Drug facilitated sexual assault with lethal outcome

DEFF Research Database (Denmark)

Mehling, Lena-Maria; Johansen, Sys Stybe; Wang, Xin

2016-01-01

A very serious case of DFSA (drug facilitated sexual assault) is presented, in which a six-year-old girl died following sedation with γ-hydroxybutyric acid (GHB). She had been sexually abused by a relative. Samples of cardiac blood, bile, vitreous humour, liver, kidney, brain tissues and hair were...

Mapping Quantitatively Regional Drug Absorption in Canines with IntelliCap System

NARCIS (Netherlands)

Becker, D.; Schütz, H.; Beyerbach, A.; Zou, H.; Shimizu, J.; Iordanov, V.P.

2011-01-01

Quantitative regional absorption of a drug under development was studied by using the novel IntelliCap system. IntelliCap is an orally swallowable programmable drug delivery capsule and capable of real-time monitoring of physiological conditions (pH, temperature), consequently allowing localization

Concomitant intake of alcohol may increase the absorption of poorly soluble drugs.

Science.gov (United States)

Fagerberg, Jonas H; Sjögren, Erik; Bergström, Christel A S

2015-01-25

Ethanol can increase the solubility of poorly soluble and hence present a higher drug concentration in the gastrointestinal tract. This may produce a faster and more effective absorption resulting in variable and/or high drug plasma concentrations, both of which can lead to adverse drug reactions. In this work we therefore studied the solubility and absorption effects of nine diverse compounds when ethanol was present. The apparent solubility was measured using the μDiss Profiler Plus (pION, MA) in four media representing gastric conditions with and without ethanol. The solubility results were combined with in-house data on solubility in intestinal fluids (with and without ethanol) and pharmacokinetic parameters extracted from the literature and used as input in compartmental absorption simulations using the software GI-Sim. Apparent solubility increased more than 7-fold for non-ionized compounds in simulated gastric fluid containing 20% ethanol. Compounds with weak base functions (cinnarizine, dipyridamole and terfenadine) were completely ionized at the studied gastric pH and their solubility was therefore unaffected by ethanol. Compounds with low solubility in intestinal media and a pronounced solubility increase due to ethanol in the upper gastric compartments showed an increased absorption in the simulations. The rate of absorption of the acidic compounds indomethacin and indoprofen was slightly increased but the extent of absorption was unaffected as the complete doses were readily absorbed even without ethanol. This was likely due to a high apparent solubility in the intestinal compartment where the weak acids are ionized. The absorption of the studied non-ionizable compounds increased when ethanol was present in the gastric and intestinal media. These results indicate that concomitant intake of alcohol may significantly increase the solubility and hence, the plasma concentration for non-ionizable, lipophilic compounds with the potential of adverse drug

Computational Studies of Drug Release, Transport and Absorption in the Human Intestines

Science.gov (United States)

Behafarid, Farhad; Brasseur, J. G.; Vijayakumar, G.; Jayaraman, B.; Wang, Y.

2016-11-01

Following disintegration of a drug tablet, a cloud of particles 10-200 μm in diameter enters the small intestine where drug molecules are absorbed into the blood. Drug release rate depends on particle size, solubility and hydrodynamic enhancements driven by gut motility. To quantify the interrelationships among dissolution, transport and wall permeability, we apply lattice Boltzmann method to simulate the drug concentration field in the 3D gut released from polydisperse distributions of drug particles in the "fasting" vs. "fed" motility states. Generalized boundary conditions allow for both solubility and gut wall permeability to be systematically varied. We apply a local 'quasi-steady state' approximation for drug dissolution using a mathematical model generalized for hydrodynamic enhancements and heterogeneity in drug release rate. We observe fundamental differences resulting from the interplay among release, transport and absorption in relationship to particle size distribution, luminal volume, motility, solubility and permeability. For example, whereas smaller volume encourages higher bulk concentrations and reduced release rate, it also encourages higher absorption rate, making it difficult to generalize predictions. Supported by FDA.

Remote controlled capsules in human drug absorption (HDA) studies.

Science.gov (United States)

Wilding, Ian R; Prior, David V

2003-01-01

The biopharmaceutical complexity of today's new drug candidates provides significant challenges for pharmaceutical scientists in terms of both candidate selection and optimizing subsequent development strategy. In addition, life cycle management of marketed drugs has become an important income stream for pharmaceutical companies, but the selection of least risk/highest benefit strategies is far from simple. The proactive adoption of human drug absorption (HDA) studies using remote controlled capsules offers the pharmaceutical scientist significant guidance for planning a route through the maze of product development. This review examines the position of HDA studies in drug development, using a variety of case histories and an insightful update on remote controlled capsules to achieve site-specific delivery.

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.

Development and Evaluation of Naproxen Sodium Gel Using Piper cubeba for Enhanced Transdermal Drug Delivery and Therapeutic Facilitation.

Science.gov (United States)

Patwardhan, Sunetra; Patil, Manohar; Sockalingam, Anbazhagan

2017-01-01

The absorption of drug through skin avoids many side effects of oral route like gastric irritation, nausea, systemic toxicity etc and thus improves patient compliance. Naproxen sodium (NPRS) is one of the potent NSAID agents. The present study was aimed to develop and evaluate the gel formulation containing NPRS for transdermal drug delivery reducing the side effects and improving patient compliance. The patents on topical delivery of NSAIDS (US 9012402 B1, US 9072659 B2, US 20150258196 A1) and patents indicating use of herbal penetration enhancers (US 20100273746A1, WO 2005009510 A2, US 6004969 A) helped in selecting the drug, excipients. Current protocol employs various extracts of Piper cubeba fruit to evaluate its role in absorption of NPRS. Various batches containing 1% NPRS and varying concentrations of synthetic permeation enhancers or the extracts were formulated in carbopol gel. Gel was evaluated for parameters like organoleptic parameters, pH, viscosity and spreadability. An ex-vivo percutaneous absorption of NPRS from gel was investigated and compared with best performing synthetic enhancer, transcutol P (TP). The batch containing 2% n-hexane extract (NHE) of Piper cubeba showed higher permeation than TP and Chloroform (CE), Methanolic (ME) and aqueous (AE) extracts as well. It showed improved % cumulative release (85.09%) and flux (278.61μg/cm2.h), as compared to TP and other extracts. Histopathology indicated the formulation safer as compared to that with synthetic enhancer. It suggests P. cubeba as effective and safer tool for transdermal delivery and acts as therapeutic facilitator for naproxen. GC-MS analysis indicates lignans & terpenes in NHE to which this permeation enhancement activity may be attributed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Analysis of Intra- and Intersubject Variability in Oral Drug Absorption in Human Bioequivalence Studies of 113 Generic Products.

Science.gov (United States)

Sugihara, Masahisa; Takeuchi, Susumu; Sugita, Masaru; Higaki, Kazutaka; Kataoka, Makoto; Yamashita, Shinji

2015-12-07

In this study, the data of 113 human bioequivalence (BE) studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time-concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (P(eff)). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low P(eff) might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of P(eff)/Do (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (P(eff)/Do high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by CYP3A4 while intersubject variability was high for drugs metabolized by CYP2D6. For CYP3A4 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of human BE study, low permeability, solubility-limited absorption, and high affinity to CYP3A4 are identified as risk factors for

Hydrodynamic Impacts on Dissolution, Transport and Absorption from Thousands of Drug Particles Moving within the Intestines

Science.gov (United States)

Behafarid, Farhad; Brasseur, James G.

