolution of a drug administered in the solid state is a pre-requisite for efficient subsequent transport within the human body. This is because only dissolved drug molecules/ions/atoms are able to diffuse, e.g. through living tissue. Thus, generally major barriers, including the mucosa of the gastro intestinal tract, can only be crossed after dissolution. Consequently, the process of dissolution is of fundamental importance for the bioavailability and, hence, therapeutic efficacy of various pharmaco-treatments. Poor aqueous solubility and/or very low dissolution rates potentially lead to insufficient availability at the site of action and, hence, failure of the treatment in vivo, despite a potentially ideal chemical structure of the drug to interact with its target site. Different physical phenomena are involved in the process of drug dissolution in an aqueous body fluid, namely the wetting of the particle's surface, breakdown of solid state bonds, solvation, diffusion through the liquid unstirred boundary layer surrounding the particle as well as convection in the surrounding bulk fluid. Appropriate mathematical equations can be used to quantify these mass transport steps, and more or less complex theories can be developed to describe the resulting drug dissolution kinetics. This article gives an overview on the current state of the art of modeling drug dissolution and points out the assumptions the different theories are based on. Various practical examples are given in order to illustrate the benefits of such models. This review is not restricted to mathematical theories considering drugs exhibiting poor aqueous solubility and/or low dissolution rates, but also addresses models quantifying drug release from controlled release dosage forms, in which the process of drug dissolution plays a major role. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. 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

    2017-09-29

    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.

  20. Sum Frequency Generation Vibrational Spectroscopy Studies on ModelPeptide Adsorption at the Hydrophobic Solid-Water and HydrophilicSolid-Water Interfaces

    Energy Technology Data Exchange (ETDEWEB)

    York, Roger L. [Univ. of California, Berkeley, CA (United States)

    2007-01-01

    Sum frequency generation (SFG) vibrational spectroscopy has been used to study the interfacial structure of several polypeptides and amino acids adsorbed to hydrophobic and hydrophilic surfaces under a variety of experimental conditions. Peptide sequence, peptide chain length, peptide hydrophobicity, peptide side-chain type, surface hydrophobicity, and solution ionic strength all affect an adsorbed peptide's interfacial structure. Herein, it is demonstrated that with the choice of simple, model peptides and amino acids, surface specific SFG vibrational spectroscopy can be a powerful tool to elucidate the interfacial structure of these adsorbates. Herein, four experiments are described. In one, a series of isosequential amphiphilic peptides are synthesized and studied when adsorbed to both hydrophobic and hydrophilic surfaces. On hydrophobic surfaces of deuterated polystyrene, it was determined that the hydrophobic part of the peptide is ordered at the solid-liquid interface, while the hydrophilic part of the peptide appears to have a random orientation at this interface. On a hydrophilic surface of silica, it was determined that an ordered peptide was only observed if a peptide had stable secondary structure in solution. In another experiment, the interfacial structure of a model amphiphilic peptide was studied as a function of the ionic strength of the solution, a parameter that could change the peptide's secondary structure in solution. It was determined that on a hydrophobic surface, the peptide's interfacial structure was independent of its structure in solution. This was in contrast to the adsorbed structure on a hydrophilic surface, where the peptide's interfacial structure showed a strong dependence on its solution secondary structure. In a third experiment, the SFG spectra of lysine and proline amino acids on both hydrophobic and hydrophilic surfaces were obtained by using a different experimental geometry that increases the SFG signal

  1. 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.

  2. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. QSAR Modeling and Prediction of Drug-Drug Interactions.

    Science.gov (United States)

    Zakharov, Alexey V; Varlamova, Ekaterina V; Lagunin, Alexey A; Dmitriev, Alexander V; Muratov, Eugene N; Fourches, Denis; Kuz'min, Victor E; Poroikov, Vladimir V; Tropsha, Alexander; Nicklaus, Marc C

    2016-02-01

    Severe adverse drug reactions (ADRs) are the fourth leading cause of fatality in the U.S. with more than 100,000 deaths per year. As up to 30% of all ADRs are believed to be caused by drug-drug interactions (DDIs), typically mediated by cytochrome P450s, possibilities to predict DDIs from existing knowledge are important. We collected data from public sources on 1485, 2628, 4371, and 27,966 possible DDIs mediated by four cytochrome P450 isoforms 1A2, 2C9, 2D6, and 3A4 for 55, 73, 94, and 237 drugs, respectively. For each of these data sets, we developed and validated QSAR models for the prediction of DDIs. As a unique feature of our approach, the interacting drug pairs were represented as binary chemical mixtures in a 1:1 ratio. We used two types of chemical descriptors: quantitative neighborhoods of atoms (QNA) and simplex descriptors. Radial basis functions with self-consistent regression (RBF-SCR) and random forest (RF) were utilized to build QSAR models predicting the likelihood of DDIs for any pair of drug molecules. Our models showed balanced accuracy of 72-79% for the external test sets with a coverage of 81.36-100% when a conservative threshold for the model's applicability domain was applied. We generated virtually all possible binary combinations of marketed drugs and employed our models to identify drug pairs predicted to be instances of DDI. More than 4500 of these predicted DDIs that were not found in our training sets were confirmed by data from the DrugBank database.

  4. High-throughput hydrophilic interaction chromatography coupled to tandem mass spectrometry for the optimized quantification of the anti-Gram-negatives antibiotic colistin A/B and its pro-drug colistimethate.

    Science.gov (United States)

    Mercier, Thomas; Tissot, Fréderic; Gardiol, Céline; Corti, Natascia; Wehrli, Stéphane; Guidi, Monia; Csajka, Chantal; Buclin, Thierry; Couet, William; Marchetti, Oscar; Decosterd, Laurent A

    2014-11-21

    Colistin is a last resort's antibacterial treatment in critically ill patients with multi-drug resistant Gram-negative infections. As appropriate colistin exposure is the key for maximizing efficacy while minimizing toxicity, individualized dosing optimization guided by therapeutic drug monitoring is a top clinical priority. Objective of the present work was to develop a rapid and robust HPLC-MS/MS assay for quantification of colistin plasma concentrations. This novel methodology validated according to international standards simultaneously quantifies the microbiologically active compounds colistin A and B, plus the pro-drug colistin methanesulfonate (colistimethate, CMS). 96-well micro-Elution SPE on Oasis Hydrophilic-Lipophilic-Balanced (HLB) followed by direct analysis by Hydrophilic Interaction Liquid Chromatography (HILIC) with Ethylene Bridged Hybrid--BEH--Amide phase column coupled to tandem mass spectrometry allows a high-throughput with no significant matrix effect. The technique is highly sensitive (limit of quantification 0.014 and 0.006 μg/mL for colistin A and B), precise (intra-/inter-assay CV 0.6-8.4%) and accurate (intra-/inter-assay deviation from nominal concentrations -4.4 to +6.3%) over the clinically relevant analytical range 0.05-20 μg/mL. Colistin A and B in plasma and whole blood samples are reliably quantified over 48 h at room temperature and at +4°C (<6% deviation from nominal values) and after three freeze-thaw cycles. Colistimethate acidic hydrolysis (1M H2SO4) to colistin A and B in plasma was completed in vitro after 15 min of sonication while the pro-drug hydrolyzed spontaneously in plasma ex vivo after 4 h at room temperature: this information is of utmost importance for interpretation of analytical results. Quantification is precise and accurate when using serum, citrated or EDTA plasma as biological matrix, while use of heparin plasma is not appropriate. This new analytical technique providing optimized quantification in real

  5. 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...

  6. Drug Policy: the "Dutch Model"

    NARCIS (Netherlands)

    van Ooijen-Houben, M.M.J.; Kleemans, E.R.

    2015-01-01

    Dutch drug policy, once considered pragmatic and lenient and rooted in a generally tolerant attitude toward drug use, has slowly but surely shifted from a primarily public health focus to an increasing focus on law enforcement. The "coffee shop" policy and the policy toward MDMA/ecstasy are

  7. Measurement and Modeling of Setschenow Constants for Selected Hydrophilic Compounds in NaCl and CaCl2 Simulated Carbon Storage Brines.

    Science.gov (United States)

    Burant, Aniela; Lowry, Gregory V; Karamalidis, Athanasios K

    2017-06-20

    Carbon capture, utilization, and storage (CCUS), a climate change mitigation strategy, along with unconventional oil and gas extraction, generates enormous volumes of produced water containing high salt concentrations and a litany of organic compounds. Understanding the aqueous solubility of organic compounds related to these operations is important for water treatment and reuse alternatives, as well as risk assessment purposes. The well-established Setschenow equation can be used to determine the effect of salts on aqueous solubility. However, there is a lack of reported Setschenow constants, especially for polar organic compounds. In this study, the Setschenow constants for selected hydrophilic organic compounds were experimentally determined, and linear free energy models for predicting the Setschenow constant of organic chemicals in concentrated brines were developed. Solid phase microextraction was employed to measure the salting-out behavior of six selected hydrophilic compounds up to 5 M NaCl and 2 M CaCl 2 and in Na-Ca-Cl brines. All compounds, which include phenol, p-cresol, hydroquinone, pyrrole, hexanoic acid, and 9-hydroxyfluorene, exhibited log-linear behavior up to these concentrations, meaning Setschenow constants previously measured at low salt concentrations can be extrapolated up to high salt concentrations for hydrophilic compounds. Setschenow constants measured in NaCl and CaCl 2 brines are additive for the compounds measured here; meaning Setschenow constants measured in single salt solutions can be used in multiple salt solutions. The hydrophilic compounds in this study were selected to elucidate differences in salting-out behavior based on their chemical structure. Using data from this study, as well as literature data, linear free energy relationships (LFERs) for prediction of NaCl, CaCl 2 , LiCl, and NaBr Setschenow constants were developed and validated. Two LFERs were improved. One LFER uses the Abraham solvation parameters, which include

  8. 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....

  9. 21 CFR 886.5925 - Soft (hydrophilic) contact lens.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Soft (hydrophilic) contact lens. 886.5925 Section 886.5925 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... against the cornea and adjacent limbal and scleral areas of the eye to correct vision conditions or act as...

  10. "Dilute-and-inject" multi-target screening assay for highly polar doping agents using hydrophilic interaction liquid chromatography high resolution/high accuracy mass spectrometry for sports drug testing.

    Science.gov (United States)

    Görgens, Christian; Guddat, Sven; Orlovius, Anne-Katrin; Sigmund, Gerd; Thomas, Andreas; Thevis, Mario; Schänzer, Wilhelm

    2015-07-01

    In the field of LC-MS, reversed phase liquid chromatography is the predominant method of choice for the separation of prohibited substances from various classes in sports drug testing. However, highly polar and charged compounds still represent a challenging task in liquid chromatography due to their difficult chromatographic behavior using reversed phase materials. A very promising approach for the separation of hydrophilic compounds is hydrophilic interaction liquid chromatography (HILIC). Despite its great potential and versatile advantages for the separation of highly polar compounds, HILIC is up to now not very common in doping analysis, although most manufacturers offer a variety of HILIC columns in their portfolio. In this study, a novel multi-target approach based on HILIC high resolution/high accuracy mass spectrometry is presented to screen for various polar stimulants, stimulant sulfo-conjugates, glycerol, AICAR, ethyl glucuronide, morphine-3-glucuronide, and myo-inositol trispyrophosphate after direct injection of diluted urine specimens. The usage of an effective online sample cleanup and a zwitterionic HILIC analytical column in combination with a new generation Hybrid Quadrupol-Orbitrap® mass spectrometer enabled the detection of highly polar analytes without any time-consuming hydrolysis or further purification steps, far below the required detection limits. The methodology was fully validated for qualitative and quantitative (AICAR, glycerol) purposes considering the parameters specificity; robustness (rRT  0.99); intra- and inter-day precision at low, medium, and high concentration levels (CV < 20%); limit of detection (stimulants and stimulant sulfo-conjugates < 10 ng/mL; norfenefrine; octopamine < 30 ng/mL; AICAR < 10 ng/mL; glycerol 100 μg/mL; ETG < 100 ng/mL); accuracy (AICAR 103.8-105.5%, glycerol 85.1-98.3% at three concentration levels) and ion suppression/enhancement effects.

  11. A "ship in a bottle" strategy to load a hydrophilic anticancer drug in porous metal organic framework nanoparticles: efficient encapsulation, matrix stabilization, and photodelivery.

    Science.gov (United States)

    di Nunzio, Maria Rosaria; Agostoni, Valentina; Cohen, Boiko; Gref, Ruxandra; Douhal, Abderrazzak

    2014-01-23

    An essential challenge in the development of nanosized metal organic framework (nanoMOF) materials in biomedicine is to develop a strategy to stabilize their supramolecular structure in biological media while being able to control drug encapsulation and release. We have developed a method to efficiently encapsulate topotecan (TPT, 1), an important cytotoxic drug, in biodegradable nanoMOFs. Once inside the pores, 1 monomers aggregate in a "ship in a bottle" fashion, thus filling practically all of the nanoMOFs' available free volume and stabilizing their crystalline supramolecular structures. Highly efficient results have been found with the human pancreatic cell line PANC1, in contrast with free 1. We also demonstrate that one- and two-photon light irradiation emerges as a highly promising strategy to promote stimuli-dependent 1 release from the nanoMOFs, hence opening new standpoints for further developments in triggered drug delivery.

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

    Science.gov (United States)

    Zhou, Hui-yun; Chen, Xi-guang

    2008-12-01

    In this study, chitosan/cellulose acetate microspheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggregated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The loading 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 different 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.

  13. 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.

  14. [A model list of high risk drugs].

    Science.gov (United States)

    Cotrina Luque, J; Guerrero Aznar, M D; Alvarez del Vayo Benito, C; Jimenez Mesa, E; Guzman Laura, K P; Fernández Fernández, L

    2013-12-01

    «High-risk drugs» are those that have a very high «risk» of causing death or serious injury if an error occurs during its use. The Institute for Safe Medication Practices (ISMP) has prepared a high-risk drugs list applicable to the general population (with no differences between the pediatric and adult population). Thus, there is a lack of information for the pediatric population. The main objective of this work is to develop a high-risk drug list adapted to the neonatal or pediatric population as a reference model for the pediatric hospital health workforce. We made a literature search in May 2012 to identify any published lists or references in relation to pediatric and/or neonatal high-risk drugs. A total of 15 studies were found, from which 9 were selected. A model list was developed mainly based on the ISMP one, adding strongly perceived pediatric risk drugs and removing those where the pediatric use was anecdotal. There is no published list that suits pediatric risk management. The list of pediatric and neonatal high-risk drugs presented here could be a «reference list of high-risk drugs » for pediatric hospitals. Using this list and training will help to prevent medication errors in each drug supply chain (prescribing, transcribing, dispensing and administration). Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  15. Context Sensitive Modeling of Cancer Drug Sensitivity.

    Directory of Open Access Journals (Sweden)

    Bo-Juen Chen

    Full Text Available Recent screening of drug sensitivity in large panels of cancer cell lines provides a valuable resource towards developing algorithms that predict drug response. Since more samples provide increased statistical power, most approaches to prediction of drug sensitivity pool multiple cancer types together without distinction. However, pan-cancer results can be misleading due to the confounding effects of tissues or cancer subtypes. On the other hand, independent analysis for each cancer-type is hampered by small sample size. To balance this trade-off, we present CHER (Contextual Heterogeneity Enabled Regression, an algorithm that builds predictive models for drug sensitivity by selecting predictive genomic features and deciding which ones should-and should not-be shared across different cancers, tissues and drugs. CHER provides significantly more accurate models of drug sensitivity than comparable elastic-net-based models. Moreover, CHER provides better insight into the underlying biological processes by finding a sparse set of shared and type-specific genomic features.

  16. Modelling drug flux through microporated skin.

    Science.gov (United States)

    Rzhevskiy, Alexey S; Guy, Richard H; Anissimov, Yuri G

    2016-11-10

    A simple mathematical equation has been developed to predict drug flux through microporated skin. The theoretical model is based on an approach applied previously to water evaporation through leaf stomata. Pore density, pore radius and drug molecular weight are key model parameters. The predictions of the model were compared with results derived from a simple, intuitive method using porated area alone to estimate the flux enhancement. It is shown that the new approach predicts significantly higher fluxes than the intuitive analysis, with transport being proportional to the total pore perimeter rather than area as intuitively anticipated. Predicted fluxes were in good general agreement with experimental data on drug delivery from the literature, and were quantitatively closer to the measured values than those derived from the intuitive, area-based approach. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Multiscale modeling of transdermal drug delivery

    Science.gov (United States)

    Rim, Jee Eun

    2006-04-01

    This study addresses the modeling of transdermal diffusion of drugs, to better understand the permeation of molecules through the skin, and especially the stratum corneum, which forms the main permeation barrier of the skin. In transdermal delivery of systemic drugs, the drugs diffuse from a patch placed on the skin through the epidermis to the underlying blood vessels. The epidermis is the outermost layer of the skin and can be further divided into the stratum corneum (SC) and the viable epidermis layers. The SC consists of keratinous cells (corneocytes) embedded in the lipid multi-bilayers of the intercellular space. It is widely accepted that the barrier properties of the skin mostly arises from the ordered structure of the lipid bilayers. The diffusion path, at least for lipophilic molecules, seems to be mainly through the lipid bilayers. Despite the advantages of transdermal drug delivery compared to other drug delivery routes such as oral dosing and injections, the low percutaneous permeability of most compounds is a major difficulty in the wide application of transdermal drug delivery. In fact, many transdermal drug formulations include one or more permeation enhancers that increase the permeation of the drug significantly. During the last two decades, many researchers have studied percutaneous absorption of drugs both experimentally and theoretically. However, many are based on pharmacokinetic compartmental models, in which steady or pseudo-steady state conditions are assumed, with constant diffusivity and partitioning for single component systems. This study presents a framework for studying the multi-component diffusion of drugs coupled with enhancers through the skin by considering the microstructure of the stratum corneum (SC). A multiscale framework of modeling the transdermal diffusion of molecules is presented, by first calculating the microscopic diffusion coefficient in the lipid bilayers of the SC using molecular dynamics (MD). Then a

  18. Animal Migraine Models for Drug Development

    DEFF Research Database (Denmark)

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

    2013-01-01

    Migraine is number seven in WHO's list of all diseases causing disability and the third most costly neurological disorder in Europe. Acute attacks are treatable by highly selective drugs such as the triptans but there is still a huge unmet therapeutic need. Unfortunately, drug development...... 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...... responses elicited by such measures are crucial. The most naturalistic way of inducing attacks is by infusion of endogenous signaling molecules that are known to cause migraine in patients. The most valid response is recording of neural activity in the trigeminal system. The most useful headache related...

  19. The effect of charged groups on hydrophilic monolithic stationary phases on their chromatographic properties.

    Science.gov (United States)

    Li, Haibin; Liu, Chusheng; Wang, Qiqin; Zhou, Haibo; Jiang, Zhengjin

    2016-10-21

    In order to investigate the effect of charged groups present in hydrophilic monolithic stationary phases on their chromatographic properties, three charged hydrophilic monomers, i.e. N,N-dimethyl-N-acryloyloxyethyl-N-(3-sulfopropyl)ammonium betaine (SPDA), [2-(acryloyloxy)ethyl]trimethylammonium chloride (AETA), and 3-sulfopropyl acrylate potassium salt (SPA) were co-polymerized with the crosslinker N,N'-methylenebisacrylamide (MBA), respectively. The physicochemical properties of the three resulting charged hydrophilic monolithic columns were evaluated using scanning electron microscopy, ζ-potential analysis and micro-HPLC. High column efficiency was obtained on the three monolithic columns at a linear velocity of 1mm/s using thiourea as test compound. Comparative characterization of the three charged HILIC phases was then carried out using a set of model compounds, including nucleobases, nucleosides, benzoic acid derivatives, phenols, β-blockers and small peptides. Depending on the combination of stationary phase/mobile phase/solute, both hydrophilic interaction and other potential secondary interactions, including electrostatic interaction, hydrogen-bonding interaction, molecular shape selectivity, could contribute to the over-all retention of the analytes. Because of the strong electrostatic interaction provided by the quaternary ammonium groups in the poly (AETA-co-MBA) monolith, this cationic HILIC monolith exhibited the strongest retention for benzoic acid derivatives and small peptides with distorted peak shapes and the weakest retention for basic β-blockers. The sulfonyl groups on the poly (SPA-co-MBA) hydrophilic monolith could provide strong electrostatic attraction and hydrogen bonding for positively charged analytes and hydrogen-donor/acceptor containing analytes, respectively. Therefore, basic drugs, nucleobases and nucleotides exhibited the strongest retention on this anionic monolith. Because of the weak but distinct cation exchange properties of

  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. Modeling chemical reactions for drug design.

    Science.gov (United States)

    Gasteiger, Johann

    2007-01-01

    Chemical reactions are involved at many stages of the drug design process. This starts with the analysis of biochemical pathways that are controlled by enzymes that might be downregulated in certain diseases. In the lead discovery and lead optimization process compounds have to be synthesized in order to test them for their biological activity. And finally, the metabolism of a drug has to be established. A better understanding of chemical reactions could strongly help in making the drug design process more efficient. We have developed methods for quantifying the concepts an organic chemist is using in rationalizing reaction mechanisms. These methods allow a comprehensive modeling of chemical reactivity and thus are applicable to a wide variety of chemical reactions, from gas phase reactions to biochemical pathways. They are empirical in nature and therefore allow the rapid processing of large sets of structures and reactions. We will show here how methods have been developed for the prediction of acidity values and of the regioselectivity in organic reactions, for designing the synthesis of organic molecules and of combinatorial libraries, and for furthering our understanding of enzyme-catalyzed reactions and of the metabolism of drugs.

  2. 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.

  3. 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)

  4. [Preparation of hydrophilic matrix sustained release tablets of total lactones from Andrographis paniculata and study on its in vitro release mechanism].

    Science.gov (United States)

    Xu, Fang-Fang; Shi, Wei; Zhang, Hui; Guo, Qing-Ming; Wang Zhen-Zhong; Bi, Yu-An; Wang, Zhi-Min; Xiao, Wei

    2015-01-01

    In this study, hydrophilic matrix sustained release tablets of total lactones from Andrographis paniculata were prepared and the in vitro release behavior were also evaluated. The optimal prescription was achieved by studying the main factor of the type and amount of hydroxypropyl methylcellulose (HPMC) using single factor test and evaluating through cumulative release of three lactones. No burst drug release from the obtained matrix tablets was observed. Drug release sustained to 14 h. The release mechanism of three lactones from A. paniculata was accessed by zero-order, first-order, Higuchi and Peppas equation. The release behavior of total lactones from A. paniculata was better agreed with Higuchi model and the drug release from the tablets was controlled by degradation of the matrix. The preparation of hydrophilic matrix sustained release tablets of total lactones from A. paniculata with good performance of drug release was simple.

  5. 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.

  6. Challenges in modelling nanoparticles for drug delivery

    International Nuclear Information System (INIS)

    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. (topical review)

  7. Investigating drug repositioning opportunities in FDA drug labels through topic modeling.

    Science.gov (United States)

    Bisgin, Halil; Liu, Zhichao; Kelly, Reagan; Fang, Hong; Xu, Xiaowei; Tong, Weida

    2012-01-01

    Drug repositioning offers an opportunity to revitalize the slowing drug discovery pipeline by finding new uses for currently existing drugs. Our hypothesis is that drugs sharing similar side effect profiles are likely to be effective for the same disease, and thus repositioning opportunities can be identified by finding drug pairs with similar side effects documented in U.S. Food and Drug Administration (FDA) approved drug labels. The safety information in the drug labels is usually obtained in the clinical trial and augmented with the observations in the post-market use of the drug. Therefore, our drug repositioning approach can take the advantage of more comprehensive safety information comparing with conventional de novo approach. A probabilistic topic model was constructed based on the terms in the Medical Dictionary for Regulatory Activities (MedDRA) that appeared in the Boxed Warning, Warnings and Precautions, and Adverse Reactions sections of the labels of 870 drugs. Fifty-two unique topics, each containing a set of terms, were identified by using topic modeling. The resulting probabilistic topic associations were used to measure the distance (similarity) between drugs. The success of the proposed model was evaluated by comparing a drug and its nearest neighbor (i.e., a drug pair) for common indications found in the Indications and Usage Section of the drug labels. Given a drug with more than three indications, the model yielded a 75% recall, meaning 75% of drug pairs shared one or more common indications. This is significantly higher than the 22% recall rate achieved by random selection. Additionally, the recall rate grows rapidly as the number of drug indications increases and reaches 84% for drugs with 11 indications. The analysis also demonstrated that 65 drugs with a Boxed Warning, which indicates significant risk of serious and possibly life-threatening adverse effects, might be replaced with safer alternatives that do not have a Boxed Warning. In

  8. Preclinical experimental models of drug metabolism and disposition in drug discovery and development

    Directory of Open Access Journals (Sweden)

    Donglu Zhang

    2012-12-01

    Full Text Available Drug discovery and development involve the utilization of in vitro and in vivo experimental models. Different models, ranging from test tube experiments to cell cultures, animals, healthy human subjects, and even small numbers of patients that are involved in clinical trials, are used at different stages of drug discovery and development for determination of efficacy and safety. The proper selection and applications of correct models, as well as appropriate data interpretation, are critically important in decision making and successful advancement of drug candidates. In this review, we discuss strategies in the applications of both in vitro and in vivo experimental models of drug metabolism and disposition.

  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 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.

  11. 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

  12. Oleic acid and docosahexaenoic acid cause an increase in the paracellular absorption of hydrophilic compounds in an experimental model of human absorptive enterocytes

    International Nuclear Information System (INIS)

    Aspenstroem-Fagerlund, Bitte; Ring, Linda; Aspenstroem, Pontus; Tallkvist, Jonas; Ilbaeck, Nils-Gunnar; Glynn, Anders W.

    2007-01-01

    Surface active compounds present in food possibly have the ability to enhance the absorption of water soluble toxic agents. Therefore, we investigated whether fatty acids such as oleic acid and docosahexaenoic acid (DHA), both commonly present in food, negatively affect the integrity of tight junctions (TJ) in the intestinal epithelium and thereby increase the absorption of poorly absorbed hydrophilic substances. Caco-2 cells, which are derived from human absorptive enterocytes, were grown on permeable filters for 20-25 days. Differentiated cell monolayers were apically exposed for 90 min to mannitol in emulsions of oleic acid (5, 15 or 30 mM) or DHA (5, 15 or 30 mM) in an experimental medium with or without Ca 2+ and Mg 2+ . Absorption of 14 C-mannitol increased and trans-epithelial electrical resistance (TEER) decreased in cell monolayers exposed to oleic acid and DHA, compared to controls. Cytotoxicity, measured as leakage of LDH, was higher in groups exposed to 30 mM oleic acid and all concentrations of DHA. Morphology of the cell monolayers was studied by using fluorescence microscopy. Exposure of cell monolayers to 5 mM DHA for 90 min resulted in a profound alteration of the cell-cell contacts as detected by staining the cells for β-catenin. Oleic acid (30 mM) treatment also induced dissolution of the cell-cell contacts but the effect was not as pronounced as with DHA. Cell monolayers were also exposed for 180 min to 250 nM cadmium (Cd) in emulsions of oleic acid (5 or 30 mM) or DHA (1 or 5 mM), in an experimental medium with Ca 2+ and Mg 2+ . Retention of Cd in Caco-2 cells was higher after exposure to 5 mM oleic acid but lower after exposure to 30 mM oleic acid and DHA. Absorption of Cd through the monolayers increased after DHA exposure but not after exposure to oleic acid. Our results indicate that fatty acids may compromise the integrity of the intestinal epithelium and that certain lipids in food may enhance the paracellular absorption of poorly

  13. Application of Model Animals in the Study of Drug Toxicology

    Science.gov (United States)

    Song, Yagang; Miao, Mingsan

    2018-01-01

    Drug safety is a key factor in drug research and development, Drug toxicology test is the main method to evaluate the safety of drugs, The body condition of an animal has important implications for the results of the study, Previous toxicological studies of drugs were carried out in normal animals in the past, There is a great deviation from the clinical practice.The purpose of this study is to investigate the necessity of model animals as a substitute for normal animals for toxicological studies, It is expected to provide exact guidance for future drug safety evaluation.

  14. Nanocapsule@xerogel microparticles containing sodium diclofenac: a new strategy to control the release of drugs.

    Science.gov (United States)

    da Fonseca, Letícia Sias; Silveira, Rodrigo Paulo; Deboni, Alberto Marçal; Benvenutti, Edilson Valmir; Costa, Tânia M H; Guterres, Sílvia S; Pohlmann, Adriana R

    2008-06-24

    The aim of this work was to evaluate the potentiality to control the drug release of a new architecture of microparticles organized at the nanoscopic scale by assembling polymeric nanocapsules at the surface of drug-loaded xerogels. Xerogel was prepared by sol-gel method using sodium diclofenac, as hydrophilic drug model, and coated by spray-drying. After coating, the surface areas decreased from 82 to 28 m(2)/g, the encapsulation efficiency was 71% and SEM analysis showed irregular microparticles coated by the nanocapsules. Formulation showed satisfactory gastro-resistance presenting drug release lower than 3% (60 min) in acid medium. In water, the pure drug dissolved 92% after 5 min, uncoated drug-loaded xerogel released 60% and nanocapsule coated drug-loaded xerogel 36%. After 60 min, uncoated drug-loaded xerogel released 82% and nanocapsule coated drug-loaded xerogel 62%. In conclusion, the new system was able to control the release of the hydrophilic drug model.

  15. 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.

  16. Lathe-cut hydrophilic contact lenses: report of 100 clinical cases.

    Science.gov (United States)

    Espy, J W

    1978-10-01

    In a review of the literature, it became apparent that there were very few articles describing the advantages, as well as the fitting techniques, of lathe-cut hydrophilic contact lenses. Few practitioners, including those who fit other types of hydrophilic lenses and hard lenses, have had any experience with this lens, and considerable interest has been generated by fragmentary reports of good results. This paper describes in detail the geometry of the first lathe-cut hydrophilic lens approved by the Federal Drug Administration, the fitting methods utilizing trial lenses, and the results of 100 patients successfully fitted.

  17. [Caffeine: traditional and new therapeutic indications and use as a dermatological model drug].

    Science.gov (United States)

    Bors, Luca; Bajza, Ágnes; Kocsis, Dorottya; Erdő, Franciska

    2018-03-01

    Coffee consumption had already been described in the 15th century. The spreading of coffee drinking was not only a consequence of its delicious aromatic taste, but also of its pharmacological effects, especially due to its caffeine content. In this review, the mechanisms behind its complex stimulatory effects and the latest studies on the possible new therapeutic indications of caffeine are summarized. Several papers reported the neuroprotective (in Alzheimer's and Parkinson's disease) and hepatoprotective profiles of caffeine, and we show the most promising new results about its preventive properties in dermal malignancies. These findings were described both in cell cultures and in vivo. The application of caffeine and coffee in cosmetology and dermatological products is based on their antioxidant property and on the above-mentioned beneficial effects. Caffeine is also presented here as a dermatological model drug due to its hydrophilic profile. It can be used for designing and comparing different novel drug formulations, although beside the transcellular route, the follicular and transappendageal pathways play also important roles in its skin penetration. Taken together, caffeine molecule has many recently discovered beneficial pharmacological effects, but one should be careful with its excessive consumption. It can result in several adverse events if overdosed and in case of regular intake of high doses, after abandonment, withdrawal symptoms may appear. Orv Hetil. 2018; 159(10): 384-390.

  18. Modeling the modified drug release from curved shape drug delivery systems - Dome Matrix®.

    Science.gov (United States)

    Caccavo, D; Barba, A A; d'Amore, M; De Piano, R; Lamberti, G; Rossi, A; Colombo, P

    2017-12-01

    The controlled drug release from hydrogel-based drug delivery systems is a topic of large interest for research in pharmacology. The mathematical modeling of the behavior of these systems is a tool of emerging relevance, since the simulations can be of use in the design of novel systems, in particular for complex shaped tablets. In this work a model, previously developed, was applied to complex-shaped oral drug delivery systems based on hydrogels (Dome Matrix®). Furthermore, the model was successfully adopted in the description of drug release from partially accessible Dome Matrix® systems (systems with some surfaces coated). In these simulations, the erosion rate was used asa fitting parameter, and its dependence upon the surface area/volume ratio and upon the local fluid dynamics was discussed. The model parameters were determined by comparison with the drug release profile from a cylindrical tablet, then the model was successfully used for the prediction of the drug release from a Dome Matrix® system, for simple module configuration and for module assembled (void and piled) configurations. It was also demonstrated that, given the same initial S/V ratio, the drug release is independent upon the shape of the tablets but it is only influenced by the S/V evolution. The model reveals itself able to describe the observed phenomena, and thus it can be of use for the design of oral drug delivery systems, even if complex shaped. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Cell physiology based pharmacodynamic modeling of antimicrobial drug combinations

    OpenAIRE

    Hethey, Christoph Philipp

    2017-01-01

    Mathematical models of bacterial growth have been successfully applied to study the relationship between antibiotic drug exposure and the antibacterial effect. Since these models typically lack a representation of cellular processes and cell physiology, the mechanistic integration of drug action is not possible on the cellular level. The cellular mechanisms of drug action, however, are particularly relevant for the prediction, analysis and understanding of interactions between antibiotics. In...

  20. A Structural Model of the Retail Market for Illicit Drugs.

    Science.gov (United States)

    Galenianos, Manolis; Gavazza, Alessandro

    2017-03-01

    We estimate a model of illicit drugs markets using data on purchases of crack cocaine. Buyers are searching for high-quality drugs, but they determine drugs' quality (i.e., their purity) only after consuming them. Hence, sellers can rip off first-time buyers or can offer higher-quality drugs to induce buyers to purchase from them again. In equilibrium, a distribution of qualities persists. The estimated model implies that if drugs were legalized, in which case purity could be regulated and hence observable, the average purity of drugs would increase by approximately 20 percent and the dispersion would decrease by approximately 80 percent. Moreover, increasing penalties may raise the purity and affordability of the drugs traded by increasing sellers’ relative profitability of targeting loyal buyers versus first-time buyers.

  1. The Food and Drug Administration and Drug Legalization: A Brief Model of Regulation

    OpenAIRE

    Kalam, Murad

    2002-01-01

    This paper offers a brief model of FDA regulation of currently illegal narcotics in the United States. Given that nearly three out of four Americans believe that the drug war has failed, recent calls from prominent liberal and conservative thinkers to legalize drugs, and state “compassionate use†ballot initiatives, future drug legalization is at least conceivable in the United States. Yet, how would the FDA regulate NLD’s under its current st...

  2. Hydrophilic and lipophilic radiopharmaceuticals as tracers in pharmaceutical development: In vitro – In vivo studies

    International Nuclear Information System (INIS)

    Terán, Mariella; Savio, Eduardo; Paolino, Andrea; Frier, Malcolm

    2005-01-01

    Scintigraphic studies have been performed to assess the release, both in vitro and in vivo, of radiotracers from tablet formulations. Four different tracers with differing physicochemical characteristics have been evaluated to assess their suitability as models for drug delivery. In-vitro disintegration and dissolution studies have been performed at pH 1, 4 and 7. In-vivo studies have been performed by scintigraphic imaging in healthy volunteers. Two hydrophilic tracers, ( 99m Tc-DTPA) and ( 99m Tc-MDP), and two lipophilic tracers, ( 99m Tc-ECD) and ( 99m Tc-MIBI), were used as drug models. Dissolution and disintegration profiles, differed depending on the drug model chosen. In vitro dissolution velocity constants indicated a probable retention of the radiotracer in the formulation. In vivo disintegration velocity constants showed important variability for each radiopharmaceutical. Pearson statistical test showed no correlation between in vitro drug release, and in vivo behaviour, for 99m Tc-DTPA, 99m Tc-ECD and 99m Tc-MIBI. High correlation coefficients were found for 99m Tc-MDP not only for in vitro dissolution and disintegration studies but also for in vivo scintigraphic studies. Scintigraphic studies have made a significant contribution to the development of drug delivery systems. It is essential, however, to choose the appropriate radiotracers as models of drug behaviour. This study has demonstrated significant differences in release patterns, depending on the model chosen. It is likely that each formulation would require the development of a specific model, rather than being able to use a generic drug model on the basis of its physicochemical characteristics

  3. 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

  4. [Semisynthetic cellulose derivatives as the base of hydrophilic gel systems].

    Science.gov (United States)

    Bajerová, M; Gajdziok, J; Dvorácková, K; Masteiková, R; Kollár, P

    2008-04-01

    The field of drug technology widely ulilizes gel systems of high-molecular substances, which have a number of advantages, such as low toxicity, availability, unique physical properties, biocompatibility, mucoadhesivity, and others. Gel systems are used in the field of local as well as general therapy, in both shape-specific and shape-non-specific dosage forms, in medicaments of the first, second, and third generations. An important group of gels employed in pharmacy are hydrophilic gels or hydrogels, most frequently composed of hydrophilic polymers of natural, semisynthetic and synthetic origin. Though cellulose derivatives as the representatives of polymers of semisynthetic origin are used in pharmaceutical technology for a long time, their research continues and their other possible uses are being searched for. Their advantages include especially safety, easy availability, and a relatively low price. The review paper describes selected cellulose derivatives, their properties and uses in pharmaceutical technology with regard to their use in the field of production of gel systems.

  5. Modeling Drug-Carrier Interaction in the Drug Release from Nanocarriers

    Directory of Open Access Journals (Sweden)

    Like Zeng

    2011-01-01

    Full Text Available Numerous nanocarriers of various compositions and geometries have been developed for the delivery and release of therapeutic and imaging agents. Due to the high specific surface areas of nanocarriers, different mechanisms such as ion pairing and hydrophobic interaction need to be explored for achieving sustained release. Recently, we developed a three-parameter model that considers reversible drug-carrier interaction and first-order drug release from liposomes. A closed-form analytical solution was obtained. Here, we further explore the ability of the model to capture the release of bioactive molecules such as drugs and growth factors from various nanocarriers. A parameter study demonstrates that the model is capable of resembling major categories of drug release kinetics. We further fit the model to 60 sets of experimental data from various drug release systems, including nanoparticles, hollow particles, fibers, and hollow fibers. Additionally, bootstrapping is used to evaluate the accuracy of parameter determination and validate the model in selected cases. The simplicity and universality of the model and the clear physical meanings of each model parameter render the model useful for the design and development of new drug delivery systems.

  6. Mathematical modeling for novel cancer drug discovery and development.

    Science.gov (United States)

    Zhang, Ping; Brusic, Vladimir

    2014-10-01

    Mathematical modeling enables: the in silico classification of cancers, the prediction of disease outcomes, optimization of therapy, identification of promising drug targets and prediction of resistance to anticancer drugs. In silico pre-screened drug targets can be validated by a small number of carefully selected experiments. This review discusses the basics of mathematical modeling in cancer drug discovery and development. The topics include in silico discovery of novel molecular drug targets, optimization of immunotherapies, personalized medicine and guiding preclinical and clinical trials. Breast cancer has been used to demonstrate the applications of mathematical modeling in cancer diagnostics, the identification of high-risk population, cancer screening strategies, prediction of tumor growth and guiding cancer treatment. Mathematical models are the key components of the toolkit used in the fight against cancer. The combinatorial complexity of new drugs discovery is enormous, making systematic drug discovery, by experimentation, alone difficult if not impossible. The biggest challenges include seamless integration of growing data, information and knowledge, and making them available for a multiplicity of analyses. Mathematical models are essential for bringing cancer drug discovery into the era of Omics, Big Data and personalized medicine.

  7. In silico modeling to predict drug-induced phospholipidosis

    International Nuclear Information System (INIS)

    Choi, Sydney S.; Kim, Jae S.; Valerio, Luis G.; Sadrieh, Nakissa

    2013-01-01

    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

  8. 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

  9. Prediction of adverse drug reactions using decision tree modeling.

    Science.gov (United States)

    Hammann, F; Gutmann, H; Vogt, N; Helma, C; Drewe, J

    2010-07-01

    Drug safety is of great importance to public health. The detrimental effects of drugs not only limit their application but also cause suffering in individual patients and evoke distrust of pharmacotherapy. For the purpose of identifying drugs that could be suspected of causing adverse reactions, we present a structure-activity relationship analysis of adverse drug reactions (ADRs) in the central nervous system (CNS), liver, and kidney, and also of allergic reactions, for a broad variety of drugs (n = 507) from the Swiss drug registry. Using decision tree induction, a machine learning method, we determined the chemical, physical, and structural properties of compounds that predispose them to causing ADRs. The models had high predictive accuracies (78.9-90.2%) for allergic, renal, CNS, and hepatic ADRs. We show the feasibility of predicting complex end-organ effects using simple models that involve no expensive computations and that can be used (i) in the selection of the compound during the drug discovery stage, (ii) to understand how drugs interact with the target organ systems, and (iii) for generating alerts in postmarketing drug surveillance and pharmacovigilance.

  10. Drug-induced cholestasis: mechanisms, models, and markers.

    Science.gov (United States)

    Chatterjee, Sagnik; Annaert, Pieter

    2018-04-27

    Drug-induced cholestasis is a risk factor in progression of drug candidates, and poses serious health hazard if not detected before going into human. Intrahepatic accumulation of bile acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. The major challenges in obtaining a complete understanding of drug-induced cholestasis lies in the complexity of BA-mediated toxicity mechanisms and the impact of bile acids at different 'targets' such as transporters, enzymes and nuclear receptors. At the same time, it is not trivial to have a relevant in vitro system that recapitulates these features. In addition, lack of sensitive and early preclinical biomarkers, relevant to the clinical situation, complicates proper detection of drug-induced cholestasis. Significant overlap in biomarker signatures between different mechanisms of drug-induced liver injury (DILI) precludes identification of specific mechanisms. Over the last decade the knowledge gaps in drug-induced cholestasis are closing due to growing mechanistic understanding of BA-mediated toxicity at (patho)physiologically relevant BA concentrations. Significant progress has been made in the mechanistic understanding of drug-induced cholestasis and associated toxicity, biomarkers and susceptibility factors. In addition, novel in vitro models are evolving which provide a holistic understanding of processes underlying drug-induced cholestasis. This review summarizes the challenges and recent understandings about drug-induced cholestasis with a potential path forward. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Mathematical modeling and computational prediction of cancer drug resistance.