2017-11-01

Following tablet disintegration, clouds of drug particles 5-200 μm in diameter pass through the intestines where drug molecules are absorbed into the blood. Release rate depends on particle size, drug solubility, local drug concentration and the hydrodynamic environment driven by patterned gut contractions. To analyze the dynamics underlying drug release and absorption, we use a 3D lattice Boltzmann model of the velocity and concentration fields driven by peristaltic contractions in vivo, combined with a mathematical model of dissolution-rate from each drug particle transported through the grid. The model is empirically extended for hydrodynamic enhancements to release rate by local convection and shear-rate, and incorporates heterogeneity in bulk concentration. Drug dosage and solubility are systematically varied along with peristaltic wave speed and volume. We predict large hydrodynamic enhancements (35-65%) from local shear-rate with minimal enhancement from convection. With high permeability boundary conditions, a quasi-equilibrium balance between release and absorption is established with volume and wave-speed dependent transport time scale, after an initial transient and before a final period of dissolution/absorption. Supported by FDA.

Multi-purposable filaments of HPMC for 3D printing of medications with tailored drug release and timed-absorption.

Science.gov (United States)

Kadry, Hossam; Al-Hilal, Taslim A; Keshavarz, Ali; Alam, Farzana; Xu, Changxue; Joy, Abraham; Ahsan, Fakhrul

2018-04-20

Three-dimensional printing (3DP), though developed for nonmedical applications and once regarded as futuristic only, has recently been deployed for the fabrication of pharmaceutical products. However, the existing feeding materials (inks and filaments) that are used for printing drug products have various shortcomings, including the lack of biocompatibility, inadequate extrudability and printability, poor drug loading, and instability. Here, we have sought to develop a filament using a single pharmaceutical polymer, with no additives, which can be multi-purposed and manipulated by computational design for the preparation of tablets with desired release and absorption patterns. As such, we have used hydroxypropyl-methylcellulose (HPMC) and diltiazem, a model drug, to prepare both drug-free and drug-impregnated filaments, and investigated their thermal and crystalline properties, studied the cytotoxicity of the filaments, designed and printed tablets with various infill densities and patterns. By alternating the drug-free and drug-impregnated filaments, we fabricated various types of tablets, studied the drug release profiles, and assessed oral absorption in rats. Both diltiazem and HPMC were stable at extrusion and printing temperatures, and the drug loading was 10% (w/w). The infill density, as well as infill patterns, influenced the drug release profile, and thus, when the infill density was increased to 100%, the percentage of drug released dramatically declined. Tablets with alternating drug-free and drug-loaded layers showed delayed and intermittent drug release, depending on when the drug-loaded layers encountered the dissolution media. Importantly, the oral absorption patterns accurately reproduced the drug release profiles and showed immediate, extended, delayed and episodic absorption of the drug from the rat gastrointestinal tract (GIT). Overall, we have demonstrated here that filaments for 3D printers can be prepared from a pharmaceutical polymer with no

Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery.

Science.gov (United States)

Pan, Dipanjan; Pham, Christine T N; Weilbaecher, Katherine N; Tomasson, Michael H; Wickline, Samuel A; Lanza, Gregory M

2016-01-01

Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a 'magic bullet' to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a 'Grail Quest' by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made 'made the turn' toward meaningful translational success. © 2015 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals, Inc.

Interplay of Drug-Metabolizing Enzymes and Transporters in Drug Absorption and Disposition.

Science.gov (United States)

Shi, Shaojun; Li, Yunqiao

2014-01-01

In recent years, the functional interplay between drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in drug absorption and disposition, as well as the complex drug interactions (DIs), has become an intriguing contention, which has also been termed the "transport-metabolism interplay". The current mechanistic understanding for this interplay is first discussed. In the present article, studies investigating the interplay between cytochrome P450 enzymes (CYPs) and efflux transporters have been systematically reviewed in vitro, in situ, in silico, in animals and humans, followed by CYPs-uptake transporters, CYPs-uptake transporters-efflux transporters, and phase II metabolic enzymes-transporters interplay studies. Although several cellular, isolated organ and whole animal studies, in conjunction with simulation and modelling, have addressed the issue that DMEs and DTs can work cooperatively to affect the bioavailability of shared substrate drugs, convincing evidences in human studies are still lacking. Furthermore, the functional interplay between DMEs and DTs will be highly substrate- and dose- dependent. Additionally, we review recent studies to evaluate the influence of genetic variations in the interplay between DMEs and DTs, which might be helpful for the prediction of pharmacokinetics (PK) and possible DIs in human more correctly. There is strong evidence of coordinately regulated DEMs and DTs gene expression and protein activity (e.g. nuclear receptors). Taken together, further investigations and analysis are urgently needed to explore the functional interplay of DMEs and DTs and to delineate the underlying mechanisms.

Functionalization of nanodiamond with vitamin E TPGS to facilitate oral absorption of curcumin.

Science.gov (United States)

Cheng, Bingchao; Pan, Hao; Liu, Dandan; Li, Dongyang; Li, Jinyu; Yu, Shihui; Tan, Guoxin; Pan, Weisan

2018-04-05

The purpose of this work was to develop a d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) decorated nanodiamond (ND) system loading water-insoluble curcumin (ND/CUR/TPGS) to improve the colloidal dispersity and oral bioavailability of the preparation. CUR was physically loaded into ND clusters, then TPGS was coated to the ND/CUR complex forming amorphous nanostructure on the interparticle nanocage of the ND substrate. The formulation of the nanocomplexes was optimized using response surface methodology, and the optimal ND/CUR/TPGS showed small particle size (196.32 nm), high drug loading efficiency (81.59%) and core-shell structure. In vitro release study demonstrated that the nanocomplexes provided a sustained release behavior. The absorptive concentration of ND/CUR/TPGS was dramatically improved in total intestinal tract compared with CUR suspension, and the absorption was controlled by multiple transcytosis mechanisms. Furthermore, the pharmacokinetic studies demonstrated that ND/CUR/TPGS had significantly higher C max (4.50-fold), larger AUC 0-t (10.67-fold), and longer MRT 0-t (3.07-fold) in contrast with that of CUR suspension. Therefore, ND/CUR/TPGS presented great potential for oral delivery of insoluble and poorly permeable drugs. Copyright © 2018 Elsevier B.V. All rights reserved.

Supersaturation-nucleation behavior of poorly soluble drugs and its impact on the oral absorption of drugs in thermodynamically high-energy forms.

Science.gov (United States)

Ozaki, Shunsuke; Minamisono, Takuma; Yamashita, Taro; Kato, Takashi; Kushida, Ikuo

2012-01-01

In order to better understand the oral absorption behavior of poorly water-soluble drugs, their supersaturation-nucleation behavior was characterized in fasted state simulated intestinal fluid. The induction time (t(ind)) for nucleation was measured for four model drugs: itraconazole, erlotinib, troglitazone, and PLX4032. Supersaturated solutions were prepared by solvent shift method, and nucleation initiation was monitored by ultraviolet detection. The relationship between t(ind) and degree of supersaturation was analyzed in terms of classical nucleation theory. The defined supersaturation stability proved to be compound specific. Clinical data on oral absorption were investigated for drugs in thermodynamically high-energy forms such as amorphous forms and salts and was compared with in vitro supersaturation-nucleation characteristics. Solubility-limited maximum absorbable dose was proportionate to intestinal effective drug concentrations, which are related to supersaturation stability and thermodynamic solubility. Supersaturation stability was shown to be an important factor in determining the effect of high-energy forms. The characterization of supersaturation-nucleation behavior by the presented method is, therefore, valuable for assessing the potential absorbability of poorly water-soluble drugs. Copyright © 2011 Wiley-Liss, Inc.

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.

Development of a Unified Dissolution and Precipitation Model and Its Use for the Prediction of Oral Drug Absorption.

Science.gov (United States)

Jakubiak, Paulina; Wagner, Björn; Grimm, Hans Peter; Petrig-Schaffland, Jeannine; Schuler, Franz; Alvarez-Sánchez, Rubén

2016-02-01

Drug absorption is a complex process involving dissolution and precipitation, along with other kinetic processes. The purpose of this work was to (1) establish an in vitro methodology to study dissolution and precipitation in early stages of drug development where low compound consumption and high throughput are necessary, (2) develop a mathematical model for a mechanistic explanation of generated in vitro dissolution and precipitation data, and (3) extrapolate in vitro data to in vivo situations using physiologically based models to predict oral drug absorption. Small-scale pH-shift studies were performed in biorelevant media to monitor the precipitation of a set of poorly soluble weak bases. After developing a dissolution-precipitation model from this data, it was integrated into a simplified, physiologically based absorption model to predict clinical pharmacokinetic profiles. The model helped explain the consequences of supersaturation behavior of compounds. The predicted human pharmacokinetic profiles closely aligned with the observed clinical data. In summary, we describe a novel approach combining experimental dissolution/precipitation methodology with a mechanistic model for the prediction of human drug absorption kinetics. The approach unifies the dissolution and precipitation theories and enables accurate predictions of in vivo oral absorption by means of physiologically based modeling.

Effects of gastric pH on oral drug absorption: In vitro assessment using a dissolution/permeation system reflecting the gastric dissolution process.

Science.gov (United States)

Kataoka, Makoto; Fukahori, Miho; Ikemura, Atsumi; Kubota, Ayaka; Higashino, Haruki; Sakuma, Shinji; Yamashita, Shinji

2016-04-01

The aim of the present study was to evaluate the effects of gastric pH on the oral absorption of poorly water-soluble drugs using an in vitro system. A dissolution/permeation system (D/P system) equipped with a Caco-2 cell monolayer was used as the in vitro system to evaluate oral drug absorption, while a small vessel filled with simulated gastric fluid (SGF) was used to reflect the gastric dissolution phase. After applying drugs in their solid forms to SGF, SGF solution containing a 1/100 clinical dose of each drug was mixed with the apical solution of the D/P system, which was changed to fasted state-simulated intestinal fluid. Dissolved and permeated amounts on applied amount of drugs were then monitored for 2h. Similar experiments were performed using the same drugs, but without the gastric phase. Oral absorption with or without the gastric phase was predicted in humans based on the amount of the drug that permeated in the D/P system, assuming that the system without the gastric phase reflected human absorption with an elevated gastric pH. The dissolved amounts of basic drugs with poor water solubility, namely albendazole, dipyridamole, and ketoconazole, in the apical solution and their permeation across a Caco-2 cell monolayer were significantly enhanced when the gastric dissolution process was reflected due to the physicochemical properties of basic drugs. These amounts resulted in the prediction of higher oral absorption with normal gastric pH than with high gastric pH. On the other hand, when diclofenac sodium, the salt form of an acidic drug, was applied to the D/P system with the gastric phase, its dissolved and permeated amounts were significantly lower than those without the gastric phase. However, the oral absorption of diclofenac was predicted to be complete (96-98%) irrespective of gastric pH because the permeated amounts of diclofenac under both conditions were sufficiently high to achieve complete absorption. These estimations of the effects of

Facilitating adverse drug event detection in pharmacovigilance databases using molecular structure similarity: application to rhabdomyolysis

Science.gov (United States)

Vilar, Santiago; Harpaz, Rave; Chase, Herbert S; Costanzi, Stefano; Rabadan, Raul

2011-01-01

Background Adverse drug events (ADE) cause considerable harm to patients, and consequently their detection is critical for patient safety. The US Food and Drug Administration maintains an adverse event reporting system (AERS) to facilitate the detection of ADE in drugs. Various data mining approaches have been developed that use AERS to detect signals identifying associations between drugs and ADE. The signals must then be monitored further by domain experts, which is a time-consuming task. Objective To develop a new methodology that combines existing data mining algorithms with chemical information by analysis of molecular fingerprints to enhance initial ADE signals generated from AERS, and to provide a decision support mechanism to facilitate the identification of novel adverse events. Results The method achieved a significant improvement in precision in identifying known ADE, and a more than twofold signal enhancement when applied to the ADE rhabdomyolysis. The simplicity of the method assists in highlighting the etiology of the ADE by identifying structurally similar drugs. A set of drugs with strong evidence from both AERS and molecular fingerprint-based modeling is constructed for further analysis. Conclusion The results demonstrate that the proposed methodology could be used as a pharmacovigilance decision support tool to facilitate ADE detection. PMID:21946238

Facilitators and barriers to the successful implementation of pediatric antibacterial drug trials: Findings from CTTI's survey of investigators

Directory of Open Access Journals (Sweden)

Amy Corneli

2018-03-01

Full Text Available An urgent need exists to develop new antibacterial drugs for children. We conducted research with investigators of pediatric antibacterial drug trials to identify facilitators and barriers in the conduct of these trials. Seventy-three investigators completed an online survey assessing the importance of 15 facilitators (grouped in 5 topical categories and the severity of 36 barriers (grouped in 6 topical categories to implementing pediatric antibacterial drug trials. Analysis focused on the identification of key factors that facilitate the successful implementation of pediatric antibacterial drug trials and the key barriers to implementation. Almost all investigators identified two factors as very important facilitators: having site personnel for enrollment and having adequate funding. Other top factors were related to staffing. Among the barriers, factors related to parent concerns and consent were prominent, particularly obtaining parental consent when there was disagreement between parents, concerns about the number of blood draws, and concerns about the number of invasive procedures. Having overly narrow eligibility criteria was also identified as a major barrier. The survey findings suggest three areas in which to focus efforts to help facilitate ongoing drug development: (1 improving engagement with parents of children who may be eligible to enroll in a pediatric antibacterial drug trial, (2 broadening inclusion criteria to allow more participants to enroll, and (3 ensuring adequate staffing and establishing sustainable financial strategies, such as funding pediatric trial networks. The pediatric antibacterial drug trials enterprise is likely to benefit from focused efforts by all stakeholders to remove barriers and enhance facilitation.

[Drug-facilitated crime and sexual abuse: a pediatric observation].

Science.gov (United States)

Rey-Salmon, C; Pépin, G

2007-11-01

Drug-facilitated crime in sexual assault situations remains insufficiently recognized by physicians. In the possible context of an assault and in front of recent neuropsychicological disturbances in a child, such an issue has to be considered. The quality of sampling, the use of ultra-sensitive and specific toxicologic methods and a clinical-biological collaboration allow to recognize this form of delinquency whose consequences are both medical and legal.