    Science.gov (United States)

    Sun, Xiaoqiang; Hu, Bin

    2017-06-23

    Diverse forms of resistance to anticancer drugs can lead to the failure of chemotherapy. Drug resistance is one of the most intractable issues for successfully treating cancer in current clinical practice. Effective clinical approaches that could counter drug resistance by restoring the sensitivity of tumors to the targeted agents are urgently needed. As numerous experimental results on resistance mechanisms have been obtained and a mass of high-throughput data has been accumulated, mathematical modeling and computational predictions using systematic and quantitative approaches have become increasingly important, as they can potentially provide deeper insights into resistance mechanisms, generate novel hypotheses or suggest promising treatment strategies for future testing. In this review, we first briefly summarize the current progress of experimentally revealed resistance mechanisms of targeted therapy, including genetic mechanisms, epigenetic mechanisms, posttranslational mechanisms, cellular mechanisms, microenvironmental mechanisms and pharmacokinetic mechanisms. Subsequently, we list several currently available databases and Web-based tools related to drug sensitivity and resistance. Then, we focus primarily on introducing some state-of-the-art computational methods used in drug resistance studies, including mechanism-based mathematical modeling approaches (e.g. molecular dynamics simulation, kinetic model of molecular networks, ordinary differential equation model of cellular dynamics, stochastic model, partial differential equation model, agent-based model, pharmacokinetic-pharmacodynamic model, etc.) and data-driven prediction methods (e.g. omics data-based conventional screening approach for node biomarkers, static network approach for edge biomarkers and module biomarkers, dynamic network approach for dynamic network biomarkers and dynamic module network biomarkers, etc.). Finally, we discuss several further questions and future directions for the use of

  12. Conductive polymer nanotube patch for fast and controlled ex vivo transdermal drug delivery.

    Science.gov (United States)

    Nguyen, Thao M; Lee, Sebin; Lee, Sang Bok

    2014-10-01

    To uptake and release hydrophilic model drugs and insulin in a novel conductive polymer (CP) nanotube transdermal patch. The externally controlled transdermal delivery of model drugs and insulin were tested ex vivo and results were compared with CP films. The unique intrinsic properties of CPs provide electrostatic interaction between the model drugs and polymer backbone. When a pulsed potential was applied, the drug delivery release profile mimics that of injection delivery. With a constant potential applied, the release rate constants of the patch system were up to three-times faster than the control (0 V) and released approximately 80% more drug molecules over 24 h. The CP nanotube transdermal patch represents a new and promising drug method, specifically for hydrophilic molecules, which have been a large obstacle for conventional transdermal drug delivery systems.

  13. Mathematical models for drug diffusion through the compartments of ...

    African Journals Online (AJOL)

    M.A. Khanday

    2016-07-26

    Jul 26, 2016 ... partments have both favourable and adverse effects on human body. The researchers ... absorption, distribution and elimination process of the drug within the body ... models can be used to understand the transport processes.

  14. 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.

  15. The effects of drugs on human models of emotional processing: an account of antidepressant drug treatment.

    Science.gov (United States)

    Pringle, Abbie; Harmer, Catherine J

    2015-12-01

    Human models of emotional processing suggest that the direct effect of successful antidepressant drug treatment may be to modify biases in the processing of emotional information. Negative biases in emotional processing are documented in depression, and single or short-term dosing with conventional antidepressant drugs reverses these biases in depressed patients prior to any subjective change in mood. Antidepressant drug treatments also modulate emotional processing in healthy volunteers, which allows the consideration of the psychological effects of these drugs without the confound of changes in mood. As such, human models of emotional processing may prove to be useful for testing the efficacy of novel treatments and for matching treatments to individual patients or subgroups of patients.

  16. Interaction of cationic drugs with liposomes.

    Science.gov (United States)

    Howell, Brett A; Chauhan, Anuj

    2009-10-20

    Interactions between cationic drugs and anionic liposomes were studied by measuring binding of drugs and the effect of binding on liposome permeability. The measurements were analyzed in the context of a continuum model based on electrostatic interactions and a Langmuir isotherm. Experiments and modeling indicate that, although electrostatic interactions are important, the fraction of drug sequestered in the double-layer is negligible. The majority of drug enters the bilayer with the charged regions interacting with the charged lipid head groups and the lipophilic regions associated with the bilayer. The partitioning of the drug can be described by a Langmuir isotherm with the electrostatic interactions increasing the sublayer concentration of the drug. The binding isotherms are similar for all tricyclic antidepressants (TCA). Bupivacaine (BUP) binds significantly less compared to TCA because its structure is such that the charged region has minimal interactions with the lipid heads once the BUP molecule partitions inside the bilayer. Conversely, the TCAs are linear with distinct hydrophilic and lipophilic regions, allowing the lipophilic regions to lie inside the bilayer and the hydrophilic regions to protrude out. This conformation maximizes the permeability of the bilayer, leading to an increased release of a hydrophilic fluorescent dye from liposomes.

  17. SEIIrR: Drug abuse model with rehabilitation

    Science.gov (United States)

    Sutanto, Azizah, Afina; Widyaningsih, Purnami; Saputro, Dewi Retno Sari

    2017-05-01

    Drug abuse in the world quite astonish and tend to increase. The increase and decrease on the number of drug abusers showed a pattern of spread that had the same characteristics with patterns of spread of infectious disease. The susceptible infected removed (SIR) and susceptible exposed infected removed (SEIR) epidemic models for infectious disease was developed to study social epidemic. In this paper, SEIR model for disease epidemic was developed to study drug abuse epidemic with rehabilitation treatment. The aims of this paper were to analogize susceptible exposed infected isolated recovered (SEIIrR) model on the drug abusers, to determine solutions of the model, to determine equilibrium point, and to do simulation on β. The solutions of SEIIrR model was determined by using fourth order of Runge-Kutta algorithm, equilibrium point obtained was free-drug equilibrium point. Solutions of SEIIrR showed that the model was able to suppress the spread of drug abuse. The increasing value of contact rate was not affect the number of infected individuals due to rehabilitation treatment.

  18. Zebrafish models in neuropsychopharmacology and CNS drug discovery.

    Science.gov (United States)

    Khan, Kanza M; Collier, Adam D; Meshalkina, Darya A; Kysil, Elana V; Khatsko, Sergey L; Kolesnikova, Tatyana; Morzherin, Yury Yu; Warnick, Jason E; Kalueff, Allan V; Echevarria, David J

    2017-07-01

    Despite the high prevalence of neuropsychiatric disorders, their aetiology and molecular mechanisms remain poorly understood. The zebrafish (Danio rerio) is increasingly utilized as a powerful animal model in neuropharmacology research and in vivo drug screening. Collectively, this makes zebrafish a useful tool for drug discovery and the identification of disordered molecular pathways. Here, we discuss zebrafish models of selected human neuropsychiatric disorders and drug-induced phenotypes. As well as covering a broad range of brain disorders (from anxiety and psychoses to neurodegeneration), we also summarize recent developments in zebrafish genetics and small molecule screening, which markedly enhance the disease modelling and the discovery of novel drug targets. © 2017 The British Pharmacological Society.

  19. 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 ...

  20. 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.

  1. Novel films for drug delivery via the buccal mucosa using model soluble and insoluble drugs.

    Science.gov (United States)

    Kianfar, Farnoosh; Chowdhry, Babur Z; Antonijevic, Milan D; Boateng, Joshua S

    2012-10-01

    Bioadhesive buccal films are innovative dosage forms with the ability to adhere to the mucosal surface and subsequently hydrate to release and deliver drugs across the buccal membrane. This study aims to formulate and characterize stable carrageenan (CAR) based buccal films with desirable drug loading capacity. The films were prepared using CAR, poloxamer (POL) 407, various grades of PEG (plasticizer) and loaded with paracetamol (PM) and indomethacin (IND) as model soluble and insoluble drugs, respectively. The films were characterized by texture analysis, thermogravimetric analysis (TGA), DSC, scanning electron microscopy, X-ray powder diffraction (XRPD), and in vitro drug release studies. Optimized films were obtained from aqueous gels comprising 2.5% w/w κ-CAR 911, 4% w/w POL 407 and 6% w/w (PM) and 6.5% w/w (IND) of PEG 600 with maximum drug loading of 1.6% w/w and 0.8 % w/w for PM and IND, respectively. TGA showed residual water content of approximately 5% of films dry weight. DSC revealed a T(g) at 22.25 and 30.77°C for PM and IND, respectively, implying the presence of amorphous forms of both drugs which was confirmed by XRPD. Drug dissolution profiles in simulated saliva showed cumulative percent release of up to 45 and 57% of PM and IND, respectively, within 40 min of contact with dissolution medium simulating saliva.

  2. Dendrimers bind antioxidant polyphenols and cisplatin drug.

    Directory of Open Access Journals (Sweden)

    Amine Abderrezak

    Full Text Available Synthetic polymers of a specific shape and size play major role in drug delivery systems. Dendrimers are unique synthetic macromolecules of nanometer dimensions with a highly branched structure and globular shape with potential applications in gene and drug delivery. We examine the interaction of several dendrimers of different compositions mPEG-PAMAM (G3, mPEG-PAMAM (G4 and PAMAM (G4 with hydrophilic and hydrophobic drugs cisplatin, resveratrol, genistein and curcumin at physiological conditions. FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyse drug binding mode, the binding constant and the effects of drug complexation on dendrimer stability and conformation. Structural analysis showed that cisplatin binds dendrimers in hydrophilic mode via Pt cation and polymer terminal NH(2 groups, while curcumin, genistein and resveratrol are located mainly in the cavities binding through both hydrophobic and hydrophilic contacts. The overall binding constants of durg-dendrimers are ranging from 10(2 M(-1 to 10(3 M(-1. The affinity of dendrimer binding was PAMAM-G4>mPEG-PAMAM-G4>mPEG-PAMAM-G3, while the order of drug-polymer stability was curcumin>cisplatin>genistein>resveratrol. Molecular modeling showed larger stability for genisten-PAMAM-G4 (ΔG = -4.75 kcal/mol than curcumin-PAMAM-G4 ((ΔG = -4.53 kcal/mol and resveratrol-PAMAM-G4 ((ΔG = -4.39 kcal/mol. Dendrimers might act as carriers to transport hydrophobic and hydrophilic drugs.

  3. Target-mediated drug disposition model and its approximations for antibody-drug conjugates.

    Science.gov (United States)

    Gibiansky, Leonid; Gibiansky, Ekaterina

    2014-02-01

    Antibody-drug conjugate (ADC) is a complex structure composed of an antibody linked to several molecules of a biologically active cytotoxic drug. The number of ADC compounds in clinical development now exceeds 30, with two of them already on the market. However, there is no rigorous mechanistic model that describes pharmacokinetic (PK) properties of these compounds. PK modeling of ADCs is even more complicated than that of other biologics as the model should describe distribution, binding, and elimination of antibodies with different toxin load, and also the deconjugation process and PK of the released toxin. This work extends the target-mediated drug disposition (TMDD) model to describe ADCs, derives the rapid binding (quasi-equilibrium), quasi-steady-state, and Michaelis-Menten approximations of the TMDD model as applied to ADCs, derives the TMDD model and its approximations for ADCs with load-independent properties, and discusses further simplifications of the system under various assumptions. The developed models are shown to describe data simulated from the available clinical population PK models of trastuzumab emtansine (T-DM1), one of the two currently approved ADCs. Identifiability of model parameters is also discussed and illustrated on the simulated T-DM1 examples.

  4. Modelling of drug release from ensembles of aspirin microcapsules ...

    African Journals Online (AJOL)

    Purpose: In order to determine the drug release profile of an ensemble of aspirin crystals or microcapsules from its particle distribution a mathematical model that considered the individual release characteristics of the component single particles was developed. The model assumed that under sink conditions the release ...

  5. Animal models of pain and migraine in drug discovery

    DEFF Research Database (Denmark)

    Munro, Gordon; Jansen-Olesen, Inger; Olesen, Jes

    2017-01-01

    of the most commonly used models and methods employed within 'pain and migraine' drug development will be presented. Recent advances within these disciplines suggest that, with the addition of a few extra carefully chosen ancillary models and/or endpoints, the relative value in terms of resources used...

  6. Toward a normalized clinical drug knowledge base in China-applying the RxNorm model to Chinese clinical drugs.

    Science.gov (United States)

    Wang, Li; Zhang, Yaoyun; Jiang, Min; Wang, Jingqi; Dong, Jiancheng; Liu, Yun; Tao, Cui; Jiang, Guoqian; Zhou, Yi; Xu, Hua

    2018-04-04

    In recent years, electronic health record systems have been widely implemented in China, making clinical data available electronically. However, little effort has been devoted to making drug information exchangeable among these systems. This study aimed to build a Normalized Chinese Clinical Drug (NCCD) knowledge base, by applying and extending the information model of RxNorm to Chinese clinical drugs. Chinese drugs were collected from 4 major resources-China Food and Drug Administration, China Health Insurance Systems, Hospital Pharmacy Systems, and China Pharmacopoeia-for integration and normalization in NCCD. Chemical drugs were normalized using the information model in RxNorm without much change. Chinese patent drugs (i.e., Chinese herbal extracts), however, were represented using an expanded RxNorm model to incorporate the unique characteristics of these drugs. A hybrid approach combining automated natural language processing technologies and manual review by domain experts was then applied to drug attribute extraction, normalization, and further generation of drug names at different specification levels. Lastly, we reported the statistics of NCCD, as well as the evaluation results using several sets of randomly selected Chinese drugs. The current version of NCCD contains 16 976 chemical drugs and 2663 Chinese patent medicines, resulting in 19 639 clinical drugs, 250 267 unique concepts, and 2 602 760 relations. By manual review of 1700 chemical drugs and 250 Chinese patent drugs randomly selected from NCCD (about 10%), we showed that the hybrid approach could achieve an accuracy of 98.60% for drug name extraction and normalization. Using a collection of 500 chemical drugs and 500 Chinese patent drugs from other resources, we showed that NCCD achieved coverages of 97.0% and 90.0% for chemical drugs and Chinese patent drugs, respectively. Evaluation results demonstrated the potential to improve interoperability across various electronic drug systems

  7. Mathematical modeling of drug release from lipid dosage forms.

    Science.gov (United States)

    Siepmann, J; Siepmann, F

    2011-10-10

    Lipid dosage forms provide an interesting potential for controlled drug delivery. In contrast to frequently used poly(ester) based devices for parenteral administration, they do not lead to acidification upon degradation and potential drug inactivation, especially in the case of protein drugs and other acid-labile active agents. The aim of this article is to give an overview on the current state of the art of mathematical modeling of drug release from this type of advanced drug delivery systems. Empirical and semi-empirical models are described as well as mechanistic theories, considering diffusional mass transport, potentially limited drug solubility and the leaching of other, water-soluble excipients into the surrounding bulk fluid. Various practical examples are given, including lipid microparticles, beads and implants, which can successfully be used to control the release of an incorporated drug during periods ranging from a few hours up to several years. The great benefit of mechanistic mathematical theories is the possibility to quantitatively predict the effects of different formulation parameters and device dimensions on the resulting drug release kinetics. Thus, in silico simulations can significantly speed up product optimization. This is particularly useful if long release periods (e.g., several months) are targeted, since experimental trial-and-error studies are highly time-consuming in these cases. In the future it would be highly desirable to combine mechanistic theories with the quantitative description of the drug fate in vivo, ideally including the pharmacodynamic efficacy of the treatments. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Preparation, characterization, drug release and computational modelling studies of antibiotics loaded amorphous chitin nanoparticles.

    Science.gov (United States)

    Gayathri, N K; Aparna, V; Maya, S; Biswas, Raja; Jayakumar, R; Mohan, C Gopi

    2017-12-01

    We present a computational investigation of binding affinity of different types of drugs with chitin nanocarriers. Understanding the chitn polymer-drug interaction is important to design and optimize the chitin based drug delivery systems. The binding affinity of three different types of anti-bacterial drugs Ethionamide (ETA) Methacycline (MET) and Rifampicin (RIF) with amorphous chitin nanoparticles (AC-NPs) were studied by integrating computational and experimental techniques. The binding energies (BE) of hydrophobic ETA, hydrophilic MET and hydrophobic RIF were -7.3kcal/mol, -5.1kcal/mol and -8.1kcal/mol respectively, with respect to AC-NPs, using molecular docking studies. This theoretical result was in good correlation with the experimental studies of AC-drug loading and drug entrapment efficiencies of MET (3.5±0.1 and 25± 2%), ETA (5.6±0.02 and 45±4%) and RIF (8.9±0.20 and 53±5%) drugs respectively. Stability studies of the drug encapsulated nanoparticles showed stable values of size, zeta and polydispersity index at 6°C temperature. The correlation between computational BE and experimental drug entrapment efficiencies of RIF, ETA and MET drugs with four AC-NPs strands were 0.999 respectively, while that of the drug loading efficiencies were 0.854 respectively. Further, the molecular docking results predict the atomic level details derived from the electrostatic, hydrogen bonding and hydrophobic interactions of the drug and nanoparticle for its encapsulation and loading in the chitin-based host-guest nanosystems. The present results thus revealed the drug loading and drug delivery insights and has the potential of reducing the time and cost of processing new antibiotic drug delivery nanosystem optimization, development and discovery. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Computational and experimental model of transdermal iontophorethic drug delivery system.

    Science.gov (United States)

    Filipovic, Nenad; Saveljic, Igor; Rac, Vladislav; Graells, Beatriz Olalde; Bijelic, Goran

    2017-11-30

    The concept of iontophoresis is often applied to increase the transdermal transport of drugs and other bioactive agents into the skin or other tissues. It is a non-invasive drug delivery method which involves electromigration and electroosmosis in addition to diffusion and is shown to be a viable alternative to conventional administration routs such as oral, hypodermic and intravenous injection. In this study we investigated, experimentally and numerically, in vitro drug delivery of dexamethasone sodium phosphate to porcine skin. Different current densities, delivery durations and drug loads were investigated experimentally and introduced as boundary conditions for numerical simulations. Nernst-Planck equation was used for calculation of active substance flux through equivalent model of homogeneous hydrogel and skin layers. The obtained numerical results were in good agreement with experimental observations. A comprehensive in-silico platform, which includes appropriate numerical tools for fitting, could contribute to iontophoretic drug-delivery devices design and correct dosage and drug clearance profiles as well as to perform much faster in-silico experiments to better determine parameters and performance criteria of iontophoretic drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Martina Aduenimaa Bonsu

    2016-01-01

    Full Text Available 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; f115 and f2<50. Drug release followed the Higuchi kinetic model which is indicative of Fickian drug diffusion.

  11. Effects of HPMC substituent pattern on water up-take, polymer and drug release: An experimental and modelling study.

    Science.gov (United States)

    Caccavo, Diego; Lamberti, Gaetano; Barba, Anna Angela; Abrahmsén-Alami, Susanna; Viridén, Anna; Larsson, Anette

    2017-08-07

    The purpose of this study was to investigate the hydration behavior of two matrix formulations containing the cellulose derivative hydroxypropyl methylcellulose (HPMC). The two HPMC batches investigated had different substitution pattern along the backbone; the first one is referred to as heterogeneous and the second as homogenous. The release of both the drug molecule theophylline and the polymer was determined. Additionally, the water concentrations at different positions in the swollen gel layers were determined by Magnetic Resonance Imaging. The experimental data was compared to predicted values obtained by the extension of a mechanistic Fickian based model. The hydration of tablets containing the more homogenous HPMC batch showed a gradual water concentration gradient in the gel layer and could be well predicted. The hydration process for the more heterogeneous batch showed a very abrupt step change in the water concentration in the gel layer and could not be well predicted. Based on the comparison between the experimental and predicted data this study suggests, for the first time, that formulations with HPMC of different heterogeneities form gels in different ways. The homogeneous HPMC batch exhibits a water sorption behavior ascribable to a Ficḱs law for the diffusion process whereas the more heterogeneous HPMC batches does not. This conclusion is important in the future development of simulation models and in the understanding of drug release mechanism from hydrophilic matrices. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Structural Model of Drug Use among Students: The Role of Spirituality, Social Modeling and Attitude to Drugs

    Directory of Open Access Journals (Sweden)

    samira yavari

    2015-06-01

    Full Text Available Objective: This study was an attempt to explore the structural relationship between religious activity, religious struggle, attitude to drugs, social modeling, spiritual well-being, and cigarette and tobacco smoking among students. Method: For this purpose, 504 male and female students from Kharazmi University, Agricultural Paradise, and Azad University of Karaj were selected by cluster sampling and they were asked to complete spiritual well-being scale, religious activity scale, religious struggle scale, social modeling scale, negative beliefs about drugs, and the tobacco section of the high-risk behavior questionnaire. Results: The results showed that the effect of religious activity on cigarette and tobacco smoking was mediated by negative beliefs about drugs, social modeling, spiritual well-being, and incentives for drug use. Similarly, the effect of religious struggle on cigarette and tobacco smoking was mediated by spiritual well-being. Conclusion: It seems that religion prevents people joining the unhealthy peer groups by the establishment of moral discipline, internal and external rules, and healthy coping styles therefore, people get less attracted to cigarette and tobacco smoking. Accordingly, these factors should be paid more attention in prevention programs for drug use, particularly cigarette and tobacco that are considered as the gateway to other drugs.

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

    Science.gov (United States)

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

    2012-07-02

    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.

  14. 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.

  15. Drug Release from ß-Cyclodextrin Complexes and Drug Transfer into Model Membranes Studied by Affinity Capillary Electrophoresis.

    Science.gov (United States)

    Darwish, Kinda A; Mrestani, Yahya; Rüttinger, Hans-Hermann; Neubert, Reinhard H H

    2016-05-01

    Is to characterize the drug release from the ß-cyclodextrin (ß-CD) cavity and the drug transfer into model membranes by affinity capillary electrophoresis. Phospholipid liposomes with and without cholesterol were used to mimic the natural biological membrane. The interaction of cationic and anionic drugs with ß-CD and the interaction of the drugs with liposomes were detected separately by measuring the drug mobility in ß-CD containing buffer and liposome containing buffer; respectively. Moreover, the kinetics of drug release from ß-CD and its transfer into liposomes with or without cholesterol was studied by investigation of changes in the migration behaviours of the drugs in samples, contained drug, ß-CD and liposome, at 1:1:1 molar ratio at different time intervals; zero time, 30 min, 1, 2, 4, 6, 8, 10 and 24 h. Lipophilic drugs such as propranolol and ibuprofen were chosen for this study, because they form complexes with ß-CD. The mobility of the both drug liposome mixtures changed with time to a final state. For samples of liposomal membranes with cholesterol the final state was faster reached than without cholesterol. The study confirmed that the drug release from the CD cavity and its transfer into the model membrane was more enhanced by the competitive displacement of the drug from the ß-CD cavity by cholesterol, the membrane component. The ACE method here developed can be used to optimize the drug release from CD complexes and the drug transfer into model membranes.

  16. Animal models of pancreatic cancer for drug research.

    Science.gov (United States)

    Kapischke, Matthias; Pries, Alexandra

    2008-10-01

    The operative and conservative results of therapy in pancreatic ductal adenocarcinoma remain appallingly poor. This underlines the demand for further research for effective anticancer drugs. The various animal models remain the essential method for the determination of efficacy of substances during preclinical phase. Unfortunately, most of these tested substances showed a good efficacy in pancreatic carcinoma in the animal model but were not confirmed during the clinical phase. The available literature in PubMed, Medline, Ovid and secondary literature was searched regarding the available animal models for drug testing against pancreatic cancer. The models were analyzed regarding their pros and cons in anticancer drug testing. The different modifications of the orthotopic model (especially in mice) seem at present to be the best model for anticancer testing in pancreatic carcinoma. The value of genetically engineered animal model (GEM) and syngeneic models is on debate. A good selection of the model concerning the questions supposed to be clarified may improve the comparability of the results of animal experiments compared to clinical trials.

  17. [Alternatives to the drug research and development model].

    Science.gov (United States)

    Velásquez, Germán

    2015-03-01

    One-third of the global population lacks access to medications; the situation is worse in poor countries, where up to 50% of the population lacks access. The failure of current incentive systems based in intellectual property to offer the necessary pharmaceutical products, especially in the global south, is a call to action. Problems related to drug access cannot be solved solely through improvements or modifications in the existing incentive models. The intellectual property system model does not offer sufficient innovation for developing countries; new mechanisms that effectively promote innovation and drug access simultaneously are needed. A binding international agreement on research and development, negotiated under the auspices of the World Health Organization, could provide an adequate framework for guaranteeing priority-setting, coordination, and sustainable financing of drugs at reasonable prices for developing countries.

  18. Multimodality imaging and mathematical modelling of drug delivery to glioblastomas.

    Science.gov (United States)

    Boujelben, Ahmed; Watson, Michael; McDougall, Steven; Yen, Yi-Fen; Gerstner, Elizabeth R; Catana, Ciprian; Deisboeck, Thomas; Batchelor, Tracy T; Boas, David; Rosen, Bruce; Kalpathy-Cramer, Jayashree; Chaplain, Mark A J

    2016-10-06

    Patients diagnosed with glioblastoma, an aggressive brain tumour, have a poor prognosis, with a median overall survival of less than 15 months. Vasculature within these tumours is typically abnormal, with increased tortuosity, dilation and disorganization, and they typically exhibit a disrupted blood-brain barrier (BBB). Although it has been hypothesized that the 'normalization' of the vasculature resulting from anti-angiogenic therapies could improve drug delivery through improved blood flow, there is also evidence that suggests that the restoration of BBB integrity might limit the delivery of therapeutic agents and hence their effectiveness. In this paper, we apply mathematical models of blood flow, vascular permeability and diffusion within the tumour microenvironment to investigate the effect of these competing factors on drug delivery. Preliminary results from the modelling indicate that all three physiological parameters investigated-flow rate, vessel permeability and tissue diffusion coefficient-interact nonlinearly to produce the observed average drug concentration in the microenvironment.

  19. Non-immunogenic, hydrophilic/cationic block copolymers and uses thereof

    Science.gov (United States)

    Scales, Charles W.; Huang, Faqing; McCormick, Charles L.

    2010-05-18

    The present invention provides novel non-immunogenic, hydrophilic/cationic block copolymers comprising a neutral-hydrophilic polymer and a cationic polymer, wherein both polymers have well-defined chain-end functionality. A representative example of such a block copolymer comprises poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) and poly(N-[3-(dimethylamino)propyl]methacrylamide) (PDMAPMA). Also provided is a synthesis method thereof in aqueous media via reversible addition fragmentation chain transfer (RAFT) polymerization. Further provided are uses of these block copolymers as drug delivery vehicles and protection agents.

  20. 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

  1. 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.

  2. 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.

  3. Quantitative modeling of selective lysosomal targeting for drug design

    DEFF Research Database (Denmark)

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

    2008-01-01

    log K ow. These findings were validated with experimental results and by a comparison to the properties of antimalarial drugs in clinical use. For ten active compounds, nine were predicted to accumulate to a greater extent in lysosomes than in other organelles, six of these were in the optimum range...... predicted by the model and three were close. Five of the antimalarial drugs were lipophilic weak dibasic compounds. The predicted optimum properties for a selective accumulation of weak bivalent bases in lysosomes are consistent with experimental values and are more accurate than any prior calculation...

  4. Addressing drug adherence using an operations management model.

    Science.gov (United States)

    Nunlee, Martin; Bones, Michelle

    2014-01-01

    OBJECTIVE To provide a model that enables health systems and pharmacy benefit managers to provide medications reliably and test for reliability and validity in the analysis of adherence to drug therapy of chronic disease. SUMMARY The quantifiable model described here can be used in conjunction with behavioral designs of drug adherence assessments. The model identifies variables that can be reproduced and expanded across the management of chronic diseases with drug therapy. By creating a reorder point system for reordering medications, the model uses a methodology commonly seen in operations research. The design includes a safety stock of medication and current supply of medication, which increases the likelihood that patients will have a continuous supply of medications, thereby positively affecting adherence by removing barriers. CONCLUSION This method identifies an adherence model that quantifies variables related to recommendations from health care providers; it can assist health care and service delivery systems in making decisions that influence adherence based on the expected order cycle days and the expected daily quantity of medication administered. This model addresses the possession of medication as a barrier to adherence.

  5. 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. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Conductive polymer nanotube patch for fast and controlled in vivo transdermal drug delivery

    Science.gov (United States)

    Nguyen, Thao M.

    Transdermal drug delivery has created new applications for existing therapies and offered an alternative to the traditional oral route where drugs can prematurely metabolize in the liver causing adverse side effects. Opening the transdermal delivery route to large hydrophilic drugs is one of the greatest challenges due to the hydrophobicity of the skin. However, the ability to deliver hydrophilic drugs using a transdermal patch would provide a solution to problems of other delivery methods for hydrophilic drugs. The switching of conductive polymers (CP) between redox states cause simultaneous changes in the polymer charge, conductivity, and volume—properties that can all be exploited in the biomedical field of controlled drug delivery. Using the template synthesis method, poly(3,4-ethylenedioxythiophene (PEDOT) nanotubes were synthesized electrochemically and a transdermal drug delivery patch was successfully designed and developed. In vitro and in vivo uptake and release of hydrophilic drugs were investigated. The relationship between the strength of the applied potential and rate of drug release were also investigated. Results revealed that the strength of the applied potential is proportional to the rate of drug release; therefore one can control the rate of drug release by controlling the applied potential. The in vitro studies focused on the kinetics of the drug delivery system. It was determined that the drug released mainly followed zero-order kinetics. In addition, it was determined that applying a releasing potential to the transdermal drug delivery system lead to a higher release rate constant (up to 7 times greater) over an extended period of time (˜24h). In addition, over 24 hours, an average of 80% more model drug molecules were released with an applied potential than without. The in vivo study showed that the drug delivery system was capable of delivering model hydrophilic drugs molecules through the dermis layer of the skin within 30 minutes

  7. 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.

  8. Drug repurposing for aging research using model organisms.

    Science.gov (United States)

    Ziehm, Matthias; Kaur, Satwant; Ivanov, Dobril K; Ballester, Pedro J; Marcus, David; Partridge, Linda; Thornton, Janet M

    2017-10-01

    Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against aging, despite many genes and pathways shown to be important in the aging process and numerous studies demonstrating that genetic interventions can lead to a healthier aging phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate aging in the invertebrates Caenorhabditis elegans and Drosophila. Our approach combines information on genetic effects on aging, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate aging. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating aging, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human aging. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  9. 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. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. Bioengineered Liver Models for Drug Testing and Cell Differentiation Studies

    Directory of Open Access Journals (Sweden)

    Gregory H. Underhill

    2018-01-01

    Full Text Available In vitro models of the human liver are important for the following: (1 mitigating the risk of drug-induced liver injury to human beings, (2 modeling human liver diseases, (3 elucidating the role of single and combinatorial microenvironmental cues on liver cell function, and (4 enabling cell-based therapies in the clinic. Methods to isolate and culture primary human hepatocytes (PHHs, the gold standard for building human liver models, were developed several decades ago; however, PHHs show a precipitous decline in phenotypic functions in 2-dimensional extracellular matrix–coated conventional culture formats, which does not allow chronic treatment with drugs and other stimuli. The development of several engineering tools, such as cellular microarrays, protein micropatterning, microfluidics, biomaterial scaffolds, and bioprinting, now allow precise control over the cellular microenvironment for enhancing the function of both PHHs and induced pluripotent stem cell–derived human hepatocyte-like cells; long-term (4+ weeks stabilization of hepatocellular function typically requires co-cultivation with liver-derived or non–liver-derived nonparenchymal cell types. In addition, the recent development of liver organoid culture systems can provide a strategy for the enhanced expansion of therapeutically relevant cell types. Here, we discuss advances in engineering approaches for constructing in vitro human liver models that have utility in drug screening and for determining microenvironmental determinants of liver cell differentiation/function. Design features and validation data of representative models are presented to highlight major trends followed by the discussion of pending issues that need to be addressed. Overall, bioengineered liver models have significantly advanced our understanding of liver function and injury, which will prove useful for drug development and ultimately cell-based therapies.

  11. 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...

  12. 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.

  13. 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.

  14. 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 sh......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...

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

    Science.gov (United States)

    Murrell, Ben; de Oliveira, Tulio; Seebregts, Chris; Kosakovsky Pond, Sergei L; Scheffler, Konrad

    2012-01-01

    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.

  16. 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.

  17. 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…

  18. Preparation of hydrophilic magnetic nanospheres with high saturation magnetization

    International Nuclear Information System (INIS)

    Xu Hong; Tong Naihu; Cui Longlan; Lu Ying; Gu Hongchen

    2007-01-01

    Well-defined silica-magnetite core-shell nanospheres were prepared via a modified sol-gel method. Sphere-like magnetite aggregates were obtained as cores of the final nanospheres by assembling in the presence of Tween 20. Characterization by transmission electron microscopy (TEM) showed spherical morphology of the nanospheres with controlled silica shell thickness from 9 to 30 nm, depending on the amount of tetraethoxysilane (TEOS) used. The nanospheres contained up to 41.7 wt% magnetite with a saturation magnetization of 21.8 emu/g. Up to 35 μg/mg of the model biomolecule streptavidin (SA) could be bound covalently to the hydrophilic silica nanospheres

  19. An attention-based effective neural model for drug-drug interactions extraction.

    Science.gov (United States)

    Zheng, Wei; Lin, Hongfei; Luo, Ling; Zhao, Zhehuan; Li, Zhengguang; Zhang, Yijia; Yang, Zhihao; Wang, Jian

    2017-10-10

    Drug-drug interactions (DDIs) often bring unexpected side effects. The clinical recognition of DDIs is a crucial issue for both patient safety and healthcare cost control. However, although text-mining-based systems explore various methods to classify DDIs, the classification performance with regard to DDIs in long and complex sentences is still unsatisfactory. In this study, we propose an effective model that classifies DDIs from the literature by combining an attention mechanism and a recurrent neural network with long short-term memory (LSTM) units. In our approach, first, a candidate-drug-oriented input attention acting on word-embedding vectors automatically learns which words are more influential for a given drug pair. Next, the inputs merging the position- and POS-embedding vectors are passed to a bidirectional LSTM layer whose outputs at the last time step represent the high-level semantic information of the whole sentence. Finally, a softmax layer performs DDI classification. Experimental results from the DDIExtraction 2013 corpus show that our system performs the best with respect to detection and classification (84.0% and 77.3%, respectively) compared with other state-of-the-art methods. In particular, for the Medline-2013 dataset with long and complex sentences, our F-score far exceeds those of top-ranking systems by 12.6%. Our approach effectively improves the performance of DDI classification tasks. Experimental analysis demonstrates that our model performs better with respect to recognizing not only close-range but also long-range patterns among words, especially for long, complex and compound sentences.

  20. Electric treatment for hydrophilic ink deinking.

    Science.gov (United States)

    Du, Xiaotang; Hsieh, Jeffery S

    2017-09-01

    Hydrophilic inks have been widely used due to higher printing speed, competitive cost and being healthy non-organic solvents. However, they cause problems in both product quality and process runnability due to their hydrophilic surface wettability, strong negative surface charge and sub-micron size. Electric treatment was shown to be able to increase the ink sizes from 60 nm to 700 nm through electrocoagulation and electrophoresis. In addition, electric treatment assisted flotation could reduce effective residual ink concentration (ERIC) by 90 ppm, compared with only 20 ppm by traditional flotation. Furthermore, the effect of electric treatment alone on ink separation was investigated by two anode materials, graphite and stainless steel. Both of them could remove hydrophilic inks with less than 1% yield loss via electroflotation and electrophoresis. But graphite is a better material as the anode because graphite reduced ERIC by an additional 100 ppm. The yield loss of flotation following electric treatment was also lower by 17% if graphite was the anode material. The difference between the two electrode materials resulted from electrocoagulation and ink redeposition during electric treatment. An electric pretreatment-flotation-hyperwashing process was conducted to understand the deinking performance in conditions similar to a paper mill, and the ERIC was reduced from 950 ppm to less than 400 ppm.

  1. 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.

  2. 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.......003). Difference in area under the headache score curve (AUC) 0-4 hours between sumatriptan and placebo was not significant ( p = 0.30). Conclusion 5-ISMN is a very powerful inducer of migraine-like headache in healthy individuals but the headache does not respond to sumatriptan. The model is not useful for future...

  3. Modeling of corneal and retinal pharmacokinetics after periocular drug administration.

    Science.gov (United States)

    Amrite, Aniruddha C; Edelhauser, Henry F; Kompella, Uday B

    2008-01-01

    the SD rat corneas. Similar pharmacokinetics models explain drug delivery to the cornea in rat and rabbit animal models. Retinal pharmacokinetics after periocular drug administration can be explained with a four-compartment (periocular space, choroid-containing transfer compartment, retina, and distribution compartment) model with elimination from the periocular space, retina, and choroid compartment. Inclusion of a dissolution-release step before the drug is available for absorption or elimination better explains retinal t(max). Good fits were obtained in both the BN (r = 0.99) and SD (r = 0.99) rats for retinal celecoxib using the same model; however, the parameter estimates differed. Corneal and retinal pharmacokinetics of small lipophilic molecules after periocular administration can be described by compartment models. The modeling analysis shows that (1) leak-back from the site of administration most likely contributes to the apparent lack of an increase phase in corneal concentrations; (2) elimination via the conjunctival or periocular blood and lymphatic systems contributes significantly to drug clearance after periocular injection; (3) corneal pharmacokinetics of small lipophilic molecules can be explained by using similar models in rats and rabbits; and (4) although there are differences in some retinal pharmacokinetics parameters between the pigmented and nonpigmented rats, the physiological basis of these differences has yet to be ascertained.

  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. 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.

  6. Improving Predictive Modeling in Pediatric Drug Development: Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Slikker, William; Young, John F.; Corley, Rick A.; Dorman, David C.; Conolly, Rory B.; Knudsen, Thomas; Erstad, Brian L.; Luecke, Richard H.; Faustman, Elaine M.; Timchalk, Chuck; Mattison, Donald R.

    2005-07-26

    A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

  7. Mechanistic systems modeling to guide drug discovery and development.

    Science.gov (United States)

    Schmidt, Brian J; Papin, Jason A; Musante, Cynthia J

    2013-02-01

    A crucial question that must be addressed in the drug development process is whether the proposed therapeutic target will yield the desired effect in the clinical population. Pharmaceutical and biotechnology companies place a large investment on research and development, long before confirmatory data are available from human trials. Basic science has greatly expanded the computable knowledge of disease processes, both through the generation of large omics data sets and a compendium of studies assessing cellular and systemic responses to physiologic and pathophysiologic stimuli. Given inherent uncertainties in drug development, mechanistic systems models can better inform target selection and the decision process for advancing compounds through preclinical and clinical research. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Modeling Human Nonalcoholic Steatohepatitis-Associated Changes in Drug Transporter Expression Using Experimental Rodent Models

    OpenAIRE

    Canet, Mark J.; Hardwick, Rhiannon N.; Lake, April D.; Dzierlenga, Anika L.; Clarke, John D.; Cherrington, Nathan J.

    2014-01-01

    Nonalcoholic fatty liver disease is a prevalent form of chronic liver disease that can progress to the more advanced stage of nonalcoholic steatohepatitis (NASH). NASH has been shown to alter drug transporter regulation and may have implications in the development of adverse drug reactions. Several experimental rodent models have been proposed for the study of NASH, but no single model fully recapitulates all aspects of the human disease. The purpose of the current study was to determine whic...

  9. Latest animal models for anti-HIV drug discovery.

    Science.gov (United States)

    Sliva, Katja

    2015-02-01

    HIV research is limited by the fact that lentiviruses are highly species specific. The need for appropriate models to promote research has led to the development of many elaborate surrogate animal models. This review looks at the history of animal models for HIV research. Although natural animal lentivirus infections and chimeric viruses such as chimera between HIV and simian immunodeficiency virus and simian-tropic HIV are briefly discussed, the main focus is on small animal models, including the complex design of the 'humanized' mouse. The review also traces the historic evolution and milestones as well as depicting current models and future prospects for HIV research. HIV research is a complex and challenging task that is highly manpower-, money- and time-consuming. Besides factors such as hypervariability and latency, the lack of appropriate animal models that exhibit and recapitulate the entire infectious process of HIV, is one of the reasons behind the failure to eliminate the lentivirus from the human population. This obstacle has led to the exploitation and further development of many sophisticated surrogate animal models for HIV research. While there is no animal model that perfectly mirrors and mimics HIV infections in humans, there are a variety of host species and viruses that complement each other. Combining the insights from each model, and critically comparing the results obtained with data from human clinical trials should help expand our understanding of HIV pathogenesis and drive future drug development.

  10. 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.

  11. Effect of ingested lipids on drug dissolution and release with concurrent digestion: a modeling approach

    Science.gov (United States)

    Buyukozturk, Fulden; Di Maio, Selena; Budil, David E.; Carrier, Rebecca L.

    2014-01-01

    Purpose To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen. Methods Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybean oil) and drug solubilized in a model SEDDS (soybean oil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model. Results Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion were observed and predicted by the developed model. 90 minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion. Conclusion A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs. PMID:24234918

  12. 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.

  13. The impact of pharmacophore modeling in drug design.

    Science.gov (United States)

    Guner, Osman F

    2005-07-01

    With the reliable use of computer simulations in scientific research, it is possible to achieve significant increases in productivity as well as a reduction in research costs compared with experimental approaches. For example, computer-simulation can substantially enchance productivity by focusing the scientist to better, more informed choices, while also driving the 'fail-early' concept to result in a significant reduction in cost. Pharmacophore modeling is a reliable computer-aided design tool used in the discovery of new classes of compounds for a given therapeutic category. This commentary will briefly review the benefits and applications of this technology in drug discovery and design, and will also highlight its historical evolution. The two most commonly used approaches for pharmacophore model development will be discussed, and several examples of how this technology was successfully applied to identify new potent leads will be provided. The article concludes with a brief outline of the controversial issue of patentability of pharmacophore models.

  14. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism

    DEFF Research Database (Denmark)

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

    2016-01-01

    )-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......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...... 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...

  15. Controlled release hydrophilic matrix tablet formulations of isoniazid: design and in vitro studies.

    Science.gov (United States)

    Hiremath, Praveen S; Saha, Ranendra N

    2008-01-01

    The aim of the present investigation was to develop oral controlled release matrix tablet formulations of isoniazid using hydroxypropyl methylcellulose (HPMC) as a hydrophilic release retardant polymer and to study the influence of various formulation factors like proportion of the polymer, polymer viscosity grade, compression force, and release media on the in vitro release characteristics of the drug. The formulations were developed using wet granulation technology. The in vitro release studies were performed using US Pharmacopoeia type 1 apparatus (basket method) in 900 ml of pH 7.4 phosphate buffer at 100 rpm. The release kinetics was analyzed using Korsmeyer-Peppas model. The release profiles were also analyzed using statistical method (one-way analysis of variance) and f (2) metric values. The release profiles found to follow Higuchi's square root kinetics model irrespective of the polymer ratio and the viscosity grade used. The results in the present investigation confirm that the release rate of the drug from the HPMC matrices is highly influenced by the drug/HPMC ratio and viscosity grade of the HPMC. Also, the effect of compression force and release media was found to be significant on the release profiles of isoniazid from HPMC matrix tablets. The release mechanism was found to be anomalous non-Fickian diffusion in all the cases. In the present investigation, a series of controlled release formulations of isoniazid were developed with different release rates and duration so that these formulations could further be assessed from the in vivo bioavailability studies. The formulations were found to be stable and reproducible.