Influences of doping mesoporous magnesium silicate on water absorption, drug release, degradability, apatite-mineralization and primary cells responses to calcium sulfate based bone cements

International Nuclear Information System (INIS)

Gu, Zhengrong; Wang, Sicheng; Weng, Weizong; Chen, Xiao; Cao, Liehu; Wei, Jie; Shin, Jung-Woog; Su, Jiacan

2017-01-01

In this study, composite cements containing mesoporous magnesium silicate (m-MS) and calcium sulfate (CS) were fabricated. The results revealed that the setting time of the m-MS/CS composite cements (m-MSC) slightly prolonged with the increase of m-MS content while the compressive strength suffered a little loss. The doping of m-MS improved the water absorption, drug release (vancomycin) and degradability of the m-MSC in Tris-HCl solution (pH = 7.4). In addition, addition of m-MS facilitated the apatite-mineralization of m-MSC in simulated body fluid (SBF), indicating good bioactivity. For cell cultural experiments, the results revealed that the m-MSC promoted the cells adhesion and proliferation, and improved the alkaline phosphatase (ALP) activity of MC3T3-E1 cells, revealing good cytocompatibility. It could be suggested that the m-MSC might be promising cements biomaterials for bone tissue regeneration. - Highlights: • The mesoporous magnesium silicate and calcium sulfate composite was fabricated. • The composite possessed good water absorption and drug release of vancomycin. • The bioactive composite could enhance the in vivo apatite formation in SBF. • The composite promoted cell adhesion, proliferation and osteogenic differentiation.

Influences of doping mesoporous magnesium silicate on water absorption, drug release, degradability, apatite-mineralization and primary cells responses to calcium sulfate based bone cements

Energy Technology Data Exchange (ETDEWEB)

Gu, Zhengrong [Department of Trauma Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); The Department of Orthopaedics, Jing' an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing' An Branch), 200040 (China); Wang, Sicheng [Department of Trauma Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Department of Orthopaedics, Zhongye Hospital, Shanghai 200941 (China); Weng, Weizong; Chen, Xiao; Cao, Liehu [Department of Trauma Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Wei, Jie [Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237 (China); Shin, Jung-Woog [Department of Biomedical Engineering, Inje University, Gimhae, 621749 (Korea, Republic of); Su, Jiacan, E-mail: jiacansu@sina.com [Department of Trauma Orthopaedics, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China)

2017-06-01

In this study, composite cements containing mesoporous magnesium silicate (m-MS) and calcium sulfate (CS) were fabricated. The results revealed that the setting time of the m-MS/CS composite cements (m-MSC) slightly prolonged with the increase of m-MS content while the compressive strength suffered a little loss. The doping of m-MS improved the water absorption, drug release (vancomycin) and degradability of the m-MSC in Tris-HCl solution (pH = 7.4). In addition, addition of m-MS facilitated the apatite-mineralization of m-MSC in simulated body fluid (SBF), indicating good bioactivity. For cell cultural experiments, the results revealed that the m-MSC promoted the cells adhesion and proliferation, and improved the alkaline phosphatase (ALP) activity of MC3T3-E1 cells, revealing good cytocompatibility. It could be suggested that the m-MSC might be promising cements biomaterials for bone tissue regeneration. - Highlights: • The mesoporous magnesium silicate and calcium sulfate composite was fabricated. • The composite possessed good water absorption and drug release of vancomycin. • The bioactive composite could enhance the in vivo apatite formation in SBF. • The composite promoted cell adhesion, proliferation and osteogenic differentiation.

Automation of cell-based drug absorption assays in 96-well format using permeable support systems.

Science.gov (United States)

Larson, Brad; Banks, Peter; Sherman, Hilary; Rothenberg, Mark

2012-06-01

Cell-based drug absorption assays, such as Caco-2 and MDCK-MDR1, are an essential component of lead compound ADME/Tox testing. The permeability and transport data they provide can determine whether a compound continues in the drug discovery process. Current methods typically incorporate 24-well microplates and are performed manually. Yet the need to generate absorption data earlier in the drug discovery process, on an increasing number of compounds, is driving the use of higher density plates. A simple, more efficient process that incorporates 96-well permeable supports and proper instrumentation in an automated process provides more reproducible data compared to manual methods. Here we demonstrate the ability to perform drug permeability and transport assays using Caco-2 or MDCKII-MDR1 cells. The assay procedure was automated in a 96-well format, including cell seeding, media and buffer exchanges, compound dispense, and sample removal using simple robotic instrumentation. Cell monolayer integrity was confirmed via transepithelial electrical resistance and Lucifer yellow measurements. Proper cell function was validated by analyzing apical-to-basolateral and basolateral-to-apical movement of rhodamine 123, a known P-glycoprotein substrate. Apparent permeability and efflux data demonstrate how the automated procedure provides a less variable method than manual processing, and delivers a more accurate assessment of a compound's absorption characteristics.

Drug-Facilitated Sexual Assault: College Women's Risk Perception and Behavioral Choices

Science.gov (United States)

Crawford, Emily; Wright, Margaret O'Dougherty; Birchmeier, Zachary

2008-01-01

Objective: The authors investigated relationships among prior victimization, risk perceptions, and behavioral choices in responding to drug-facilitated sexual assault in a college party where alcohol is available. Participants and Methods: From fall 2003 to spring 2004, over 400 female undergraduates rated risk perception following an acquaintance…

Piracetam, an AMPAkine drug, facilitates memory consolidation in the day-old chick.

Science.gov (United States)

Samartgis, Jodi R; Schachte, Leslie; Hazi, Agnes; Crowe, Simon F

2012-12-01

Piracetam is an AMPAkine drug that may have a range of different mechanisms at the cellular level, and which has been shown to facilitate memory, amongst its other effects. This series of experiments demonstrated that a 10mg/kg dose of piracetam facilitated memory consolidation in the day-old chick when injected from immediately until 120min after weak training (i.e. using a 20% v/v concentration of methyl anthranilate) with the passive avoidance learning task. Administration of piracetam immediately after training led to memory facilitation which lasted for up to 24h following training. This dose of the AMPAkine was not shown to facilitate memory reconsolidation. These findings support the contention that application of the AMPAkine piracetam facilitates memory using a weak training task, and extend the range of actions previously noted with NMDA-related agents to those which also facilitate the AMPA receptor. Copyright © 2012 Elsevier Inc. All rights reserved.

pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs.

Science.gov (United States)

Wang, Xue-Qing; Zhang, Qiang

2012-10-01

pH-sensitive polymeric nanoparticles are promising for oral drug delivery, especially for peptide/protein drugs and poorly water-soluble medicines. This review describes current status of pH-sensitive polymeric nanoparticles for oral drug delivery and introduces the mechanisms of drug release from them as well as possible reasons for absorption improvement, with emphasis on our contribution to this field. pH-sensitive polymeric nanoparticles are prepared mainly with polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of drug release are the result of carriers' dissolution, swelling or both of them at specific pH. The possible reasons for improvement of oral bioavailability include the following: improve drug stability, enhance mucoadhesion, prolong resident time in GI tract, ameliorate intestinal permeability and increase saturation solubility and dissolution rate for poorly water-soluble drugs. As for the advantages of pH-sensitive nanoparticles over conventional nanoparticles, we conclude that (1) most carriers used are enteric-coating materials and their safety has been approved. (2) The rapid dissolution or swelling of carriers at specific pH results in quick drug release and high drug concentration gradient, which is helpful for absorption. (3) At the specific pH carriers dissolve or swell, and the bioadhesion of carriers to mucosa becomes high because nanoparticles turn from solid to gel, which can facilitate drug absorption. Copyright © 2012 Elsevier B.V. All rights reserved.

Mechanism of enhanced oral absorption of morin by phospholipid complex based self-nanoemulsifying drug delivery system.

Science.gov (United States)

Zhang, Jinjie; Li, Jianbo; Ju, Yuan; Fu, Yao; Gong, Tao; Zhang, Zhirong

2015-02-02

Phospholipid complex (PLC) based self-nanoemulsifying drug delivery system (PLC-SNEDDS) has been developed for efficient delivery of drugs with poor solubility and low permeability. In the present study, a BCS class IV drug and a P-glycoprotein (P-gp) substrate, morin, was selected as the model drug to elucidate the oral absorption mechanism of PLC-SNEDDS. PLC-SNEDDS was superior to PLC in protecting morin from degradation by intestinal enzymes in vitro. In situ perfusion study showed increased intestinal permeability by PLC was duodenum-specific. In contrast, PLC-SNEDDS increased morin permeability in all intestinal segments and induced a change in the main absorption site of morin from colon to ileum. Moreover, ileum conducted the lymphatic transport of PLC-SNEDDS, which was proven by microscopic intestinal visualization of Nile red labeled PLC-SNEDDS and lymph fluids in vivo. Low cytotoxicity and increased Caco-2 cell uptake suggested a safe and efficient delivery of PLC-SNEDDS. The increased membrane fluidity and disrupted actin filaments were closely associated with the increased cell uptake of PLC-SNEDDS. PLC-SNEDDS could be internalized into enterocytes as an intact form in a cholesterol-dependent manner via clathrin-mediated endocytosis and macropinocytosis. The enhanced oral absorption of morin was attributed to the P-gp inhibition by Cremophor RH and the intact internalization of M-PLC-SNEDDS into Caco-2 cells bypassing P-gp recognition. Our findings thus provide new insights into the development of novel nanoemulsions for poorly absorbed drugs.

An analytical solution for percutaneous drug absorption: application and removal of the vehicle.

Science.gov (United States)

Simon, L; Loney, N W

2005-10-01

The methods of Laplace transform were used to solve a mathematical model developed for percutaneous drug absorption. This model includes application and removal of the vehicle from the skin. A system of two linear partial differential equations was solved for the application period. The concentration of the medicinal agent in the skin at the end of the application period was used as the initial condition to determine the distribution of the drug in the skin following instantaneous removal of the vehicle. The influences of the diffusion and partition coefficients, clearance factor and vehicle layer thickness on the amount of drug in the vehicle and the skin were discussed.

A global epidemiological perspective on the toxicology of drug-facilitated sexual assault: A systematic review.

Science.gov (United States)

Anderson, Laura Jane; Flynn, Asher; Pilgrim, Jennifer Lucinda

2017-04-01

A systematic review was undertaken to determine the current global prevalence of drug-facilitated sexual assault (DFSA) reported in adults in order to identify trends in the toxicology findings in DFSA around the world over the past 20 years. Databases PubMed, PsycINFO and Scopus were systematically searched using the terms: "drug-facilitated sexual assault", "chemical submission", "date rape", "rape drugs" and "drink-spiking" to identify relevant studies for inclusion in the review. This study focused on adult victims of suspected DFSA aged 16 years and above in which toxicology results were reported. The majority of studies included were published in the United States, followed by the United Kingdom, with only a single study dedicated to this area in both Australia and Europe. Epidemiology, prevalence rates, and toxicology for DFSA appear broadly commensurate across different continents, although there are some differences in how "drug-facilitated sexual assault" is defined, as well as differences in the sensitivity of toxicological analyses. Nonetheless, alcohol is the most commonly detected substance and co-occurrence with other drugs is common. Aside from alcohol there was no other specific drug category associated with DFSA. Cannabinoids and benzodiazepines were frequently detected, but a lack of contextual information made it difficult to establish the extent that these substances contributed to suspected cases of DFSA. This comprehensive review suggests that alcohol intoxication combined with voluntary drug consumption presents the greatest risk factor for DFSA, despite populist perceptions that covert drink-spiking is a common occurrence. There is a need to develop policies that encourage early responders to suspected DFSA (e.g., law enforcement agencies, medical staff, support agencies, etc), to collect detailed information about the individual's licit and illicit drug consumption history, in order to assist in providing appropriate and more thorough

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

Facilitation of Drug Transport across the Blood–Brain Barrier with Ultrasound and Microbubbles

OpenAIRE

Meairs, Stephen

2015-01-01

Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood–brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This techni...

Hair analysis in toxicological investigation of drug-facilitated crimes in Denmark over a 8-year period.

Science.gov (United States)

Wang, Xin; Johansen, Sys Stybe; Nielsen, Marie Katrine Klose; Linnet, Kristian

2018-04-01

Hair can serve as a specimen for identifying past drug exposure. Segmental hair analysis may differentiate a single exposure from chronic use. Consequently, segmental hair analysis is useful for disclosing a single drug ingestion, as well as for determining repeated exposures in drug-facilitated crimes (DFCs). This paper presents an overview of toxicological investigations that have used hair analysis in DFC cases from 2009 to 2016 in Denmark. Hair concentrations were determined for 24 DFC-related drugs and metabolites, including benzodiazepines and other hypnotics, antihistamines, opioid analgesics, antipsychotics, barbiturates, and illicit drugs from DFC cases. Drug detection in hair in DFC cases following a single or few intakes of chlorprothixene, codeine, diphenhydramine, oxazepam, oxycodone, promethazine, and phenobarbital is reported for the first time in forensic toxicology. A literature review on concentrations in the published DFC-related hair cases and on concentrations in hair of these substances after single and multiple doses is included. These cases demonstrate the value of segmental hair analysis in DFCs and facilitate future interpretations of results. Copyright © 2018 Elsevier B.V. All rights reserved.

Ethanol-drug absorption interaction: potential for a significant effect on the plasma pharmacokinetics of ethanol vulnerable formulations.

Science.gov (United States)

Lennernäs, Hans

2009-01-01

Generally, gastric emptying of a drug to the small intestine is controlled by gastric motor activity and is the main factor affecting the onset of absorption. Accordingly, the emptying rate from the stomach is mainly affected by the digestive state, the properties of the pharmaceutical formulation and the effect of drugs, posture and circadian rhythm. Variability in the gastric emptying of drugs is reflected in variability in the absorption rate and the shape of the plasma pharmacokinetic profile. When ethanol interacts with an oral controlled release product, such that the mechanism controlling drug release is impaired, the delivery of the dissolved dose into the small intestine and the consequent absorption may result in dangerously high plasma concentrations. For example, the maximal plasma concentration of hydromorphone has individually been shown to be increased as much as 16 times through in vivo testing as a result of this specific pharmacokinetic ethanol-drug formulation interaction. Thus, a pharmacokinetic ethanol-drug interaction is a very serious safety concern when substantially the entire dose from a controlled release product is rapidly emptied into the small intestine (dose dumping), having been largely dissolved in a strong alcoholic beverage in the stomach during a sufficient lag-time in gastric emptying. Based on the literature, a two hour time frame for screening the in vitro dissolution profile of a controlled release product in ethanol concentrations of up to 40% is strongly supported and may be considered as the absolute minimum standard. It is also evident that the dilution, absorption and metabolism of ethanol in the stomach are processes with a minor effect on the local ethanol concentration and that ethanol exposure will be highly dependent on the volume and ethanol concentration of the fluid ingested, together with the rate of intake and gastric emptying. When and in which patients a clinically significant dose dumping will happen is

Correlation between octanol/water and liposome/water distribution coefficients and drug absorption of a set of pharmacologically active compounds.