  16. Effects of ultrasound and sodium lauryl sulfate on the transdermal delivery of hydrophilic permeants: Comparative in vitro studies with full-thickness and split-thickness pig and human skin.

    Science.gov (United States)

    Seto, Jennifer E; Polat, Baris E; Lopez, Renata F V; Blankschtein, Daniel; Langer, Robert

    2010-07-01

    The simultaneous application of ultrasound and the surfactant sodium lauryl sulfate (referred to as US/SLS) to skin enhances transdermal drug delivery (TDD) in a synergistic mechanical and chemical manner. Since full-thickness skin (FTS) and split-thickness skin (STS) differ in mechanical strength, US/SLS treatment may have different effects on their transdermal transport pathways. Therefore, we evaluated STS as an alternative to the well-established US/SLS-treated FTS model for TDD studies of hydrophilic permeants. We utilized the aqueous porous pathway model to compare the effects of US/SLS treatment on the skin permeability and the pore radius of pig and human FTS and STS over a range of skin electrical resistivity values. Our findings indicate that the US/SLS-treated pig skin models exhibit similar permeabilities and pore radii, but the human skin models do not. Furthermore, the US/SLS-enhanced delivery of gold nanoparticles and quantum dots (two model hydrophilic macromolecules) is greater through pig STS than through pig FTS, due to the presence of less dermis that acts as an artificial barrier to macromolecules. In spite of greater variability in correlations between STS permeability and resistivity, our findings strongly suggest the use of 700microm-thick pig STS to investigate the in vitro US/SLS-enhanced delivery of hydrophilic macromolecules. 2010 Elsevier B.V. All rights reserved.

  17. A Systems Dynamic Model for Drug Abuse and Drug-Related Crime in the Western Cape Province of South Africa

    Directory of Open Access Journals (Sweden)

    Farai Nyabadza

    2017-01-01

    Full Text Available The complex problem of drug abuse and drug-related crimes in communities in the Western Cape province cannot be studied in isolation but through the system they are embedded in. In this paper, a theoretical model to evaluate the syndemic of substance abuse and drug-related crimes within the Western Cape province of South Africa is constructed and explored. The dynamics of drug abuse and drug-related crimes within the Western Cape are simulated using STELLA software. The simulation results are consistent with the data from SACENDU and CrimeStats SA, highlighting the usefulness of such a model in designing and planning interventions to combat substance abuse and its related problems.

  18. A theory of drug tolerance and dependence II: the mathematical model.

    Science.gov (United States)

    Peper, Abraham

    2004-08-21

    The preceding paper presented a model of drug tolerance and dependence. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of exogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary in dependence and addiction or when the drug administration bypasses the natural-oral-route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behaviour to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. The present paper discusses the mathematical model in terms of its design. The model is a nonlinear, learning feedback system, fully satisfying control theoretical principles. It accepts any form of the stimulus-the drug intake-and describes how the physiological processes involved affect the distribution of the drug through the body and the stability of the regulation loop. The mathematical model verifies the proposed theory and provides a basis for the implementation of mathematical models of specific physiological processes.

  19. DFT application for chlorin derivatives photosensitizer drugs modeling

    Science.gov (United States)

    Machado, Neila; Carvalho, B. G.; Téllez Soto, C. A.; Martin, A. A.; Favero, P. P.

    2018-04-01

    Photodynamic therapy is an alternative form of cancer treatment that meets the desire for a less aggressive approach to the body. It is based on the interaction between a photosensitizer, activating light, and molecular oxygen. This interaction results in a cascade of reactions that leads to localized cell death. Many studies have been conducted to discover an ideal photosensitizer, which aggregates all the desirable characteristics of a potent cell killer and generates minimal side effects. Using Density Functional Theory (DFT) implemented in the program Vienna Ab-initio Simulation Package, new chlorin derivatives with different functional groups were simulated to evaluate the different absorption wavelengths to permit resonant absorption with the incident laser. Gaussian 09 program was used to determine vibrational wave numbers and Natural Bond Orbitals. The chosen drug with the best characteristics for the photosensitizer was a modified model of the original chlorin, which was called as Thiol chlorin. According to our calculations it is stable and is 19.6% more efficient at optical absorption in 708 nm in comparison to the conventional chlorin e6. Vibrational modes, optical and electronic properties were predicted. In conclusion, this study is an attempt to improve the development of new photosensitizer drugs through computational methods that save time and contribute to decrease the numbers of animals for model application.

  20. Analyzing research trends on drug safety using topic modeling.

    Science.gov (United States)

    Zou, Chen

    2018-04-06

    Published drug safety data has evolved in the past decade due to scientific and technological advances in the relevant research fields. Considering that a vast amount of scientific literature has been published in this area, it is not easy to identify the key information. Topic modeling has emerged as a powerful tool to extract meaningful information from a large volume of unstructured texts. Areas covered: We analyzed the titles and abstracts of 4347 articles in four journals dedicated to drug safety from 2007 to 2016. We applied Latent Dirichlet allocation (LDA) model to extract 50 main topics, and conducted trend analysis to explore the temporal popularity of these topics over years. Expert Opinion/Commentary: We found that 'benefit-risk assessment and communication', 'diabetes' and 'biologic therapy for autoimmune diseases' are the top 3 most published topics. The topics relevant to the use of electronic health records/observational data for safety surveillance are becoming increasingly popular over time. Meanwhile, there is a slight decrease in research on signal detection based on spontaneous reporting, although spontaneous reporting still plays an important role in benefit-risk assessment. The topics related to medical conditions and treatment showed highly dynamic patterns over time.

  1. 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...

  2. A developmental etiological model for drug abuse in men.

    Science.gov (United States)

    Kendler, Kenneth S; Ohlsson, Henrik; Edwards, Alexis C; Sundquist, Jan; Sundquist, Kristina

    2017-10-01

    We attempt to develop a relatively comprehensive structural model of risk factors for drug abuse (DA) in Swedish men that illustrates developmental and mediational processes. We examined 20 risk factors for DA in 48,369 men undergoing conscription examinations in 1969-70 followed until 2011 when 2.34% (n=1134) of them had DA ascertained in medical, criminal and pharmacy registries. Risk factors were organized into four developmental tiers reflecting i) birth, ii) childhood/early adolescence, iii) late adolescence, and iv) young adulthood. Structural equational model fitting was performed using Mplus. The best fitting model explained 47.8% of the variance in DA. The most prominent predictors, in order, were: early adolescent externalizing behavior, early adult criminal behavior, early adolescent internalizing behavior, early adult unemployment, early adult alcohol use disorder, and late adolescent drug use. Two major inter-connecting pathways emerged reflecting i) genetic/familial risk and ii) family dysfunction and psychosocial adversity. Generated on a first and tested on a second random half of the sample, a model from these variables predicted DA with an ROC area under the curve of 83.6%. Fifty-nine percent of DA cases arose from subjects in the top decile of risk. DA in men is a highly multifactorial syndrome with risk arising from familial-genetic, psychosocial, behavioral and psychological factors acting and interacting over development. Among the multiple predisposing factors for DA, a range of psychosocial adversities, externalizing psychopathology and lack of social constraints in early adulthood are predominant. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. 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.

  4. Solubility and dissolution enhancement of flurbiprofen by solid dispersion using hydrophilic carriers

    Directory of Open Access Journals (Sweden)

    Bhaskar Daravath

    2018-05-01

    Full Text Available ABSTRACT The intent of the current work is to study the effect of polyethylene glycol 8000 and polyethylene glycol 10000 as hydrophilic carriers on dissolution behaviour of flurbiprofen. In the present study, solvent evaporation method was used to prepare flurbiprofen solid dispersions and evaluated for physico-chemical properties, drug-carrier compatibility studies and dissolution behaviour of drug. Solubility studies showed more solubility in higher pH values and formulations SD4 and SD8 were selected to prepare the fast dissolving tablets. FTIR and DSC study showed no interaction and drug was dispersed molecularly in hydrophilic carrier. XRD studies revealed that there was change in the crystallinity of the drug. The results of In vitro studies showed SD8 formulation confer significant improvement (p<0.05 in drug release, Q20 was 99.08±1.35% compared to conventional and marketed tablets (47.31±0.74% and 56.86±1.91%. The mean dissolution time (MDT was reduced to 8.79 min compared to conventional and marketed tablets (25.76 and 22.22 min. indicating faster drug release. The DE (% dissolution efficiency was increased by 2.5 folds (61.63% compared to conventional tablets (23.71%. From the results, it is evident that polyethylene glycol solid dispersions in less carrier ratio may enhance the solubility and there by improve the dissolution rate of flurbiprofen.

  5. 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.

  6. 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. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. A rapid hydrophilic interaction liquid chromatographic determination of glimepiride in pharmaceutical formulations

    Directory of Open Access Journals (Sweden)

    Si Zhou

    2017-09-01

    Full Text Available Glimepiride is one of the most widely prescribed antidiabetic drugs and contains both hydrophobic and hydrophilic functional groups in its molecules, and thus could be analyzed by either reversed-phase high performance liquid chromatography (HPLC or hydrophilic interaction liquid chromatography (HILIC. In the literature, however, only reversed-phase HPLC has been reported. In this study, a simple, rapid and accurate hydrophilic interaction liquid chromatographic method was developed for the determination of glimepiride in pharmaceutical formulations. The analytical method comprised a fast ultrasound-assisted extraction with acetonitrile as a solvent followed by HILIC separation and quantification using a Waters Spherisorb S5NH2 hydrophilic column with a mobile phase consisting of acetonitrile and aqueous acetate buffer (5.0 mM. The retention time of glimepiride increased slightly with decrease of mobile phase pH value from 6.8 to 5.8 and of acetonitrile content from 60% to 40%, indicating that both hydrophilic, ionic, and hydrophobic interactions were involved in the HILIC retention and elution mechanisms. Quantitation was carried out with a mobile phase of 40% acetonitrile and 60% aqueous acetate buffer (5.0 mM at pH 6.3, by relating the peak area of glimepiride to that of the internal standard, with a detection limit of 15.0 μg/L. UV light absorption responses at 228 nm were linear over a wide concentration range from 50.0 μg/L to 6.00 mg/L. The recoveries of the standard added to pharmaceutical tablet samples were 99.4–103.0% for glimepiride, and the relative standard deviation for the analyte was less than 1.0%. This method has been successfully applied to determine the glimepiride contents in pharmaceutical formulations.

  8. Hydration layers trapped between graphene and a hydrophilic substrate

    International Nuclear Information System (INIS)

    Temmen, M; Reichling, M; Bollmann, T R J; Ochedowski, O; Schleberger, M

    2014-01-01

    Graphene is mechanically exfoliated on CaF 2 (111) under ambient conditions. We demonstrate the formation of a several monolayer thick hydration layer on the hydrophilic substrate and its response to annealing at temperatures up to 750 K in an ultra-high vacuum environment. Upon heating, water is released, however, it is impossible to remove the first layer. The initially homogeneous film separates into water-containing and water-free domains by two-dimensional Ostwald ripening. Upon severe heating, thick graphene multilayers undergo rupture, while nanoblisters confining sealed water appear on thinner sheets, capable of the storage and release of material. From modeling the dimensions of the nanoblisters, we estimate the graphene/CaF 2 (111) interfacial adhesion energy to be 0.33±0.13 J m −2 , thereby viable for polymer-assisted transfer printing. (paper)

  9. On the hydrophilicity of electrodes for capacitive energy extraction

    International Nuclear Information System (INIS)

    Lian, Cheng; East China University of Science and Technology, Shanghai; Kong, Xian; Tsinghua University, Beijing; Liu, Honglai; Wu, Jianzhong

    2016-01-01

    The so-called Capmix technique for energy extraction is based on the cyclic expansion of electrical double layers to harvest dissipative energy arising from the salinity difference between freshwater and seawater. Its optimal performance requires a careful selection of the electrical potentials for the charging and discharging processes, which must be matched with the pore characteristics of the electrode materials. While a number of recent studies have examined the effects of the electrode pore size and geometry on the capacitive energy extraction processes, there is little knowledge on how the surface properties of the electrodes affect the thermodynamic efficiency. In this paper, we investigate the Capmix processes using the classical density functional theory for a realistic model of electrolyte solutions. The theoretical predictions allow us to identify optimal operation parameters for capacitive energy extraction with porous electrodes of different surface hydrophobicity. Finally, in agreement with recent experiments, we find that the thermodynamic efficiency can be much improved by using most hydrophilic electrodes.

  10. 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.

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

    KAUST Repository

    Fetsch, Corinna; Grossmann, Arlett; Holz, Lisa; Nawroth, Jonas F.; Luxenhofer, Robert

    2011-01-01

    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.

  12. Molecular Dynamics Simulations of Hydrophilic Pores in Lipid Bilayers

    NARCIS (Netherlands)

    Leontiadou, Hari; Mark, Alan E.; Marrink, Siewert J.

    Hydrophilic pores are formed in peptide free lipid bilayers under mechanical stress. It has been proposed that the transport of ionic species across such membranes is largely determined by the existence of such meta-stable hydrophilic pores. To study the properties of these structures and understand

  13. Neutral hydrophilic cathode catalyst binders for microbial fuel cells

    KAUST Repository

    Saito, Tomonori; Roberts, Timothy H.; Long, Timothy E.; Logan, Bruce E.; Hickner, Michael A.

    2011-01-01

    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

  14. A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

    Science.gov (United States)

    Cherkaoui-Rbati, Mohammed H; Paine, Stuart W; Littlewood, Peter; Rauch, Cyril

    2017-01-01

    All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

  15. A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

    Directory of Open Access Journals (Sweden)

    Mohammed H Cherkaoui-Rbati

    Full Text Available All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs of new chemical entities (NCEs and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit, located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level. A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

  16. 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.

  17. Illicit drugs and the media: models of media effects for use in drug policy research.

    Science.gov (United States)

    Lancaster, Kari; Hughes, Caitlin E; Spicer, Bridget; Matthew-Simmons, Francis; Dillon, Paul

    2011-07-01

    Illicit drugs are never far from the media gaze and although identified almost a decade ago as 'a new battleground' for the alcohol and other drug (AOD) field there has been limited research examining the role of the news media and its effects on audiences and policy. This paper draws together media theories from communication literature to examine media functions. We illustrate how each function is relevant for media and drugs research by drawing upon the existing literature examining Australian media coverage during the late 1990s of escalating heroin-related problems and proposed solutions. Media can influence audiences in four key ways: by setting the agenda and defining public interest; framing issues through selection and salience; indirectly shaping individual and community attitudes towards risk; and feeding into political debate and decision making. Each has relevance for the AOD field. For example, media coverage of the escalating heroin-related problems in Australia played a strong role in generating interest in heroin overdoses, framing public discourse in terms of a health and/or criminal issue and affecting political decisions. Implications AND CONCLUSION: Media coverage in relation to illicit drugs can have multifarious effects. Incorporating media communication theories into future research and actions is critical to facilitate understanding of the short- and long-term impacts of media coverage on illicit drugs and the avenues by which the AOD field can mitigate or inform future media debates on illicit drugs. © 2010 Australasian Professional Society on Alcohol and other Drugs.

  18. [Categories and characteristics of BPH drug evaluation models: a comparative study].

    Science.gov (United States)

    Huang, Dong-Yan; Wu, Jian-Hui; Sun, Zu-Yue

    2014-02-01

    Benign prostatic hyperplasia (BPH) is a worldwide common disease in men over 50 years old, and the exact cause of BPH remains largely unknown. In order to elucidate its pathogenesis and screen effective drugs for the treatment of BPH, many BPH models have been developed at home and abroad. This article presents a comprehensive analysis of the categories and characteristics of BPH drug evaluation models, highlighting the application value of each model, to provide a theoretical basis for the development of BPH drugs.

  19. Preparation and Evaluation of Taste Masked Famotidine Formulation Using Drug/β-cyclodextrin/Polymer Ternary Complexation Approach

    OpenAIRE

    Patel, Ashok R.; Vavia, Pradeep R.

    2008-01-01

    The main aim of the present study was to evaluate potential of ternary complexation (comprising of drug, cyclodextrin and polymer) as an approach for taste masking. For this purpose famotidine with property of bitter taste was selected as a model drug. Improvement in taste masking capability of cyclodextrin towards famotidine was evaluated by formulating a ternary complex including hydrophilic polymer hydroxyl propyl methyl cellulose (HPMC 5 cps) as the third component. Phase solubility analy...

  20. Peramivir analogues bearing hydrophilic side chains exhibit higher activities against H275Y mutant than wild-type influenza virus.

    Science.gov (United States)

    Chiu, Din-Chi; Lin, Tzu-Chen; Huang, Wen-I; Cheng, Ting-Jen; Tsai, Keng-Chang; Fang, Jim-Min

    2017-11-29

    Peramivir is an effective anti-influenza drug in the clinical treatment of influenza, but its efficacy toward the H275Y mutant is reduced. The previously reported cocrystal structures of inhibitors in the mutant neuraminidase (NA) suggest that the hydrophobic side chain should be at the origin of reduced binding affinity. In contrast, zanamivir having a hydrophilic glycerol side chain still possesses high affinity toward the H275Y NA. We thus designed five peramivir analogues (5-9) carrying hydrophilic glycol or glycerol side chains, and evaluated their roles in anti-influenza activity, especially for the H275Y mutant. The synthetic sequence involves a key step of (3 + 2) cycloaddition reactions between alkenes and nitrile oxides to construct the scaffold of peramivir carrying the desired hydrophilic side chains and other appropriate functional groups. The molecular docking experiments reveal that the hydrophilic side chain can provide extra hydrogen bonding with the translocated Glu-276 residue in the H275Y NA active site. Thus, the H275Y mutant may be even more sensitive than wild-type virus toward the peramivir analogues bearing hydrophilic side chains. Notably, the peramivir analogue bearing a glycerol side chain inhibits the H275Y mutant with an IC 50 value of 35 nM, which is better than the WSN virus by 9 fold.

  1. 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.

  2. In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models.

    Science.gov (United States)

    Sjögren, Erik; Thörn, Helena; Tannergren, Christer

    2016-06-06

    Gastrointestinal (GI) drug absorption is a complex process determined by formulation, physicochemical and biopharmaceutical factors, and GI physiology. Physiologically based in silico absorption models have emerged as a widely used and promising supplement to traditional in vitro assays and preclinical in vivo studies. However, there remains a lack of comparative studies between different models. The aim of this study was to explore the strengths and limitations of the in silico absorption models Simcyp 13.1, GastroPlus 8.0, and GI-Sim 4.1, with respect to their performance in predicting human intestinal drug absorption. This was achieved by adopting an a priori modeling approach and using well-defined input data for 12 drugs associated with incomplete GI absorption and related challenges in predicting the extent of absorption. This approach better mimics the real situation during formulation development where predictive in silico models would be beneficial. Plasma concentration-time profiles for 44 oral drug administrations were calculated by convolution of model-predicted absorption-time profiles and reported pharmacokinetic parameters. Model performance was evaluated by comparing the predicted plasma concentration-time profiles, Cmax, tmax, and exposure (AUC) with observations from clinical studies. The overall prediction accuracies for AUC, given as the absolute average fold error (AAFE) values, were 2.2, 1.6, and 1.3 for Simcyp, GastroPlus, and GI-Sim, respectively. The corresponding AAFE values for Cmax were 2.2, 1.6, and 1.3, respectively, and those for tmax were 1.7, 1.5, and 1.4, respectively. Simcyp was associated with underprediction of AUC and Cmax; the accuracy decreased with decreasing predicted fabs. A tendency for underprediction was also observed for GastroPlus, but there was no correlation with predicted fabs. There were no obvious trends for over- or underprediction for GI-Sim. The models performed similarly in capturing dependencies on dose and

  3. Testing antidepressant compounds in a neuropsychological model of drug action

    NARCIS (Netherlands)

    Cerit, Hilal

    2015-01-01

    Although much research effort has been put into the development of new antidepressant drugs, the process of developing a drug often fails at the stage of large randomized controlled trials (RCTs) in which an initially promising compound appears to lack efficacy after all. Several experimental

  4. Pitfalls in TDM of antibiotic drugs : Analytical and modelling issues

    NARCIS (Netherlands)

    Neef, C.; Touw, D. J.; Harteveld, A. R.; Eerland, J. J.; Uges, D. R. A.

    2006-01-01

    The quality assurance program of the Dutch KKGT [Association for Quality Assessment in therapeutic drug monitoring (TDM) and Clinical Toxicology] has been running for more than 25 years. One of these programs concerns TDM of the antibiotic drugs gentamicin, tobramycin, amikacin, and vancomycin. We

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

    African Journals Online (AJOL)

    Administrator

    The spread of HIV among drug and alcohol users, as a high-risk group, is a significant problem in Africa, as in other ... alcohol and drug addiction in many ... training in providing addiction recovery ..... because of its large scale availability and.

  6. 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.

  7. Model for Microcapsule Drug Release with Ultrasound-Activated Enhancement.

    Science.gov (United States)

    Tsao, Nadia H; Hall, Elizabeth A H

    2017-11-14

    Microbubbles and microcapsules of silane-polycaprolactone (SiPCL) have been filled with a fluorescent acridium salt (lucigenin) as a model for a drug-loaded delivery vehicle. The uptake and delivery were studied and compared with similar microbubbles and microcapsules of silica/mercaptosilica (S/M/S). Positively charged lucigenin was encapsulated through an electrostatic mechanism, following a Type I Langmuir isotherm as expected, but with an additional multilayer uptake that leads to a much higher loading for the SiPCL system (∼280 μg/2.4 × 10 9 microcapsules compared with ∼135 μg/2.4 × 10 9 microcapsules for S/M/S). Whereas the lucigenin release from the S/M/S bubbles and capsules loaded below the solubility limit is consistent with diffusion from a monolithic structure, the SiPCL structures show distinct release patterns; the Weibull function predicts a general trend for diffusion from normal Euclidean space at short times tending toward diffusion out of fractal spaces with increasing time. As a slow release system, the dissolution time (T d ) increases from 1 to 2 days for the S/M/S and for the low concentration, loaded SiPCl vehicles to ∼10 days for the high loaded microcapsules. However, T d can be reduced on insonation to 2 days, indicating the potential to gain control over the local enhanced release with ultrasound. This was tested for a docetaxel model and its effect on C4-2B prostate cancer cells, showing improved cell toxicity for concentrations below the normal EC 50 in solution.

  8. 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.

  9. Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling: Screening Polymers for Drug Release, Drug-Polymer Miscibility and Printability.

    Science.gov (United States)

    Solanki, Nayan G; Tahsin, Md; Shah, Ankita V; Serajuddin, Abu T M

    2018-01-01

    The primary aim of this study was to identify pharmaceutically acceptable amorphous polymers for producing 3D printed tablets of a model drug, haloperidol, for rapid release by fused deposition modeling. Filaments for 3D printing were prepared by hot melt extrusion at 150°C with 10% and 20% w/w of haloperidol using Kollidon ® VA64, Kollicoat ® IR, Affinsiol ™ 15 cP, and HPMCAS either individually or as binary blends (Kollidon ® VA64 + Affinisol ™ 15 cP, 1:1; Kollidon ® VA64 + HPMCAS, 1:1). Dissolution of crushed extrudates was studied at pH 2 and 6.8, and formulations demonstrating rapid dissolution rates were then analyzed for drug-polymer, polymer-polymer and drug-polymer-polymer miscibility by film casting. Polymer-polymer (1:1) and drug-polymer-polymer (1:5:5 and 2:5:5) mixtures were found to be miscible. Tablets with 100% and 60% infill were printed using MakerBot printer at 210°C, and dissolution tests of tablets were conducted at pH 2 and 6.8. Extruded filaments of Kollidon ® VA64-Affinisol ™ 15 cP mixtures were flexible and had optimum mechanical strength for 3D printing. Tablets containing 10% drug with 60% and 100% infill showed complete drug release at pH 2 in 45 and 120 min, respectively. Relatively high dissolution rates were also observed at pH 6.8. The 1:1-mixture of Kollidon ® VA64 and Affinisol ™ 15 cP was thus identified as a suitable polymer system for 3D printing and rapid drug release. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  10. Systematic synergy modeling: understanding drug synergy from a systems biology perspective.

    Science.gov (United States)

    Chen, Di; Liu, Xi; Yang, Yiping; Yang, Hongjun; Lu, Peng

    2015-09-16

    Owing to drug synergy effects, drug combinations have become a new trend in combating complex diseases like cancer, HIV and cardiovascular diseases. However, conventional synergy quantification methods often depend on experimental dose-response data which are quite resource-demanding. In addition, these methods are unable to interpret the explicit synergy mechanism. In this review, we give representative examples of how systems biology modeling offers strategies toward better understanding of drug synergy, including the protein-protein interaction (PPI) network-based methods, pathway dynamic simulations, synergy network motif recognitions, integrative drug feature calculations, and "omic"-supported analyses. Although partially successful in drug synergy exploration and interpretation, more efforts should be put on a holistic understanding of drug-disease interactions, considering integrative pharmacology and toxicology factors. With a comprehensive and deep insight into the mechanism of drug synergy, systems biology opens a novel avenue for rational design of effective drug combinations.

  11. Stimuli-Responsive Liposomes for Controlled Drug Delivery

    KAUST Repository

    Li, Wengang

    2014-01-01

    Liposomes are promising drug delivery vesicles due to their biodegradibility, large volume and biocompatibility towards both hydrophilic and hydrophobic drugs. They suffer, however, from poor stability which limits their use in controlled delivery

  12. 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.

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

    International Nuclear Information System (INIS)

    Ferreira, Tiago Hilário; Soares, Daniel Crístian Ferreira; Moreira, Luciana Mara Costa; Ornelas da Silva, Paulo Roberto; Gouvêa dos Santos, Raquel; Barros de Sousa, Edésia Martins

    2013-01-01

    In the present study, Boron Nitride Nanotubes (BNNTs) were synthesized and functionalized with organic hydrophilic agents constituted by glucosamine (GA), polyethylene glycol (PEG) 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. Antioxidant activity and possible bioactive components in hydrophilic and lipophilic fractions from the seaweed Halimeda incrassata

    Directory of Open Access Journals (Sweden)

    Alexis Vidal Novoa

    2011-02-01

    Full Text Available Hydrophilic and lipophilic fractions, obtained from the marine algae Halimeda incrassata (J.Ellis J.V.Lamouroux, Halimedaceae, were studied by using the ²-carotene-linoleate assay system. In case of hydrophilic fractions, the total phenolic compounds were quantified and two of their components were identified as salicylic and ferulic acids. From the lipophilic fraction, fatty acid composition was studied. The highest antioxidant activities values were found on the polar fractions containing phenolic acids. The total phenolics content on the hydrophilic fractions was 255 μg of gallic acid equivalents/g of fresh seaweed. To further characterize H. incrassata chemical composition, the total lipid content was quantified (7.4 mg per gram of dried algae as well as the saturated and unsaturated fatty acids ratio (1:1.46. In summary, this paper adds more convincing evidences in support of the antioxidant abilities of the lyophilized aqueous extract of Halimeda incrassata and it also relates this bioactivity, for the first time, with particular phenolic components of the extract. Altogether, these results represent another step towards the use of this natural product as drug candidates.

  15. 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.

  16. 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…

  17. Retrospective use of PBPK modelling to understand a clinical drug-drug interaction between dextromethorphan and GSK1034702.

    Science.gov (United States)

    Hobbs, Michael J; Bloomer, Jackie; Dear, Gordon

    2017-08-01

    1. In a clinical trial, a strong drug-drug interaction (DDI) was observed between dextromethorphan (DM, the object or victim drug) and GSK1034702 (the precipitant or perpetrator drug), following single and repeat doses. This study determined the inhibition parameters of GSK1034702 in vitro and applied PBPK modelling approaches to simulate the clinical observations and provide mechanistic hypotheses to understand the DDI. 2. In vitro assays were conducted to determine the inhibition parameters of human CYP2D6 by GSK1034702. PBPK models were populated with the in vitro parameters and DDI simulations conducted and compared to the observed data from a clinical study with DM and GSK1034702. 3. GSK1034702 was a potent direct and metabolism-dependent inhibitor of human CYP2D6, with inhibition parameters of: IC 50  =   1.6 μM, K inact  = 3.7 h -1 and K I  = 0.8 μM. Incorporating these data into PBPK models predicted a DDI after repeat, but not single, 5 mg doses of GSK1034702. 4. The DDI observed with repeat administration of GSK1034702 (5 mg) can be attributed to metabolism-dependent inhibition of CYP2D6. Further, in vitro data were generated and several potential mechanisms proposed to explain the interaction observed following a single dose of GSK1034702.

  18. 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.

  19. Blood-brain barrier in vitro models as tools in drug discovery: assessment of the transport ranking of antihistaminic drugs.

    Science.gov (United States)

    Neuhaus, W; Mandikova, J; Pawlowitsch, R; Linz, B; Bennani-Baiti, B; Lauer, R; Lachmann, B; Noe, C R

    2012-05-01

    In the course of our validation program testing blood-brain barrier (BBB) in vitro models for their usability as tools in drug discovery it was evaluated whether an established Transwell model based on porcine cell line PBMEC/C1-2 was able to differentiate between the transport properties of first and second generation antihistaminic drugs. First generation antihistamines can permeate the BBB and act in the central nervous system (CNS), whereas entry to the CNS of second generation antihistamines is restricted by efflux pumps such as P-glycoprotein (P-gP) located in brain endothelial cells. P-gP functionality of PBMEC/C1-2 cells grown on Transwell filter inserts was proven by transport studies with P-gP substrate rhodamine 123 and P-gP blocker verapamil. Subsequent drug transport studies with the first generation antihistamines promethazine, diphenhydramine and pheniramine and the second generation antihistamines astemizole, ceterizine, fexofenadine and loratadine were accomplished in single substance as well as in group studies. Results were normalised to diazepam, an internal standard for the transcellular transport route. Moreover, effects after addition of P-gP inhibitor verapamil were investigated. First generation antihistamine pheniramine permeated as fastest followed by diphenhydramine, diazepam, promethazine and second generation antihistaminic drugs ceterizine, fexofenadine, astemizole and loratadine reflecting the BBB in vivo permeability ranking well. Verapamil increased the transport rates of all second generation antihistamines, which suggested involvement of P-gP during their permeation across the BBB model. The ranking after addition of verapamil was significantly changed, only fexofenadine and ceterizine penetrated slower than internal standard diazepam in the presence of verapamil. In summary, permeability data showed that the BBB model based on porcine cell line PBMEC/C1-2 was able to reflect the BBB in vivo situation for the transport of

  20. 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

  1. Nanotoxicity comparison of four amphiphilic polymeric micelles with similar hydrophilic or hydrophobic structure.

    Science.gov (United States)

    Zhao, Bo; Wang, Xue-Qing; Wang, Xiao-You; Zhang, Hua; Dai, Wen-Bing; Wang, Jun; Zhong, Zhen-Lin; Wu, Hou-Nan; Zhang, Qiang

    2013-10-03

    Nanocarriers represent an attractive means of drug delivery, but their biosafety must be established before their use in clinical research. Four kinds of amphiphilic polymeric (PEG-PG-PCL, PEEP-PCL, PEG-PCL and PEG-DSPE) micelles with similar hydrophilic or hydrophobic structure were prepared and their in vitro and in vivo safety were evaluated and compared. In vitro nanotoxicity evaluations included assessments of cell morphology, cell volume, inflammatory effects, cytotoxicity, apoptosis and membrane fluidity. An umbilical vein cell line (Eahy.926) and a kind of macrophages (J774.A1) were used as cell models considering that intravenous route is dominant for micelle delivery systems. In vivo analyses included complete blood count, lymphocyte subset analysis, detection of plasma inflammatory factors and histological observations of major organs after intravenous administration to KM mice. All the micelles enhanced inflammatory molecules in J774.A1 cells, likely resulting from the increased ROS levels. PEG-PG-PCL and PEEP-PCL micelles were found to increase the J774.A1 cell volume. This likely correlated with the size of PEG-PG-PCL micelles and the polyphosphoester structure in PEEP-PCL. PEG-DSPE micelles inhibited the growth of Eahy.926 cells via inducing apoptosis. This might relate to the structure of DSPE, which is a type of phospholipid and has good affinity with cell membrane. No evidence was found for cell membrane changes after treatment with these micelles for 24 h. In the in vivo study, during 8 days of 4 time injection, each of the four nanocarriers altered the hematic phase differently without changes in inflammatory factors or pathological changes in target organs. These results demonstrate that the micelles investigated exhibit diverse nanotoxicity correlated with their structures, their biosafety is different in different cell model, and there is no in vitro and in vivo correlation found. We believe that this study will certainly provide more

  2. New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition.

    Science.gov (United States)

    Peletier, Lambertus A; Gabrielsson, Johan

    2018-05-14

    In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between-individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such.

  3. A reaction limited in vivo dissolution model for the study of drug absorption: Towards a new paradigm for the biopharmaceutic classification of drugs.

    Science.gov (United States)

    Macheras, Panos; Iliadis, Athanassios; Melagraki, Georgia

    2018-05-30

    The aim of this work is to develop a gastrointestinal (GI) drug absorption model based on a reaction limited model of dissolution and consider its impact on the biopharmaceutic classification of drugs. Estimates for the fraction of dose absorbed as a function of dose, solubility, reaction/dissolution rate constant and the stoichiometry of drug-GI fluids reaction/dissolution were derived by numerical solution of the model equations. The undissolved drug dose and the reaction/dissolution rate constant drive the dissolution rate and determine the extent of absorption when high-constant drug permeability throughout the gastrointestinal tract is assumed. Dose is an important element of drug-GI fluids reaction/dissolution while solubility exclusively acts as an upper limit for drug concentrations in the lumen. The 3D plots of fraction of dose absorbed as a function of dose and reaction/dissolution rate constant for highly soluble and low soluble drugs for different "stoichiometries" (0.7, 1.0, 2.0) of the drug-reaction/dissolution with the GI fluids revealed that high extent of absorption was found assuming high drug- reaction/dissolution rate constant and high drug solubility. The model equations were used to simulate in vivo supersaturation and precipitation phenomena. The model developed provides the theoretical basis for the interpretation of the extent of drug's absorption on the basis of the parameters associated with the drug-GI fluids reaction/dissolution. A new paradigm emerges for the biopharmaceutic classification of drugs, namely, a model independent biopharmaceutic classification scheme of four drug categories based on either the fulfillment or not of the current dissolution criteria and the high or low % drug metabolism. Copyright © 2018. Published by Elsevier B.V.

  4. Sex differences and ovarian hormones in animal models of drug dependence.

    Science.gov (United States)

    Carroll, Marilyn E; Anker, Justin J

    2010-06-01

    Increasing evidence indicates the presence of sex differences in many aspects of drug abuse. Most studies reveal that females exceed males during the initiation, escalation, extinction, and reinstatement (relapse) of drug-seeking behavior, but males are more sensitive than females to the aversive effects of drugs such as drug withdrawal. Findings from human and animal research indicate that circulating levels of ovarian steroid hormones account for these sex differences. Estrogen (E) facilitates drug-seeking behavior, while progesterone (P) and its metabolite, allopregnanalone (ALLO), counteract the effects of E and reduce drug seeking. Estrogen and P influence other behaviors that are affiliated with drug abuse such as drug-induced locomotor sensitization and conditioned place preference. The enhanced vulnerability to drug seeking in females vs. males is also additive with the other risk factors for drug abuse (e.g., adolescence, sweet preference, novelty reactivity, and impulsivity). Finally, treatment studies using behavioral or pharmacological interventions, including P and ALLO, also indicate that females show greater treatment effectiveness during several phases of the addiction process. The neurobiological basis of sex differences in drug abuse appears to be genetic and involves the influence of ovarian hormones and their metabolites, the hypothalamic pituitary adrenal (HPA) axis, dopamine (DA), and gamma-hydroxy-butyric acid (GABA). Overall, sex and hormonal status along with other biological risk factors account for a continuum of addiction-prone and -resistant animal models that are valuable for studying drug abuse prevention and treatment strategies. Copyright 2009. Published by Elsevier Inc.

  5. In vitro and in vivo models for testing arrhythmogenesis in drugs.

    Science.gov (United States)

    Carlsson, L

    2006-01-01

    The steadily increasing list of drugs associated with prolongation of the QT interval and torsades de pointes (TdP) constitute a medical problem of major concern. Hence, there is a need at an early stage to identify drug candidates with an inherent capacity to induce repolarization-related proarrhythmias, avoiding exposure of large populations to potentially harmful drugs. Furthermore, the availability of clinically relevant and predictive animal models should reduce the risk that effective and potentially life-saving drugs never reach the market. This review will discuss the pros and cons of some in vivo and in vitro animal models for assessing proarrhythmia liability.

  6. Evaluation of the whole body physiologically based pharmacokinetic (WB-PBPK) modeling of drugs.

    Science.gov (United States)

    Munir, Anum; Azam, Shumaila; Fazal, Sahar; Bhatti, A I

    2018-08-14

    The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption. The aim of this scientific study is to hypothesize a WB-PBPK model through integrating absorption, distribution, metabolism, and elimination processes with the existing PBPK model.Absorption, distribution, metabolism, and elimination models are designed, integrated with PBPK model and validated. For validation purposes, clinical records of few drugs are collected from the literature. The developed WB-PBPK model is affirmed by comparing the simulations produced by the model against the searched clinical data. . It is proposed that the WB-PBPK model may be used in pharmaceutical industries to create of the pharmacokinetic profiles of drug candidates for better outcomes, as it is advance PBPK model and creates comprehensive PK profiles for drug ADME in concentration-time plots. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Development and characterization of glutathione-conjugated albumin nanoparticles for improved brain delivery of hydrophilic fluorescent marker.

    Science.gov (United States)

    Patel, Prerak J; Acharya, Niyati S; Acharya, Sanjeev R

    2013-01-01

    The glutathione-conjugated bovine serum albumin (BSA) nanoparticles were constructed in the present exploration as a novel biodegradable carrier for brain-specific drug delivery with evaluation of its in vitro and in vivo delivery properties. BSA nanocarriers were activated and conjugated to the distal amine functions of the glutathione via carbodiimide chemistry using EDAC as a mediator. These nanoparticles were characterized for particle shape, average size, SPAN value, drug entrapment and in vitro drug release. Further, presence of glutathione on the surface of BSA nanoparticles was confirmed by Ellman's assay, which has suggested that approximately 750 units of glutathione were conjugated per BSA nanoparticle. To evaluate the brain delivery properties of the glutathione-conjugated BSA nanoparticles fluorescein sodium was used as a model hydrophilic compound. Permeability and neuronal uptake properties of developed formulations were evaluated against the MDCK-MDR1 endothelial and neuro-glial cells, respectively. The permeability of glutathione-conjugated BSA nanoparticles across the monolayer of MDCK-MDR1 endothelial tight junction was shown significantly higher than that of unconjugated nanoparticles and fluorescein sodium solution. Similarly, glutathione-conjugated nanoparticles exhibited considerably higher uptake by neuro-glial cells which was inferred by high fluorescence intensity under microscope in comparison to unconjugated nanoparticles and fluorescein sodium solution. Following an intravenous administration, nearly three folds higher fluorescein sodium was carried to the rat brain by glutathione-conjugated nanoparticles as compared to unconjugated nanoparticles. The significant in vitro and in vivo results suggest that glutathione-conjugated BSA nanoparticles is a promising brain drug delivery system with low toxicity.

  8. Preparation and characterization of novel PVDF nanofiltration membranes with hydrophilic property for filtration of dye aqueous solution

    Energy Technology Data Exchange (ETDEWEB)

    Nikooe, Naeme, E-mail: naeme.nikooe@stu.um.ac.ir; Saljoughi, Ehsan, E-mail: saljoughi@um.ac.ir

    2017-08-15

    Highlights: • Preparation of novel PVDF nanofiltration membranes with noticeable hydrophilicity. • Simultaneous achievement of hydrophilicity and dye removal via addition of Brij-58. • In situ modification and stability of hydrophilic property via addition of Brij-58. - Abstract: In the present research, for the first time PVDF/Brij-58 blend nanofiltration membranes with remarkable performance in filtration of dye aqueous solution were prepared via immersion precipitation. A noticeable improvement in water permeation and fouling resistance of the PVDF membranes was achieved by using Brij-58 surfactant as a hydrophilic additive. Scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FT-IR) and water contact angle were applied for the investigation of membrane morphology, detection of the surface chemical composition and relative hydrophilicity/hydrophobicity, respectively. The membrane performance was studied and compared by determination of pure water flux (PWF) and filtration of synthetic reactive dye aqueous solutions as well as bovine serum albumin (BSA) as foulant model. It was found out that addition of 4 wt.% Brij-58 to the casting solution results in formation of membrane with remarkable hydrophilicity and fouling resistance (contact angle of 46° and flux recovery ratio (FRR) = 90%), higher porosity and consequently noticeable PWF (31.2 L/m{sup 2} h) and recognized dye rejection value (90%) in comparison with the pristine PVDF nanofiltration membrane. Addition of Brij-58 surfactant to the casting solution resulted in formation of NF membrane with higher hydrophilicity and permeability as well as higher dye rejection value in comparison with the addition of PEG 400 additive.

  9. Mathematical modeling of efficacy and safety for anticancer drugs clinical development.

    Science.gov (United States)

    Lavezzi, Silvia Maria; Borella, Elisa; Carrara, Letizia; De Nicolao, Giuseppe; Magni, Paolo; Poggesi, Italo

    2018-01-01

    Drug attrition in oncology clinical development is higher than in other therapeutic areas. In this context, pharmacometric modeling represents a useful tool to explore drug efficacy in earlier phases of clinical development, anticipating overall survival using quantitative model-based metrics. Furthermore, modeling approaches can be used to characterize earlier the safety and tolerability profile of drug candidates, and, thus, the risk-benefit ratio and the therapeutic index, supporting the design of optimal treatment regimens and accelerating the whole process of clinical drug development. Areas covered: Herein, the most relevant mathematical models used in clinical anticancer drug development during the last decade are described. Less recent models were considered in the review if they represent a standard for the analysis of certain types of efficacy or safety measures. Expert opinion: Several mathematical models have been proposed to predict overall survival from earlier endpoints and validate their surrogacy in demonstrating drug efficacy in place of overall survival. An increasing number of mathematical models have also been developed to describe the safety findings. Modeling has been extensively used in anticancer drug development to individualize dosing strategies based on patient characteristics, and design optimal dosing regimens balancing efficacy and safety.

  10. HIV prevention among drug and alcohol users: models of ...

    African Journals Online (AJOL)

    The spread of HIV among drug and alcohol users, as a high-risk group, is a significant problem in Africa, as in other parts of the world. Few programs have been implemented in Africa to deal specifically with this issue. Since November 2006, the AED Capable Partners Program in Kenya project has provided technical ...

  11. Dynamics of synthetic drugs transmission model with psychological addicts and general incidence rate

    Science.gov (United States)

    Ma, Mingju; Liu, Sanyang; Xiang, Hong; Li, Jun

    2018-02-01

    Synthetic drugs are replacing traditional ones and becoming the main popular ones gradually, which have given rise to serious social issues in recent years. In this paper, a synthetic drugs transmission model with psychological addicts and general contact rate is proposed. The local and global stabilities are decided by the basic reproduction number R0. By analyzing the sensitivity of parameters, we obtain that controlling psychological addiction is better than drugs treatment. These results are verified by numerical simulations.

  12. Drug and Vaccine evaluation in the Human Aotus Plasmodium falciparum Model

    Science.gov (United States)

    2011-05-01

    and phenyl ring systems is anticipated to yield a valuable new antimalarial drug (33). The antimalarial activity and pharmacology of a series of...remains essentially unchanged since 1976, viz. to ascertain the antimalarial activity of drugs against P. falciparum and P. vivax in Aotus. The...Present data on the evaluation of potential antimalarial activity of drugs in the pre-clinical model of Aotus l. lemurinus (Panamanian night

  13. 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

  14. Opacification of hydrophilic intraocular lenses after Descemet stripping automated endothelial keratoplasty

    Directory of Open Access Journals (Sweden)

    Morgan-Warren PJ

    2015-02-01

    Full Text Available Peter J Morgan-Warren, Walter Andreatta, Amit K Patel Department of Ophthalmology, Solihull Hospital, Heart of England NHS Foundation Trust, Birmingham, UK Purpose: Opacification of hydrophilic acrylic intraocular lenses (IOLs is an emerging complication following Descemet stripping automated endothelial keratoplasty (DSAEK. We report six cases and review the current literature.Methods: In this retrospective, noncomparative, observational case series, patients with IOL opacification after previous DSAEK surgery were identified from corneal clinic records. Case notes were reviewed for demographic details, indication for DSAEK, IOL model, incidence of rebubbling, and postoperative course.Results: Six patients developed IOL opacification after DSAEK. All patients had Fuchs’ endothelial dystrophy and had previously received hydrophilic acrylic IOL models. Central anterior IOL opacification was noted in all six cases. Five cases (83% had required rebubbling due to dislocated graft tissue, and one had an early postoperative intraocular pressure (IOP rise. Five cases (83% were managed conservatively, and one case with a failed graft underwent redo DSAEK and IOL exchange.Conclusion: Repeated exposure to intracameral air, raised IOP, and other patient influences may be major etiological factors for IOL opacification after DSAEK. We advise avoiding hydrophilic acrylic IOL models in patients who may require future endothelial keratoplasty. Keywords: IOL, DSAEK, lamellar keratoplasty, endothelial corneal transplantation

  15. 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.

  16. POLYCAPROLACTONE-POLY (ETHYLENE GLYCOL) BLOCK COPOLYMER Ⅲ DRUG RELEASE BEHAVIOR

    Institute of Scientific and Technical Information of China (English)

    BEI Jianzhong; WANG Zhifeng; WANG Shenguo

    1995-01-01

    The drug release behavior of degradable polymer - polycaprolactone-poly (ethylene glycol)block copolymer(PCE) in vitro was investigated by using 5-Fluoro-uracil (5-Fu) as a model drug under a condition of pH 7.4 at 37℃. It is found that the release rate of 5-Fu from PCE increased with increasing polyether content of the copolymer. The results show that the increasing polyether content of the copolymer caused increasing hydrophilicity and decreasing crystallinity of the PCE copolymer. Thus, the drug release behavior and the degradable property of the PCE can be controlled by adjusting the composition of the copolymer.

  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. 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.

  19. Host-guest chemistry of dendrimer-drug complexes. 6. Fully acetylated dendrimers as biocompatible drug vehicles using dexamethasone 21-phosphate as a model drug.

    Science.gov (United States)

    Yang, Kun; Weng, Liang; Cheng, Yiyun; Zhang, Hongfeng; Zhang, Jiahai; Wu, Qinglin; Xu, Tongwen

    2011-03-17

    Fully acetylated poly(amidoamine) (PAMAM) dendrimer was proposed as a biocompatible drug vehicle using dexamethasone 21-phosphate (Dp21) as a model drug. NMR techniques including (1)H NMR and 2D NOE NMR were used to characterize the host-guest chemistry of acetylated dendrimer/Dp21 and cationic dendrimer/Dp21 complexes. The pH-dependent micellization, complexation, and inclusion behaviors of Dp21 were observed in the presence of acetylated and cationic PAMAM dendrimers. Acetylated dendrimer only encapsulates Dp21 at acidic conditions, while cationic dendrimer can host Dp21 at both acidic and neutral conditions. The orientation of Dp21 molecules in the dendrimer cavities depends on the quaternization degree of tertiary amine groups of dendrimer and the protonation ratio of phosphate group of Dp21. A distinctive pH-dependent release behavior of Dp21 from the acetylated and nonacetylated dendritic matrix was observed: Dp21 exhibits a much slower release rate from acetylated dendrimer at lower pH conditions and a much faster release rate from nonacetylated dendrimer with decreasing pH values. Cytotoxicity studies further confirmed the biocompatibility of acetylated dendrimers, which are much safer in the delivery of therapeutics for the treatment of various diseases than nonacetylated dendrimers. The dendrimer-drug binding and release mechanisms provide a new insight for the design and optimization of biocompatible dendrimer-based drug delivery systems. © 2011 American Chemical Society

  20. 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.

  1. 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

  2. Effect of membrane hydrophilization on ultrafiltration performance for biomolecules separation

    International Nuclear Information System (INIS)

    Susanto, H.; Roihatin, A.; Aryanti, N.; Anggoro, D.D.; Ulbricht, M.

    2012-01-01

    This paper compares the performance of different hydrophilization methods to prepare low fouling ultrafiltration (UF) membranes. The methods include post-modification with hydrophilic polymer and blending of hydrophilic agent during either conventional or reactive phase separation (PS). The post-modification was done by photograft copolymerization of water-soluble monomer, poly(ethylene glycol) methacrylate (PEGMA), onto a commercial polyethersulfone (PES) UF membrane. Hydrophilization via blend polymer membrane with hydrophilic additive was performed using non-solvent induced phase separation (NIPS). In reactive PS method, the cast membrane was UV-irradiated before coagulation. The resulting membrane characteristic, the performance and hydrophilization stability were systematically compared. The investigated membrane characteristics include surface hydrophilicity (by contact angle /CA/), surface chemistry (by FTIR spectroscopy), and surface morphology (by scanning electron microscopy). The membrane performance was examined by investigation of adsorptive fouling and ultrafiltration using solution of protein or polysaccharide or humic acid. The results suggest that all methods could increase the hydrophilicity of the membrane yielding less fouling. Post-modification decreased CA from 44.8 ± 4.2 o to 37.8 ± 4.2 o to 42.5 ± 4.3 o depending on the degree of grafting (DG). The hydrophilization via polymer blend decreased CA from from 65 deg. to 54 deg. for PEG concentration of 5%. Nevertheless, decreasing hydraulic permeability was observed after post-modification as well as during polymer blend modification. Stability examination showed that there was leaching out of modifier agent from the membrane matrix prepared via conventional PS after 10 days soaking in both water and NaOH. Reactive PS could increase the stability of the modifier agent in membrane matrix. Highlights: ► We compared different methods to prepare low fouling ultrafiltration (UF) membranes.

  3. Effect of membrane hydrophilization on ultrafiltration performance for biomolecules separation

    Energy Technology Data Exchange (ETDEWEB)

    Susanto, H., E-mail: heru.susanto@undip.ac.id [Department of Chemical Engineering, Universitas Diponegoro, Jl. Prof. Sudarto-Tembalang, Semarang (Indonesia); Roihatin, A.; Aryanti, N.; Anggoro, D.D. [Department of Chemical Engineering, Universitas Diponegoro, Jl. Prof. Sudarto-Tembalang, Semarang (Indonesia); Ulbricht, M. [Lehrstuhl fuer Technische Chemie, Universitaet Duisburg-Essen, Germany, Universitaetstr. 5, Essen (Germany)

    2012-10-01

    This paper compares the performance of different hydrophilization methods to prepare low fouling ultrafiltration (UF) membranes. The methods include post-modification with hydrophilic polymer and blending of hydrophilic agent during either conventional or reactive phase separation (PS). The post-modification was done by photograft copolymerization of water-soluble monomer, poly(ethylene glycol) methacrylate (PEGMA), onto a commercial polyethersulfone (PES) UF membrane. Hydrophilization via blend polymer membrane with hydrophilic additive was performed using non-solvent induced phase separation (NIPS). In reactive PS method, the cast membrane was UV-irradiated before coagulation. The resulting membrane characteristic, the performance and hydrophilization stability were systematically compared. The investigated membrane characteristics include surface hydrophilicity (by contact angle /CA/), surface chemistry (by FTIR spectroscopy), and surface morphology (by scanning electron microscopy). The membrane performance was examined by investigation of adsorptive fouling and ultrafiltration using solution of protein or polysaccharide or humic acid. The results suggest that all methods could increase the hydrophilicity of the membrane yielding less fouling. Post-modification decreased CA from 44.8 {+-} 4.2{sup o} to 37.8 {+-} 4.2{sup o} to 42.5 {+-} 4.3{sup o} depending on the degree of grafting (DG). The hydrophilization via polymer blend decreased CA from from 65 deg. to 54 deg. for PEG concentration of 5%. Nevertheless, decreasing hydraulic permeability was observed after post-modification as well as during polymer blend modification. Stability examination showed that there was leaching out of modifier agent from the membrane matrix prepared via conventional PS after 10 days soaking in both water and NaOH. Reactive PS could increase the stability of the modifier agent in membrane matrix. Highlights: Black-Right-Pointing-Pointer We compared different methods to prepare low

  4. 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.

  5. 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. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. 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.

  7. Effects of chronic administration of drugs of abuse on impulsive choice (delay discounting) in animal models.

    Science.gov (United States)

    Setlow, Barry; Mendez, Ian A; Mitchell, Marci R; Simon, Nicholas W

    2009-09-01

    Drug-addicted individuals show high levels of impulsive choice, characterized by preference for small immediate over larger but delayed rewards. Although the causal relationship between chronic drug use and elevated impulsive choice in humans has been unclear, a small but growing body of literature over the past decade has shown that chronic drug administration in animal models can cause increases in impulsive choice, suggesting that a similar causal relationship may exist in human drug users. This article reviews this literature, with a particular focus on the effects of chronic cocaine administration, which have been most thoroughly characterized. The potential mechanisms of these effects are described in terms of drug-induced neural alterations in ventral striatal and prefrontal cortical brain systems. Some implications of this research for pharmacological treatment of drug-induced increases in impulsive choice are discussed, along with suggestions for future research in this area.

  8. 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.

  9. Modeling attitude towards drug treament: the role of internal motivation, external pressure, and dramatic relief.

    Science.gov (United States)

    Conner, Bradley T; Longshore, Douglas; Anglin, M Douglas

    2009-04-01

    Motivation for change has historically been viewed as the crucial element affecting responsiveness to drug treatment. Various external pressures, such as legal coercion, may engender motivation in an individual previously resistant to change. Dramatic relief may be the change process that is most salient as individuals internalize such external pressures. Results of structural equation modeling on data from 465 drug users (58.9% male; 21.3% Black, 34.2% Hispanic/Latino, and 35.1% White) entering drug treatment indicated that internal motivation and external pressure significantly and positively predicted dramatic relief and that dramatic relief significantly predicted attitudes towards drug treatment: chi (2) = 142.20, df = 100, p relief is also likely to be high. When dramatic relief is high, attitudes towards drug treatment are likely to be positive. The findings indicate that interventions to get individuals into drug treatment should include processes that promote Dramatic Relief. Implications for addictions health services are discussed.

  10. Enhancing the biofuel upgrade performance for Pd nanoparticles via increasing the support hydrophilicity of metal-organic frameworks.

    Science.gov (United States)

    Sun, Qi; Chen, Meng; Aguila, Briana; Nguyen, Nicholas; Ma, Shengqian

    2017-09-08

    In this work, the influence of the hydrophilic/hydrophobic nature of metal-organic framework (MOF) materials on the catalytic performance of supported Pd nanoparticles for biofuel upgrade was studied. We show that the introduction of hydrophilic groups on a MOF can greatly enhance the performance of the resultant catalyst. Specifically, Pd nanoparticles supported on MIL-101-SO 3 Na with superhydrophilicity (Pd/MIL-101-SO 3 Na) far outperforms pristine MIL-101 and the benchmark catalyst Pd/C in the hydrodeoxygenation reaction of vanillin, a model component of pyrolysis oil derived from the lignin fraction. This is attributed to a favorable mode of adsorption of the highly water soluble reactants on the more hydrophilic support in the vicinity of the catalytically active Pd nanoparticles, thereby promoting their transformation.

  11. Evaluation and modeling of the eutectic composition of various drug-polyethylene glycol solid dispersions.

    Science.gov (United States)

    Baird, Jared A; Taylor, Lynne S

    2011-06-01

    The purpose of this study was to gain a better understanding of which factors contribute to the eutectic composition of drug-polyethylene glycol (PEG) blends and to compare experimental values with predictions from the semi-empirical model developed by Lacoulonche et al. Eutectic compositions of various drug-PEG 3350 solid dispersions were predicted, assuming athermal mixing, and compared to experimentally determined eutectic points. The presence or absence of specific interactions between the drug and PEG 3350 were investigated using Fourier transform infrared (FT-IR) spectroscopy. The eutectic composition for haloperidol-PEG and loratadine-PEG solid dispersions was accurately predicted using the model, while predictions for aceclofenac-PEG and chlorpropamide-PEG were very different from those experimentally observed. Deviations in the model prediction from ideal behavior for the systems evaluated were confirmed to be due to the presence of specific interactions between the drug and polymer, as demonstrated by IR spectroscopy. Detailed analysis showed that the eutectic composition prediction from the model is interdependent on the crystal lattice energy of the drug compound (evaluated from the melting temperature and the heat of fusion) as well as the nature of the drug-polymer interactions. In conclusion, for compounds with melting points less than 200°C, the model is ideally suited for predicting the eutectic composition of systems where there is an absence of drug-polymer interactions.

  12. Mathematical Modeling and Experimental Validation of Nanoemulsion-Based Drug Transport across Cellular Barriers.

    Science.gov (United States)

    Kadakia, Ekta; Shah, Lipa; Amiji, Mansoor M

    2017-07-01

    Nanoemulsions have shown potential in delivering drug across epithelial and endothelial cell barriers, which express efflux transporters. However, their transport mechanisms are not entirely understood. Our goal was to investigate the cellular permeability of nanoemulsion-encapsulated drugs and apply mathematical modeling to elucidate transport mechanisms and sensitive nanoemulsion attributes. Transport studies were performed in Caco-2 cells, using fish oil nanoemulsions and a model substrate, rhodamine-123. Permeability data was modeled using a semi-mechanistic approach, capturing the following cellular processes: endocytotic uptake of the nanoemulsion, release of rhodamine-123 from the nanoemulsion, efflux and passive permeability of rhodamine-123 in aqueous solution. Nanoemulsions not only improved the permeability of rhodamine-123, but were also less sensitive to efflux transporters. The model captured bidirectional permeability results and identified sensitive processes, such as the release of the nanoemulsion-encapsulated drug and cellular uptake of the nanoemulsion. Mathematical description of cellular processes, improved our understanding of transport mechanisms, such as nanoemulsions don't inhibit efflux to improve drug permeability. Instead, their endocytotic uptake, results in higher intracellular drug concentrations, thereby increasing the concentration gradient and transcellular permeability across biological barriers. Modeling results indicated optimizing nanoemulsion attributes like the droplet size and intracellular drug release rate, may further improve drug permeability.

  13. 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.

  14. 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.

  15. Surfactant-assisted water exposed electrospinning of novel super hydrophilic polycaprolactone based fibers.

    Science.gov (United States)

    Zargarian, S Sh; Haddadi-Asl, V

    2017-08-01

    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.

  16. Modeling and implementing a database on drugs into a hospital intranet.

    Science.gov (United States)

    François, M; Joubert, M; Fieschi, D; Fieschi, M

    1998-09-01

    Our objective was to develop a drug information service, implementing a database on drugs in our university hospitals information system. Thériaque is a database, maintained by a group of pharmacists and physicians, on all the drugs available in France. Before its implementation we modeled its content (chemical classes, active components, excipients, indications, contra-indications, side effects, and so on) according to an object-oriented method. Then we designed HTML pages whose appearance translates the structure of classes of objects of the model. Fields in pages are dynamically fulfilled by the results of queries to a relational database in which information on drugs is stored. This allowed a fast implementation and did not imply to port a client application on the thousands of workstations over the network. The interface provides end-users with an easy-to-use and natural way to access information related to drugs in an internet environment.

  17. [Health care models for users of alcohol and other drugs: political discourse, knowledge, and practices].

    Science.gov (United States)

    Alves, Vânia Sampaio

    2009-11-01

    This article aims to characterize health care models for users of alcohol and other drugs in the Brazilian context. Discourse analysis was performed on public drug policy in Brazil from the 1970s. This analysis was contextualized by a brief digression on the main political positions identified in several countries of the world in relation to drug use problems. Beginning in the current decade, drug policies in Brazil have been receptive to harm reduction approaches, resulting in reorientation of the health care model. In conclusion, the structuring and strengthening of a network of care for users of alcohol and other drugs and their families, based on community care and the harm reduction approach and combined with other social and health services, is now a key public health challenge for the country.

  18. Study on hydrophilicity of polymer surfaces improved by plasma treatment

    International Nuclear Information System (INIS)

    Lai Jiangnan; Sunderland, Bob; Xue Jianming; Yan, Sha; Zhao Weijiang; Folkard, Melvyn; Michael, Barry D.; Wang Yugang

    2006-01-01

    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=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

  19. Hydrophilization of graphite using plasma above/in a solution

    Science.gov (United States)

    Hoshino, Shuhei; Kawahara, Kazuma; Takeuchi, Nozomi

    2018-01-01

    A hydrophilization method for graphite is required for applications such as conductive ink. In typical chemical oxidation methods for graphite have the problems of producing many defects in graphite and a large environmental impact. In recent years, the plasma treatment has attracted attention because of the high quality of the treated samples and the low environmental impact. In this study, we proposed an above-solution plasma treatment with a high contact probability of graphite and plasma since graphite accumulates on the solution surface due to its hydrophobicity, which we compared with a so-called solution plasma treatment. Graphite was hydrophilized via reactions with OH radicals generated by the plasma. It was confirmed that hydroxyl and carboxyl groups were modified to the graphite and the dispersibility was improved. The above-solution plasma achieved more energy-efficient hydrophilization than the solution plasma and it was possible to enhance the dispersibility by increasing the plasma-solution contact area.

  20. Copolymers for soft hydrophilic contact lenses: development and investigations

    International Nuclear Information System (INIS)

    Schwach, G.W.

    1978-05-01

    Low esters of methacrylic acid which may be polymerized by different methods are used predominantly for producing soft hydrophilic contact lenses. Compounds of the vinyl-type often are added to improve the optical and mechanical qualities. Composition as well as possibilities of polymerization by irradiation were tested so long until copolymers were found which finally allowed the production of soft hydrophilic contact lenses. Swelling characteristics and permeability of the different elastomeres are to be investigated in order to guarantee sufficient compatibility of contact lenses. Contamination of the lens materials by microorganisms is also a point of special interest. The effects on the hydrophilic contact lens-copolymers by different substances used for cleaning and storage solutions have been investigated as well. (author)

  1. Modeling the development of drug addiction in male and female animals.

    Science.gov (United States)

    Lynch, Wendy J

    2018-01-01

    An increasing emphasis has been placed on the development and use of animal models of addiction that capture defining features of human drug addiction, including escalation/binge drug use, enhanced motivation for the drug, preference for the drug over other reward options, use despite negative consequences, and enhanced drug-seeking/relapse vulnerability. The need to examine behavior in both males and females has also become apparent given evidence demonstrating that the addiction process occurs differently in males and females. This review discusses the procedures that are used to model features of addiction in animals, as well as factors that influence their development. Individual differences are also discussed, with a particular focus on sex differences. While no one procedure consistently produces all characteristics, different models have been developed to focus on certain characteristics. A history of escalating/binge patterns of use appears to be critical for producing other features characteristic of addiction, including an enhanced motivation for the drug, enhanced drug seeking, and use despite negative consequences. These characteristics tend to emerge over abstinence, and appear to increase rather than decrease in magnitude over time. In females, these characteristics develop sooner during abstinence and/or following less drug exposure as compared to males, and for psychostimulant addiction, may require estradiol. Although preference for the drug over other reward options has been demonstrated in non-human primates, it has been more difficult to establish in rats. Future research is needed to define the parameters that optimally induce each of these features of addiction in the majority of animals. Such models are essential for advancing our understanding of human drug addiction and its treatment in men and women. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. 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.

  3. METHODOLOGY OF THE DRUGS MARKET VOLUME MODELING ON THE EXAMPLE OF HEMOPHILIA A

    OpenAIRE

    N. B. Molchanova

    2015-01-01

    Hemophilia A is a serious genetic disease, which may lead to disability of a patient even in early ages without a required therapy. The only one therapeutic approach is a replacement therapy with drugs of bloodcoagulation factor VIII (FVIII). The modeling of coagulation drugs market volume will allow evaluation of the level of patients’ provision with a necessary therapy. Modeling of a “perfect” market of drugs and its comparison with the real one was the purpose of the study. During the mode...

  4. Alcohol and drug policy model for the Canadian upstream petroleum industry

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2007-09-15

    This alcohol and drug policy model was developed to help employers manage and reduce the risks associated with drug and alcohol use in the workplace. The policy model outlined guidelines for establishing and implementing drug and alcohol policies, and discussed treatment programs and opportunities for re-employment. The model was developed by Enform, the upstream petroleum industry's safety and training arm, who used a previous guide developed by the Construction Owner's Association of Alberta (COAA) as a model. Enform's model provided a summary of key accountabilities across all levels of industry as well as the accepted minimum criteria for developing alcohol and drug policies. The model included guidelines and recommendations for employees, supervisors, and owners, employers, and contractors. The responsibilities of associations, organizations, and private companies were also outlined. An overview of recommended implementation plans was provided, as well as details of alcohol and drug use education programs and workplace rules. A supervisor's guide to implementation provided outlines of the causes of drug use among employees. tabs.

  5. Desolvation of polymers by ultrafast heating: Influence of hydrophilicity

    Science.gov (United States)

    Sun, Si Neng; Urbassek, Herbert M.

    2010-10-01

    Using molecular-dynamics simulation, we investigate the consequences of ultrafast laser-induced heating of a small water droplet containing a solvated polymer. Two polymers are studied: polyethylene as an example of a hydrophobic, and polyketone as an example of a hydrophilic polymer. In both cases, when the droplet is heated below the critical temperature of water, strong water evaporation is started, but the polymer remains in contact with a central water cluster. However, upon heating beyond the critical temperature, the hydrophilic polyethylene becomes completely desolvated, while polyketone still remains solvated. We analyze this behavior in terms of the intermolecular interactions and of the expansion dynamics of the heated droplet.

  6. 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

  7. Mining FDA drug labels using an unsupervised learning technique--topic modeling.

    Science.gov (United States)

    Bisgin, Halil; Liu, Zhichao; Fang, Hong; Xu, Xiaowei; Tong, Weida

    2011-10-18

    The Food and Drug Administration (FDA) approved drug labels contain a broad array of information, ranging from adverse drug reactions (ADRs) to drug efficacy, risk-benefit consideration, and more. However, the labeling language used to describe these information is free text often containing ambiguous semantic descriptions, which poses a great challenge in retrieving useful information from the labeling text in a consistent and accurate fashion for comparative analysis across drugs. Consequently, this task has largely relied on the manual reading of the full text by experts, which is time consuming and labor intensive. In this study, a novel text mining method with unsupervised learning in nature, called topic modeling, was applied to the drug labeling with a goal of discovering "topics" that group drugs with similar safety concerns and/or therapeutic uses together. A total of 794 FDA-approved drug labels were used in this study. First, the three labeling sections (i.e., Boxed Warning, Warnings and Precautions, Adverse Reactions) of each drug label were processed by the Medical Dictionary for Regulatory Activities (MedDRA) to convert the free text of each label to the standard ADR terms. Next, the topic modeling approach with latent Dirichlet allocation (LDA) was applied to generate 100 topics, each associated with a set of drugs grouped together based on the probability analysis. Lastly, the efficacy of the topic modeling was evaluated based on known information about the therapeutic uses and safety data of drugs. The results demonstrate that drugs grouped by topics are associated with the same safety concerns and/or therapeutic uses with statistical significance (P<0.05). The identified topics have distinct context that can be directly linked to specific adverse events (e.g., liver injury or kidney injury) or therapeutic application (e.g., antiinfectives for systemic use). We were also able to identify potential adverse events that might arise from specific

  8. Mining FDA drug labels using an unsupervised learning technique - topic modeling

    Science.gov (United States)

    2011-01-01

    Background The Food and Drug Administration (FDA) approved drug labels contain a broad array of information, ranging from adverse drug reactions (ADRs) to drug efficacy, risk-benefit consideration, and more. However, the labeling language used to describe these information is free text often containing ambiguous semantic descriptions, which poses a great challenge in retrieving useful information from the labeling text in a consistent and accurate fashion for comparative analysis across drugs. Consequently, this task has largely relied on the manual reading of the full text by experts, which is time consuming and labor intensive. Method In this study, a novel text mining method with unsupervised learning in nature, called topic modeling, was applied to the drug labeling with a goal of discovering “topics” that group drugs with similar safety concerns and/or therapeutic uses together. A total of 794 FDA-approved drug labels were used in this study. First, the three labeling sections (i.e., Boxed Warning, Warnings and Precautions, Adverse Reactions) of each drug label were processed by the Medical Dictionary for Regulatory Activities (MedDRA) to convert the free text of each label to the standard ADR terms. Next, the topic modeling approach with latent Dirichlet allocation (LDA) was applied to generate 100 topics, each associated with a set of drugs grouped together based on the probability analysis. Lastly, the efficacy of the topic modeling was evaluated based on known information about the therapeutic uses and safety data of drugs. Results The results demonstrate that drugs grouped by topics are associated with the same safety concerns and/or therapeutic uses with statistical significance (P<0.05). The identified topics have distinct context that can be directly linked to specific adverse events (e.g., liver injury or kidney injury) or therapeutic application (e.g., antiinfectives for systemic use). We were also able to identify potential adverse events that

  9. 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. © The Author(s) 2016.

  10. Sulcus depth reproduction with polyvinyl siloxane impression material: effects of hydrophilicity and impression temperature.

    Science.gov (United States)

    Takahashi, Hidekazu; Finger, Werner J; Kurokawa, Rie; Furukawa, Masae; Komatsu, Masashi

    2010-03-01

    To determine the sulcus penetration ability of hydrophilic and hydrophobic polyvinyl siloxane (PVS) impression materials by impression technique, temperature, and sulcus width. Hydrophilic Flexitime (FLE; Heraeus Kulzer) and its hydrophobic counterpart (EXP) without surfactant were investigated, using light (L), monophase (M), and heavy (H) consistencies. A truncated steel cone surrounded by a 2-mm-deep and 50-, 100-, or 200-microm-wide sulcus, simulating the gingival tissue with agar, served as the test model. Impressions were made with single-mix (L or M) and double-mix (LM or LH) techniques at 23 degrees C and 37 degrees C, respectively. The reproduced sulcus heights were measured with a 3D laser scanner. Data were analyzed by ANOVA and Tukey HSD (P 1.9 mm); FLE-M, -LM, and-LH reproductions were shorter with narrow sulci. Reproductions of 50- and 100-microm sulci with EXP-L were shallower than with FLE-L. The shortest reproduction was, however, greater than 1.6 mm. In spite of some significant differences found in sulcus-reproducing ability with hydrophilic and hydrophobic impression materials applied at different impression-making temperatures and with different techniques, the practical relevance is limited.

  11. 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.

  12. 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

  13. Zero-inflated Poisson model based likelihood ratio test for drug safety signal detection.

    Science.gov (United States)

    Huang, Lan; Zheng, Dan; Zalkikar, Jyoti; Tiwari, Ram

    2017-02-01

    In recent decades, numerous methods have been developed for data mining of large drug safety databases, such as Food and Drug Administration's (FDA's) Adverse Event Reporting System, where data matrices are formed by drugs such as columns and adverse events as rows. Often, a large number of cells in these data matrices have zero cell counts and some of them are "true zeros" indicating that the drug-adverse event pairs cannot occur, and these zero counts are distinguished from the other zero counts that are modeled zero counts and simply indicate that the drug-adverse event pairs have not occurred yet or have not been reported yet. In this paper, a zero-inflated Poisson model based likelihood ratio test method is proposed to identify drug-adverse event pairs that have disproportionately high reporting rates, which are also called signals. The maximum likelihood estimates of the model parameters of zero-inflated Poisson model based likelihood ratio test are obtained using the expectation and maximization algorithm. The zero-inflated Poisson model based likelihood ratio test is also modified to handle the stratified analyses for binary and categorical covariates (e.g. gender and age) in the data. The proposed zero-inflated Poisson model based likelihood ratio test method is shown to asymptotically control the type I error and false discovery rate, and its finite sample performance for signal detection is evaluated through a simulation study. The simulation results show that the zero-inflated Poisson model based likelihood ratio test method performs similar to Poisson model based likelihood ratio test method when the estimated percentage of true zeros in the database is small. Both the zero-inflated Poisson model based likelihood ratio test and likelihood ratio test methods are applied to six selected drugs, from the 2006 to 2011 Adverse Event Reporting System database, with varying percentages of observed zero-count cells.

  14. 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

  15. Progress with modeling activity landscapes in drug discovery.

    Science.gov (United States)

    Vogt, Martin

    2018-04-19

    Activity landscapes (ALs) are representations and models of compound data sets annotated with a target-specific activity. In contrast to quantitative structure-activity relationship (QSAR) models, ALs aim at characterizing structure-activity relationships (SARs) on a large-scale level encompassing all active compounds for specific targets. The popularity of AL modeling has grown substantially with the public availability of large activity-annotated compound data sets. AL modeling crucially depends on molecular representations and similarity metrics used to assess structural similarity. Areas covered: The concepts of AL modeling are introduced and its basis in quantitatively assessing molecular similarity is discussed. The different types of AL modeling approaches are introduced. AL designs can broadly be divided into three categories: compound-pair based, dimensionality reduction, and network approaches. Recent developments for each of these categories are discussed focusing on the application of mathematical, statistical, and machine learning tools for AL modeling. AL modeling using chemical space networks is covered in more detail. Expert opinion: AL modeling has remained a largely descriptive approach for the analysis of SARs. Beyond mere visualization, the application of analytical tools from statistics, machine learning and network theory has aided in the sophistication of AL designs and provides a step forward in transforming ALs from descriptive to predictive tools. To this end, optimizing representations that encode activity relevant features of molecules might prove to be a crucial step.

  16. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model -

    Directory of Open Access Journals (Sweden)

    Himanshu R Gupta

    2016-12-01

    exposure times used in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs.

  17. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs: - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model.

    Science.gov (United States)

    Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty; Thakur, Mansee

    2016-12-01

    model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs.

  18. Mechanistic modelling of drug release from polymer-coated and swelling and dissolving polymer matrix systems.

    Science.gov (United States)

    Kaunisto, Erik; Marucci, Mariagrazia; Borgquist, Per; Axelsson, Anders

    2011-10-10

    The time required for the design of a new delivery device can be sensibly reduced if the release mechanism is understood and an appropriate mathematical model is used to characterize the system. Once all the model parameters are obtained, in silico experiments can be performed, to provide estimates of the release from devices with different geometries and compositions. In this review coated and matrix systems are considered. For coated formulations, models describing the diffusional drug release, the osmotic pumping drug release, and the lag phase of pellets undergoing cracking in the coating due to the build-up of a hydrostatic pressure are reviewed. For matrix systems, models describing pure polymer dissolution, diffusion in the polymer and drug release from swelling and eroding polymer matrix formulations are reviewed. Importantly, the experiments used to characterize the processes occurring during the release and to validate the models are presented and discussed. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. 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..

  20. Orphan Drug Pricing: An Original Exponential Model Relating Price to the Number of Patients

    Directory of Open Access Journals (Sweden)

    Andrea Messori

    2016-10-01

    Full Text Available In managing drug prices at the national level, orphan drugs represent a special case because the price of these agents is higher than that determined according to value-based principles. A common practice is to set the orphan drug price in an inverse relationship with the number of patients, so that the price increases as the number of patients decreases. Determination of prices in this context generally has a purely empirical nature, but a theoretical basis would be needed. The present paper describes an original exponential model that manages the relationship between price and number of patients for orphan drugs. Three real examples are analysed in detail (eculizumab, bosentan, and a data set of 17 orphan drugs published in 2010. These analyses have been aimed at identifying some objective criteria to rationally inform this relationship between prices and patients and at converting these criteria into explicit quantitative rules.

  1. Floating solid cellulose nanofibre nanofoams for sustained release of the poorly soluble model drug furosemide

    DEFF Research Database (Denmark)

    Svagan, Anna Justina; Müllertz, Anette; Löbmann, Korbinian

    2017-01-01

    OBJECTIVES: This study aimed to prepare a furosemide-loaded sustained release cellulose nanofibre (CNF)-based nanofoams with buoyancy. METHODS: Dry foams consisting of CNF and the model drug furosemide at concentrations of 21% and 50% (w/w) have been prepared by simply foaming a CNF-drug suspension...... followed by drying. The resulting foams were characterized towards their morphology, solid state properties and dissolution kinetics. KEY FINDINGS: Solid state analysis of the resulting drug-loaded foams revealed that the drug was present as an amorphous sodium furosemide salt and in form of furosemide...... form I crystals embedded in the CNF foam cell walls. The foams could easily be shaped and were flexible, and during the drug release study, the foam pieces remained intact and were floating on the surface due to their positive buoyancy. Both foams showed a sustained furosemide release compared...

  2. Hydrophilic solute transport across the rat blood-brain barrier

    International Nuclear Information System (INIS)

    Lucchesi, K.J.

    1987-01-01

    Brain capillary permeability-surface area products (PS) of hydrophilic solutes ranging in size from 180 to 5,500 Daltons were measured in rats according to the method of Ohno, Pettigrew and Rapoport. The distribution volume of 70 KD dextran at 10 minutes after i.v. injection was also measured to determine the residual volume of blood in brain tissue at the time of sacrifice. Small test solutes were injected in pairs in order to elucidate whether their transfer into the brain proceeds by diffusion through water- or lipid-filled channels or by vesicular transport. This issue was examined in rats whose blood-brain barrier (BBB) was presumed to be intact (untreated) and in rats that received intracarotid infusions to open the BBB (isosmotic salt (ISS) and hyperosmolar arabinose). Ohno PS values of 3 H-inulin and 14 C-L-glucose in untreated rats were found to decrease as the labelling time was lengthened. This was evidence that a rapidly equilibrating compartment exists between blood and brain that renders the Ohno two-compartment model inadequate for computing true transfer rate constants. When the data were reanalyzed using a multi-compartment graphical analysis, solutes with different molecular radii were found to enter the brain at approximately equal rates. Furthermore, unidirectional transport is likely to be initiated by solute adsorption to a glycocalyx coat on the luminal surface of brain capillary endothelium. Apparently, more inulin than L-glucose was adsorbed, which may account for its slightly faster transfer across the BBB. After rats were treated with intracarotid infusions of ISS or hyperosmolar arabinose, solute PS values were significantly increased, but the ratio of PS for each of the solute pairs approached that of their free-diffusion coefficients

  3. Hydrophilic polyurethane matrix promotes chondrogenesis of mesenchymal stem cells☆

    Science.gov (United States)

    Nalluri, Sandeep M.; Krishnan, G. Rajesh; Cheah, Calvin; Arzumand, Ayesha; Yuan, Yuan; Richardson, Caley A.; Yang, Shuying; Sarkar, Debanjan

    2016-01-01

    Segmental polyurethanes exhibit biphasic morphology and can control cell fate by providing distinct matrix guided signals to increase the chondrogenic potential of mesenchymal stem cells (MSCs). Polyethylene glycol (PEG) based hydrophilic polyurethanes can deliver differential signals to MSCs through their matrix phases where hard segments are cell-interactive domains and PEG based soft segments are minimally interactive with cells. These coordinated communications can modulate cell–matrix interactions to control cell shape and size for chondrogenesis. Biphasic character and hydrophilicity of polyurethanes with gel like architecture provide a synthetic matrix conducive for chondrogenesis of MSCs, as evidenced by deposition of cartilage-associated extracellular matrix. Compared to monophasic hydrogels, presence of cell interactive domains in hydrophilic polyurethanes gels can balance cell–cell and cell–matrix interactions. These results demonstrate the correlation between lineage commitment and the changes in cell shape, cell–matrix interaction, and cell–cell adhesion during chondrogenic differentiation which is regulated by polyurethane phase morphology, and thus, represent hydrophilic polyurethanes as promising synthetic matrices for cartilage regeneration. PMID:26046282

  4. Hydrophilic polyurethane matrix promotes chondrogenesis of mesenchymal stem cells.

    Science.gov (United States)

    Nalluri, Sandeep M; Krishnan, G Rajesh; Cheah, Calvin; Arzumand, Ayesha; Yuan, Yuan; Richardson, Caley A; Yang, Shuying; Sarkar, Debanjan

    2015-09-01

    Segmental polyurethanes exhibit biphasic morphology and can control cell fate by providing distinct matrix guided signals to increase the chondrogenic potential of mesenchymal stem cells (MSCs). Polyethylene glycol (PEG) based hydrophilic polyurethanes can deliver differential signals to MSCs through their matrix phases where hard segments are cell-interactive domains and PEG based soft segments are minimally interactive with cells. These coordinated communications can modulate cell-matrix interactions to control cell shape and size for chondrogenesis. Biphasic character and hydrophilicity of polyurethanes with gel like architecture provide a synthetic matrix conducive for chondrogenesis of MSCs, as evidenced by deposition of cartilage-associated extracellular matrix. Compared to monophasic hydrogels, presence of cell interactive domains in hydrophilic polyurethanes gels can balance cell-cell and cell-matrix interactions. These results demonstrate the correlation between lineage commitment and the changes in cell shape, cell-matrix interaction, and cell-cell adhesion during chondrogenic differentiation which is regulated by polyurethane phase morphology, and thus, represent hydrophilic polyurethanes as promising synthetic matrices for cartilage regeneration. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Analysis of moniliformin in maize plants using hydrophilic interaction chromatography

    DEFF Research Database (Denmark)

    Sørensen, Jens Laurids; Nielsen, Kristian Fog; Thrane, Ulf

    2007-01-01

    A novel HPLC method was developed for detection of the Fusarium mycotoxin, moniliformin in whole maize plants. The method is based on hydrophilic interaction chromatography (HILIC) on a ZIC zwitterion column combined with diode array detection and negative electrospray mass spectrometry (ESI...

  6. Development of breathable hydrophobic/hydrophilic functional textiles

    NARCIS (Netherlands)

    Agrawal, P. (Pramod); Brink, G.J. (Ger)

    2013-01-01

    The proposed bi-functional protective structure intended to have hydrophilic interior towards the skin surface and hydrophobic exterior for protection, ensuring fast transfer of moisture between body and external environment. The sandwich structure is prepared using 100% wool jersey and varieties of

  7. Forces involved in bacterial adhesion to hydrophilic and hydrophobic surfaces

    NARCIS (Netherlands)

    Boks, N.P.; Norde, W.; Meil, H.C.; Busscher, H.J.

    2008-01-01

    Using a parallel-plate flow chamber, the hydrodynamic shear forces to prevent bacterial adhesion (F-prev) and to detach adhering bacteria (F-det) were evaluated for hydrophilic glass, hydrophobic, dimethyldichlorosilane (DDS)-coated glass and six different bacterial strains, in order to test the

  8. Materials comprising polydienes and hydrophilic polymers and related methods

    Science.gov (United States)

    Mays, Jimmy W [Knoxville, TN; Deng, Suxiang [Knoxville, TN; Mauritz, Kenneth A [Hattiesburg, MS; Hassan, Mohammad K [Hattiesburg, MS; Gido, Samuel P [Hadley, MA

    2011-11-22

    Materials prepared from polydienes, such as poly(cyclohexadiene), and hydrophilic polymers, such as poly(alkylene oxide), are described. Methods of making the materials and their use in fuel cell membranes, batteries, breathable chemical-biological protective materials, and templates for sol-gel polymerization are also provided. The materials can be crosslinked and sulfonated, and can include copolymers and polymer blends.

  9. Current advances in mathematical modeling of anti-cancer drug penetration into tumor tissues.

    Science.gov (United States)

    Kim, Munju; Gillies, Robert J; Rejniak, Katarzyna A

    2013-11-18

    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.

  10. Application of PBPK modelling in drug discovery and development at Pfizer.

    Science.gov (United States)

    Jones, Hannah M; Dickins, Maurice; Youdim, Kuresh; Gosset, James R; Attkins, Neil J; Hay, Tanya L; Gurrell, Ian K; Logan, Y Raj; Bungay, Peter J; Jones, Barry C; Gardner, Iain B

    2012-01-01

    Early prediction of human pharmacokinetics (PK) and drug-drug interactions (DDI) in drug discovery and development allows for more informed decision making. Physiologically based pharmacokinetic (PBPK) modelling can be used to answer a number of questions throughout the process of drug discovery and development and is thus becoming a very popular tool. PBPK models provide the opportunity to integrate key input parameters from different sources to not only estimate PK parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. Using examples from the literature and our own company, we have shown how PBPK techniques can be utilized through the stages of drug discovery and development to increase efficiency, reduce the need for animal studies, replace clinical trials and to increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however, some limitations need to be addressed to realize its application and utility more broadly.

  11. 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.