Science.gov (United States)

Esteves, Freddy; Moutinho, Carla; Matos, Carla

2013-06-01

Absorption and consequent therapeutic action are key issues in the development of new drugs by the pharmaceutical industry. In this sense, different models can be used to simulate biological membranes to predict the absorption of a drug. This work compared the octanol/water and the liposome/water models. The parameters used to relate the two models were the distribution coefficients between liposomes and water and octanol and water and the fraction of drug orally absorbed. For this study, 66 drugs were collected from literature sources and divided into four groups according to charge and ionization degree: neutral; positively charged; negatively charged; and partially ionized/zwitterionic. The results show a satisfactory linear correlation between the octanol and liposome systems for the neutral (R²= 0.9324) and partially ionized compounds (R²= 0.9367), contrary to the positive (R²= 0.4684) and negatively charged compounds (R²= 0.1487). In the case of neutral drugs, results were similar in both models because of the high fraction orally absorbed. However, for the charged drugs (positively, negatively, and partially ionized/zwitterionic), the liposomal model has a more-appropriate correlation with absorption than the octanol model. These results show that the neutral compounds only interact with membranes through hydrophobic bonds, whereas charged drugs favor electrostatic interactions established with the liposomes. With this work, we concluded that liposomes may be a more-appropriate biomembrane model than octanol for charged compounds.

The Effect of Digestion and Drug Load on Halofantrine Absorption from Self-nanoemulsifying Drug Delivery System (SNEDDS)

DEFF Research Database (Denmark)

Michaelsen, Maria Hotoft; Wasan, Kishor M.; Sivak, Olena

2016-01-01

A super-saturated self-nanoemulsifying drug delivery system (super-SNEDDS), containing the poorly water-soluble drug halofantrine (Hf) at 150% of equilibrium solubility (Seq), was compared in vitro and in vivo with a conventional SNEDDS (75% of Seq) with respect to bioavailability and digestibility....... Further, the effect of digestion on oral absorption of Hf from SNEDDS and super-SNEDDS was assessed by incorporation of the lipase inhibitor tetrahydrolipstatin (orlistat) into the SNEDDS. The SNEDDS contained soybean oil/Maisine 34-I (1:1), Kolliphor RH40, and ethanol at a ratio of 55:35:10, w/w percent....... For the dynamic in vitro lipolysis, the precipitation of Hf at 60 min was significantly larger for the super-SNEDDS (66.8 ± 16.4%) than for the SNEDDS (18.5 ± 9.2%). The inhibition of the in vitro digestion by orlistat (1% (w/w)) lowered drug precipitation significantly for both the super-SNEDDS (36.8 ± 1...

Radiological absorption characteristics of sedatives, hypnotic drugs and psychopharmaceuticals with respect to drug intoxications in suicides

International Nuclear Information System (INIS)

Melchert, H.

1980-01-01

When in cases of patients with severe intoxication aspiration is suspected clinically, an X-ray image of the thorax is made in order to prevent that atelectases or inflammatory pulmonary infiltrations remain undetected, in addition, an X-ray image of the abdomen should be made in each in which the swallowed preparation has not been identified, because our investigations have proved that any drugs of any kind with an absorption coefficient above 0.23 are radiologically detectable, when the resorption process is not finished yet. In shadow-producing pharmaceuticals these abdominal X-ray images allow not only the examination and supervision of the toxic resorption of an enterally taken preparation, but also the possible identification of the type the drug belongs to. Moreover, information about quantity, resorption, and localisation of the tablets being somewhere in the gastrointestinal tract can be obtained. (orig.) [de

Using servant leadership to facilitate healing after a drug diversion experience.

Science.gov (United States)

Ramer, Lynne Marie

2008-08-01

Although much has been written about substance abuse in nursing, little attention has been paid to the reaction of a nurse's coworkers after he or she has been caught diverting drugs. The remaining staff members may enter into a grieving process, which can have a serious effect on the delivery of patient care and staff satisfaction. Devoting time and energy to addressing the challenges faced by staff members after a drug diversion experience is essential to reestablishing equilibrium in the department. Using the servant leadership model, managers can exemplify the characteristics of commitment, persuasion, awareness, and foresight to facilitate the grieving process and solidify staff cohesion to help ensure quality patient care.

Detection of the antipsychotic drug quetiapine in the blood, urine and hair samples of the victim of a drug-facilitated sexual assault

DEFF Research Database (Denmark)

Johansen, Sys Stybe

2017-01-01

A drug rape facilitated with the sedative antipsychotic drug quetiapine is presented here. A teenage girl and her girlfriend went to the home of an adult couple they had met at a bar. Here, the teenage girl (victim) felt tired after consuming some alcoholic drinks and fell asleep. While she......-three hours after the suspected drug-facilitated sexual assault (DFSA), blood and urine samples were collected and the initial toxicological screening detected quetiapine. Confirmation and quantification by ultra high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) revealed...... a concentration of 0.007mg/kg quetiapine in blood and 0.19mg/l in urine. Six months after the DFSA, a hair sample was collected and segmental hair analysis was performed on four washed segments (0-3cm, 3-5cm, 5-7cm, and 7-9cm). The last segment contained 0.011ng/mg of quetiapine, whereas the other segments were...

In vivo assessment of the impact of efflux transporter on oral drug absorption using portal vein-cannulated rats.

Science.gov (United States)

Matsuda, Yoshiki; Konno, Yoshihiro; Hashimoto, Takashi; Nagai, Mika; Taguchi, Takayuki; Satsukawa, Masahiro; Yamashita, Shinji

2013-08-01

The purpose of this study was to evaluate the impact of intestinal efflux transporters on the in vivo oral absorption process. Three model drugs-fexofenadine (FEX), sulfasalazine (SASP), and topotecan (TPT)-were selected as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and P-gp and BCRP substrates, respectively. The drugs were orally administered to portal vein-cannulated rats after pretreatment with zosuquidar (ZSQ), P-gp inhibitor, and/or Ko143, BCRP inhibitor. Intestinal availability (Fa·Fg) of the drugs was calculated from the difference between portal and systemic plasma concentrations. When rats were orally pretreated with ZSQ, Fa·Fg of FEX increased 4-fold and systemic clearance decreased to 75% of the control. In contrast, intravenous pretreatment with ZSQ did not affect Fa·Fg of FEX, although systemic clearance decreased significantly. These data clearly show that the method presented herein using portal vein-cannulated rats can evaluate the effects of intestinal transporters on Fa·Fg of drugs independently of variable systemic clearance. In addition, it was revealed that 71% of FEX taken up into enterocytes underwent selective efflux via P-gp to the apical surface, while 79% of SASP was effluxed by Bcrp. In the case of TPT, both transporters were involved in its oral absorption. Quantitative analysis indicated a 3.5-fold higher contribution from Bcrp than P-gp. In conclusion, the use of portal vein-cannulated rats enabled the assessment of the impact of efflux transporters on intestinal absorption of model drugs. This experimental system is useful for clarifying the cause of low bioavailability of various drugs.

Absorption-desorption of drugs in porous polymers obtained by plasma

International Nuclear Information System (INIS)

Gonzalez T, M.

2016-01-01

A study about drug absorption and release in plasma polymers is presented in this work, these materials can be used as implants in the human body. In these applications the polymer should be biocompatible and/or biodegradable. Poly pyrroles and poly allylamine s synthesized by plasma have amine groups in their structure which makes them biocompatible with potential as drug carriers. In this function, the polymers were lyophilized to induce pores where the drug can be hosted. Drug-polymer mixtures with 1:10 ratio were prepared. The mixture morphology was studied by Scanning Electron Microscopy while their chemical structure was studied by Infrared Spectroscopy and X-ray Photoelectron Spectroscopy. Two models were studied to assess drug release, dynamic and static, in two solutions: water and Krebs Ringer (Kr) using the UV characteristic absorbance of each drug. In the static model release, 5 mg of the mixture were placed in 10 ml of solution. In the dynamic model, the release was performed with 5 mg of the mixture in 10 ml of solution, 1.5 ml of release medium was removed for UV analysis and replaced with an equal volume of fresh medium. The results indicate that the morphology of the polymers was modified with the lyophilization, in Poly pyrrole pores were induced with diameter in the range of 0.7 to 19 μm, while in Polyallyl amine the surface changed from smooth to rough. Drugs were absorbed in Poly pyrrole by filling the pores first and then coating the polymer with a drug layer. In Poly allylamine the drugs adhered to the polymer surface. Analyzing the atomic orbitals of the mixtures, it was found that the drugs interacted with the polymer. The most affected orbital was S2p, whose separation between 1/2 and 3/2 sub orbitals increased from 0.9 eV in Dapsone and Heparin to 4 eV in the mixtures, where the oxidation state changed from valence 6 to 6 and 2 in the mixtures. This suggests physicochemical interaction between drug and polymer. The drugs were released

[A prospective study of drug-facilitated sexual assault in Barcelona].