  12. 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

  13. A Multiple Indicators Multiple Causes (MIMIC) model of internal barriers to drug treatment in China.

    Science.gov (United States)

    Qi, Chang; Kelly, Brian C; Liao, Yanhui; He, Haoyu; Luo, Tao; Deng, Huiqiong; Liu, Tieqiao; Hao, Wei; Wang, Jichuan

    2015-03-01

    Although evidence exists for distinct barriers to drug abuse treatment (BDATs), investigations of their inter-relationships and the effect of individual characteristics on the barrier factors have been sparse, especially in China. A Multiple Indicators Multiple Causes (MIMIC) model is applied for this target. A sample of 262 drug users were recruited from three drug rehabilitation centers in Hunan Province, China. We applied a MIMIC approach to investigate the effect of gender, age, marital status, education, primary substance use, duration of primary drug use, and drug treatment experience on the internal barrier factors: absence of problem (AP), negative social support (NSS), fear of treatment (FT), and privacy concerns (PC). Drug users of various characteristics were found to report different internal barrier factors. Younger participants were more likely to report NSS (-0.19, p=0.038) and PC (-0.31, p<0.001). Compared to other drug users, ice users were more likely to report AP (0.44, p<0.001) and NSS (0.25, p=0.010). Drug treatment experiences related to AP (0.20, p=0.012). In addition, differential item functioning (DIF) occurred in three items when participant from groups with different duration of drug use, ice use, or marital status. Individual characteristics had significant effects on internal barriers to drug treatment. On this basis, BDAT perceived by different individuals could be assessed before tactics were utilized to successfully remove perceived barriers to drug treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    International Nuclear Information System (INIS)

    Chatterjee, Sagnik; Richert, Lysiane; Augustijns, Patrick; Annaert, Pieter

    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

  15. 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

  16. Precision-cut intestinal slices: alternative model for drug transport, metabolism, and toxicology research.

    Science.gov (United States)

    Li, Ming; de Graaf, Inge A M; Groothuis, Geny M M

    2016-01-01

    The absorption, distribution, metabolism, excretion and toxicity (ADME-tox) processes of drugs are of importance and require preclinical investigation intestine in addition to the liver. Various models have been developed for prediction of ADME-tox in the intestine. In this review, precision-cut intestinal slices (PCIS) are discussed and highlighted as model for ADME-tox studies. This review provides an overview of the applications and an update of the most recent research on PCIS as an ex vivo model to study the transport, metabolism and toxicology of drugs and other xenobiotics. The unique features of PCIS and the differences with other models as well as the translational aspects are also discussed. PCIS are a simple, fast, and reliable ex vivo model for drug ADME-tox research. Therefore, PCIS are expected to become an indispensable link in the in vitro-ex vivo-in vivo extrapolation, and a bridge in translation of animal data to the human situation. In the future, this model may be helpful to study the effects of interorgan interactions, intestinal bacteria, excipients and drug formulations on the ADME-tox properties of drugs. The optimization of culture medium and the development of a (cryo)preservation technique require more research.

  17. Modelling the encapsulation of the anticancer drug cisplatin into carbon nanotubes

    International Nuclear Information System (INIS)

    Hilder, Tamsyn A; Hill, James M

    2007-01-01

    The proposed use of nanocapsules in drug delivery systems promises many advantages over current procedures. The major advantage is the potential for patients to have significantly reduced side effects from taking the drug, especially for highly toxic drugs such as those used for cancer treatments. Nanotubes have been suggested as one such carrier to deliver a drug to a specific site, giving rise to the notion of the 'magic bullet'. The aim of this paper is to determine whether a particular nanotube would accept a particular drug, and to determine the radius of the nanotube that provides the maximum uptake of the drug molecule. In particular, this paper looks at the drug cisplatin, a platinum based anticancer drug widely used in the treatment of tumours. Three orientations of cisplatin, a polar molecule, are investigated as it enters the nanotube. It is shown that, for all three orientations of cisplatin to be accepted into the carbon nanotube, the minimum radius must be at least 4.785 A, which is slightly smaller than a (9, 5) nanotube and that the maximum suction energy occurs when the carbon nanotube radius is approximately 5.3 A, which is approximately equivalent to a (11, 4) nanotube. This paper presents for the first time a calculation of this nature, and although the model represents only a first approximation, it constitutes a necessary preliminary calculation which might provide medical scientists with some overall guidelines

  18. Some Remarks on Prediction of Drug-Target Interaction with Network Models.

    Science.gov (United States)

    Zhang, Shao-Wu; Yan, Xiao-Ying

    2017-01-01

    System-level understanding of the relationships between drugs and targets is very important for enhancing drug research, especially for drug function repositioning. The experimental methods used to determine drug-target interactions are usually time-consuming, tedious and expensive, and sometimes lack reproducibility. Thus, it is highly desired to develop computational methods for efficiently and effectively analyzing and detecting new drug-target interaction pairs. With the explosive growth of different types of omics data, such as genome, pharmacology, phenotypic, and other kinds of molecular networks, numerous computational approaches have been developed to predict Drug-Target Interactions (DTI). In this review, we make a survey on the recent advances in predicting drug-target interaction with network-based models from the following aspects: i) Available public data sources and benchmark datasets; ii) Drug/target similarity metrics; iii) Network construction; iv) Common network algorithms; v) Performance comparison of existing network-based DTI predictors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. 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)

  20. Considerations for a business model for the effective integration of novel biomarkers into drug development.

    Science.gov (United States)

    Frueh, Felix W

    2008-11-01

    It is 10 years since the introduction of trastuzumab into the US market, and we are still waiting for a validation of the business case for biomarker-driven drug development. While many reasons for the lack of duplication of this model may exist, the need for accelerated innovation in drug development paired with the opportunity of integrating biomarker-driven research into drug development programs may lead to new and creative ways of fostering the cooperation between drug developers and test manufacturers. The rapid increase in knowledge about biomarkers and our understanding of disease and disease mechanisms open unprecedented prospects to make not only better, more informed decisions regarding patient care, but also strategic decisions during drug development. This requires that a biomarker strategy becomes an integral part of (early) drug development and that new, innovative paths are tried towards a model that combines the scientific approach with an economically feasible implementation strategy. Collaborative research, the use of new communication tools, the exploration of alternative ways to position a product in the market, and other considerations are part of such a strategy. This perspective article illustrates the current landscape and takes a look at some of these new ways for more effectively integrating biomarkers into drug development.

  1. 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.

  2. Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates

    Directory of Open Access Journals (Sweden)

    Fatma E. El-Khouly

    2017-10-01

    Full Text Available Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG, patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB. We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%—carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole—are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG.

  3. Using a 3-d model system to screen for drugs effective on solid tumors

    OpenAIRE

    Fayad, Walid

    2011-01-01

    There is a large medical need for the development of effective anticancer agents with minimal side effects. The present thesis represents an attempt to identify potent drugs for treatment of solid tumors. We used a strategy where 3-D multicellular tumor spheroids (cancer cells grown in three dimensional culture) were utilized as in vitro models for solid tumors. Drug libraries were screened using spheroids as targets and using apoptosis induction and loss of cell viability as endpoints. The h...

  4. Modeling Attitude towards Drug Treament: The Role of Internal Motivation, External Pressure, and Dramatic Relief

    OpenAIRE

    Conner, Bradley T.; Longshore, Douglas; Anglin, M. Douglas

    2008-01-01

    Motivation for change has historically been viewed as the crucial element affecting responsiveness to drug treatment. Various external pressures, such as legal coercion, may engender motivation in an individual previously resistant to change. Dramatic relief may be the change process that is most salient as individuals internalize such external pressures. Results of structural equation modeling on data from 465 drug users (58.9% male; 21.3% Black, 34.2% Hispanic/Latino, and 35.1% White) enter...

  5. Modelling irradiation by EM waves of multifunctionalized iron oxide nanoparticles and subsequent drug release

    International Nuclear Information System (INIS)

    Wang, Feng; Calvayrac, Florent; Montembault, Véronique; Fontaine, Laurent

    2015-01-01

    Thermal transport in the environment close to the periphery of the nanoparticle, from a few angstroms to less than a nanometer scale, is becoming increasingly important with the advent of several biomedical applications of multifunctional magnetic nanoparticles, including drug delivery, magnetic resonance imaging, and hyperthermia therapy. We present a multiscale and multiphysics model of the irradiation by electromagnetic waves of radiofrequency of iron oxide nanoparticles functionalized by drug-releasing polymers used as new multifunctional therapeutic compounds against tumors. We compute ab initio the thermal conductivity of the polymer chains as a function of the length, model the unfolding of the polymer after heat transfer from the nanoparticle by molecular mechanics, and develop a multiscale thermodynamic and heat transfer model including the surrounding medium (water) in order to model the drug release. (paper)

  6. Does the performance of wet granulation and tablet hardness affect the drug dissolution profile of carvedilol in matrix tablets?

    Science.gov (United States)

    Košir, Darjan; Ojsteršek, Tadej; Vrečer, Franc

    2018-06-14

    Wet granulation is mostly used process for manufacturing matrix tablets. Compared to the direct compression method, it allows for a better flow and compressibility properties of compression mixtures. Granulation, including process parameters and tableting, can influence critical quality attributes (CQAs) of hydrophilic matrix tablets. One of the most important CQAs is the drug release profile. We studied the influence of granulation process parameters (type of nozzle and water quantity used as granulation liquid) and tablet hardness on the drug release profile. Matrix tablets contained HPMC K4M hydrophilic matrix former and carvedilol as a model drug. The influence of selected HPMC characteristics on the drug release profile was also evaluated using two additional HPMC batches. For statistical evaluation, partial least square (PLS) models were generated for each time point of the drug release profile using the same number of latent factors. In this way, it was possible to evaluate how the importance of factors influencing drug dissolution changes in dependence on time throughout the drug release profile. The results of statistical evaluation show that the granulation process parameters (granulation liquid quantity and type of nozzle) and tablet hardness significantly influence the release profile. On the other hand, the influence of HPMC characteristics is negligible in comparison to the other factors studied. Using a higher granulation liquid quantity and the standard nozzle type results in larger granules with a higher density and lower porosity, which leads to a slower drug release profile. Lower tablet hardness also slows down the release profile.

  7. Incorporation of lysosomal sequestration in the mechanistic model for prediction of tissue distribution of basic drugs.

    Science.gov (United States)

    Assmus, Frauke; Houston, J Brian; Galetin, Aleksandra

    2017-11-15

    The prediction of tissue-to-plasma water partition coefficients (Kpu) from in vitro and in silico data using the tissue-composition based model (Rodgers & Rowland, J Pharm Sci. 2005, 94(6):1237-48.) is well established. However, distribution of basic drugs, in particular into lysosome-rich lung tissue, tends to be under-predicted by this approach. The aim of this study was to develop an extended mechanistic model for the prediction of Kpu which accounts for lysosomal sequestration and the contribution of different cell types in the tissue of interest. The extended model is based on compound-specific physicochemical properties and tissue composition data to describe drug ionization, distribution into tissue water and drug binding to neutral lipids, neutral phospholipids and acidic phospholipids in tissues, including lysosomes. Physiological data on the types of cells contributing to lung, kidney and liver, their lysosomal content and lysosomal pH were collated from the literature. The predictive power of the extended mechanistic model was evaluated using a dataset of 28 basic drugs (pK a ≥7.8, 17 β-blockers, 11 structurally diverse drugs) for which experimentally determined Kpu data in rat tissue have been reported. Accounting for the lysosomal sequestration in the extended mechanistic model improved the accuracy of Kpu predictions in lung compared to the original Rodgers model (56% drugs within 2-fold or 88% within 3-fold of observed values). Reduction in the extent of Kpu under-prediction was also evident in liver and kidney. However, consideration of lysosomal sequestration increased the occurrence of over-predictions, yielding overall comparable model performances for kidney and liver, with 68% and 54% of Kpu values within 2-fold error, respectively. High lysosomal concentration ratios relative to cytosol (>1000-fold) were predicted for the drugs investigated; the extent differed depending on the lysosomal pH and concentration of acidic phospholipids among

  8. Micellar Structures of Hydrophilic/Lipophilic and Hydrophilic/Fluorophilic Poly(2-oxazoline) Diblock Copolymers in Water

    DEFF Research Database (Denmark)

    Ivanova, Ruzha; Komenda, Thomas; Bonné, Tune B.

    2008-01-01

    Amphiphilic poly(2-alkyl-2-oxazoline) diblock copolymers of 2-methyl-2-oxazoline (MOx) building the hydrophilic block and either 2-nonyl-2-oxazoline (NOx) for the hydrophobic or 2-(1H,1H',2H,2H'-perfluorohexyl)-2-oxazoline (FOx) for the fluorophilic block were synthesized by sequential living...

  9. 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.

  10. 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. © 2013 Published by Elsevier Ltd.

  11. Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

    Science.gov (United States)

    Germovsek, Eva; Barker, Charlotte I S; Sharland, Mike; Standing, Joseph F

    2018-04-19

    Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies.

  12. Glutathione metabolism modelling: 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

  13. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

    Science.gov (United States)

    de Witte, Wilhelmus E A; Wong, Yin Cheong; Nederpelt, Indira; Heitman, Laura H; Danhof, Meindert; van der Graaf, Piet H; Gilissen, Ron A H J; de Lange, Elizabeth C M

    2016-01-01

    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 binding kinetics in drug discovery. A meaningful application of in vitro drug-target binding kinetics in drug discovery requires insight into the relation between in vivo drug effect and in vitro measured drug-target binding kinetics. In this review, the authors discuss both the relation between in vitro and in vivo measured binding kinetics and the relation between in vivo binding kinetics, target occupancy and effect profiles. More scientific evidence is required for the rational selection and development of drug-candidates on the basis of in vitro estimates of drug-target binding kinetics. To elucidate the value of in vitro binding kinetics measurements, it is necessary to obtain information on system-specific properties which influence the kinetics of target occupancy and drug effect. Mathematical integration of this information enables the identification of drug-specific properties which lead to optimal target occupancy and drug effect in patients.

  14. Hydrophilic Polymer Embolism: Implications for Manufacturing, Regulation, and Postmarket Surveillance of Coated Intravascular Medical Devices.

    Science.gov (United States)

    Mehta, Rashi I; Mehta, Rupal I

    2018-03-19

    Hydrophilic polymers are ubiquitously applied as surface coatings on catheters and intravascular medical technologies. Recent clinical literature has heightened awareness on the complication of hydrophilic polymer embolism, the phenomenon wherein polymer coating layers separate from catheter and device surfaces, and may be affiliated with a range of unanticipated adverse reactions. Significant system barriers have limited and delayed reporting on this iatrogenic complication, the full effects of which remain underrecognized by healthcare providers and manufacturers of various branded devices. In 2015, the United States Food and Drug Administration acknowledged rising clinical concerns and stated that the agency would work with stakeholders to further evaluate gaps that exist in current national and international device standards for coated intravascular medical technologies. The present article reviews current knowledge on this complication as well as factors that played a role in delaying detection and dissemination of information and new knowledge once hazards and clinical risks were identified. Furthermore, organ-specific effects and adverse reaction patterns are summarized, along with implications for device manufacturing, safety assurance, and regulation. Qualitative and quantitative particulate testing are needed to optimize coated intravascular device technologies. Moreover, general enhanced processes for medical device surveillance are required for timely adverse event management and to ensure patient safety.

  15. 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.

  16. 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

  17. Anisotropic wetting characteristics versus roughness on machined surfaces of hydrophilic and hydrophobic materials

    International Nuclear Information System (INIS)

    Liang, Yande; Shu, Liming; Natsu, Wataru; He, Fuben

    2015-01-01

    Graphical abstract: - Highlights: • The aim is to investigate the influence of roughness on anisotropic wetting on machined surfaces. • The relationship between roughness and anisotropic wetting is modeled by thermodynamical analysis. • The effect of roughness on anisotropic wetting on hydrophilic materials is stronger than that on hydrophobic materials. • The energy barrier existing in the direction perpendicular to the lay is one of the main reasons for the anisotropic wetting. • The contact angle in the parallel direction is larger than that in the perpendicular direction. - Abstract: Anisotropic wetting of machined surfaces is widely applied in industries which can be greatly affected by roughness and solid's chemical properties. However, there has not been much work on it. A free-energy thermodynamic model is presented by analyzing geometry morphology of machined surfaces (2-D model surfaces), which demonstrates the influence of roughness on anisotropic wetting. It can be concluded that the energy barrier is one of the main reasons for the anisotropic wetting existing in the direction perpendicular to the lay. In addition, experiments in investigating anisotropic wetting, which was characterized by the static contact angle and droplet's distortion, were performed on machined surfaces with different roughness on hydrophilic and hydrophobic materials. The droplet's anisotropy found on machined surfaces increased with mean slope of roughness profile Kr. It indicates that roughness on anisotropic wetting on hydrophilic materials has a stronger effect than that on hydrophobic materials. Furthermore, the contact angles predicted by the model are basically consistent with the experimentally ones

  18. 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

  19. Computational modeling of drug-resistant bacteria. Final report

    International Nuclear Information System (INIS)

    2015-01-01

    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.

  20. 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.

  1. S-protected thiolated chitosan for oral delivery of hydrophilic macromolecules: evaluation of permeation enhancing and efflux pump inhibitory properties.

    Science.gov (United States)

    Dünnhaupt, Sarah; Barthelmes, Jan; Rahmat, Deni; Leithner, Katharina; Thurner, Clemens C; Friedl, Heike; Bernkop-Schnürch, Andreas

    2012-05-07

    The objective of this study was the investigation of permeation enhancing and P-glycoprotein (P-gp) inhibition effects of a novel thiolated chitosan, the so-named S-protected thiolated chitosan. Mediated by a carbodiimide, increasing amounts of thioglycolic acid (TGA) were covalently bound to chitosan (CS) in the first step of modification. In the second step, these thiol groups of thiolated chitosan were protected by disulfide bond formation with the thiolated aromatic residue 6-mercaptonicotinamide (6-MNA). Mucoadhesive properties of all conjugates were evaluated in vitro on porcine intestinal mucosa based on tensile strength investigations. Permeation enhancing effects were evaluated ex vivo using rat intestinal mucosa and in vitro via Caco-2 cells using the hydrophilic macromolecule FD(4) as the model drug. Caco-2 cells were further used to show P-gp inhibition effects by using Rho-123 as P-gp substrate. Apparent permeability coefficients (P(app)) were calculated and compared to values obtained from each buffer control. Three different thiolated chitosans were generated in the first step of modification, which displayed increasing amounts of covalently attached free thiol groups on the polymer backbone. In the second modification step, more than 50% of these free thiol groups were covalently linked with 6-MNA. Within 3 h of permeation studies on excised rat intestine, P(app) values of all S-protected chitosans were at least 1.3-fold higher compared to those of corresponding thiomers and more than twice as high as that of unmodified chitosan. Additional permeation studies on Caco-2 cells confirmed these results. Because of the chemical modification and higher amount of reactive thiol groups, all S-protected thiolated chitosans exhibit at least 1.4-fold pronounced P-gp inhibition effects in contrast to their corresponding thiomers. These features approve S-protected thiolated chitosan as a promising excipient for various drug delivery systems providing improved

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

    Science.gov (United States)

    2015-09-01

    Your credit card order has been processed on  Tuesday  2 December 2014 at 3:05 PM. Status: Complete 12/3/2014 Oasis, The Online Abstract Submission System...pharmacokinetic models. Toxicol Ind Health, 1997. 13(4): p. 407-84. PMID: 9249929 4. Davies, B. and T. Morris , Physiological parameters in laboratory animals and humans. Pharm Res, 1993. 10(7): p. 1093-5. PMID: 8378254

  3. Environmental modulation of drug taking: Nonhuman primate models of cocaine abuse and PET neuroimaging.

    Science.gov (United States)

    Nader, Michael A; Banks, Matthew L

    2014-01-01

    The current review highlights the importance of environmental variables on cocaine self-administration in nonhuman primate models of drug abuse. In addition to describing the behavioral consequences, potential mechanisms of action are discussed, based on imaging results using the non-invasive and translational technique of positron emission tomography (PET). In this review, the role of three environmental variables - both positive and negative - are described: alternative non-drug reinforcers; social rank (as an independent variable) and punishment of cocaine self-administration. These environmental stimuli can profoundly influence brain function and drug self-administration. We focus on environmental manipulations involving non-drug alternatives (e.g., food reinforcement) using choice paradigms. Manipulations such as response cost and social variables (e.g., social rank, social stress) also influence the behavioral effects of drugs. Importantly, these manipulations are amenable to brain imaging studies. Taken together, these studies emphasize the profound impact environmental variables can have on drug taking, which should provide important information related to individual-subject variability in treatment responsiveness, and the imaging work may highlight pharmacological targets for medications related to treating drug abuse. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Cognitive Enhancers for Facilitating Drug Cue Extinction: Insights from Animal Models

    Science.gov (United States)

    Nic Dhonnchadha, Bríd Áine; Kantak, Kathleen M.

    2011-01-01

    Given the success of cue exposure (extinction) therapy combined with a cognitive enhancer for reducing anxiety, it is anticipated that this approach will prove more efficacious than exposure therapy alone in preventing relapse in individuals with substance use disorders. Several factors may undermine the efficacy of exposure therapy for substance use disorders, but we suspect that neurocognitive impairments associated with chronic drug use are an important contributing factor. Numerous insights on these issues are gained from research using animal models of addiction. In this review, the relationship between brain sites whose learning, memory and executive functions are impaired by chronic drug use and brain sites that are important for effective drug cue extinction learning is explored first. This is followed by an overview of animal research showing improved treatment outcome for drug addiction (e.g. alcohol, amphetamine, cocaine, heroin) when explicit extinction training is conducted in combination with acute dosing of a cognitive-enhancing drug. The mechanism by which cognitive enhancers are thought to exert their benefits is by facilitating consolidation of drug cue extinction memory after activation of glutamatergic receptors. Based on the encouraging work in animals, factors that may be important for the treatment of drug addiction are considered. PMID:21295059

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

    Science.gov (United States)

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

    2011-05-30

    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 multi-criteria model that fully takes into account the evidence on efficacy and adverse drug reactions. Our approach is based on the stochastic multi-criteria acceptability analysis methodology, which allows us to compute the typical value judgments that support a decision, to quantify decision uncertainty, and to compute a comprehensive BR profile. We construct a multi-criteria model for the therapeutic group of second-generation antidepressants. We assess fluoxetine and venlafaxine together with placebo according to incidence of treatment response and three common adverse drug reactions by using data from a published study. Our model shows that there are clear trade-offs among the treatment alternatives. Copyright © 2011 John Wiley & Sons, Ltd.

  6. Modelling Illicit Drug Fate in Sewers for Wastewater-Based Epidemiology

    DEFF Research Database (Denmark)

    Ramin, Pedram

    was found during festival period as compared to normal weekdays. Wastewater-based epidemiology is a truly interdisciplinary approach in which engineering tools, including models developed and tested in this thesis, can be beneficial for the accurate estimation of drug consumption in urban areas........ Sewer systems can be considered as biological reactors, in which the concentration of organic chemicals present in wastewater can be impacted by in-sewer processes during hydraulic residence time. Illicit drug biomarkers, as trace organic chemicals in the range of nanograms to micrograms per liter...... on sorption and transformation of drug biomarkers in raw wastewater and sewer biofilms; and (ii) developing modelling tools – by combining and extending existing modelling frameworks – to predict such processes. To achieve this goal, a substantial part of this thesis was dedicated to the experimental...

  7. 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 (c) ad-prompted actions were influenced by both ad trust and ad attitude.

  8. Modeling of drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls to treat vulnerable plaques

    KAUST Repository

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

    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.

  9. METHODOLOGY OF THE DRUGS MARKET VOLUME MODELING ON THE EXAMPLE OF HEMOPHILIA A

    Directory of Open Access Journals (Sweden)

    N. B. Molchanova

    2015-01-01

    Full Text Available Hemophilia A is a serious genetic disease, which may lead to disability of a patient even in early ages without a required therapy. The only one therapeutic approach is a replacement therapy with drugs of bloodcoagulation factor VIII (FVIII. The modeling of coagulation drugs market volume will allow evaluation of the level of patients’ provision with a necessary therapy. Modeling of a “perfect” market of drugs and its comparison with the real one was the purpose of the study. During the modeling of market volume we have used the data about the number of hamophilia A patients on the basis of the federal registry, Russian and international morbidity indices, and the data of a real practice about average consumption of drugs of bloodcoagulation factors and data about the drugs prescription according to the standards and protocols of assistance rendering. According to the standards of care delivery, average annual volume of FVIII drugs consumption amounted to 406 325 244 IU for children and 964 578 678 IU for adults, i.e. an average volume of a “perfect” market is equal to 1 370 903 922 IU for all patients. The market volume is 1.8 times bigger than a real volume of FVIII drugs which, according to the data of IMS marketing agency, amounted to 765 000 000 IU in 2013. The modeling conducted has shown that despite a relatively high patients’ coverage there is a potential for almost double growth.

  10. 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.

  11. 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.

  12. 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.

  13. Reverse micelle-loaded lipid nano-emulsions: new technology for nano-encapsulation of hydrophilic materials.

    Science.gov (United States)

    Anton, Nicolas; Mojzisova, Halina; Porcher, Emilien; Benoit, Jean-Pierre; Saulnier, Patrick

    2010-10-15

    This study presents novel, recently patented technology for encapsulating hydrophilic species in lipid nano-emulsions. The method is based on the phase-inversion temperature method (the so-called PIT method), which follows a low-energy and solvent-free process. The nano-emulsions formed are stable for months, and exhibit droplet sizes ranging from 10 to 200 nm. Hydrophilic model molecules of fluorescein sodium salt are encapsulated in the oily core of these nano-emulsion droplets through their solubilisation in the reverse micellar system. As a result, original, multi-scaled nano-objects are generated with a 'hydrophilic molecule in a reverse-micelles-in-oil-in-water' structure. Once fluorescein has been encapsulated it remains stable, for thermodynamic reasons, and the encapsulation yields can reach 90%. The reason why such complex objects can be formed is due to the soft method used (PIT method) which allows the conservation of the structure of the reverse micelles throughout the formulation process, up to their entrapment in the nano-emulsion droplets. In this study, we focus the investigation on the process itself, revealing its potential and limits. Since the formulation of nanocarriers for the encapsulation of hydrophilic substances still remains a challenge, this study may constitute a significant advance in this field. Copyright 2010 Elsevier B.V. All rights reserved.

  14. Preparation and characterization of novel PVDF nanofiltration membranes with hydrophilic property for filtration of dye aqueous solution

    Science.gov (United States)

    Nikooe, Naeme; Saljoughi, Ehsan

    2017-08-01

    In the present research, for the first time PVDF/Brij-58 blend nanofiltration membranes with remarkable performance in filtration of dye aqueous solution were prepared via immersion precipitation. A noticeable improvement in water permeation and fouling resistance of the PVDF membranes was achieved by using Brij-58 surfactant as a hydrophilic additive. Scanning electron microscopy (SEM), fourier transform infrared spectroscopy (FT-IR) and water contact angle were applied for the investigation of membrane morphology, detection of the surface chemical composition and relative hydrophilicity/hydrophobicity, respectively. The membrane performance was studied and compared by determination of pure water flux (PWF) and filtration of synthetic reactive dye aqueous solutions as well as bovine serum albumin (BSA) as foulant model. It was found out that addition of 4 wt.% Brij-58 to the casting solution results in formation of membrane with remarkable hydrophilicity and fouling resistance (contact angle of 46° and flux recovery ratio (FRR) = 90%), higher porosity and consequently noticeable PWF (31.2 L/m2 h) and recognized dye rejection value (90%) in comparison with the pristine PVDF nanofiltration membrane. Addition of Brij-58 surfactant to the casting solution resulted in formation of NF membrane with higher hydrophilicity and permeability as well as higher dye rejection value in comparison with the addition of PEG 400 additive.

  15. 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 .

  16. 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.

  17. In vitro models to evaluate the permeability of poorly soluble drug entities: Challenges and perspectives

    DEFF Research Database (Denmark)

    Buckley, S. T.; Fischer, S. M.; Fricker, G.

    2012-01-01

    The application of in vitro models in drug permeability studies represents a useful screening tool for assessing the biopharmaceutical appropriateness of new chemical entities (NCEs). Of note, there remains an ever-increasing number of NCEs which exhibit poor aqueous solubility. However, in their......The application of in vitro models in drug permeability studies represents a useful screening tool for assessing the biopharmaceutical appropriateness of new chemical entities (NCEs). Of note, there remains an ever-increasing number of NCEs which exhibit poor aqueous solubility. However...

  18. 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.

  19. Enhanced dissolution and oral bioavailability of valsartan solid dispersions prepared by a freeze-drying technique using hydrophilic polymers.

    Science.gov (United States)

    Xu, Wei-Juan; Xie, Hong-Juan; Cao, Qing-Ri; Shi, Li-Li; Cao, Yue; Zhu, Xiao-Yin; Cui, Jing-Hao

    2016-01-01

    This study aimed to improve the dissolution rate and oral bioavailability of valsartan (VAL), a poorly soluble drug using solid dispersions (SDs). The SDs were prepared by a freeze-drying technique with polyethylene glycol 6000 (PEG6000) and hydroxypropylmethylcellulose (HPMC 100KV) as hydrophilic polymers, sodium hydroxide (NaOH) as an alkalizer, and poloxamer 188 as a surfactant without using any organic solvents. In vitro dissolution rate and physicochemical properties of the SDs were characterized using the USP paddle method, differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier transform-infrared (FT-IR) spectroscopy, respectively. In addition, the oral bioavailability of SDs in rats was evaluated by using VAL (pure drug) as a reference. The dissolution rates of the SDs were significantly improved at pH 1.2 and pH 6.8 compared to those of the pure drug. The results from DSC, XRD showed that VAL was molecularly dispersed in the SDs as an amorphous form. The FT-IR results suggested that intermolecular hydrogen bonding had formed between VAL and its carriers. The SDs exhibited significantly higher values of AUC 0-24 h and Cmax in comparison with the pure drug. In conclusion, hydrophilic polymer-based SDs prepared by a freeze-drying technique can be a promising method to enhance dissolution rate and oral bioavailability of VAL.

  20. Agreement between PRE2DUP register data modeling method and comprehensive drug use interview among older persons

    Science.gov (United States)

    Taipale, Heidi; Tanskanen, Antti; Koponen, Marjaana; Tolppanen, Anna-Maija; Tiihonen, Jari; Hartikainen, Sirpa

    2016-01-01

    Background PRE2DUP is a modeling method that generates drug use periods (ie, when drug use started and ended) from drug purchases recorded in dispensing-based register data. It is based on the evaluation of personal drug purchasing patterns and considers hospital stays, possible stockpiling of drugs, and package information. Objective The objective of this study was to investigate person-level agreement between self-reported drug use in the interview and drug use modeled from dispensing data with PRE2DUP method for various drug classes used by older persons. Methods Self-reported drug use was assessed from the GeMS Study including a random sample of persons aged ≥75 years from the city of Kuopio, Finland, in 2006. Drug purchases recorded in the Prescription register data of these persons were modeled to determine drug use periods with PRE2DUP modeling method. Agreement between self-reported drug use on the interview date and drug use calculated from register-based data was compared in order to find the frequently used drugs and drug classes, which was evaluated by Cohen’s kappa. Kappa values 0.61–0.80 were considered to represent good and 0.81–1.00 as very good agreement. Results Among 569 participants with mean age of 82 years, the agreement between interview and register data was very good for 75% and very good or good for 93% of the studied drugs or drug classes. Good or very good agreement was observed for drugs that are typically used on regular bases, whereas “as needed” drugs represented poorer results. Conclusion PRE2DUP modeling method validly describes regular drug use among older persons. For most of drug classes investigated, PRE2DUP-modeled register data described drug use as well as interview-based data which are more time-consuming to collect. Further studies should be conducted by comparing it with other methods and in different drug user populations. PMID:27785101

  1. Fabrication, characterization and in vitro drug release behavior of electrospun PLGA/chitosan nanofibrous scaffold

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Z.X.; Zheng, W.; Li, L. [Center for Biomedical Materials and Engineering, Harbin Engineering University, Harbin 150001 (China); Zheng, Y.F., E-mail: yfzheng@pku.edu.cn [Center for Biomedical Materials and Engineering, Harbin Engineering University, Harbin 150001 (China); Department of Advanced Materials and Nanotechnology, College of Engineering, Peking University, Beijing 100871 (China)

    2011-02-15

    Graphical abstract: The fenbufen loaded PLGA/chitosan nanofibrous scaffolds were fabricated by electrospinning. The hydrophilicity of nanofibrous scaffold was enhanced with the increase of chitosan content. The drug release also is accelerated with chitosan increasing because the higher hydrophilicity makes drug diffusing from scaffold more easily. Research highlights: {yields} The average diameter increased with the increase of chitosan content and then decreased. {yields} The release rate of fenbufen increased with the increase of chitosan. {yields} The aligned nanofibrous scaffold exhibits lower drug release rate. {yields} The drug release could be controlled by crosslinking in glutaraldehyde vapor. - Abstract: In this study both aligned and randomly oriented poly(D,L-lactide-co-glycolide) (PLGA)/chitosan nanofibrous scaffold have been prepared by electrospinning. The ratio of PLGA to chitosan was adjusted to get smooth nanofiber surface. Morphological characterization using scanning electron microscopy showed that the aligned nanofiber diameter distribution obtained by electrospinning of polymer blend increased with the increase of chitosan content which was similar to that of randomly oriented nanofibers. The release characteristic of model drug fenbufen (FBF) from the FBF-loaded aligned and randomly oriented PLGA and PLGA/chitosan nanofibrous scaffolds was investigated. The drug release rate increased with the increase of chitosan content because the addition of chitosan enhanced the hydrophilicity of the PLGA/chitosan composite scaffold. Moreover, for the aligned PLGA/chitosan nanofibrous scaffold the release rate was lower than that of randomly oriented PLGA/chitosan nanofibrous scaffold, which indicated that the nanofiber arrangement would influence the release behavior. In addition, crosslinking in glutaraldehyde vapor would decrease the burst release of FBF from FBF-loaded PLGA/chitosan nanofibrous scaffold with a PLGA/chitosan ratio less than 9/1, which

  2. Fabrication, characterization and in vitro drug release behavior of electrospun PLGA/chitosan nanofibrous scaffold

    International Nuclear Information System (INIS)

    Meng, Z.X.; Zheng, W.; Li, L.; Zheng, Y.F.

    2011-01-01

    Graphical abstract: The fenbufen loaded PLGA/chitosan nanofibrous scaffolds were fabricated by electrospinning. The hydrophilicity of nanofibrous scaffold was enhanced with the increase of chitosan content. The drug release also is accelerated with chitosan increasing because the higher hydrophilicity makes drug diffusing from scaffold more easily. Research highlights: → The average diameter increased with the increase of chitosan content and then decreased. → The release rate of fenbufen increased with the increase of chitosan. → The aligned nanofibrous scaffold exhibits lower drug release rate. → The drug release could be controlled by crosslinking in glutaraldehyde vapor. - Abstract: In this study both aligned and randomly oriented poly(D,L-lactide-co-glycolide) (PLGA)/chitosan nanofibrous scaffold have been prepared by electrospinning. The ratio of PLGA to chitosan was adjusted to get smooth nanofiber surface. Morphological characterization using scanning electron microscopy showed that the aligned nanofiber diameter distribution obtained by electrospinning of polymer blend increased with the increase of chitosan content which was similar to that of randomly oriented nanofibers. The release characteristic of model drug fenbufen (FBF) from the FBF-loaded aligned and randomly oriented PLGA and PLGA/chitosan nanofibrous scaffolds was investigated. The drug release rate increased with the increase of chitosan content because the addition of chitosan enhanced the hydrophilicity of the PLGA/chitosan composite scaffold. Moreover, for the aligned PLGA/chitosan nanofibrous scaffold the release rate was lower than that of randomly oriented PLGA/chitosan nanofibrous scaffold, which indicated that the nanofiber arrangement would influence the release behavior. In addition, crosslinking in glutaraldehyde vapor would decrease the burst release of FBF from FBF-loaded PLGA/chitosan nanofibrous scaffold with a PLGA/chitosan ratio less than 9/1, which would be beneficial

  3. 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

    Friction forces have long been associated with the famous Amontons' rule that states that the friction force is linearly dependent on the applied normal load, with the proportionality constant being known as the friction coefficient. Amontons' rule is however purely phenomenological and does...... not in itself provide any information on why the friction coefficient is different for different material combinations. In this study, friction forces between a colloidal probe and nanostructured particle coated surfaces in an aqueous environment exhibiting different roughness length scales were measured...... 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...

  4. Micro- and nanoscale characterization of hydrophobic and hydrophilic leaf surfaces

    International Nuclear Information System (INIS)

    Bhushan, Bharat; Jung, Yong Chae

    2006-01-01

    Superhydrophobic surfaces as well as low adhesion and friction are desirable for various industrial applications. Certain plant leaves are known to be hydrophobic in nature due to their roughness and the presence of a thin wax film on the surface of the leaf. The purpose of this study is to fully characterize the leaf surfaces on the micro- and nanoscale while separating out the effects of the micro- and the nanobumps of hydrophobic leaves on the hydrophobicity. Hydrophilic leaves were also studied to better understand the role of wax and roughness. Furthermore, the adhesion and friction properties of hydrophobic and hydrophilic leaves were studied. Using an optical profiler and an atomic/friction force microscope (AFM/FFM), measurements were made to fully characterize the leaf surfaces. It is shown that the nanobumps play a more important role than the microbumps in the hydrophobic nature as well as friction of the leaf. This study will be useful in developing superhydrophobic surfaces

  5. Luminescence stability of porous Si terminated by hydrophilic organic molecules

    Science.gov (United States)

    Matsumoto, Kimihisa; Kamiguchi, Masao; Kamiya, Kazuhide; Nomura, Takashi; Suzuki, Shinya

    2016-02-01

    The effects of the surface termination of a porous Si surface by propionic acid and by undecylenic acid on their hydrophilicity and luminescence stability were studied. In the measurements of the contact angle of water droplets on porous Si films, the hydrophilicity of porous Si is improved by the surface termination each types of organic molecule. The PL intensity of as-prepared porous Si decreased with increasing aging time in ambient air. As PL quenching involves PL blue shift and increasing Si-O bonds density, nonradiative recombination centers are formed in the surface oxide. After the hydrosilylation process of propionic acid and undecylenic acid, PL intensity decreased and became 30% that of as-prepared porous Si film. However, the PL intensity was stable and exceeded that of the as-prepared film after 1000 min of aging in the ambient air. The PL stabilities are contributed to the termination by organic molecules that inhibits surface oxidation.

  6. Pretreatment and Membrane Hydrophilic Modification to Reduce Membrane Fouling

    Directory of Open Access Journals (Sweden)

    Huaqiang Chu

    2013-09-01

    Full Text Available The application of low pressure membranes (microfiltration/ultrafiltration has undergone accelerated development for drinking water production. However, the major obstacle encountered in its popularization is membrane fouling caused by natural organic matter (NOM. This paper firstly summarizes the two factors causing the organic membrane fouling, including molecular weight (MW and hydrophilicity/hydrophobicity of NOM, and then presents a brief introduction of the methods which can prevent membrane fouling such as pretreatment of the feed water (e.g., coagulation, adsorption, and pre-oxidation and membrane hydrophilic modification (e.g., plasma modification, irradiation grafting modification, surface coating modification, blend modification, etc.. Perspectives of further research are also discussed.

  7. Hydrophilic nanoporous polystyrenes and 1,2-polybutadienes

    DEFF Research Database (Denmark)

    Guo, Fengxiao; Jankova Atanasova, Katja; Vigild, Martin Etchells

    2008-01-01

    Nanoporous polymers from ordered block copolymers having hydrophilic cavity surfaces were successfully prepared by two methodologies: ' 1. Nanoporous polystyrenes fromPtBA-b-PS diblock or PDMS-b-PtBA-b-PS triblock copolymer precursors by atom transfer radical polymerization (ATRP), or combination...... of living anionic polymerization~ and ATRP r~spectively. The one, PtBA block, can be modified to the hydrophilic PAA, where the dther, polydimethysiloxane (PDMS) block, can be fully degraded. Deprotection of the tert-butyl groups in PtBA and the selective etching of PDMS· chains were accomplished...... by applying HF or TFA in one step. Thus both the di- and triblock copolymers after such a treatment resulted. in nanoporous polystyrenes with hexagonal cavities of different nanosizes (6-11 nm, Figure 1). 2. Nanoporous I,2-polybutadienes (I,2-PB) by grafting various acrylic monomers onto the pore. surfaces...

  8. Polyethylene/hydrophilic polymer blends for biomedical applications.

    Science.gov (United States)

    Brynda, E; Houska, M; Novikova, S P; Dobrova, N B

    1987-01-01

    Polyethylene blends with poly(2-hydroxyethyl methacrylate) [poly(HEMA)] or poly(2,3-dihydroxypropyl methacrylate) [poly(DHPMA)] were prepared by swelling polyethylene with HEMA or 2,3-epoxypropyl methacrylate (EPMA) and by polymerization of the respective monomers. Poly(EPMA) in blends was hydrolysed to poly(DHPMA) with acetic acid. The blends had similar surface and bulk compositions. Swelling with water and surface wettability were proportional to the content of the hydrophilic component; at the same content the polyethylene/poly(DHPMA) blends appeared more hydrophilic than those of polyethylene/poly(HEMA). Thrombus formation in contact with blood examined ex vivo and in vivo was considerably slower on the blends than on unmodified polyethylene. The tests indicated optima in composition; the best biological response was achieved with the blends containing about 14% poly(HEMA) or 16% poly(DHPMA).

  9. Bayesian joint modelling of benefit and risk in drug development.

    Science.gov (United States)

    Costa, Maria J; Drury, Thomas

    2018-05-01

    To gain regulatory approval, a new medicine must demonstrate that its benefits outweigh any potential risks, ie, that the benefit-risk balance is favourable towards the new medicine. For transparency and clarity of the decision, a structured and consistent approach to benefit-risk assessment that quantifies uncertainties and accounts for underlying dependencies is desirable. This paper proposes two approaches to benefit-risk evaluation, both based on the idea of joint modelling of mixed outcomes that are potentially dependent at the subject level. Using Bayesian inference, the two approaches offer interpretability and efficiency to enhance qualitative frameworks. Simulation studies show that accounting for correlation leads to a more accurate assessment of the strength of evidence to support benefit-risk profiles of interest. Several graphical approaches are proposed that can be used to communicate the benefit-risk balance to project teams. Finally, the two approaches are illustrated in a case study using real clinical trial data. Copyright © 2018 John Wiley & Sons, Ltd.

  10. Non-Clinical Models for Neurodegenerative Diseases: Therapeutic Approach and Drug Validation in Animal Models

    Directory of Open Access Journals (Sweden)

    Caridad Ivette Fernandez

    2017-12-01

    Full Text Available In 2016, 19.8% of the Cuban population was aged 60 or over. As a result, age-associated degenerative diseases and other diseases have become priority targets from a prophylactic, diagnostic and therapeutic perspective. As a result, the Cuban biomedical scientific community has addressed its basic, preclinical and epidemiological research in order to rise up to the challenge. A firm step in this direction has been the international congress “State of the art in non-clinical models for neurodegenerative diseases” which has brought together preclinical and clinical researchers, technicians and regulatory staff members from different countries to review the state of the art in neurodegenerations, find unifying ideas, objectives and collaborations or partnership. The objective is to expose the perspectives of new biotechnological products from Cuba and other countries from the diagnostic, therapeutic and neuroprotective point of view. It is crucial, therefore, that the irreplaceable role of laboratory animals in achieving these objectives is understood but they must be used in rational, adequate and ethical manner. We expose the current development trends in this field, being of common interest to the work directed to the search for potential drugs, diagnostic tools and the promotion of changes in lifestyle as a preventive projection.

  11. Influence of pH on Drug Absorption from the Gastrointestinal Tract: A Simple Chemical Model

    Science.gov (United States)

    Hickman, Raymond J. S.; Neill, Jane

    1997-07-01

    A simple model of the gastrointestinal tract is obtained by placing ethyl acetate in contact with water at pH 2 and pH 8 in separate test tubes. The ethyl acetate corresponds to the lipid material lining the tract while the water corresponds to the aqueous contents of the stomach (pH 2) and intestine (pH 8). The compounds aspirin, paracetamol and 3-aminophenol are used as exemplars of acidic, neutral and basic drugs respectively to illustrate the influence which pH has on the distribution of each class of drug between the aqueous and organic phases of the model. The relative concentration of drug in the ethyl acetate is judged by applying microlitre-sized samples of ethyl acetate to a layer of fluorescent silica which, after evaporation of the ethyl acetate, is viewed under an ultraviolet lamp. Each of the three drugs, if present in the ethyl acetate, becomes visible as a dark spot on the silica layer. The observations made in the model system correspond well to the patterns of drug absorption from the gastrointestinal tract described in pharmacology texts and these observations are convincingly explained in terms of simple acid-base chemistry.

  12. EXTRACTION OF MONOAZO DYES BY HYDROPHILIC EXTRACTANTS FROM AQUEOUS SOLUTIONS

    Directory of Open Access Journals (Sweden)

    Y. I. Korenman

    2012-01-01

    Full Text Available The extraction of mono azo dyes E102, E122, E110, E124, E129 from aqueous solutions with hydrophilic solvents (alcohols, esters, ketones and polymers (poly-N-vinylamides, polyethylene glycol was studied. The main regularities of extraction are established. The distribution coefficients and degree of extraction of dyes was estimate. The influence of the nature of solvents and polymers on the extraction of dyes from aqueous solutions are established.

  13. A systematic investigation of computation models for predicting Adverse Drug Reactions (ADRs.

    Directory of Open Access Journals (Sweden)

    Qifan Kuang

    Full Text Available Early and accurate identification of adverse drug reactions (ADRs is critically important for drug development and clinical safety. Computer-aided prediction of ADRs has attracted increasing attention in recent years, and many computational models have been proposed. However, because of the lack of systematic analysis and comparison of the different computational models, there remain limitations in designing more effective algorithms and selecting more useful features. There is therefore an urgent need to review and analyze previous computation models to obtain general conclusions that can provide useful guidance to construct more effective computational models to predict ADRs.In the current study, the main work is to compare and analyze the performance of existing computational methods to predict ADRs, by implementing and evaluating additional algorithms that have been earlier used for predicting drug targets. Our results indicated that topological and intrinsic features were complementary to an extent and the Jaccard coefficient had an important and general effect on the prediction of drug-ADR associations. By comparing the structure of each algorithm, final formulas of these algorithms were all converted to linear model in form, based on this finding we propose a new algorithm called the general weighted profile method and it yielded the best overall performance among the algorithms investigated in this paper.Several meaningful conclusions and useful findings regarding the prediction of ADRs are provided for selecting optimal features and algorithms.

  14. A systematic investigation of computation models for predicting Adverse Drug Reactions (ADRs).

    Science.gov (United States)

    Kuang, Qifan; Wang, MinQi; Li, Rong; Dong, YongCheng; Li, Yizhou; Li, Menglong

    2014-01-01

    Early and accurate identification of adverse drug reactions (ADRs) is critically important for drug development and clinical safety. Computer-aided prediction of ADRs has attracted increasing attention in recent years, and many computational models have been proposed. However, because of the lack of systematic analysis and comparison of the different computational models, there remain limitations in designing more effective algorithms and selecting more useful features. There is therefore an urgent need to review and analyze previous computation models to obtain general conclusions that can provide useful guidance to construct more effective computational models to predict ADRs. In the current study, the main work is to compare and analyze the performance of existing computational methods to predict ADRs, by implementing and evaluating additional algorithms that have been earlier used for predicting drug targets. Our results indicated that topological and intrinsic features were complementary to an extent and the Jaccard coefficient had an important and general effect on the prediction of drug-ADR associations. By comparing the structure of each algorithm, final formulas of these algorithms were all converted to linear model in form, based on this finding we propose a new algorithm called the general weighted profile method and it yielded the best overall performance among the algorithms investigated in this paper. Several meaningful conclusions and useful findings regarding the prediction of ADRs are provided for selecting optimal features and algorithms.

  15. 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.

  16. Method for the production of a hydrophilic polymer product

    International Nuclear Information System (INIS)

    Cordrey, P.W.; Frankland, J.D.; Highgate, D.J.

    1976-01-01

    It has been found that by subjecting mixtures containing hydrophilic monomer materials to radiation it is possible to obtain polymers capable of absorbing up to five times or more their weight of water. These polymers are very suitable for use in contact with living tissue since they contain none of the harmful contaminants derived from initiators used in conventional polymerisation. A method for the production of these polymers comprises subjecting to irradiation polymerisation a mixture containing (1) at least one hydrophilic monomer selected from N-vinyl pyrrolidones and hydroxyalkyl methacrylates and at least one hydrophobic monomer selected from alkyl acrylates, alkyl methacrylates and styrene, or (2) at least one hydrophilic monomer such as N-vinyl-2-pyrrolidone or hydroxyethyl methacrylate and at least one hydrophobic polymer selected from nylons, polyamides and terephthalic acid, with one or more alkyl substituted hexamethylene diamines, polyalkyl acrylates, polyalkyl methacrylates, polystyrenes, polyvinyl chloride and bisphenol polycarbonate. The irradiation may be gamma-ray, and the dosage 2 to 5 MR over one to 48 hours. The polymerisation may be carried out in the presence of a cross-linking agent such as alkyl methacrylate, divinylbenzene, or ethylene glycol dimethacrylate and in an oxygen-free or inert atmosphere, or in vacuo. Examples of application of the method are given. (U.K.)

  17. Preparation and characterization of dopamine-decorated hydrophilic carbon black

    Energy Technology Data Exchange (ETDEWEB)

    Zhu Lijun; Lu Yonglai [State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029 (China); Key Laboratory of Beijing City on Preparation and Processing of Novel Polymer Materials, Beijing 100029 (China); Wang Yiqing [State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029 (China); Key Laboratory of Carbon Fiber and Functional Polymers, Ministry of Education, Beijing 100029 (China); Zhang Liqun [State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029 (China); Key Laboratory of Beijing City on Preparation and Processing of Novel Polymer Materials, Beijing 100029 (China); Wang Wencai, E-mail: wangw@mail.buct.edu.cn [State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing 100029 (China); Key Laboratory of Carbon Fiber and Functional Polymers, Ministry of Education, Beijing 100029 (China)

    2012-05-01

    Inspired by the bio-adhesive proteins secreted by mussels for attachment to almost all wet substrates, a facile method involving oxidative polymerization of dopamine was proposed to prepare highly hydrophilic carbon black (CB) particles. A self-assembled polydopamine (PDA) ad-layer was formed via the oxidative polymerization of dopamine on the surface of CB simply by dipping the CB into an alkaline dopamine solution and mildly stirring at room temperature. The process is simple, controllable, and environment-friendly. The surface composition and structure of the CB were characterized by X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). The surface morphology of the CB was observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results showed that the PDA ad-layer was successfully deposited on the CB surfaces. The PDA-functionalized CB (CB-PDA) gave a stable colloidal dispersion in water. Contact angle measurement results indicated that the hydrophilicity of CB was significantly improved after dopamine modification. TGA results confirmed that the modified CB maintained good heat resistance. The method provided a facile route to prepare hydrophilic CB having terminal hydroxyl groups.

  18. Hydrophilic-impermeable modified polyethylene terephthalate for selective endothelialization

    Science.gov (United States)

    Chetouane, D.; Fafet, J. F.; Barbet, R.; Dieval, F.

    2017-10-01

    The aim of this study was to create a modified polyethylene terephthalate (PET) responding to vascular implants’ requirements, mainly with a surface promoting selective endothelialization. The surface alteration was carried out by hydrophilic functionalization in an alkaline solution with the presence of specific surfactant (TA). The carboxylic groups resulting from this reaction were quantified by colorimetric titration using bleu toluidine O dye (TBO). A single-sided coating process was then optimized to cover the PET surface by micro spherical structures’ polymeric layer. This coating provided to the PET surface high impermeability to the water under a pressure of 120 mmHg and enhanced its hydrophilic property. This spherical topography reduced the adhesion of Mesenchymal Stem Cells (MSC) by 37% and inhibited their proliferation after 3 days by 50%. The hydrophilic functionalized PET (PET-TA) surface decreased the MSC adhesion by 50% and promoted HUVEC attachment with a number twice more important than the number of HUVEC adhered onto non treated-PET.

  19. Encapsulation systems for the delivery of hydrophilic nutraceuticals: Food application.

    Science.gov (United States)

    Aditya, N P; Espinosa, Yadira Gonzalez; Norton, Ian T

    2017-07-01

    Increased health risk associated with the sedentary life style is forcing the food manufacturers to look for food products with specific or general health benefits e.g. beverages enriched with nutraceuticals like catechin, curcumin rutin. Compounds like polyphenols, flavonoids, vitamins are the good choice of bioactive compounds that can be used to fortify the food products to enhance their functionality. However due to low stability and bioavailability of these bioactives (both hydrophobic and hydrophilic) within the heterogeneous food microstructure and in the Gastro Intestinal Tract (GIT), it becomes extremely difficult to pass on the real health benefits to the consumers. Recent developments in the application of nano-delivery systems for food product development is proving to be a game changer which has raised the expectations of the researchers, food manufacturers and consumers regarding possibility of enhancing the functionality of bioactives within the fortified food products. In this direction, nano/micro delivery systems using lipids, surfactants and other materials (carbohydrates, polymers, complexes, protein) have been fabricated to stabilize and enhance the biological activity of the bioactive compounds. In the present review, current status of the various delivery systems that are used for the delivery of hydrophilic bioactives and future prospects for using other delivery systems that have been not completely explored for the delivery of hydrophilic bioactives e.g. niosomes; bilosomes, cubosomes are discussed. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Role of mass drug administration in elimination of Plasmodium falciparum malaria: a consensus modelling study.

    Science.gov (United States)

    Brady, Oliver J; Slater, Hannah C; Pemberton-Ross, Peter; Wenger, Edward; Maude, Richard J; Ghani, Azra C; Penny, Melissa A; Gerardin, Jaline; White, Lisa J; Chitnis, Nakul; Aguas, Ricardo; Hay, Simon I; Smith, David L; Stuckey, Erin M; Okiro, Emelda A; Smith, Thomas A; Okell, Lucy C

    2017-07-01

    Mass drug administration for elimination of Plasmodium falciparum malaria is recommended by WHO in some settings. We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission. We collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models. We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels. The outcome of interest was the percentage reduction in annual mean prevalence of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration. The models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors. Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone. Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels. Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels. The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds. Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest. Mass drug administration has the potential to reduce transmission for a limited time, but is not an effective replacement for existing

  1. HIV Prevention and Rehabilitation Models for Women Who Inject Drugs in Russia and Ukraine

    Directory of Open Access Journals (Sweden)

    Roman Yorick

    2012-01-01

    Full Text Available Women who inject drugs require gender-specific approaches to drug rehabilitation, modification of risk behaviors, and psychosocial adaptation. Improved outcomes have been demonstrated when the specific needs of women’s subpopulations have been addressed. Special services for women include prenatal care, child care, women-only programs, supplemental workshops on women-focused topics, mental health services, and comprehensive programs that include several of the above components. To address the special needs of women injecting drug user (IDU subpopulations, such as HIV-positive pregnant women and women with young children, recently released female prisoners, and street-involved girls and young women, HealthRight International and its local partners in Russia and Ukraine have developed innovative service models. This paper presents each of these models and discusses their effectiveness and implementation challenges specific to local contexts in Russia and Ukraine.

  2. Experimental methods and transport models for drug delivery across the blood-brain barrier.

    Science.gov (United States)

    Fu, Bingmei M

    2012-06-01

    The blood-brain barrier (BBB) is a dynamic barrier essential for maintaining the micro-environment of the brain. Although the special anatomical features of the BBB determine its protective role for the central nervous system (CNS) from blood-born neurotoxins, however, the BBB extremely limits the therapeutic efficacy of drugs into the CNS, which greatly hinders the treatment of major brain diseases. This review summarized the unique structures of the BBB, described a variety of in vivo and in vitro experimental methods for determining the transport properties of the BBB, e.g., the permeability of the BBB to water, ions, and solutes including nutrients, therapeutic agents and drug carriers, and presented newly developed mathematical models which quantitatively correlate the anatomical structures of the BBB with its barrier functions. Finally, on the basis of the experimental observations and the quantitative models, several strategies for drug delivery through the BBB were proposed.

  3. Dual process interaction model of HIV-risk behaviors among drug offenders.

    Science.gov (United States)

    Ames, Susan L; Grenard, Jerry L; Stacy, Alan W

    2013-03-01

    This study evaluated dual process interaction models of HIV-risk behavior among drug offenders. A dual process approach suggests that decisions to engage in appetitive behaviors result from a dynamic interplay between a relatively automatic associative system and an executive control system. One synergistic type of interplay suggests that executive functions may dampen or block effects of spontaneously activated associations. Consistent with this model, latent variable interaction analyses revealed that drug offenders scoring higher in affective decision making were relatively protected from predictive effects of spontaneous sex associations promoting risky sex. Among drug offenders with lower levels of affective decision making ability, spontaneous sexually-related associations more strongly predicted risky sex (lack of condom use and greater number of sex partners). These findings help elucidate associative and control process effects on appetitive behaviors and are important for explaining why some individuals engage in risky sex, while others are relatively protected.

  4. What is a new drug worth? An innovative model for performance-based pricing.

    Science.gov (United States)

    Dranitsaris, G; Dorward, K; Owens, R C; Schipper, H

    2015-05-01

    This article focuses on a novel method to derive prices for new pharmaceuticals by making price a function of drug performance. We briefly review current models for determining price for a new product and discuss alternatives that have historically been favoured by various funding bodies. The progressive approach to drug pricing, proposed herein, may better address the views and concerns of multiple stakeholders in a developed healthcare system by acknowledging and incorporating input from disparate parties via comprehensive and successive negotiation stages. In proposing a valid construct for performance-based pricing, the following model seeks to achieve several crucial objectives: earlier and wider access to new treatments; improved transparency in drug pricing; multi-stakeholder involvement through phased pricing negotiations; recognition of innovative product performance and latent changes in value; an earlier and more predictable return for developers without sacrificing total return on investment (ROI); more involved and informed risk sharing by the end-user. © 2014 John Wiley & Sons Ltd.

  5. Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development

    Science.gov (United States)

    Swat, MJ; Moodie, S; Wimalaratne, SM; Kristensen, NR; Lavielle, M; Mari, A; Magni, P; Smith, MK; Bizzotto, R; Pasotti, L; Mezzalana, E; Comets, E; Sarr, C; Terranova, N; Blaudez, E; Chan, P; Chard, J; Chatel, K; Chenel, M; Edwards, D; Franklin, C; Giorgino, T; Glont, M; Girard, P; Grenon, P; Harling, K; Hooker, AC; Kaye, R; Keizer, R; Kloft, C; Kok, JN; Kokash, N; Laibe, C; Laveille, C; Lestini, G; Mentré, F; Munafo, A; Nordgren, R; Nyberg, HB; Parra-Guillen, ZP; Plan, E; Ribba, B; Smith, G; Trocóniz, IF; Yvon, F; Milligan, PA; Harnisch, L; Karlsson, M; Hermjakob, H; Le Novère, N

    2015-01-01

    The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps. PMID:26225259

  6. Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development.

    Science.gov (United States)

    Swat, M J; Moodie, S; Wimalaratne, S M; Kristensen, N R; Lavielle, M; Mari, A; Magni, P; Smith, M K; Bizzotto, R; Pasotti, L; Mezzalana, E; Comets, E; Sarr, C; Terranova, N; Blaudez, E; Chan, P; Chard, J; Chatel, K; Chenel, M; Edwards, D; Franklin, C; Giorgino, T; Glont, M; Girard, P; Grenon, P; Harling, K; Hooker, A C; Kaye, R; Keizer, R; Kloft, C; Kok, J N; Kokash, N; Laibe, C; Laveille, C; Lestini, G; Mentré, F; Munafo, A; Nordgren, R; Nyberg, H B; Parra-Guillen, Z P; Plan, E; Ribba, B; Smith, G; Trocóniz, I F; Yvon, F; Milligan, P A; Harnisch, L; Karlsson, M; Hermjakob, H; Le Novère, N

    2015-06-01

    The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.

  7. Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction.

    Science.gov (United States)

    Engleman, Eric A; Katner, Simon N; Neal-Beliveau, Bethany S

    2016-01-01

    Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH's effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system-dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine neurotransmission

  8. Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction

    Science.gov (United States)

    Engleman, Eric A.; Katner, Simon N.; Neal-Beliveau, Bethany S.

    2016-01-01

    Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH’s effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system–dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine

  9. Placental Drug Transport-on-a-Chip: A Microengineered In Vitro Model of Transporter-Mediated Drug Efflux in the Human Placental Barrier.

    Science.gov (United States)

    Blundell, Cassidy; Yi, Yoon-Suk; Ma, Lin; Tess, Emily R; Farrell, Megan J; Georgescu, Andrei; Aleksunes, Lauren M; Huh, Dongeun

    2018-01-01

    The current lack of knowledge about the effect of maternally administered drugs on the developing fetus is a major public health concern worldwide. The first critical step toward predicting the safety of medications in pregnancy is to screen drug compounds for their ability to cross the placenta. However, this type of preclinical study has been hampered by the limited capacity of existing in vitro and ex vivo models to mimic physiological drug transport across the maternal-fetal interface in the human placenta. Here the proof-of-principle for utilizing a microengineered model of the human placental barrier to simulate and investigate drug transfer from the maternal to the fetal circulation is demonstrated. Using the gestational diabetes drug glyburide as a model compound, it is shown that the microphysiological system is capable of reconstituting efflux transporter-mediated active transport function of the human placental barrier to limit fetal exposure to maternally administered drugs. The data provide evidence that the placenta-on-a-chip may serve as a new screening platform to enable more accurate prediction of drug transport in the human placenta. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Methodologies Related to Computational models in View of Developing Anti-Alzheimer Drugs: An Overview.

    Science.gov (United States)

    Baheti, Kirtee; Kale, Mayura Ajay

    2018-04-17

    Since last two decades, there has been more focus on the development strategies related to Anti-Alzheimer's drug research. This may be attributed to the fact that most of the Alzheimer's cases are still mostly unknown except for a few cases, where genetic differences have been identified. With the progress of the disease, the symptoms involve intellectual deterioration, memory impairment, abnormal personality and behavioural patterns, confusion, aggression, mood swings, irritability Current therapies available for this disease give only symptomatic relief and do not focus on manipulations of biololecular processes. Nearly all the therapies to treat Alzheimer's disease, target to change the amyloid cascade which is considered to be an important in AD pathogenesis. New drug regimens are not able to keep pace with the ever-increasing understanding about dementia at molecular level. Looking into these aggravated problems, we though to put forth molecular modeling as a drug discovery approach for developing novel drugs to treat Alzheimer disease. The disease is incurable and it gets worst as it advances and finally causes death. Due to this, the design of drugs to treat this disease has become an utmost priority for research. One of the most important emerging technologies applied for this has been Computer-assisted drug design (CADD). It is a research tool that employs large scale computing strategies in an attempt to develop a model receptor site which can be used for designing of an anti-Alzheimer drug. The various models of amyloid-based calcium channels have been computationally optimized. Docking and De novo evolution are used to design the compounds. These are further subjected to absorption, distribution, metabolism, excretion and toxicity (ADMET) studies to finally bring about active compounds that are able to cross BBB. Many novel compounds have been designed which might be promising ones for the treatment of AD. The present review describes the research

  11. Multi-Step Usage of in Vivo Models During Rational Drug Design and Discovery

    Directory of Open Access Journals (Sweden)

    Charles H. Williams

    2011-04-01

    Full Text Available In this article we propose a systematic development method for rational drug design while reviewing paradigms in industry, emerging techniques and technologies in the field. Although the process of drug development today has been accelerated by emergence of computational methodologies, it is a herculean challenge requiring exorbitant resources; and often fails to yield clinically viable results. The current paradigm of target based drug design is often misguided and tends to yield compounds that have poor absorption, distribution, metabolism, and excretion, toxicology (ADMET properties. Therefore, an in vivo organism based approach allowing for a multidisciplinary inquiry into potent and selective molecules is an excellent place to begin rational drug design. We will review how organisms like the zebrafish and Caenorhabditis elegans can not only be starting points, but can be used at various steps of the drug development process from target identification to pre-clinical trial models. This systems biology based approach paired with the power of computational biology; genetics and developmental biology provide a methodological framework to avoid the pitfalls of traditional target based drug design.

  12. A model of directional selection applied to the evolution of drug resistance in HIV-1.

    Science.gov (United States)

    Seoighe, Cathal; Ketwaroo, Farahnaz; Pillay, Visva; Scheffler, Konrad; Wood, Natasha; Duffet, Rodger; Zvelebil, Marketa; Martinson, Neil; McIntyre, James; Morris, Lynn; Hide, Winston

    2007-04-01

    Understanding how pathogens acquire resistance to drugs is important for the design of treatment strategies, particularly for rapidly evolving viruses such as HIV-1. Drug treatment can exert strong selective pressures and sites within targeted genes that confer resistance frequently evolve far more rapidly than the neutral rate. Rapid evolution at sites that confer resistance to drugs can be used to help elucidate the mechanisms of evolution of drug resistance and to discover or corroborate novel resistance mutations. We have implemented standard maximum likelihood methods that are used to detect diversifying selection and adapted them for use with serially sampled reverse transcriptase (RT) coding sequences isolated from a group of 300 HIV-1 subtype C-infected women before and after single-dose nevirapine (sdNVP) to prevent mother-to-child transmission. We have also extended the standard models of codon evolution for application to the detection of directional selection. Through simulation, we show that the directional selection model can provide a substantial improvement in sensitivity over models of diversifying selection. Five of the sites within the RT gene that are known to harbor mutations that confer resistance to nevirapine (NVP) strongly supported the directional selection model. There was no evidence that other mutations that are known to confer NVP resistance were selected in this cohort. The directional selection model, applied to serially sampled sequences, also had more power than the diversifying selection model to detect selection resulting from factors other than drug resistance. Because inference of selection from serial samples is unlikely to be adversely affected by recombination, the methods we describe may have general applicability to the analysis of positive selection affecting recombining coding sequences when serially sampled data are available.

  13. Supersaturating drug delivery systems

    DEFF Research Database (Denmark)

    Laitinen, Riikka; Löbmann, Korbinian; Grohganz, Holger

    2017-01-01

    of the bioavailability of poorly water-soluble drugs by increasing the driving force for drug absorption. However, ASDs often require a high weight percentage of carrier (usually a hydrophilic polymer) to ensure molecular mixing of the drug in the carrier and stabilization of the supersaturated state, often leading......Amorphous solid dispersions (ASDs) are probably the most common and important supersaturating drug delivery systems for the formulation of poorly water-soluble compounds. These delivery systems are able to achieve and maintain a sustained drug supersaturation which enables improvement...... strategy for poorly-soluble drugs. While the current research on co-amorphous formulations is focused on preparation and characterization of these systems, more detailed research on their supersaturation and precipitation behavior and the effect of co-formers on nucleation and crystal growth inhibition...

  14. 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

    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...

  15. A state-of-the-art multi-criteria model for drug benefit-risk analysis

    NARCIS (Netherlands)

    Tervonen, T.; Hillege, H.L.; Buskens, E.; Postmus, D.

    2010-01-01

    Drug benefit-risk analysis is based on firm clinical evidence related to various safety and efficacy outcomes, such as tolerability, treatment response, and adverse events. In this paper, we propose a new approach for constructing a supporting multi-criteria model that fully takes into account this

  16. Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction

    Directory of Open Access Journals (Sweden)

    Ijaz Ahmad

    2016-01-01

    Full Text Available Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model.

  17. PockDrug: A Model for Predicting Pocket Druggability That Overcomes Pocket Estimation Uncertainties.

    Science.gov (United States)

    Borrel, Alexandre; Regad, Leslie; Xhaard, Henri; Petitjean, Michel; Camproux, Anne-Claude

    2015-04-27

    Predicting protein druggability is a key interest in the target identification phase of drug discovery. Here, we assess the pocket estimation methods' influence on druggability predictions by comparing statistical models constructed from pockets estimated using different pocket estimation methods: a proximity of either 4 or 5.5 Å to a cocrystallized ligand or DoGSite and fpocket estimation methods. We developed PockDrug, a robust pocket druggability model that copes with uncertainties in pocket boundaries. It is based on a linear discriminant analysis from a pool of 52 descriptors combined with a selection of the most stable and efficient models using different pocket estimation methods. PockDrug retains the best combinations of three pocket properties which impact druggability: geometry, hydrophobicity, and aromaticity. It results in an average accuracy of 87.9% ± 4.7% using a test set and exhibits higher accuracy (∼5-10%) than previous studies that used an identical apo set. In conclusion, this study confirms the influence of pocket estimation on pocket druggability prediction and proposes PockDrug as a new model that overcomes pocket estimation variability.

  18. Hindered disulfide bonds to regulate release rate of model drug from mesoporous silica.

    Science.gov (United States)

    Nadrah, Peter; Maver, Uroš; Jemec, Anita; Tišler, Tatjana; Bele, Marjan; Dražić, Goran; Benčina, Mojca; Pintar, Albin; Planinšek, Odon; Gaberšček, Miran

    2013-05-01

    With the advancement of drug delivery systems based on mesoporous silica nanoparticles (MSNs), a simple and efficient method regulating the drug release kinetics is needed. We developed redox-responsive release systems with three levels of hindrance around the disulfide bond. A model drug (rhodamine B dye) was loaded into MSNs' mesoporous voids. The pore opening was capped with β-cyclodextrin in order to prevent leakage of drug. Indeed, in absence of a reducing agent the systems exhibited little leakage, while the addition of dithiothreitol cleaved the disulfide bonds and enabled the release of cargo. The release rate and the amount of released dye were tuned by the level of hindrance around disulfide bonds, with the increased hindrance causing a decrease in the release rate as well as in the amount of released drug. Thus, we demonstrated the ability of the present mesoporous systems to intrinsically control the release rate and the amount of the released cargo by only minor structural variations. Furthermore, an in vivo experiment on zebrafish confirmed that the present model delivery system is nonteratogenic.

  19. A paradigm shift in pharmacokinetic-pharmacodynamic (PKPD) modeling: rule of thumb for estimating free drug level in tissue compared with plasma to guide drug design.

    Science.gov (United States)

    Poulin, Patrick

    2015-07-01

    A basic assumption in pharmacokinetics-pharmacodynamics research is that the free drug concentration is similar in plasma and tissue, and, hence, in vitro plasma data can be used to estimate the in vivo condition in tissue. However, in a companion manuscript, it has been demonstrated that this assumption is violated for the ionized drugs. Nonetheless, these observations focus on in vitro static environments and do not challenge data with an in vivo dynamic system. Therefore, an extension from an in vitro to an in vivo system becomes the necessary next step. The objective of this study was to perform theoretical simulations of the free drug concentration in tissue and plasma by using a physiologically based pharmacokinetics (PBPK) model reproducing the in vivo conditions in human. Therefore, the effects of drug ionization, lipophilicity, and clearance have been taken into account in a dynamic system. This modeling exercise was performed as a proof of concept to demonstrate that free drug concentration in tissue and plasma may also differ in a dynamic system for passively permeable drugs that are ionized at the physiological pH. The PBPK model simulations indicated that free drug concentrations in tissue cells and plasma significantly differ for the ionized drugs because of the pH gradient effect between cells and interstitial space. Hence, a rule of thumb for potentially performing more accurate PBPK/PD modeling is suggested, which states that the free drug concentration in tissue and plasma will differ for the ionizable drugs in contrast to the neutral drugs. In addition to the pH gradient effect for the ionizable drugs, lipophilicity and clearance effects will increase or decrease the free drug concentration in tissue and plasma for each class of drugs; thus, higher will be the drug lipophilicity and clearance, lower would be the free drug concentration in plasma, and, hence, in tissue, in a dynamic in vivo system. Therefore, only considering the value of free

  20. Advanced progress of microencapsulation technologies: in vivo and in vitro models for studying oral and transdermal drug deliveries.

    Science.gov (United States)

    Lam, P L; Gambari, R

    2014-03-28

    This review provides an overall discussion of microencapsulation systems for both oral and transdermal drug deliveries. Clinically, many drugs, especially proteins and peptides, are susceptible to the gastrointestinal tract and the first-pass metabolism after oral administration while some drugs exhibit low skin permeability through transdermal delivery route. Medicated microcapsules as oral and transdermal drug delivery vehicles are believed to offer an extended drug effect at a relatively low dose and provide a better patient compliance. The polymeric microcapsules can be produced by different microencapsulation methods and the drug microencapsulation technology provides the quality preservation for drug stabilization. The release of the entrapped drug is controlled and prolonged for specific usages. Some recent studies have focused on the evaluation of drug containing microcapsules on potential biological and therapeutic applications. For the oral delivery, in vivo animal models were used for evaluating possible treatment effects of drug containing microcapsules. For the transdermal drug delivery, skin delivery models were introduced to investigate the potential skin delivery of medicated microcapsules. Finally, the challenges and limitations of drug microencapsulation in real life are discussed and the commercially available drug formulations using microencapsulation technology for oral and transdermal applications are shown. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Turning theory into practice: the development of modern transdermal drug delivery systems and future trends.

    Science.gov (United States)

    Perumal, O; Murthy, S N; Kalia, Y N

    2013-01-01

    Despite its remarkable barrier function, the skin remains an attractive site for systemic drug delivery given its easy accessibility, large surface area and the possibility to bypass the gastrointestinal tract and the liver and so modify drug absorption kinetics. The pioneering work of Scheuplein, Higuchi and others in the 1960s helped to explain the processes involved in passive percutaneous absorption and led to the development of mathematical models to describe transdermal drug delivery. The intervening years have seen these theories turned to practice and a significant number of transdermal systems are now available including some that employ active drug delivery. This review briefly discusses the evolution of transdermal therapeutic systems over the years and the potential of newer transdermal technologies to deliver hydrophilic drugs and macromolecules through the skin. © 2013 S. Karger AG, Basel.

  2. Low temperature fused deposition modeling (FDM) 3D printing of thermolabile drugs.

    Science.gov (United States)

    Kollamaram, Gayathri; Croker, Denise M; Walker, Gavin M; Goyanes, Alvaro; Basit, Abdul W; Gaisford, Simon

    2018-07-10

    Fused deposition modelling (FDM) is the most commonly investigated 3D printing technology for the manufacture of personalized medicines, however, the high temperatures used in the process limit its wider application. The objective of this study was to print low-melting and thermolabile drugs by reducing the FDM printing temperature. Two immediate release polymers, Kollidon VA64 and Kollidon 12PF were investigated as potential candidates for low-temperature FDM printing. Ramipril was used as the model low melting temperature drug (109 °C); to the authors' knowledge this is the lowest melting point drug investigated to date by FDM printing. Filaments loaded with 3% drug were obtained by hot melt extrusion at 70 °C and ramipril printlets with a dose equivalent of 8.8 mg were printed at 90 °C. HPLC analysis confirmed that the drug was stable with no signs of degradation and dissolution studies revealed that drug release from the printlets reached 100% within 20-30 min. Variable temperature Raman and solid state nuclear magnetic resonance (SSNMR) spectroscopy techniques were used to evaluate drug stability over the processing temperature range. These data indicated that ramipril did not undergo degradation below its melting point (which is above the processing temperature range: 70-90 °C) but it was transformed into the impurity diketopiperazine upon exposure to temperatures higher than its melting point. The use of the excipients Kollidon VA64 and Kollidon 12PF in FDM was further validated by printing with the drug 4-aminosalicylic acid (4-ASA), which in previous work was reported to undergo degradation in FDM printing, but here it was found to be stable. This work demonstrates that the selection and use of new excipients can overcome one of the major disadvantages in FDM printing, drug degradation due to thermal heating, making this technology suitable for drugs with lower melting temperatures. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model.

    Science.gov (United States)

    Lin, Wen; Ji, Tao; Einolf, Heidi; Ayalasomayajula, Surya; Lin, Tsu-Han; Hanna, Imad; Heimbach, Tycho; Breen, Christopher; Jarugula, Venkateswar; He, Handan

    2017-05-01

    Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin C max by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CL int,T ) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves C max that coincide with the low C max of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase. Copyright © 2017. Published by Elsevier Inc.

  4. Computational Models of the Gastrointestinal Environment. 2. Phase Behavior and Drug Solubilization Capacity of a Type I Lipid-Based Drug Formulation after Digestion.

    Science.gov (United States)

    Birru, Woldeamanuel A; Warren, Dallas B; Han, Sifei; Benameur, Hassan; Porter, Christopher J H; Pouton, Colin W; Chalmers, David K

    2017-03-06

    Lipid-based drug formulations can greatly enhance the bioavailability of poorly water-soluble drugs. Following the oral administration of formulations containing tri- or diglycerides, the digestive processes occurring within the gastrointestinal (GI) tract hydrolyze the glycerides to mixtures of free fatty acids and monoglycerides that are, in turn, solubilized by bile. The behavior of drugs within the resulting colloidal mixtures is currently not well characterized. This work presents matched in vitro experimental and molecular dynamics (MD) theoretical models of the GI microenvironment containing a digested triglyceride-based (Type I) drug formulation. Both the experimental and theoretical models consist of molecular species representing bile (glycodeoxycholic acid), digested triglyceride (1:2 glyceryl-1-monooleate and oleic acid), and water. We have characterized the phase behavior of the physical system using nephelometry, dynamic light scattering, and polarizing light microscopy and compared these measurements to phase behavior observed in multiple MD simulations. Using this model microenvironment, we have investigated the dissolution of the poorly water-soluble drug danazol experimentally using LC-MS and theoretically by MD simulation. The results show how the formulation lipids alter the environment of the GI tract and improve the solubility of danazol. The MD simulations successfully reproduce the experimental results showing the utility of MD in modeling the fate of drugs after digestion of lipid-based formulations within the intestinal lumen.

  5. Phenotypic and genomic comparison of Mycobacterium aurum and surrogate model species to Mycobacterium tuberculosis: implications for drug discovery.

    Science.gov (United States)

    Namouchi, Amine; Cimino, Mena; Favre-Rochex, Sandrine; Charles, Patricia; Gicquel, Brigitte

    2017-07-13

    Tuberculosis (TB) is caused by Mycobacterium tuberculosis and represents one of the major challenges facing drug discovery initiatives worldwide. The considerable rise in bacterial drug resistance in recent years has led to the need of new drugs and drug regimens. Model systems are regularly used to speed-up the drug discovery process and circumvent biosafety issues associated with manipulating M. tuberculosis. These include the use of strains such as Mycobacterium smegmatis and Mycobacterium marinum that can be handled in biosafety level 2 facilities, making high-throughput screening feasible. However, each of these model species have their own limitations. We report and describe the first complete genome sequence of Mycobacterium aurum ATCC23366, an environmental mycobacterium that can also grow in the gut of humans and animals as part of the microbiota. This species shows a comparable resistance profile to that of M. tuberculosis for several anti-TB drugs. The aims of this study were to (i) determine the drug resistance profile of a recently proposed model species, Mycobacterium aurum, strain ATCC23366, for anti-TB drug discovery as well as Mycobacterium smegmatis and Mycobacterium marinum (ii) sequence and annotate the complete genome sequence of this species obtained using Pacific Bioscience technology (iii) perform comparative genomics analyses of the various surrogate strains with M. tuberculosis (iv) discuss how the choice of the surrogate model used for drug screening can affect the drug discovery process. We describe the complete genome sequence of M. aurum, a surrogate model for anti-tuberculosis drug discovery. Most of the genes already reported to be associated with drug resistance are shared between all the surrogate strains and M. tuberculosis. We consider that M. aurum might be used in high-throughput screening for tuberculosis drug discovery. We also highly recommend the use of different model species during the drug discovery screening process.

  6. A hepatitis C virus infection model with time-varying drug effectiveness: solution and analysis.

    Directory of Open Access Journals (Sweden)

    Jessica M Conway

    2014-08-01

    Full Text Available Simple models of therapy for viral diseases such as hepatitis C virus (HCV or human immunodeficiency virus assume that, once therapy is started, the drug has a constant effectiveness. More realistic models have assumed either that the drug effectiveness depends on the drug concentration or that the effectiveness varies over time. Here a previously introduced varying-effectiveness (VE model is studied mathematically in the context of HCV infection. We show that while the model is linear, it has no closed-form solution due to the time-varying nature of the effectiveness. We then show that the model can be transformed into a Bessel equation and derive an analytic solution in terms of modified Bessel functions, which are defined as infinite series, with time-varying arguments. Fitting the solution to data from HCV infected patients under therapy has yielded values for the parameters in the model. We show that for biologically realistic parameters, the predicted viral decay on therapy is generally biphasic and resembles that predicted by constant-effectiveness (CE models. We introduce a general method for determining the time at which the transition between decay phases occurs based on calculating the point of maximum curvature of the viral decay curve. For the parameter regimes of interest, we also find approximate solutions for the VE model and establish the asymptotic behavior of the system. We show that the rate of second phase decay is determined by the death rate of infected cells multiplied by the maximum effectiveness of therapy, whereas the rate of first phase decline depends on multiple parameters including the rate of increase of drug effectiveness with time.

  7. Financial Effect of a Drug Distribution Model Change on a Health System.

    Science.gov (United States)

    Turingan, Erin M; Mekoba, Bijan C; Eberwein, Samuel M; Roberts, Patricia A; Pappas, Ashley L; Cruz, Jennifer L; Amerine, Lindsey B

    2017-06-01

    Background: Drug manufacturers change distribution models based on patient safety and product integrity needs. These model changes can limit health-system access to medications, and the financial impact on health systems can be significant. Objective: The primary aim of this study was to determine the health-system financial impact of a manufacturer's change from open to limited distribution for bevacizumab (Avastin), rituximab (Rituxan), and trastuzumab (Herceptin). The secondary aim was to identify opportunities to shift administration to outpatient settings to support formulary change. Methods: To assess the financial impact on the health system, the cost minus discount was applied to total drug expenditure during a 1-year period after the distribution model change. The opportunity analysis was conducted for three institutions within the health system through chart review of each inpatient administration. Opportunity cost was the sum of the inpatient administration cost and outpatient administration margin. Results: The total drug expenditure for the study period was $26 427 263. By applying the cost minus discount, the financial effect of the distribution model change was $1 393 606. A total of 387 administrations were determined to be opportunities to be shifted to the outpatient setting. During the study period, the total opportunity cost was $1 766 049. Conclusion: Drug expenditure increased for the health system due to the drug distribution model change and loss of cost minus discount. The opportunity cost of shifting inpatient administrations could offset the increase in expenditure. It is recommended to restrict bevacizumab, rituximab, and trastuzumab through Pharmacy & Therapeutics Committees to outpatient use where clinically appropriate.

  8. 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

    limited experimental information exists about the effects of α1-adrenergic receptor activity of antipsychotic drugs in pro-arrhythmic models, we have decided to investigate this. In this study we show that four antipsychotic drugs all have high affinity for α1-adrenergic receptor (sertindole>risperidone>haloperidol......>olanzapine) and all block IKr (sertindole>haloperidol>risperidone>olanzapine). In canine Purkinje fibres, α1-adrenergic stimulation prolonged action potential duration; however, the stimulation does not cause afterdepolarizations, even in the presence of dofetilide-induced delayed repolarization. We showed...

  9. Theoretical modelling of physiologically stretched vessel in magnetisable stent assisted magnetic drug targeting application

    International Nuclear Information System (INIS)

    Mardinoglu, Adil; Cregg, P.J.; Murphy, Kieran; Curtin, Maurice; Prina-Mello, Adriele

    2011-01-01

    The magnetisable stent assisted magnetic targeted drug delivery system in a physiologically stretched vessel is considered theoretically. The changes in the mechanical behaviour of the vessel are analysed under the influence of mechanical forces generated by blood pressure. In this 2D mathematical model a ferromagnetic, coiled wire stent is implanted to aid collection of magnetic drug carrier particles in an elastic tube, which has similar mechanical properties to the blood vessel. A cyclic mechanical force is applied to the elastic tube to mimic the mechanical stress and strain of both the stent and vessel while in the body due to pulsatile blood circulation. The magnetic dipole-dipole and hydrodynamic interactions for multiple particles are included and agglomeration of particles is also modelled. The resulting collection efficiency of the mathematical model shows that the system performance can decrease by as much as 10% due to the effects of the pulsatile blood circulation. - Research highlights: →Theoretical modelling of magnetic drug targeting on a physiologically stretched stent-vessel system. →Cyclic mechanical force applied to mimic the mechanical stress and strain of both stent and vessel. →The magnetic dipole-dipole and hydrodynamic interactions for multiple particles is modelled. →Collection efficiency of the mathematical model is calculated for different physiological blood flow and magnetic field strength.

  10. Critical analysis of 3-D organoid in vitro cell culture models for high-throughput drug candidate toxicity assessments.

    Science.gov (United States)

    Astashkina, Anna; Grainger, David W

    2014-04-01

    Drug failure due to toxicity indicators remains among the primary reasons for staggering drug attrition rates during clinical studies and post-marketing surveillance. Broader validation and use of next-generation 3-D improved cell culture models are expected to improve predictive power and effectiveness of drug toxicological predictions. However, after decades of promising research significant gaps remain in our collective ability to extract quality human toxicity information from in vitro data using 3-D cell and tissue models. Issues, challenges and future directions for the field to improve drug assay predictive power and reliability of 3-D models are reviewed. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. A Mechanistic Model for Drug Release in PLGA Biodegradable Stent Coatings Coupled with Polymer Degradation and Erosion

    Science.gov (United States)

    Zhu, Xiaoxiang; Braatz, Richard D.