Science.gov (United States)

Xifró-Collsamata, Alexandre; Pujol-Robinat, Amadeo; Barbería-Marcalain, Eneko; Arroyo-Fernández, Amparo; Bertomeu-Ruiz, Antonia; Montero-Núñez, Francisco; Medallo-Muñiz, Jordi

2015-05-08

To determine the frequency and characteristics of suspected drug-facilitated sexual assault (DFSA) among the victims of sexual assault in Barcelona. Prospective study of every adult consulting an emergency service because of alleged sexual assault and receiving forensic assessment in the city of Barcelona in 2011. A total of 35 of 114 cases (30.7%) met suspected DFSA criteria. Compared with the other victims, suspected DFSA cases were more likely to experience amnesia, to have been assaulted by night, after a social situation and by a recently acquainted man, to have used alcohol before the assault and to be foreigners. In this group ethanol was detected in blood or urine in 48.4% of analyzed cases; their mean back calculated blood alcohol concentration was 2.29g/l (SD 0.685). Also, at least one central nervous system drug other than ethanol was detected in 60,6%, mainly stimulant drugs of abuse. Suspected DFSA is frequent among victims of alleged sexual assault in Barcelona nowadays. The depressor substance most commonly encountered is alcohol, which contributes to victims' vulnerability. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Aminoclay–lipid hybrid composite as a novel drug carrier of fenofibrate for the enhancement of drug release and oral absorption

Directory of Open Access Journals (Sweden)

Yang L

2016-03-01

Full Text Available Liang Yang, Yating Shao, Hyo-Kyung Han BK Plus Project Team, College of Pharmacy, Dongguk University, Goyang, South Korea Abstract: This study aimed to prepare the aminoclay–lipid hybrid composite to enhance the drug release and improve the oral bioavailability of poorly water-soluble fenofibrate. Antisolvent precipitation coupled with an immediate freeze-drying method was adopted to incorporate fenofibrate into aminoclay–lipid hybrid composite (ALC. The optimal composition of the ALC formulation was determined as the ratios of aminoclay to krill oil of 3:1 (w/w, krill oil to fenofibrate of 2:1 (w/w, and antisolvent to solvent of 6:4 (v/v. The morphological characteristics of ALC formulation were determined using scanning electron microscopy, differential scanning calorimetry, and X-ray powder diffraction, which indicated microcrystalline state of fenofibrate in ALC formulation. The ALC formulation achieved almost complete dissolution within 30 minutes, whereas the untreated powder and physical mixture exhibited less than 15% drug release. Furthermore, ALC formulation effectively increased the peak plasma concentration (Cmax and area under the curve (AUC of fenofibric acid (an active metabolite in rats by approximately 13- and seven-fold, respectively. Furthermore, ALC formulation exhibited much lower moisture sorption behavior than the lyophilized formulation using sucrose as a cryoprotectant. Taken together, the present findings suggest that ALC formulation is promising for improving the oral absorption of poorly soluble fenofibrate. Keywords: aminoclay, omega-3 phospholipids, fenofibrate, drug release, oral absorption 

Polymeric nanoparticles for increased oral bioavailability and rapid absorption using celecoxib as a model of a low-solubility, high-permeability drug.

Science.gov (United States)

Morgen, Michael; Bloom, Corey; Beyerinck, Ron; Bello, Akintunde; Song, Wei; Wilkinson, Karen; Steenwyk, Rick; Shamblin, Sheri

2012-02-01

To demonstrate drug/polymer nanoparticles can increase the rate and extent of oral absorption of a low-solubility, high-permeability drug. Amorphous drug/polymer nanoparticles containing celecoxib were prepared using ethyl cellulose and either sodium caseinate or bile salt. Nanoparticles were characterized using dynamic light scattering, transmission and scanning electron microscopy, and differential scanning calorimetry. Drug release and resuspension studies were performed using high-performance liquid chromatography. Pharmacokinetic studies were performed in dogs and humans. A physical model is presented describing the nanoparticle state of matter and release performance. Nanoparticles dosed orally in aqueous suspensions provided higher systemic exposure and faster attainment of peak plasma concentrations than commercial capsules, with median time to maximum drug concentration (Tmax) of 0.75 h in humans for nanoparticles vs. 3 h for commercial capsules. Nanoparticles released celecoxib rapidly and provided higher dissolved-drug concentrations than micronized crystalline drug. Nanoparticle suspensions are stable for several days and can be spray-dried to form dry powders that resuspend in water. Drug/polymer nanoparticles are well suited for providing rapid oral absorption and increased bioavailability of BCS Class II drugs.

Folate absorption

International Nuclear Information System (INIS)

Baker, S.J.

1976-01-01

Folate is the generic term given to numerous compounds of pteroic acid with glutamic acid. Knowledge of absorption is limited because of the complexities introduced by the variety of compounds and because of the inadequacy of investigational methods. Two assay methods are in use, namely microbiological and radioactive. Techniques used to study absorption include measurement of urinary excretion, serum concentration, faecal excretion, intestinal perfusion, and haematological response. It is probably necessary to test absorption of both pteroylmonoglutamic acid and one or more polyglutamates, and such tests would be facilitated by availability of synthesized compounds labelled with radioactive tracers at specifically selected sites. (author)

Drug Delivery and Transport into the Central Circulation: An Example of Zero-Order In vivo Absorption of Rotigotine from a Transdermal Patch Formulation.

Science.gov (United States)

Cawello, Willi; Braun, Marina; Andreas, Jens-Otto

2018-01-13

Pharmacokinetic studies using deconvolution methods and non-compartmental analysis to model clinical absorption of drugs are not well represented in the literature. The purpose of this research was (1) to define the system of equations for description of rotigotine (a dopamine receptor agonist delivered via a transdermal patch) absorption based on a pharmacokinetic model and (2) to describe the kinetics of rotigotine disposition after single and multiple dosing. The kinetics of drug disposition was evaluated based on rotigotine plasma concentration data from three phase 1 trials. In two trials, rotigotine was administered via a single patch over 24 h in healthy subjects. In a third trial, rotigotine was administered once daily over 1 month in subjects with early-stage Parkinson's disease (PD). A pharmacokinetic model utilizing deconvolution methods was developed to describe the relationship between drug release from the patch and plasma concentrations. Plasma-concentration over time profiles were modeled based on a one-compartment model with a time lag, a zero-order input (describing a constant absorption via skin into central circulation) and first-order elimination. Corresponding mathematical models for single- and multiple-dose administration were developed. After single-dose administration of rotigotine patches (using 2, 4 or 8 mg/day) in healthy subjects, a constant in vivo absorption was present after a minor time lag (2-3 h). On days 27 and 30 of the multiple-dose study in patients with PD, absorption was constant during patch-on periods and resembled zero-order kinetics. Deconvolution based on rotigotine pharmacokinetic profiles after single- or multiple-dose administration of the once-daily patch demonstrated that in vivo absorption of rotigotine showed constant input through the skin into the central circulation (resembling zero-order kinetics). Continuous absorption through the skin is a basis for stable drug exposure.