    2015-01-01

    Biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) coating for applications in drug-eluting stents has been receiving increasing interest as a result of its unique properties compared with biodurable polymers in delivering drug for reducing stents-related side effects. In this work, a mathematical model for describing the PLGA degradation and erosion and coupled drug release from PLGA stent coating is developed and validated. An analytical expression is derived for PLGA mass loss that predicts multiple experimental studies in the literature. An analytical model for the change of the number-average degree of polymerization (or molecular weight) is also derived. The drug transport model incorporates simultaneous drug diffusion through both the polymer solid and the liquid-filled pores in the coating, where an effective drug diffusivity model is derived taking into account factors including polymer molecular weight change, stent coating porosity change, and drug partitioning between solid and aqueous phases. The model is used to describe in vitro sirolimus release from PLGA stent coating, and demonstrates the significance of simultaneous sirolimus release via diffusion through both polymer solid and pore space. The proposed model is compared to existing drug transport models, and the impact of model parameters, limitations and possible extensions of the model are also discussed. PMID:25345656

  12. Formulating a poorly water soluble drug into an oral solution suitable for paediatric patients; lorazepam as a model drug

    NARCIS (Netherlands)

    A.C. Van Der Vossen (Anna C.); I. Van Der Velde (Iris); O. Smeets (Oscar); Postma, D.J.; Eckhardt, M.; A. Vermes (Andras); B.C.P. Koch (Birgit C. P.); A.G. Vulto (Arnold); L.M. Hanff (Lidwien)

    2017-01-01

    textabstractIntroduction Many drugs are unavailable in suitable oral paediatric dosage forms, and pharmacists often have to compound drugs to provide paediatric patients with an acceptable formulation in the right dose. Liquid formulations offer the advantage of dosing flexibility and ease of

  13. The effect of pH and ionic strength of dissolution media on in-vitro release of two model drugs of different solubilities from HPMC matrices.

    Science.gov (United States)

    Asare-Addo, Kofi; Conway, Barbara R; Larhrib, Hassan; Levina, Marina; Rajabi-Siahboomi, Ali R; Tetteh, John; Boateng, Joshua; Nokhodchi, Ali

    2013-11-01

    The evaluation of the effects of different media ionic strengths and pH on the release of hydrochlorothiazide, a poorly soluble drug, and diltiazem hydrochloride, a cationic and soluble drug, from a gel forming hydrophilic polymeric matrix was the objective of this study. The drug to polymer ratio of formulated tablets was 4:1. Hydrochlorothiazide or diltiazem HCl extended release (ER) matrices containing hypromellose (hydroxypropyl methylcellulose (HPMC)) were evaluated in media with a pH range of 1.2-7.5, using an automated USP type III, Bio-Dis dissolution apparatus. The ionic strength of the media was varied over a range of 0-0.4M to simulate the gastrointestinal fed and fasted states and various physiological pH conditions. Sodium chloride was used for ionic regulation due to its ability to salt out polymers in the midrange of the lyotropic series. The results showed that the ionic strength had a profound effect on the drug release from the diltiazem HCl K100LV matrices. The K4M, K15M and K100M tablets however withstood the effects of media ionic strength and showed a decrease in drug release to occur with an increase in ionic strength. For example, drug release after the 1h mark for the K100M matrices in water was 36%. Drug release in pH 1.2 after 1h was 30%. An increase of the pH 1.2 ionic strength to 0.4M saw a reduction of drug release to 26%. This was the general trend for the K4M and K15M matrices as well. The similarity factor f2 was calculated using drug release in water as a reference. Despite similarity occurring for all the diltiazem HCl matrices in the pH 1.2 media (f2=64-72), increases of ionic strength at 0.2M and 0.4M brought about dissimilarity. The hydrochlorothiazide tablet matrices showed similarity at all the ionic strength tested for all polymers (f2=56-81). The values of f2 however reduced with increasing ionic strengths. DSC hydration results explained the hydrochlorothiazide release from their HPMC matrices. There was an increase in

  14. Assessing the Impact of Antidrug Advertising on Adolescent Drug Consumption: Results From a Behavioral Economic Model

    Science.gov (United States)

    Block, Lauren G.; Morwitz, Vicki G.; Putsis, William P.; Sen, Subrata K.

    2002-01-01

    Objectives. This study examined whether adolescents’ recall of antidrug advertising is associated with a decreased probability of using illicit drugs and, given drug use, a reduced volume of use. Methods. A behavioral economic model of influences on drug consumption was developed with survey data from a nationally representative sample of adolescents to determine the incremental impact of antidrug advertising. Results. The findings provided evidence that recall of antidrug advertising was associated with a lower probability of marijuana and cocaine/crack use. Recall of such advertising was not associated with the decision of how much marijuana or cocaine/crack to use. Results suggest that individuals predisposed to try marijuana are also predisposed to try cocaine/crack. Conclusions. The present results provide support for the effectiveness of antidrug advertising programs. (Am J Public Health. 2002;92:1346–1351) PMID:12144995

  15. Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers.

    Science.gov (United States)

    Ahuja, Naveen; Katare, Om Prakash; Singh, Bhupinder

    2007-01-01

    Role of various water-soluble carriers was studied for dissolution enhancement of a poorly soluble model drug, rofecoxib, using solid dispersion approach. Diverse carriers viz. polyethylene glycols (PEG 4000 and 6000), polyglycolized fatty acid ester (Gelucire 44/14), polyvinylpyrollidone K25 (PVP), poloxamers (Lutrol F127 and F68), polyols (mannitol, sorbitol), organic acid (citric acid) and hydrotropes (urea, nicotinamide) were investigated for the purpose. Phase-solubility studies revealed AL type of curves for each carrier, indicating linear increase in drug solubility with carrier concentration. The sign and magnitude of the thermodynamic parameter, Gibbs free energy of transfer, indicated spontaneity of solubilization process. All the solid dispersions showed dissolution improvement vis-à-vis pure drug to varying degrees, with citric acid, PVP and poloxamers as the most promising carriers. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as Fickian diffusion. Solid state characterization of the drug-poloxamer binary system using XRD, FTIR, DSC and SEM techniques revealed distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement in dissolution rate.

  16. The effectiveness of the Minnesota Model approach in the treatment of adolescent drug abusers.

    Science.gov (United States)

    Winters, K C; Stinchfield, R D; Opland, E; Weller, C; Latimer, W W

    2000-04-01

    The treatment outcome of drug-abusing adolescents treated with a 12-Step approach. The study compares drug use outcome data at 6 and 12 months post-treatment among three groups of adolescents: those who completed treatment, those who did not and those on a waiting list. Also, among treatment completers, residential and outpatient samples were compared on outcome. The treatment site is located in the Minneapolis/St Paul area of Minnesota. Two hundred and forty-five drug clinic-referred adolescents (12-18 years old), all of whom met at least one DSM-III-R substance dependence disorder. One hundred and seventy-nine subjects received either complete or incomplete 12-Step, Minnesota Model treatment and 66 were waiting list subjects. In addition to demographics and clinical background variables, measures included treatment involvement, treatment setting and drug use frequency at intake and follow-up. Absolute and relative outcome analyses indicated that completing treatment was associated with far superior outcome compared to those who did not complete treatment or receive any at all. The percentage of treatment completers who reported either abstinence or a minor lapse for the 12 months following treatment was 53%, compared to 15 and 28% for the incompleter and waiting list groups, respectively. Favorable treatment outcome for drug abuse was about two to three times more likely if treatment was completed. Also, there were no outcome differences between residential and outpatient groups. Alcohol was the most common drug used during the follow-up period, despite cannabis being the preferred drug at intake.

  17. PBPK Modeling - A Predictive, Eco-Friendly, Bio-Waiver Tool for Drug Research.

    Science.gov (United States)

    De, Baishakhi; Bhandari, Koushik; Mukherjee, Ranjan; Katakam, Prakash; Adiki, Shanta K; Gundamaraju, Rohit; Mitra, Analava

    2017-01-01

    The world has witnessed growing complexities in disease scenario influenced by the drastic changes in host-pathogen- environment triadic relation. Pharmaceutical R&Ds are in constant search of novel therapeutic entities to hasten transition of drug molecules from lab bench to patient bedside. Extensive animal studies and human pharmacokinetics are still the "gold standard" in investigational new drug research and bio-equivalency studies. Apart from cost, time and ethical issues on animal experimentation, burning questions arise relating to ecological disturbances, environmental hazards and biodiversity issues. Grave concerns arises when the adverse outcomes of continued studies on one particular disease on environment gives rise to several other pathogenic agents finally complicating the total scenario. Thus Pharma R&Ds face a challenge to develop bio-waiver protocols. Lead optimization, drug candidate selection with favorable pharmacokinetics and pharmacodynamics, toxicity assessment are vital steps in drug development. Simulation tools like Gastro Plus™, PK Sim®, SimCyp find applications for the purpose. Advanced technologies like organ-on-a chip or human-on-a chip where a 3D representation of human organs and systems can mimic the related processes and activities, thereby linking them to major features of human biology can be successfully incorporated in the drug development tool box. PBPK provides the State of Art to serve as an optional of animal experimentation. PBPK models can successfully bypass bio-equivalency studies, predict bioavailability, drug interactions and on hyphenation with in vitro-in vivo correlation can be extrapolated to humans thus serving as bio-waiver. PBPK can serve as an eco-friendly bio-waiver predictive tool in drug development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs

    Science.gov (United States)

    Gupta, Himanshu R; Patil, Yogesh; Singh, Dipty

    2016-01-01

    in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs. PMID:28127503

  19. Feasibility study of silica sol as the carrier of a hydrophobic drug in aqueous solution using enrofloxacin as the model

    International Nuclear Information System (INIS)

    Song Meirong; Song Junling; Ning Aimin; Cui Baoan; Cui Shumin; Zhou Yaobing; An Wankai; Dong Xuesong; Zhang Gege

    2010-01-01

    The aim of this study was to determine the feasibility of using silica sol to carry a hydrophobic drug in aqueous solution. Enrofloxacin, which was selected as the model drug because it is a broad-spectrum antibiotic drug with poor solubility in water, was adsorbed onto silica sol in aqueous solution during cooling from 60 deg. C to room temperature. The drug-loaded silica sol was characterized by transmission electron microscopy, Fourier transform infrared spectrum, thermal gravimetric analysis and ultraviolet-visible light spectroscopy. The results showed that enrofloxacin was adsorbed by silica sol without degradation at a loading of 15.23 wt.%. In contrast to the rapid release from pure enrofloxacin, the drug-loaded silica sol showed a slower release over a longer time. Kinetics analysis suggested the drug release from silica sol was mainly a diffusion-controlled process. Therefore, silica sol can be used to carry a hydrophobic drug in aqueous solution for controlled drug delivery.

  20. Predictive modeling of structured electronic health records for adverse drug event detection.

    Science.gov (United States)

    Zhao, Jing; Henriksson, Aron; Asker, Lars; Boström, Henrik

    2015-01-01

    The digitization of healthcare data, resulting from the increasingly widespread adoption of electronic health records, has greatly facilitated its analysis by computational methods and thereby enabled large-scale secondary use thereof. This can be exploited to support public health activities such as pharmacovigilance, wherein the safety of drugs is monitored to inform regulatory decisions about sustained use. To that end, electronic health records have emerged as a potentially valuable data source, providing access to longitudinal observations of patient treatment and drug use. A nascent line of research concerns predictive modeling of healthcare data for the automatic detection of adverse drug events, which presents its own set of challenges: it is not yet clear how to represent the heterogeneous data types in a manner conducive to learning high-performing machine learning models. Datasets from an electronic health record database are used for learning predictive models with the purpose of detecting adverse drug events. The use and representation of two data types, as well as their combination, are studied: clinical codes, describing prescribed drugs and assigned diagnoses, and measurements. Feature selection is conducted on the various types of data to reduce dimensionality and sparsity, while allowing for an in-depth feature analysis of the usefulness of each data type and representation. Within each data type, combining multiple representations yields better predictive performance compared to using any single representation. The use of clinical codes for adverse drug event detection significantly outperforms the use of measurements; however, there is no significant difference over datasets between using only clinical codes and their combination with measurements. For certain adverse drug events, the combination does, however, outperform using only clinical codes. Feature selection leads to increased predictive performance for both data types, in isolation and

  1. Methamphetamine-alcohol interactions in murine models of sequential and simultaneous oral drug-taking.

    Science.gov (United States)

    Fultz, Elissa K; Martin, Douglas L; Hudson, Courtney N; Kippin, Tod E; Szumlinski, Karen K

    2017-08-01

    A high degree of co-morbidity exists between methamphetamine (MA) addiction and alcohol use disorders and both sequential and simultaneous MA-alcohol mixing increases risk for co-abuse. As little preclinical work has focused on the biobehavioral interactions between MA and alcohol within the context of drug-taking behavior, we employed simple murine models of voluntary oral drug consumption to examine how prior histories of either MA- or alcohol-taking influence the intake of the other drug. In one study, mice with a 10-day history of binge alcohol-drinking [5,10, 20 and 40% (v/v); 2h/day] were trained to self-administer oral MA in an operant-conditioning paradigm (10-40mg/L). In a second study, mice with a 10-day history of limited-access oral MA-drinking (5, 10, 20 and 40mg/L; 2h/day) were presented with alcohol (5-40% v/v; 2h/day) and then a choice between solutions of 20% alcohol, 10mg/L MA or their mix. Under operant-conditioning procedures, alcohol-drinking mice exhibited less MA reinforcement overall, than water controls. However, when drug availability was not behaviorally-contingent, alcohol-drinking mice consumed more MA and exhibited greater preference for the 10mg/L MA solution than drug-naïve and combination drug-experienced mice. Conversely, prior MA-drinking history increased alcohol intake across a range of alcohol concentrations. These exploratory studies indicate the feasibility of employing procedurally simple murine models of sequential and simultaneous oral MA-alcohol mixing of relevance to advancing our biobehavioral understanding of MA-alcohol co-abuse. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Multiple model predictive control for optimal drug administration of mixed immunotherapy and chemotherapy of tumours.

    Science.gov (United States)

    Sharifi, N; Ozgoli, S; Ramezani, A

    2017-06-01

    Mixed immunotherapy and chemotherapy of tumours is one of the most efficient ways to improve cancer treatment strategies. However, it is important to 'design' an effective treatment programme which can optimize the ways of combining immunotherapy and chemotherapy to diminish their imminent side effects. Control engineering techniques could be used for this. The method of multiple model predictive controller (MMPC) is applied to the modified Stepanova model to induce the best combination of drugs scheduling under a better health criteria profile. The proposed MMPC is a feedback scheme that can perform global optimization for both tumour volume and immune competent cell density by performing multiple constraints. Although current studies usually assume that immunotherapy has no side effect, this paper presents a new method of mixed drug administration by employing MMPC, which implements several constraints for chemotherapy and immunotherapy by considering both drug toxicity and autoimmune. With designed controller we need maximum 57% and 28% of full dosage of drugs for chemotherapy and immunotherapy in some instances, respectively. Therefore, through the proposed controller less dosage of drugs are needed, which contribute to suitable results with a perceptible reduction in medicine side effects. It is observed that in the presence of MMPC, the amount of required drugs is minimized, while the tumour volume is reduced. The efficiency of the presented method has been illustrated through simulations, as the system from an initial condition in the malignant region of the state space (macroscopic tumour volume) transfers into the benign region (microscopic tumour volume) in which the immune system can control tumour growth. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Interstitial fluid flow and drug delivery in vascularized tumors: a computational model.

    Directory of Open Access Journals (Sweden)

    Michael Welter

    Full Text Available Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider-with the help of a theoretical model-the tumor IFP, interstitial fluid flow (IFF and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law and sources (vessels and sinks (lymphatics for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss

  4. Interstitial fluid flow and drug delivery in vascularized tumors: a computational model.

    Science.gov (United States)

    Welter, Michael; Rieger, Heiko

    2013-01-01

    Interstitial fluid is a solution that bathes and surrounds the human cells and provides them with nutrients and a way of waste removal. It is generally believed that elevated tumor interstitial fluid pressure (IFP) is partly responsible for the poor penetration and distribution of therapeutic agents in solid tumors, but the complex interplay of extravasation, permeabilities, vascular heterogeneities and diffusive and convective drug transport remains poorly understood. Here we consider-with the help of a theoretical model-the tumor IFP, interstitial fluid flow (IFF) and its impact upon drug delivery within tumor depending on biophysical determinants such as vessel network morphology, permeabilities and diffusive vs. convective transport. We developed a vascular tumor growth model, including vessel co-option, regression, and angiogenesis, that we extend here by the interstitium (represented by a porous medium obeying Darcy's law) and sources (vessels) and sinks (lymphatics) for IFF. With it we compute the spatial variation of the IFP and IFF and determine its correlation with the vascular network morphology and physiological parameters like vessel wall permeability, tissue conductivity, distribution of lymphatics etc. We find that an increased vascular wall conductivity together with a reduction of lymph function leads to increased tumor IFP, but also that the latter does not necessarily imply a decreased extravasation rate: Generally the IF flow rate is positively correlated with the various conductivities in the system. The IFF field is then used to determine the drug distribution after an injection via a convection diffusion reaction equation for intra- and extracellular concentrations with parameters guided by experimental data for the drug Doxorubicin. We observe that the interplay of convective and diffusive drug transport can lead to quite unexpected effects in the presence of a heterogeneous, compartmentalized vasculature. Finally we discuss various

  5. Stem cells: a model for screening, discovery and development of drugs

    Directory of Open Access Journals (Sweden)

    Kitambi SS

    2011-09-01

    Full Text Available Satish Srinivas Kitambi1, Gayathri Chandrasekar21Department of Medical Biochemistry and Biophysics; 2Department of Biosciences, Karolinska Institutet, Stockholm, SwedenAbstract: The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.Keywords: therapeutics, stem cells, cancer stem cells, screening models, drug development, high throughput screening

  6. Mesoporous silica for drug delivery: Interactions with model fluorescent lipid vesicles and live cells.

    Science.gov (United States)

    Bardhan, Munmun; Majumdar, Anupa; Jana, Sayantan; Ghosh, Tapas; Pal, Uttam; Swarnakar, Snehasikta; Senapati, Dulal

    2018-01-01

    Formulated mesoporous silica nanoparticle (MSN) systems offer the best possible drug delivery system through the release of drug molecules from the accessible pores. In the present investigation, steady state and time resolved fluorescence techniques along with the fluorescence imaging were applied to investigate the interactions of dye loaded MSN with fluorescent unilamellar vesicles and live cells. Here 1,2-dimyristoyl-sn-glycero-3-phospocholine (DMPC) was used to prepare Small Unilamellar Vesicles (SUVs) as the model membrane with fluorescent 1,6-diphenyl-1,3,5-hexatriene (DPH) molecule incorporated inside the lipid bilayer. The interaction of DPH incorporated DMPC membrane with Fluorescein loaded MSN lead to the release of Fluorescein (Fl) dye from the interior pores of MSN systems. The extent of release of Fl and spatial distribution of the DPH molecule has been explored by monitoring steady-state fluorescence intensity and fluorescence lifetime at physiological condition. To investigate the fate of drug molecule released from MSN, fluorescence anisotropy has been used. The drug delivery efficiency of the MSN as a carrier for doxorubicin (DOX), a fluorescent chemotherapeutic drug, has also been investigated at physiological conditions. The study gives a definite confirmation for high uptake and steady release of DOX in primary oral mucosal non-keratinized squamous cells in comparison to naked DOX treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Drug-disease modeling in the pharmaceutical industry - where mechanistic systems pharmacology and statistical pharmacometrics meet.

    Science.gov (United States)

    Helmlinger, Gabriel; Al-Huniti, Nidal; Aksenov, Sergey; Peskov, Kirill; Hallow, Karen M; Chu, Lulu; Boulton, David; Eriksson, Ulf; Hamrén, Bengt; Lambert, Craig; Masson, Eric; Tomkinson, Helen; Stanski, Donald

    2017-11-15

    Modeling & simulation (M&S) methodologies are established quantitative tools, which have proven to be useful in supporting the research, development (R&D), regulatory approval, and marketing of novel therapeutics. Applications of M&S help design efficient studies and interpret their results in context of all available data and knowledge to enable effective decision-making during the R&D process. In this mini-review, we focus on two sets of modeling approaches: population-based models, which are well-established within the pharmaceutical industry today, and fall under the discipline of clinical pharmacometrics (PMX); and systems dynamics models, which encompass a range of models of (patho-)physiology amenable to pharmacological intervention, of signaling pathways in biology, and of substance distribution in the body (today known as physiologically-based pharmacokinetic models) - which today may be collectively referred to as quantitative systems pharmacology models (QSP). We next describe the convergence - or rather selected integration - of PMX and QSP approaches into 'middle-out' drug-disease models, which retain selected mechanistic aspects, while remaining parsimonious, fit-for-purpose, and able to address variability and the testing of covariates. We further propose development opportunities for drug-disease systems models, to increase their utility and applicability throughout the preclinical and clinical spectrum of pharmaceutical R&D. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Effect of the surfactant on the availability of piroxicam as a poorly hydrosoluble drug from suppositories.

    Science.gov (United States)

    Dal Zorro, M; Franceschinis, E; Punchina, A; Realdon, N

    2012-01-01

    The use of surfactants in suppository formulations has been suggested to improve availability of poorly soluble drugs. In the present study, different kinds of surfactants have been investigated to clarify the influence on piroxicam release from suppositories formulated with both lipophilic and hydrophilic bases. Two hydrophilic glucose-derivate surfactants, and a polyoxylglyceride amphiphilic surfactant, all with high HLB values, were investigated for their use in improving drug availability. The two glucose derivate surfactants reduced drug availability from both lipophilic suppositories and hydrophilic formulations, according to longer disintegration times and drug micellization. The more complex surfactant, a lauroyl macrogolglyceride, showed an increase in piroxicam availability from lipophilic suppositories at the higher tested concentrations (15% and 20%). Otherwise, when used in hydrophilic formulations, it was less effective in promoting drug release and even reduced drug availability.

  9. Mobile phase effects on the retention on polar columns with special attention to the dual hydrophilic interaction-reversed-phase liquid chromatography mechanism, a review.

    Science.gov (United States)

    Jandera, Pavel; Hájek, Tomáš

    2018-01-01

    Hydrophilic interaction liquid chromatography on polar columns in aqueous-organic mobile phases has become increasingly popular for the separation of many biologically important compounds in chemical, environmental, food, toxicological, and other samples. In spite of many new applications appearing in literature, the retention mechanism is still controversial. This review addresses recent progress in understanding of the retention models in hydrophilic interaction liquid chromatography. The main attention is focused on the role of water, both adsorbed by the column and contained in the bulk mobile phase. Further, the theoretical retention models in the isocratic and gradient elution modes are discussed. The dual hydrophilic interaction liquid chromatography reversed-phase retention mechanism on polar columns is treated in detail, especially with respect to the practical use in one- and two-dimensional liquid chromatography separations. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Increase in the Hydrophilicity and Lewis Acid-Base Properties of Solid Surfaces Achieved by Electric Gliding Discharge in Humid Air: Effects on Bacterial Adherence

    International Nuclear Information System (INIS)

    Kamgang, J. O.; Brisset, J.-L.; Naitali, M.; Herry, J.-M.; Bellon-Fontaine, M.-N.; Briandet, R.

    2009-01-01

    This study addressed the effects of treatment with gliding discharge plasma on the surface properties of solid materials, as well as the consequences concerning adherence of a model bacterium. As evaluated by contact angles with selected liquids, plasma treatment caused an increase in surface hydrophilicity and in the Lewis acid-base components of the surface energy of all materials tested. These modifications were more marked for low density polyethylene and stainless steel than for polytetrafluoroethylene. After treatment, the hydrophilicity of the materials remained relatively stable for at least 20 days. Moreover, analysis of the topography of the materials by atomic force microscopy revealed that the roughness of both polymers was reduced by glidarc plasma treatment. As a result of all these modifications, solid substrates were activated towards micro-organisms and the adherence of S. epidermidis, a negatively charged Lewis-base and mildly hydrophilic strain selected as the model, was increased in almost all the cases tested. (plasma technology)

  11. A prediction model of drug-induced ototoxicity developed by an optimal support vector machine (SVM) method.

    Science.gov (United States)

    Zhou, Shu; Li, Guo-Bo; Huang, Lu-Yi; Xie, Huan-Zhang; Zhao, Ying-Lan; Chen, Yu-Zong; Li, Lin-Li; Yang, Sheng-Yong

    2014-08-01

    Drug-induced ototoxicity, as a toxic side effect, is an important issue needed to be considered in drug discovery. Nevertheless, current experimental methods used to evaluate drug-induced ototoxicity are often time-consuming and expensive, indicating that they are not suitable for a large-scale evaluation of drug-induced ototoxicity in the early stage of drug discovery. We thus, in this investigation, established an effective computational prediction model of drug-induced ototoxicity using an optimal support vector machine (SVM) method, GA-CG-SVM. Three GA-CG-SVM models were developed based on three training sets containing agents bearing different risk levels of drug-induced ototoxicity. For comparison, models based on naïve Bayesian (NB) and recursive partitioning (RP) methods were also used on the same training sets. Among all the prediction models, the GA-CG-SVM model II showed the best performance, which offered prediction accuracies of 85.33% and 83.05% for two independent test sets, respectively. Overall, the good performance of the GA-CG-SVM model II indicates that it could be used for the prediction of drug-induced ototoxicity in the early stage of drug discovery. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations

    NARCIS (Netherlands)

    Yamamoto, Yumi; Valitalo, Pyry A.; van den Berg, Dirk-Jan; Hartman, Robin; van den Brink, Willem; Wong, Yin Cheong; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Bakshi, Suruchi; Aranzana-Climent, Vincent; Marchand, Sandrine; Dahyot-Fizelier, Claire; Couet, William; Danhof, Meindert; van Hasselt, Johan G. C.; de lange, Elizabeth C. M.

    Purpose Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human

  13. The characters of self-assembly core/shell nanoparticles of amphiphilic hyperbranched polyethers as drug carriers

    International Nuclear Information System (INIS)

    Ajun Wan; Yuxia, Kou

    2008-01-01

    The characters of self-assembly core/shell nanoparticles of amphiphilic hyperbranched polyethers (HP-g-PEO) as drug carriers were investigated. The HP-g-PEO consisting of hydrophobic HP-g-PEO core and hydrophilic poly(ethylene glycol) arms was prepared by the cation ring-opening polymerization. A series of HP-g-PEO samples with different degree of branching (DB) were synthesized under various reaction temperatures. Nanoparticles (NP) were obtained by self-assembly of HP-g-PEO in aqueous media. The structure of resulting HP-g-PEO was characterized by IR, 13 CNMR and GPC. Dynamic light scattering and transmission electron microscopy were applied to characterize the sizes and size distributions of NP. The results demonstrated that the mean diameters of NP were less than 100 nm, which exhibited uniform spherical formations and narrow size distributions. Using hydrophobic drug Probucol (PRO) as model drug, the particle sizes of drug loaded NP were larger than relative blank NP. The drug loading efficiency (LE) and incorporation efficiency (IE) of these NP were achieved to 35 and 89%, respectively. The in vitro release of PRO from the NP exhibited a sustained release and the cumulative drugs released for more than 600 h. The most important factor to affect drug release was the value of DB of HP-g-PEO. With the DB of HP-g-PEO increasing, the size and size distribution of NP decreased as well as the release rate. However, the small DB was beneficial to the LE of NP. Nanoparticle size and size distribution, LE, IE, and drug release rate were slightly affected by the initial solution concentration of polyethers. The co-incorporated hydrophilic drug had influence slightly on the release of drug from drug loaded NP. The results of in vitro drug release suggested that the core/shell NP performed good controlled release behaviors with potential practice as novelty drug delivery vehicles

  14. Eyelid skin as a potential site for drug delivery to conjunctiva and ocular tissues.

    Science.gov (United States)

    See, Gerard Lee; Sagesaka, Ayano; Sugasawa, Satoko; Todo, Hiroaki; Sugibayashi, Kenji

    2017-11-25

    The feasibility of topical application onto the (lower) eyelid skin to deliver hydrophilic and lipophilic compounds into the conjunctiva and ocular tissues was evaluated by comparing with conventional eye drop application. Skin permeation and the concentration of several model compounds, and skin impedance were determined utilizing eyelid skin from hairless rats, as well as abdominal skin in the same animals for comparison. In vitro static diffusion cells were used to assess the skin permeation in order to provide key insights into the relationship between the skin sites and drugs. The obtained results revealed that drug permeation through the eyelid skin was much higher than that through abdominal skin regardless of the drug lipophilicity. Specifically, diclofenac sodium salt and tranilast exhibited approximately 6-fold and 11-fold higher permeability coefficients, respectively, through eyelid skin compared with abdominal skin. Histomorphological evaluation and in vivo distribution of model fluorescent dyes were also examined in the conjunctiva and skin after eyelid administration by conventional microscope and confocal laser scanning microscope analyses. The result revealed that eyelid skin has a thinner stratum corneum, thereby showing lower impedance, which could be the reason for the higher drug permeation through eyelid skin. Comparative evaluation of lipophilic and hydrophilic model compounds administered via the eyelid skin over 8h revealed stronger fluorescence intensity in the skin and surrounding tissues compared with eye drop administration. These results suggested that the (lower) eyelid skin is valuable as a prospective site for ophthalmic medicines. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. In silico modeling predicts drug sensitivity of patient-derived cancer cells.

    Science.gov (United States)

    Pingle, Sandeep C; Sultana, Zeba; Pastorino, Sandra; Jiang, Pengfei; Mukthavaram, Rajesh; Chao, Ying; Bharati, Ila Sri; Nomura, Natsuko; Makale, Milan; Abbasi, Taher; Kapoor, Shweta; Kumar, Ansu; Usmani, Shahabuddin; Agrawal, Ashish; Vali, Shireen; Kesari, Santosh

    2014-05-21

    Glioblastoma (GBM) is an aggressive disease associated with poor survival. It is essential to account for the complexity of GBM biology to improve diagnostic and therapeutic strategies. This complexity is best represented by the increasing amounts of profiling ("omics") data available due to advances in biotechnology. The challenge of integrating these vast genomic and proteomic data can be addressed by a comprehensive systems modeling approach. Here, we present an in silico model, where we simulate GBM tumor cells using genomic profiling data. We use this in silico tumor model to predict responses of cancer cells to targeted drugs. Initially, we probed the results from a recent hypothesis-independent, empirical study by Garnett and co-workers that analyzed the sensitivity of hundreds of profiled cancer cell lines to 130 different anticancer agents. We then used the tumor model to predict sensitivity of patient-derived GBM cell lines to different targeted therapeutic agents. Among the drug-mutation associations reported in the Garnett study, our in silico model accurately predicted ~85% of the associations. While testing the model in a prospective manner using simulations of patient-derived GBM cell lines, we compared our simulation predictions with experimental data using the same cells in vitro. This analysis yielded a ~75% agreement of in silico drug sensitivity with in vitro experimental findings. These results demonstrate a strong predictability of our simulation approach using the in silico tumor model presented here. Our ultimate goal is to use this model to stratify patients for clinical trials. By accurately predicting responses of cancer cells to targeted agents a priori, this in silico tumor model provides an innovative approach to personalizing therapy and promises to improve clinical management of cancer.

  16. Photoluminescence of hydrophilic silicon nanocrystals in aqueous solutions

    International Nuclear Information System (INIS)

    Prtljaga, Nikola; D'Amato, Elvira; Pitanti, Alessandro; Guider, Romain; Froner, Elena; Larcheri, Silvia; Scarpa, Marina; Pavesi, Lorenzo

    2011-01-01

    Stable aqueous solutions of undecylenic-acid-grafted silicon nanocrystals (Si-nc) were prepared. The time evolution of the photoluminescence properties of these hydrophilic silicon nanocrystals has been followed on different timescales (hours and days). On a short timescale (hours), Si-nc tend to agglomerate while the PL lineshape and intensity are stable. Agglomeration can be reduced by using suitable surfactants. On a long timescale (days), oxidation of Si-nc occurs even in the presence of surfactants. These two observations render Si-nc very useful as a labeling agent for biosensing.

  17. Photoluminescence of hydrophilic silicon nanocrystals in aqueous solutions

    Science.gov (United States)

    Prtljaga, Nikola; D'Amato, Elvira; Pitanti, Alessandro; Guider, Romain; Froner, Elena; Larcheri, Silvia; Scarpa, Marina; Pavesi, Lorenzo

    2011-05-01

    Stable aqueous solutions of undecylenic-acid-grafted silicon nanocrystals (Si-nc) were prepared. The time evolution of the photoluminescence properties of these hydrophilic silicon nanocrystals has been followed on different timescales (hours and days). On a short timescale (hours), Si-nc tend to agglomerate while the PL lineshape and intensity are stable. Agglomeration can be reduced by using suitable surfactants. On a long timescale (days), oxidation of Si-nc occurs even in the presence of surfactants. These two observations render Si-nc very useful as a labeling agent for biosensing.

  18. Photoluminescence of hydrophilic silicon nanocrystals in aqueous solutions

    Energy Technology Data Exchange (ETDEWEB)

    Prtljaga, Nikola; D' Amato, Elvira; Pitanti, Alessandro; Guider, Romain; Froner, Elena; Larcheri, Silvia; Scarpa, Marina; Pavesi, Lorenzo, E-mail: nikolap@science.unitn.it [Department of Physics, University of Trento, Via Sommarive 14, I-38123 Trento (Italy)

    2011-05-27

    Stable aqueous solutions of undecylenic-acid-grafted silicon nanocrystals (Si-nc) were prepared. The time evolution of the photoluminescence properties of these hydrophilic silicon nanocrystals has been followed on different timescales (hours and days). On a short timescale (hours), Si-nc tend to agglomerate while the PL lineshape and intensity are stable. Agglomeration can be reduced by using suitable surfactants. On a long timescale (days), oxidation of Si-nc occurs even in the presence of surfactants. These two observations render Si-nc very useful as a labeling agent for biosensing.

  19. Zebrafish Embryo as an In Vivo Model for Behavioral and Pharmacological Characterization of Methylxanthine Drugs

    Directory of Open Access Journals (Sweden)

    Ram Manohar Basnet

    2017-03-01

    Full Text Available Zebrafish embryo is emerging as an important tool for behavior analysis as well as toxicity testing. In this study, we compared the effect of nine different methylxanthine drugs using zebrafish embryo as a model. We performed behavioral analysis, biochemical assay and Fish Embryo Toxicity (FET test in zebrafish embryos after treatment with methylxanthines. Each drug appeared to behave in different ways and showed a distinct pattern of results. Embryos treated with seven out of nine methylxanthines exhibited epileptic-like pattern of movements, the severity of which varied with drugs and doses used. Cyclic AMP measurement showed that, despite of a significant increase in cAMP with some compounds, it was unrelated to the observed movement behavior changes. FET test showed a different pattern of toxicity with different methylxanthines. Each drug could be distinguished from the other based on its effect on mortality, morphological defects and teratogenic effects. In addition, there was a strong positive correlation between the toxic doses (TC50 calculated in zebrafish embryos and lethal doses (LD50 in rodents obtained from TOXNET database. Taken together, all these findings elucidate the potentiality of zebrafish embryos as an in vivo model for behavioral and toxicity testing of methylxanthines and other related compounds.

  20. Experimental protocols for behavioral imaging: seeing animal models of drug abuse in a new light.

    Science.gov (United States)

    Aarons, Alexandra R; Talan, Amanda; Schiffer, Wynne K

    2012-01-01

    Behavioral neuroimaging is a rapidly evolving discipline that represents a marriage between the fields of behavioral neuroscience and preclinical molecular imaging. This union highlights the changing role of imaging in translational research. Techniques developed for humans are now widely applied in the study of animal models of brain disorders such as drug addiction. Small animal or preclinical imaging allows us to interrogate core features of addiction from both behavioral and biological endpoints. Snapshots of brain activity allow us to better understand changes in brain function and behavior associated with initial drug exposure, the emergence of drug escalation, and repeated bouts of drug withdrawal and relapse. Here we review the development and validation of new behavioral imaging paradigms and several clinically relevant radiotracers used to capture dynamic molecular events in behaving animals. We will discuss ways in which behavioral imaging protocols can be optimized to increase throughput and quantitative methods. Finally, we discuss our experience with the practical aspects of behavioral neuroimaging, so investigators can utilize effective animal models to better understand the addicted brain and behavior.

  1. Photokinetic Drug Delivery: Light-Enhanced Permeation in an In Vitro Eye Model.

    Science.gov (United States)

    Godley, Bernard F; Kraft, Edward R; Giannos, Steven A; Zhao, Zhen-Yang; Haag, Anthony M; Wen, Julie W

    2015-12-01

    To investigate light-enhanced molecular movement as a potential technology for drug delivery. To do this, we developed an in vitro eye model while representing similar concentration gradient conditions and compositions found in the eye. The eye model unit was fabricated by inserting a cross-linked type I collagen membrane in a spectrophotometer cuvette with 1% hyaluronic acid as the drug recipient medium. Photokinetic delivery was studied by illuminating 1 mg/mL methotrexate (MTX) placed in the drug donor compartment on top of the membrane, with noncoherent 450 nm light at 8.2 mW from an LED source pulsed at 25 cycles per second, placed in contact with the solution. A modified UV-visual spectrophotometer was employed to rapidly determine the concentration of MTX, at progressive 1 mm distances away from the membrane, within the viscous recipient medium of the model eye after 1 h. A defined, progressive concentration gradient was observed within the nonagitated drug recipient media, diminishing with greater distances from the membrane. Transport of MTX through the membrane was significantly enhanced (ranging from 2 to 3 times, P < 0.05 to P ≤ 0.001) by photokinetic methods compared with control conditions by determining drug concentrations at 4 defined distances from the membrane. According to scanning electron microscopy images, no structural damage or shunts were created on the surface of the cross-linked gelatin membrane. The application of pulsed noncoherent visible light significantly enhances the permeation of MTX through a cross-linked collagen membrane and hyaluronic acid recipient medium without causing structural damage to the membrane.

  2. A multi-scale modeling framework for individualized, spatiotemporal prediction of drug effects and toxicological risk

    Directory of Open Access Journals (Sweden)

    Juan Guillermo eDiaz Ochoa

    2013-01-01

    Full Text Available In this study, we focus on a novel multi-scale modeling approach for spatiotemporal prediction of the distribution of substances and resulting hepatotoxicity by combining cellular models, a 2D liver model, and whole-body model. As a case study, we focused on predicting human hepatotoxicity upon treatment with acetaminophen based on in vitro toxicity data and potential inter-individual variability in gene expression and enzyme activities. By aggregating mechanistic, genome-based in silico cells to a novel 2D liver model and eventually to a whole body model, we predicted pharmacokinetic properties, metabolism, and the onset of hepatotoxicity in an in silico patient. Depending on the concentration of acetaminophen in the liver and the accumulation of toxic metabolites, cell integrity in the liver as a function of space and time as well as changes in the elimination rate of substances were estimated. We show that the variations in elimination rates also influence the distribution of acetaminophen and its metabolites in the whole body. Our results are in agreement with experimental results. What is more, the integrated model also predicted variations in drug toxicity depending on alterations of metabolic enzyme activities. Variations in enzyme activity, in turn, reflect genetic characteristics or diseases of individuals. In conclusion, this framework presents an important basis for efficiently integrating inter-individual variability data into models, paving the way for personalized or stratified predictions of drug toxicity and efficacy.

  3. Thermodynamic models to elucidate the enantioseparation of drugs with two stereogenic centers by micellar electrokinetic chromatography.

    Science.gov (United States)

    Guo, Xuming; Liu, Qiuxia; Hu, Shaoqiang; Guo, Wenbo; Yang, Zhuo; Zhang, Yonghua

    2017-08-25

    An equilibrium model depicting the simultaneous protonation of chiral drugs and partitioning of protonated ions and neutral molecules into chiral micelles in micellar electrokinetic chromatography (MEKC) has been introduced. It was used for the prediction and elucidation of complex changes in migration order patterns with experimental conditions in the enantioseparation of drugs with two stereogenic centers. Palonosetron hydrochloride (PALO), a weakly basic drug with two stereogenic centers, was selected as a model drug. Its four stereoisomers were separated by MEKC using sodium cholate (SC) as chiral selector and surfactant. Based on the equilibrium model, equations were derived for a calculation of the effective mobility and migration time of each stereoisomer at a certain pH. The migration times of four stereoisomers at different pHs were calculated and then the migration order patterns were constructed with derived equations. The results were in accord with the experiment. And the contribution of each mechanism to the separation and its influence on the migration order pattern was analyzed separately by introducing virtual isomers, i.e., hypothetical stereoisomers with only one parameter changed relative to a real PALO stereoisomer. A thermodynamic model for a judgment of the correlation of interactions between two stereogenic centers of stereoisomers and chiral selector was also proposed. According to this model, the interactions of two stereogenic centers of PALO stereoisomers in both neutral molecules and protonated ions with chiral selector are not independent, so the chiral recognition in each pair of enantiomers as well as the recognition for diastereomers is not simply the algebraic sum of the contributions of two stereogenic centers due to their correlation. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.

    Science.gov (United States)

    Aflaki, Elma; Stubblefield, Barbara K; Maniwang, Emerson; Lopez, Grisel; Moaven, Nima; Goldin, Ehud; Marugan, Juan; Patnaik, Samarjit; Dutra, Amalia; Southall, Noel; Zheng, Wei; Tayebi, Nahid; Sidransky, Ellen

    2014-06-11

    Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. Available cell lines modeling Gaucher disease do not demonstrate lysosomal storage of glycolipids; therefore, we set out to develop two macrophage models of Gaucher disease that exhibit appropriate substrate accumulation. We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candidate drugs for its treatment. We generated and characterized monocyte-derived macrophages from 20 patients carrying different Gaucher disease mutations. In addition, we created induced pluripotent stem cell (iPSC)-derived macrophages from five fibroblast lines taken from patients with type 1 or type 2 Gaucher disease. Macrophages derived from patient monocytes or iPSCs showed reduced glucocerebrosidase activity and increased storage of glucocerebroside and glucosylsphingosine in lysosomes. These macrophages showed efficient phagocytosis of bacteria but reduced production of intracellular reactive oxygen species and impaired chemotaxis. The disease phenotype was reversed with a noninhibitory small-molecule chaperone drug that enhanced glucocerebrosidase activity in the macrophages, reduced glycolipid storage, and normalized chemotaxis and production of reactive oxygen species. Macrophages differentiated from patient monocytes or patient-derived iPSCs provide cellular models that can be used to investigate disease pathogenesis and facilitate drug development. Copyright © 2014, American Association for the Advancement of Science.

  5. Blinded prospective evaluation of computer-based mechanistic schizophrenia disease model for predicting drug response.

    Directory of Open Access Journals (Sweden)

    Hugo Geerts

    Full Text Available The tremendous advances in understanding the neurobiological circuits involved in schizophrenia have not translated into more effective treatments. An alternative strategy is to use a recently published 'Quantitative Systems Pharmacology' computer-based mechanistic disease model of cortical/subcortical and striatal circuits based upon preclinical physiology, human pathology and pharmacology. The physiology of 27 relevant dopamine, serotonin, acetylcholine, norepinephrine, gamma-aminobutyric acid (GABA and glutamate-mediated targets is calibrated using retrospective clinical data on 24 different antipsychotics. The model was challenged to predict quantitatively the clinical outcome in a blinded fashion of two experimental antipsychotic drugs; JNJ37822681, a highly selective low-affinity dopamine D(2 antagonist and ocaperidone, a very high affinity dopamine D(2 antagonist, using only pharmacology and human positron emission tomography (PET imaging data. The model correctly predicted the lower performance of JNJ37822681 on the positive and negative syndrome scale (PANSS total score and the higher extra-pyramidal symptom (EPS liability compared to olanzapine and the relative performance of ocaperidone against olanzapine, but did not predict the absolute PANSS total score outcome and EPS liability for ocaperidone, possibly due to placebo responses and EPS assessment methods. Because of its virtual nature, this modeling approach can support central nervous system research and development by accounting for unique human drug properties, such as human metabolites, exposure, genotypes and off-target effects and can be a helpful tool for drug discovery and development.

  6. Influences on the fraction of hydrophobic and hydrophilic black carbon in the atmosphere

    Directory of Open Access Journals (Sweden)

    G. R. McMeeking

    2011-05-01

    Full Text Available Black carbon (BC is a short term climate forcer that directly warms the atmosphere, slows convection, and hinders quantification of the effect of greenhouse gases on climate change. The atmospheric lifetime of BC particles with respect to nucleation scavenging in clouds is controlled by their ability to serve as cloud condensation nuclei (CCN. To serve as CCN under typical conditions, hydrophobic BC particles must acquire hygroscopic coatings. However, the quantitative relationship between coatings and hygroscopic properties for ambient BC particles is not known nor is the time scale for hydrophobic-to-hydrophilic conversion. Here we introduce a method for measuring the hygroscopicity of externally and internally mixed BC particles by coupling a single particle soot photometer with a humidified tandem differential mobility analyzer. We test this technique using uncoated and coated laboratory generated model BC compounds and apply it to characterize the hygroscopicity distribution of ambient BC particles. From these data we derive that the observed number fraction of BC that is CCN active at 0.2 % supersaturation is generally low in an urban area near sources and that it varies with the trajectory of the airmass. We anticipate that our method can be combined with measures of air parcel physical and photochemical age to provide the first quantitative estimates for characterizing hydrophobic-to-hydrophilic conversion rates in the atmosphere.

  7. A unified algorithm for predicting partition coefficients for PBPK modeling of drugs and environmental chemicals

    International Nuclear Information System (INIS)

    Peyret, Thomas; Poulin, Patrick; Krishnan, Kannan

    2010-01-01

    The algorithms in the literature focusing to predict tissue:blood PC (P tb ) for environmental chemicals and tissue:plasma PC based on total (K p ) or unbound concentration (K pu ) for drugs differ in their consideration of binding to hemoglobin, plasma proteins and charged phospholipids. The objective of the present study was to develop a unified algorithm such that P tb , K p and K pu for both drugs and environmental chemicals could be predicted. The development of the unified algorithm was accomplished by integrating all mechanistic algorithms previously published to compute the PCs. Furthermore, the algorithm was structured in such a way as to facilitate predictions of the distribution of organic compounds at the macro (i.e. whole tissue) and micro (i.e. cells and fluids) levels. The resulting unified algorithm was applied to compute the rat P tb , K p or K pu of muscle (n = 174), liver (n = 139) and adipose tissue (n = 141) for acidic, neutral, zwitterionic and basic drugs as well as ketones, acetate esters, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons and ethers. The unified algorithm reproduced adequately the values predicted previously by the published algorithms for a total of 142 drugs and chemicals. The sensitivity analysis demonstrated the relative importance of the various compound properties reflective of specific mechanistic determinants relevant to prediction of PC values of drugs and environmental chemicals. Overall, the present unified algorithm uniquely facilitates the computation of macro and micro level PCs for developing organ and cellular-level PBPK models for both chemicals and drugs.

  8. Drug release control and system understanding of sucrose esters matrix tablets by artificial neural networks.

    Science.gov (United States)

    Chansanroj, Krisanin; Petrović, Jelena; Ibrić, Svetlana; Betz, Gabriele

    2011-10-09

    Artificial neural networks (ANNs) were applied for system understanding and prediction of drug release properties from direct compacted matrix tablets using sucrose esters (SEs) as matrix-forming agents for controlled release of a highly water soluble drug, metoprolol tartrate. Complexity of the system was presented through the effects of SE concentration and tablet porosity at various hydrophilic-lipophilic balance (HLB) values of SEs ranging from 0 to 16. Both effects contributed to release behaviors especially in the system containing hydrophilic SEs where swelling phenomena occurred. A self-organizing map neural network (SOM) was applied for visualizing interrelation among the variables and multilayer perceptron neural networks (MLPs) were employed to generalize the system and predict the drug release properties based on HLB value and concentration of SEs and tablet properties, i.e., tablet porosity, volume and tensile strength. Accurate prediction was obtained after systematically optimizing network performance based on learning algorithm of MLP. Drug release was mainly attributed to the effects of SEs, tablet volume and tensile strength in multi-dimensional interrelation whereas tablet porosity gave a small impact. Ability of system generalization and accurate prediction of the drug release properties proves the validity of SOM and MLPs for the formulation modeling of direct compacted matrix tablets containing controlled release agents of different material properties. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Non-alcoholic fatty liver disease (NAFLD) models in drug discovery.

    Science.gov (United States)

    Cole, Banumathi K; Feaver, Ryan E; Wamhoff, Brian R; Dash, Ajit

    2018-02-01

    The progressive disease spectrum of non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), is a rapidly emerging public health crisis with no approved therapy. The diversity of various therapies under development highlights the lack of consensus around the most effective target, underscoring the need for better translatable preclinical models to study the complex progressive disease and effective therapies. Areas covered: This article reviews published literature of various mouse models of NASH used in preclinical studies, as well as complex organotypic in vitro and ex vivo liver models being developed. It discusses translational challenges associated with both kinds of models, and describes some of the studies that validate their application in NAFLD. Expert opinion: Animal models offer advantages of understanding drug distribution and effects in a whole body context, but are limited by important species differences. Human organotypic in vitro and ex vivo models with physiological relevance and translatability need to be used in a tiered manner with simpler screens. Leveraging newer technologies, like metabolomics, proteomics, and transcriptomics, and the future development of validated disease biomarkers will allow us to fully utilize the value of these models to understand disease and evaluate novel drugs in isolation or combination.

  10. An examination of the Sport Drug Control Model with elite Australian athletes.

    Science.gov (United States)

    Gucciardi, Daniel F; Jalleh, Geoffrey; Donovan, Robert J

    2011-11-01

    This study presents an opportunistic examination of the theoretical tenets outlined in the Sport Drug Control Model(1) using questionnaire items from a survey of 643 elite Australian athletes. Items in the questionnaire that related to the concepts in the model were identified and structural equation modelling was employed to test the hypothesised model. Morality (cheating), benefit appraisal (performance), and threat appraisal (enforcement) evidenced the strongest relationships with attitude to doping, which in turn was positively associated with doping susceptibility. Self-esteem, perceptions of legitimacy and reference group opinions showed small non-significant associations with attitude to doping. The hypothesised model accounted for 30% and 11% of the variance in attitudes to doping and doping susceptibility, respectively. These present findings provide support for the model even though the questionnaire items were not constructed to specifically measure concepts contained in it. Thus, the model appears useful for understanding influences on doping. Nevertheless, there is a need to further explore individual and social factors that may influence athletes' use of performance enhancing drugs. Copyright © 2011 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  11. Models of policy-making and their relevance for drug research.

    Science.gov (United States)

    Ritter, Alison; Bammer, Gabriele

    2010-07-01

    Researchers are often frustrated by their inability to influence policy. We describe models of policy-making to provide new insights and a more realistic assessment of research impacts on policy. We describe five prominent models of policy-making and illustrate them with examples from the alcohol and drugs field, before drawing lessons for researchers. Policy-making is a complex and messy process, with different models describing different elements. We start with the incrementalist model, which highlights small amendments to policy, as occurs in school-based drug education. A technical/rational approach then outlines the key steps in a policy process from identification of problems and their causes, through to examination and choice of response options, and subsequent implementation and evaluation. There is a clear role for research, as we illustrate with the introduction of new medications, but this model largely ignores the dominant political aspects of policy-making. Such political aspects include the influence of interest groups, and we describe models about power and pressure groups, as well as advocacy coalitions, and the challenges they pose for researchers. These are illustrated with reference to the alcohol industry, and interest group conflicts in establishing a Medically Supervised Injecting Centre. Finally, we describe the multiple streams framework, which alerts researchers to 'windows of opportunity', and we show how these were effectively exploited in policy for cannabis law reform in Western Australia. Understanding models of policy-making can help researchers maximise the uptake of their work and advance evidence-informed policy.

  12. Sufficient conditions for optimality for a mathematical model of drug treatment with pharmacodynamics

    Directory of Open Access Journals (Sweden)

    Maciej Leszczyński

    2017-01-01

    Full Text Available We consider an optimal control problem for a general mathematical model of drug treatment with a single agent. The control represents the concentration of the agent and its effect (pharmacodynamics is modelled by a Hill function (i.e., Michaelis-Menten type kinetics. The aim is to minimize a cost functional consisting of a weighted average related to the state of the system (both at the end and during a fixed therapy horizon and to the total amount of drugs given. The latter is an indirect measure for the side effects of treatment. It is shown that optimal controls are continuous functions of time that change between full or no dose segments with connecting pieces that take values in the interior of the control set. Sufficient conditions for the strong local optimality of an extremal controlled trajectory in terms of the existence of a solution to a piecewise defined Riccati differential equation are given.

  13. Physiologically Based Pharmacokinetic Modeling: Methodology, Applications, and Limitations with a Focus on Its Role in Pediatric Drug Development

    Directory of Open Access Journals (Sweden)

    Feras Khalil

    2011-01-01

    Full Text Available The concept of physiologically based pharmacokinetic (PBPK modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision-making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more “confirmatory” rather than “exploratory”.

  14. Experimental psychiatric illness and drug abuse models: from human to animal, an overview.

    Science.gov (United States)

    Edwards, Scott; Koob, George F

    2012-01-01

    Preclinical animal models have supported much of the recent rapid expansion of neuroscience research and have facilitated critical discoveries that undoubtedly benefit patients suffering from psychiatric disorders. This overview serves as an introduction for the following chapters describing both in vivo and in vitro preclinical models of psychiatric disease components and briefly describes models related to drug dependence and affective disorders. Although there are no perfect animal models of any psychiatric disorder, models do exist for many elements of each disease state or stage. In many cases, the development of certain models is essentially restricted to the human clinical laboratory domain for the purpose of maximizing validity, whereas the use of in vitro models may best represent an adjunctive, well-controlled means to model specific signaling mechanisms associated with psychiatric disease states. The data generated by preclinical models are only as valid as the model itself, and the development and refinement of animal models for human psychiatric disorders continues to be an important challenge. Collaborative relationships between basic neuroscience and clinical modeling could greatly benefit the development of new and better models, in addition to facilitating medications development.

  15. The fitness of drug-resistant malaria parasites in a rodent model: multiplicity of infection

    OpenAIRE

    Huijben, Silvie; Sim, Derek G.; Nelson, William, A.; Read, Andrew F.

    2011-01-01

    Malaria infections normally consist of more than one clonally-replicating lineage. Within-host interactions between sensitive and resistant parasites can have profound effects on the evolution of drug resistance. Here, using the Plasmodium chabaudi mouse malaria model, we ask whether the costs and benefits of resistance are affected by the number of co-infecting strains competing with a resistant clone. We found strong competitive suppression of resistant parasites in untreated infections and...

  16. Animal models to guide clinical drug development in ADHD: lost in translation?

    Science.gov (United States)

    Wickens, Jeffery R; Hyland, Brian I; Tripp, Gail

    2011-01-01

    We review strategies for developing animal models for examining and selecting compounds with potential therapeutic benefit in attention-deficit hyperactivity disorder (ADHD). ADHD is a behavioural disorder of unknown aetiology and pathophysiology. Current understanding suggests that genetic factors play an important role in the aetiology of ADHD. The involvement of dopaminergic and noradrenergic systems in the pathophysiology of ADHD is probable. We review the clinical features of ADHD including inattention, hyperactivity and impulsivity and how these are operationalized for laboratory study. Measures of temporal discounting (but not premature responding) appear to predict known drug effects well (treatment validity). Open-field measures of overactivity commonly used do not have treatment validity in human populations. A number of animal models have been proposed that simulate the symptoms of ADHD. The most commonly used are the spontaneously hypertensive rat (SHR) and the 6-hydroxydopamine-lesioned (6-OHDA) animals. To date, however, the SHR lacks treatment validity, and the effects of drugs on symptoms of impulsivity and inattention have not been studied extensively in 6-OHDA-lesioned animals. At the present stage of development, there are no in vivo models of proven effectiveness for examining and selecting compounds with potential therapeutic benefit in ADHD. However, temporal discounting is an emerging theme in theories of ADHD, and there is good evidence of increased value of delayed reward following treatment with stimulant drugs. Therefore, operant behaviour paradigms that measure the effects of drugs in situations of delayed reinforcement, whether in normal rats or selected models, show promise for the future. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21480864

  17. Modeling drug release from functionalized magnetic nanoparticles actuated by non-heating low frequency magnetic field

    Energy Technology Data Exchange (ETDEWEB)

    Golovin, Y., E-mail: nano@tsutmb.ru [M.V. Lomonosov Moscow State University, School of Chemistry (Russian Federation); Golovin, D. [G.R. Derzhavin Tambov State University (Russian Federation); Klyachko, N.; Majouga, A.; Kabanov, A. [M.V. Lomonosov Moscow State University, School of Chemistry (Russian Federation)

    2017-02-15

    Various plausible acceleration mechanisms of drug release from nanocarriers composed of a single-domain magnetic nanoparticle core with attached long macromolecule chains activated by low frequency non-heating alternating magnetic field (AMF) are discussed. The most important system characteristics affecting the AMF exposure impact are determined. Impact of several reasonable mechanisms is estimated analytically or obtained using numerical modeling. Some conditions providing manifold release acceleration as a result from exposure in AMF are found.

  18. Modeling drug release from functionalized magnetic nanoparticles actuated by non-heating low frequency magnetic field

    International Nuclear Information System (INIS)

    Golovin, Y.; Golovin, D.; Klyachko, N.; Majouga, A.; Kabanov, A.

    2017-01-01

    Various plausible acceleration mechanisms of drug release from nanocarriers composed of a single-domain magnetic nanoparticle core with attached long macromolecule chains activated by low frequency non-heating alternating magnetic field (AMF) are discussed. The most important system characteristics affecting the AMF exposure impact are determined. Impact of several reasonable mechanisms is estimated analytically or obtained using numerical modeling. Some conditions providing manifold release acceleration as a result from exposure in AMF are found.

  19. Fabrication of zero contact angle ultra-super hydrophilic surfaces.

    Science.gov (United States)

    Jothi Prakash, C G; Clement Raj, C; Prasanth, R

    2017-06-15

    Zero contact angle surfaces have been created with the combined effect of nanostructure and UV illumination. The contact angle of titanium surface has been optimized to 3.25°±1°. with nanotubular structures through electrochemical surface modification. The porosity and surface energy of tubular TiO 2 layer play critical role over the surface wettability and the hydrophilicity of the surface. The surface free energy has been enhanced from 23.72mJ/m 2 (bare titanium surface) to 87.11mJ/m 2 (nanotubular surface). Similar surface with TiO 2 nanoparticles coating shows superhydrophilicity with contact angle up to 5.63°±0.95°. This implies liquid imbibition and surface curvature play a crucial role in surface hydrophilicity. The contact angle has been further reduced to 0°±0.86° by illuminating the surface with UV radiation. Results shows that by tuning the nanotube morphology, highly porous surfaces can be fabricated to reduce contact angle and enhance wettability. This study provides an insight into the inter-relationship between surface structural factors and ultra-superhydrophilic surfaces which can help to optimize thermal hydraulic and self cleaning surfaces. Copyright © 2017. Published by Elsevier Inc.

  20. EUS-guided biliary rendezvous using a short hydrophilic guidewire.

    Science.gov (United States)

    Dhir, Vinay; Kwek, Boon Eu Andrew; Bhandari, Suryaprakash; Bapat, Mukta; Maydeo, Amit

    2011-10-01

    BACKGROUND AND STUDY AIMS: EUS-guided rendezvous technique for biliary access requires expert manipulation of the guidewire across the downstream stricture or papilla. Published literature reports usage of the long-wire system to prevent loss of wire during scope exchange. We studied the efficacy of using a short hydrophilic guidewire in EUS-guided rendezvous. PATIENTS AND METHODS: This is a retrospective study conducted in a tertiary care referral centre. 15 patients underwent EUS-guided biliary rendezvous with short wire. EUS-guided transduodenal/transgastric puncture of the biliary system was performed, followed by anterograde placement of a hydrophilic short-wire (260 cm) across the downstream stricture and/or papilla. Retrograde access was then achieved by retrieving the trans-papillary wire, followed by standard ERCP intervention. Main outcome measurements were rates of procedural success and complications. RESULTS: EUS-guided biliary rendezvous was successful in 14 patients (93.3%). Failure was seen in one patient due to a tight malignant biliary stricture. One patient had peri-choledochal bile tracking which did not require any specific treatment. CONCLUSIONS: Short-wire system in EUS-guided biliary rendezvous is highly effective and safe. It is a useful salvage procedure for biliary cannulation in patients with accessible papilla.

  1. A novel chemo-enzymatic synthesis of hydrophilic phytosterol derivatives.

    Science.gov (United States)

    He, Wen-Sen; Hu, Di; Wang, Yu; Chen, Xue-Yan; Jia, Cheng-Sheng; Ma, Hai-Le; Feng, Biao

    2016-02-01

    In this study, a novel method was developed for chemo-enzymatic synthesis of hydrophilic phytosterol derivatives, phytosteryl polyethylene glycol succinate (PPGS), through an intermediate phytosteryl hemisuccinate (PSHS), which was first chemically prepared and subsequently coupled with polyethylene glycol (PEG) through lipase-catalyzed esterification. The chemical structure of intermediate and goal product were finally confirmed to be PSHS and PPGS by FT-IR, MS and NMR, suggesting that hydrophilic phytosterol derivatives were successfully synthesized. The effects of various parameters on the conversion of PSHS to PPGS were investigated and the highest conversion (>78%) was obtained under the selected conditions: 75 mmol/L PSHS, 1:2M ratio of PSHS to PEG, 50 g/L Novozym 435, 120 g/L 3 Å molecular sieves in tert-butanol, 55 °C, 96 h and 200 rpm. The solubility of phytosterols in water was significantly improved by coupling with PEG, facilitating the incorporation into a variety of foods containing water. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Research on Hydrophilic Nature of Polyvinylpyrrolidone on Polysulfone Membrane Filtration

    Science.gov (United States)

    Tiron, L. G.; Vlad, M.; Baltă, Ş.

    2018-06-01

    The membranes used in wastewater filtration are obtained from polymers, this technique is widely applied because of the small installations and low costs as against conventional systems. The polymeric membranes have high mechanical strength and flexibility, but is a challenge to improve in the same time the permeability and retention capacity of the membranes. A process that can improve the membrane properties is the addition of additives to the polymer solution, resulting in noticeable changes in the resulting membrane structure. Polyvinylpyrrolidone (PVP) is a highly hydrophilic polymer, used as a food additive that acts as stabilizer and thickening agent, which brings improvements in membrane properties. This study analyses the effect of polyvinylpyrrolidone (PVP) on the casting solution of the prepared membranes. The polymer solution was prepared from polysulfone (PSf) and N-methyl-2-pyrrolidone (NMP) at different concentrations. The membranes were obtained by phase inversion method. The PSf/PVP/NMP membranes with different concentrations were characterized by contact angle measurements, surface roughness, morphological structure and permeation tests. The results show that the hydrophilic nature of PVP improve the pure water flux, the contact angle and exhibit a higher anti-fouling property.

  3. Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction.

    Science.gov (United States)

    Cadoni, Cristina

    2016-01-01

    Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40-60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant

  4. Fischer 344 and Lewis rat strains as a model of genetic vulnerability to drug addiction

    Directory of Open Access Journals (Sweden)

    Cristina eCadoni

    2016-02-01

    Full Text Available Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40-60 % of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis to differences in mesolimbic dopamine (DA transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neurons functionality.Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigations, results from the reviewed studies might open new vistas in

  5. A Comparative Study on Micellar and Solubilizing Behavior of Three EO-PO Based Star Block Copolymers Varying in Hydrophobicity and Their Application for the In Vitro Release of Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Bijal Vyas

    2018-01-01

    Full Text Available The temperature and pH dependent self-assembly of three star shaped ethylene oxide-propylene oxide (EO-PO block copolymers (Tetronics® 304, 904 and 908 with widely different hydrophobicity was examined in aqueous solutions. Physico-chemical methods viz. viscosity, cloud point, solubilization along with thermal, scattering and spectral techniques shows strongly temperature and salt dependent solution behavior. T304 possessing low molecular weight did not form micelles; moderately hydrophilic T904 remained as micelles at ambient temperature and showed micellar growth while very hydrophilic T908 formed micelles at elevated temperatures. The surface activity/micellization/solubilization power was favored in the presence of salt. The copolymers turn more hydrophilic in acidic pH due to protonation of central ethylene diamine moiety that hinders micelle formation. The solubilization of a model insoluble azo dye 1-(o-Tolylazo-2-naphthol (Orange OT and hydrophobic drugs (quercetin and curcumin for copolymer solutions in aqueous and salt solutions are also reported. Among the three copolymers, T904 showed maximum solubility of dye and drugs, hence the in vitro release of drugs from T904 micelles was estimated and the effect on cytotoxicity of loading the drugs in T904 micelles was compared with the cytotoxicity of free drugs on the CHO-K1 cells. The results from the present work provide a better insight in selection of Tetronics® for their application in different therapeutic applications.

  6. Research on the Hydrophilic Modified of LDPE for the New Biological Suspended Filler

    Directory of Open Access Journals (Sweden)

    Kang Weijia

    2016-01-01

    Full Text Available Urban sewage is one of the main pollution sources of the city, which pollute soil, deteriorate the water quality and increase the water shortages and urban load. LDPE is low cost and widely used as the basic material of wastewater treatment, but LDPE’s hydrophilic is not good enough to meet the need of suspended filler in wastewater treatment. In this paper the hydrophilic modified of LDPE for the new biological suspended filler was studied and the preparation and processing technique based on LDPE was researched. The hydrophilic and mechanic performance of the hydrophilic modified materials was tested. Results shown that the new type of hydrophilic modified materials has good hydrophilic and meets the demand of urban sewage treatment. The research on the new suspended filler materials has great meaning in solving the problem of urban sewage and recycling.

  7. Enhancing hit identification in Mycobacterium tuberculosis drug discovery using validated dual-event Bayesian models.

    Directory of Open Access Journals (Sweden)

    Sean Ekins

    Full Text Available High-throughput screening (HTS in whole cells is widely pursued to find compounds active against Mycobacterium tuberculosis (Mtb for further development towards new tuberculosis (TB drugs. Hit rates from these screens, usually conducted at 10 to 25 µM concentrations, typically range from less than 1% to the low single digits. New approaches to increase the efficiency of hit identification are urgently needed to learn from past screening data. The pharmaceutical industry has for many years taken advantage of computational approaches to optimize compound libraries for in vitro testing, a practice not fully embraced by academic laboratories in the search for new TB drugs. Adapting these proven approaches, we have recently built and validated Bayesian machine learning models for predicting compounds with activity against Mtb based on publicly available large-scale HTS data from the Tuberculosis Antimicrobial Acquisition Coordinating Facility. We now demonstrate the largest prospective validation to date in which we computationally screened 82,403 molecules with these Bayesian models, assayed a total of 550 molecules in vitro, and identified 124 actives against Mtb. Individual hit rates for the different datasets varied from 15-28%. We have identified several FDA approved and late stage clinical candidate kinase inhibitors with activity against Mtb which may represent starting points for further optimization. The computational models developed herein and the commercially available molecules derived from them are now available to any group pursuing Mtb drug discovery.

  8. Mathematical modeling of antibody drug conjugates with the target and tubulin dynamics to predict AUC.

    Science.gov (United States)

    Byun, Jong Hyuk; Jung, Il Hyo

    2018-04-14

    Antibody drug conjugates (ADCs)are one of the most recently developed chemotherapeutics to treat some types of tumor cells. They consist of monoclonal antibodies (mAbs), linkers, and potent cytotoxic drugs. Unlike common chemotherapies, ADCs combine selectively with a target at the surface of the tumor cell, and a potent cytotoxic drug (payload) effectively prevents microtubule polymerization. In this work, we construct an ADC model that considers both the target of antibodies and the receptor (tubulin) of the cytotoxic payloads. The model is simulated with brentuximab vedotin, one of ADCs, and used to investigate the pharmacokinetic (PK) characteristics of ADCs in vivo. It also predicts area under the curve (AUC) of ADCs and the payloads by identifying the half-life. The results show that dynamical behaviors fairly coincide with the observed data and half-life and capture AUC. Thus, the model can be used for estimating some parameters, fitting experimental observations, predicting AUC, and exploring various dynamical behaviors of the target and the receptor. Copyright © 2018 Elsevier Ltd. All rights reserved.

  9. Optimization of bilayer floating tablet containing metoprolol tartrate as a model drug for gastric retention.

    Science.gov (United States)

    Narendra, C; Srinath, M S; Babu, Ganesh

    2006-04-07

    The purpose of the present study was to develop an optimized gastric floating drug delivery system (GFDDS) containing metoprolol tartrate (MT) as a model drug by the optimization technique. A 2(3) factorial design was employed in formulating the GFDDS with total polymer content-to-drug ratio (X1), polymer-to-polymer ratio (X2), and different viscosity grades of hydroxypropyl methyl cellulose (HPMC) (X3) as independent variables. Four dependent variables were considered: percentage of MT release at 8 hours, T50%, diffusion coefficient, and floating time. The main effect and interaction terms were quantitatively evaluated using a mathematical model. The results indicate that X1 and X2 significantly affected the floating time and release properties, but the effect of different viscosity grades of HPMC (K4M and K10M) was nonsignificant. Regression analysis and numerical optimization were performed to identify the best formulation. Fickian release transport was confirmed as the release mechanism from the optimized formulation. The predicted values agreed well with the experimental values, and the results demonstrate the feasibility of the model in the development of GFDDS.

  10. Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm.

    Science.gov (United States)

    Kesisoglou, Filippos; Mitra, Amitava

    2015-09-01

    Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

  11. Drug Nanoparticle Formulation Using Ascorbic Acid Derivatives

    Directory of Open Access Journals (Sweden)

    Kunikazu Moribe

    2011-01-01

    Full Text Available Drug nanoparticle formulation using ascorbic acid derivatives and its therapeutic uses have recently been introduced. Hydrophilic ascorbic acid derivatives such as ascorbyl glycoside have been used not only as antioxidants but also as food and pharmaceutical excipients. In addition to drug solubilization, drug nanoparticle formation was observed using ascorbyl glycoside. Hydrophobic ascorbic acid derivatives such as ascorbyl mono- and di-n-alkyl fatty acid derivatives are used either as drugs or carrier components. Ascorbyl n-alkyl fatty acid derivatives have been formulated as antioxidants or anticancer drugs for nanoparticle formulations such as micelles, microemulsions, and liposomes. ASC-P vesicles called aspasomes are submicron-sized particles that can encapsulate hydrophilic drugs. Several transdermal and injectable formulations of ascorbyl n-alkyl fatty acid derivatives were used, including ascorbyl palmitate.

  12. Detection of Cases of Noncompliance to Drug Treatment in Patient Forum Posts: Topic Model Approach.

    Science.gov (United States)

    Abdellaoui, Redhouane; Foulquié, Pierre; Texier, Nathalie; Faviez, Carole; Burgun, Anita; Schück, Stéphane

    2018-03-14

    Medication nonadherence is a major impediment to the management of many health conditions. A better understanding of the factors underlying noncompliance to treatment may help health professionals to address it. Patients use peer-to-peer virtual communities and social media to share their experiences regarding their treatments and diseases. Using topic models makes it possible to model themes present in a collection of posts, thus to identify cases of noncompliance. The aim of this study was to detect messages describing patients' noncompliant behaviors associated with a drug of interest. Thus, the objective was the clustering of posts featuring a homogeneous vocabulary related to nonadherent attitudes. We focused on escitalopram and aripiprazole used to treat depression and psychotic conditions, respectively. We implemented a probabilistic topic model to identify the topics that occurred in a corpus of messages mentioning these drugs, posted from 2004 to 2013 on three of the most popular French forums. Data were collected using a Web crawler designed by Kappa Santé as part of the Detec't project to analyze social media for drug safety. Several topics were related to noncompliance to treatment. Starting from a corpus of 3650 posts related to an antidepressant drug (escitalopram) and 2164 posts related to an antipsychotic drug (aripiprazole), the use of latent Dirichlet allocation allowed us to model several themes, including interruptions of treatment and changes in dosage. The topic model approach detected cases of noncompliance behaviors with a recall of 98.5% (272/276) and a precision of 32.6% (272/844). Topic models enabled us to explore patients' discussions on community websites and to identify posts related with noncompliant behaviors. After a manual review of the messages in the noncompliance topics, we found that noncompliance to treatment was present in 6.17% (276/4469) of the posts. ©Redhouane Abdellaoui, Pierre Foulquié, Nathalie Texier, Carole

  13. Modeling Cancer Cell Growth Dynamics In vitro in Response to Antimitotic Drug Treatment

    KAUST Repository

    Lorz, Alexander

    2017-08-30

    Investigating the role of intrinsic cell heterogeneity emerging from variations in cell-cycle parameters and apoptosis is a crucial step toward better informing drug administration. Antimitotic agents, widely used in chemotherapy, target exclusively proliferative cells and commonly induce a prolonged mitotic arrest followed by cell death via apoptosis. In this paper, we developed a physiologically motivated mathematical framework for describing cancer cell growth dynamics that incorporates the intrinsic heterogeneity in the time individual cells spend in the cell-cycle and apoptosis process. More precisely, our model comprises two age-structured partial differential equations for the proliferative and apoptotic cell compartments and one ordinary differential equation for the quiescent compartment. To reflect the intrinsic cell heterogeneity that governs the growth dynamics, proliferative and apoptotic cells are structured in “age,” i.e., the amount of time remaining to be spent in each respective compartment. In our model, we considered an antimitotic drug whose effect on the cellular dynamics is to induce mitotic arrest, extending the average cell-cycle length. The prolonged mitotic arrest induced by the drug can trigger apoptosis if the time a cell will spend in the cell cycle is greater than the mitotic arrest threshold. We studied the drug\\'s effect on the long-term cancer cell growth dynamics using different durations of prolonged mitotic arrest induced by the drug. Our numerical simulations suggest that at confluence and in the absence of the drug, quiescence is the long-term asymptotic behavior emerging from the cancer cell growth dynamics. This pattern is maintained in the presence of small increases in the average cell-cycle length. However, intermediate increases in cell-cycle length markedly decrease the total number of cells and can drive the cancer population to extinction. Intriguingly, a large “switch-on/ switch-off” increase in the average

  14. Distribution of Spiked Drugs between Milk Fat, Skim Milk, Whey, Curd, and Milk Protein Fractions: Expansion of Partitioning Models.

    Science.gov (United States)

    Lupton, Sara J; Shappell, Nancy W; Shelver, Weilin L; Hakk, Heldur

    2018-01-10

    The distributions of eight drugs (acetaminophen, acetylsalicylic acid/salicylic acid, ciprofloxacin, clarithromycin, flunixin, phenylbutazone, praziquantel, and thiamphenicol) were determined in milk products (skim milk, milk fat, curd, whey, and whey protein) and used to expand a previous model (from 7 drugs to 15 drugs) for predicting drug distribution. Phenylbutazone and praziquantel were found to distribute with the lipid and curd phases (≥50%). Flunixin distribution was lower but similar in direction (12% in milk fat, 39% in curd). Acetaminophen, ciprofloxacin, and praziquantel preferentially associated with casein proteins, whereas thiamphenicol and clarithromycin associated preferentially to whey proteins. Regression analyses for log [milk fat]/[skim milk] and log [curd]/[whey] had r 2 values of 0.63 and 0.67, respectively, with p of <0.001 for 15 drugs (7 previously tested and 8 currently tested). The robustness of the distribution model was enhanced by doubling the number of drugs originally tested.

  15. A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat.

    Science.gov (United States)

    Diack, C; Ackaert, O; Ploeger, B A; van der Graaf, P H; Gurrell, R; Ivarsson, M; Fairman, D

    2011-12-01

    Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across species. The EEG shows frequent transitions between specific sleep states leading to multiple correlated sojourns in these states. We have developed a Markov model to consider the high correlation in the data and quantitatively compared sleep disturbance in telemetered rats induced by methylphenidate, which is known to disturb sleep, and of a new chemical entity (NCE). It was assumed that these drugs could either accelerate or decelerate the transitions between the sleep states. The difference in sleep disturbance of methylphenidate and the NCE were quantitated and different mechanisms of action on rebound sleep were identified. The estimated effect showed that both compounds induce sleep fragmentation with methylphenidate being fivefold more potent compared to the NCE.

  16. Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening.

    Science.gov (United States)

    Sharma, Arun; Wu, Joseph C; Wu, Sean M

    2013-12-24

    Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scientists as a promising cell source for replacement therapy. However, ongoing issues such as cell immaturity, scale of production, inter-line variability, and cell purity will need to be resolved before human clinical trials can begin. Meanwhile, the use of hiPSCs to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. For example, hiPSC-CMs have been shown to recapitulate disease phenotypes from patients with monogenic cardiovascular disorders. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. This review will highlight recent advances in utilizing hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The advantages and disadvantages of using hiPSC-CMs for drug screening purposes will be explored as well.

  17. The Separation and Quantitation of Peptides with and without Oxidation of Methionine and Deamidation of Asparagine Using Hydrophilic Interaction Liquid Chromatography with Mass Spectrometry (HILIC-MS)

    Science.gov (United States)

    Badgett, Majors J.; Boyes, Barry; Orlando, Ron

    2017-05-01

    Peptides with deamidated asparagine residues and oxidized methionine residues are often not resolved sufficiently to allow quantitation of their native and modified forms using reversed phase (RP) chromatography. The accurate quantitation of these modifications is vital in protein biotherapeutic analysis because they can affect a protein's function, activity, and stability. We demonstrate here that hydrophilic interaction liquid chromatography (HILIC) adequately and predictably separates peptides with these modifications from their native counterparts. Furthermore, coefficients describing the extent of the hydrophilicity of these modifications have been derived and were incorporated into a previously made peptide retention prediction model that is capable of predicting the retention times of peptides with and without these modifications.

  18. Mouse Models for Drug Discovery. Can New Tools and Technology Improve Translational Power?

    Science.gov (United States)

    Zuberi, Aamir; Lutz, Cathleen

    2016-01-01

    Abstract The use of mouse models in biomedical research and preclinical drug evaluation is on the rise. The advent of new molecular genome-altering technologies such as CRISPR/Cas9 allows for genetic mutations to be introduced into the germ line of a mouse faster and less expensively than previous methods. In addition, the rapid progress in the development and use of somatic transgenesis using viral vectors, as well as manipulations of gene expression with siRNAs and antisense oligonucleotides, allow for even greater exploration into genomics and systems biology. These technological advances come at a time when cost reductions in genome sequencing have led to the identification of pathogenic mutations in patient populations, providing unprecedented opportunities in the use of mice to model human disease. The ease of genetic engineering in mice also offers a potential paradigm shift in resource sharing and the speed by which models are made available in the public domain. Predictively, the knowledge alone that a model can be quickly remade will provide relief to resources encumbered by licensing and Material Transfer Agreements. For decades, mouse strains have provided an exquisite experimental tool to study the pathophysiology of the disease and assess therapeutic options in a genetically defined system. However, a major limitation of the mouse has been the limited genetic diversity associated with common laboratory mice. This has been overcome with the recent development of the Collaborative Cross and Diversity Outbred mice. These strains provide new tools capable of replicating genetic diversity to that approaching the diversity found in human populations. The Collaborative Cross and Diversity Outbred strains thus provide a means to observe and characterize toxicity or efficacy of new therapeutic drugs for a given population. The combination of traditional and contemporary mouse genome editing tools, along with the addition of genetic diversity in new modeling

  19. Characterization and validation of an in silico toxicology model to predict the mutagenic potential of drug impurities*

    Energy Technology Data Exchange (ETDEWEB)

    Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov [Science and Research Staff, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993–0002 (United States); Cross, Kevin P. [Leadscope, Inc., 1393 Dublin Road, Columbus, OH, 43215–1084 (United States)

    2012-05-01

    Control and minimization of human exposure to potential genotoxic impurities found in drug substances and products is an important part of preclinical safety assessments of new drug products. The FDA's 2008 draft guidance on genotoxic and carcinogenic impurities in drug substances and products allows use of computational quantitative structure–activity relationships (QSAR) to identify structural alerts for known and expected impurities present at levels below qualified thresholds. This study provides the information necessary to establish the practical use of a new in silico toxicology model for predicting Salmonella t. mutagenicity (Ames assay outcome) of drug impurities and other chemicals. We describe the model's chemical content and toxicity fingerprint in terms of compound space, molecular and structural toxicophores, and have rigorously tested its predictive power using both cross-validation and external validation experiments, as well as case studies. Consistent with desired regulatory use, the model performs with high sensitivity (81%) and high negative predictivity (81%) based on external validation with 2368 compounds foreign to the model and having known mutagenicity. A database of drug impurities was created from proprietary FDA submissions and the public literature which found significant overlap between the structural features of drug impurities and training set chemicals in the QSAR model. Overall, the model's predictive performance was found to be acceptable for screening drug impurities for Salmonella mutagenicity. -- Highlights: ► We characterize a new in silico model to predict mutagenicity of drug impurities. ► The model predicts Salmonella mutagenicity and will be useful for safety assessment. ► We examine toxicity fingerprints and toxicophores of this Ames assay model. ► We compare these attributes to those found in drug impurities known to FDA/CDER. ► We validate the model and find it has a desired predictive

  20. Characterization and validation of an in silico toxicology model to predict the mutagenic potential of drug impurities*

    International Nuclear Information System (INIS)

    Valerio, Luis G.; Cross, Kevin P.

    2012-01-01

    Control and minimization of human exposure to potential genotoxic impurities found in drug substances and products is an important part of preclinical safety assessments of new drug products. The FDA's 2008 draft guidance on genotoxic and carcinogenic impurities in drug substances and products allows use of computational quantitative structure–activity relationships (QSAR) to identify structural alerts for known and expected impurities present at levels below qualified thresholds. This study provides the information necessary to establish the practical use of a new in silico toxicology model for predicting Salmonella t. mutagenicity (Ames assay outcome) of drug impurities and other chemicals. We describe the model's chemical content and toxicity fingerprint in terms of compound space, molecular and structural toxicophores, and have rigorously tested its predictive power using both cross-validation and external validation experiments, as well as case studies. Consistent with desired regulatory use, the model performs with high sensitivity (81%) and high negative predictivity (81%) based on external validation with 2368 compounds foreign to the model and having known mutagenicity. A database of drug impurities was created from proprietary FDA submissions and the public literature which found significant overlap between the structural features of drug impurities and training set chemicals in the QSAR model. Overall, the model's predictive performance was found to be acceptable for screening drug impurities for Salmonella mutagenicity. -- Highlights: ► We characterize a new in silico model to predict mutagenicity of drug impurities. ► The model predicts Salmonella mutagenicity and will be useful for safety assessment. ► We examine toxicity fingerprints and toxicophores of this Ames assay model. ► We compare these attributes to those found in drug impurities known to FDA/CDER. ► We validate the model and find it has a desired predictive performance.

  1. HSA-based multi-target combination therapy: regulating drugs' release from HSA and overcoming single drug resistance in a breast cancer model.

    Science.gov (United States)

    Gou, Yi; Zhang, Zhenlei; Li, Dongyang; Zhao, Lei; Cai, Meiling; Sun, Zhewen; Li, Yongping; Zhang, Yao; Khan, Hamid; Sun, Hongbing; Wang, Tao; Liang, Hong; Yang, Feng

    2018-11-01

    Multi-drug delivery systems, which may be promising solution to overcome obstacles, have limited the clinical success of multi-drug combination therapies to treat cancer. To this end, we used three different anticancer agents, Cu(BpT)Br, NAMI-A, and doxorubicin (DOX), to build human serum albumin (HSA)-based multi-drug delivery systems in a breast cancer model to investigate the therapeutic efficacy of overcoming single drug (DOX) resistance to cancer cells in vivo, and to regulate the drugs' release from HSA. The HSA complex structure revealed that NAMI-A and Cu(BpT)Br bind to the IB and IIA sub-domain of HSA by N-donor residue replacing a leaving group and coordinating to their metal centers, respectively. The MALDI-TOF mass spectra demonstrated that one DOX molecule is conjugated with lysine of HSA by a pH-sensitive linker. Furthermore, the release behavior of three agents form HSA can be regulated at different pH levels. Importantly, in vivo results revealed that the HSA-NAMI-A-Cu(BpT)Br-DOX complex not only increases the targeting ability compared with a combination of the three agents (the NAMI-A/Cu(BpT)Br/DOX mixture), but it also overcomes DOX resistance to drug-resistant breast cancer cell lines.

  2. Studying Host-Pathogen Interactions In 3-D: Organotypic Models For Infectious Disease And Drug Development

    Science.gov (United States)

    Nickerson, Cheryl A.; Richter, Emily G.; Ott, C. Mark

    2006-01-01

    Representative, reproducible and high-throughput models of human cells and tissues are critical for a meaningful evaluation of host-pathogen interactions and are an essential component of the research developmental pipeline. The most informative infection models - animals, organ explants and human trials - are not suited for extensive evaluation of pathogenesis mechanisms and screening of candidate drugs. At the other extreme, more cost effective and accessible infection models such as conventional cell culture and static co-culture may not capture physiological and three-dimensional aspects of tissue biology that are important in assessing pathogenesis, and effectiveness and cytotoxicity of therapeutics. Our lab has used innovative bioengineering technology to establish biologically meaningful 3-D models of human tissues that recapitulate many aspects of the differentiated structure and function of the parental tissue in vivo, and we have applied these models to study infectious disease. We have establish