Improved oral absorption of tacrolimus by a solid dispersion with hypromellose and sodium lauryl sulfate.

Science.gov (United States)

Jung, Hyuck Jun; Ahn, Hye In; Park, Ji Yeon; Ho, Myoung Jin; Lee, Dae Ro; Cho, Ha Ra; Park, Jun Seo; Choi, Yong Seok; Kang, Myung Joo

2016-02-01

A novel surfactant-incorporated hydroxypropyl methylcellulose (HPMC) solid dispersion (SD) system was constructed in order to facilitate the release rate and oral absorption of tacrolimus (FK506), a poorly water-soluble immunosuppressant. Several emulsifiers including sodium lauryl sulfate (SLS), as drug release promotors, were employed with HPMC to fabricate SD using the solvent wetting method. The solid state characteristics using differential scanning calorimetry and X-ray powder diffraction, revealed that FK506 was molecularly distributed within all dispersions in amorphous form. The dissolution rates of FK506 in SLS-incorporated SDs were much higher than those in SDs prepared with HPMC alone, and even with stearoyl polyoxyl-32 glycerides or tocopheryl polyethylene glycol 1000 succinate. In particular, the greatest dissolution enhancement was obtained from the SD consisting of the drug, HPMC, and SLS in a weight ratio of 1:1:3, providing a 50-fold higher drug concentration within 15 min, compared with HPMC SD. In vivo absorption study in rats demonstrates that the optimized formula remarkably increased the oral absorption of FK506, providing about 4.0-fold greater bioavailability (p<0.05) compared with the marketed product (Prograf®, Astellas Pharma). These data suggest that a novel SLS/HPMC SD may be an advantageous dosage form of FK506, boosting the dissolution and absorption in gastrointestinal tract. Copyright © 2015 Elsevier B.V. All rights reserved.

Hair analysis in toxicological investigation of drug-facilitated crimes in Denmark over a 8-year period

DEFF Research Database (Denmark)

Wang, Xin; Johansen, Sys Stybe; Nielsen, Marie Katrine Klose

2018-01-01

analgesics, antipsychotics, barbiturates, and illicit drugs from DFC cases. Drug detection in hair in DFC cases following a single or few intakes of chlorprothixene, codeine, diphenhydramine, oxazepam, oxycodone, promethazine, and phenobarbital is reported for the first time in forensic toxicology......Hair can serve as a specimen for identifying past drug exposure. Segmental hair analysis may differentiate a single exposure from chronic use. Consequently, segmental hair analysis is useful for disclosing a single drug ingestion, as well as for determining repeated exposures in drug......-facilitated crimes (DFCs). This paper presents an overview of toxicological investigations that have used hair analysis in DFC cases from 2009 to 2016 in Denmark. Hair concentrations were determined for 24 DFC-related drugs and metabolites, including benzodiazepines and other hypnotics, antihistamines, opioid...

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

Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application

Science.gov (United States)

Dancik, Yuri; Anissimov, Yuri G; Jepps, Owen G; Roberts, Michael S

2012-01-01

AIMS To relate the varying dermal, subcutaneous and muscle microdialysate concentrations found in man after topical application to the nature of the drug applied and to the underlying physiology. METHODS We developed a physiologically based pharmacokinetic model in which transport to deeper tissues was determined by tissue diffusion, blood, lymphatic and intersitial flow transport and drug properties. The model was applied to interpret published human microdialysis data, estimated in vitro dermal diffusion and protein binding affinity of drugs that have been previously applied topically in vivo and measured in deep cutaneous tissues over time. RESULTS Deeper tissue microdialysis concentrations for various drugs in vivo vary widely. Here, we show that carriage by the blood to the deeper tissues below topical application sites facilitates the transport of highly plasma protein bound drugs that penetrate the skin, leading to rapid and significant concentrations in those tissues. Hence, the fractional concentration for the highly plasma protein bound diclofenac in deeper tissues is 0.79 times that in a probe 4.5 mm below a superficial probe whereas the corresponding fractional concentration for the poorly protein bound nicotine is 0.02. Their corresponding estimated in vivo lag times for appearance of the drugs in the deeper probes were 1.1 min for diclofenac and 30 min for nicotine. CONCLUSIONS Poorly plasma protein bound drugs are mainly transported to deeper tissues after topical application by tissue diffusion whereas the transport of highly plasma protein bound drugs is additionally facilitated by convective blood, lymphatic and interstitial transport to deep tissues. PMID:21999217

Curcumin-carboxymethyl chitosan (CNC) conjugate and CNC/LHR mixed polymeric micelles as new approaches to improve the oral absorption of P-gp substrate drugs.

Science.gov (United States)

Ni, Jiang; Tian, Fengchun; Dahmani, Fatima Zohra; Yang, Hui; Yue, Deren; He, Shuwang; Zhou, Jianping; Yao, Jing

2016-11-01

The low oral bioavailability of numerous drugs has been mostly attributed to the significant effect of P-gp-mediated efflux on intestinal drug transport. Herein, we developed mixed polymeric micelles (MPMs) comprised of curcumin-carboxymethyl chitosan (CNC) conjugate, as a potential inhibitor of P-gp-mediated efflux and gastrointestinal absorption enhancer, and low-molecular-weight heparin-all-trans-retinoid acid (LHR) conjugate, as loading material, with the aim to improve the oral absorption of P-gp substrate drugs. CNC conjugate was synthesized by chemical bonding of curcumin (Cur) and carboxymethyl chitosan (CMCS) taking advantage of the inhibition of intestinal P-gp-mediated secretion by Cur and the intestinal absorption enhancement by CMCS. The chemical structure of CNC conjugate was characterized by 1 H NMR with a degree of substitution of Cur of 4.52-10.20%. More importantly, CNC conjugate markedly improved the stability of Cur in physiological pH. Cyclosporine A-loaded CNC/LHR MPMs (CsA-CNC/LHR MPMs) were prepared by dialysis method, with high drug loading 25.45% and nanoscaled particle size (∼200 nm). In situ single-pass perfusion studies in rats showed that both CsA + CNC mixture and CsA-CNC/LHR MPMs achieved significantly higher K a and P eff than CsA suspension in the duodenum and jejunum segments (p CNC mixture and CsA-CNC/LHR MPMs significantly increased the oral bioavailability of CsA as compared to CsA suspension. These results suggest that CNC conjugate might be considered as a promising gastrointestinal absorption enhancer, while CNC/LHR MPMs had the potential to improve the oral absorption of P-gp substrate drugs.

Absorption and Metabolism of Xanthophylls

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Eiichi Kotake-Nara

2011-06-01

Full Text Available Dietary carotenoids, especially xanthophylls, have attracted significant attention because of their characteristic biological activities, including anti-allergic, anti-cancer, and anti-obese actions. Although no less than forty carotenoids are ingested under usual dietary habits, only six carotenoids and their metabolites have been found in human tissues, suggesting selectivity in the intestinal absorption of carotenoids. Recently, facilitated diffusion in addition to simple diffusion has been reported to mediate the intestinal absorption of carotenoids in mammals. The selective absorption of carotenoids may be caused by uptake to the intestinal epithelia by the facilitated diffusion and an unknown excretion to intestinal lumen. It is well known that β-carotene can be metabolized to vitamin A after intestinal absorption of carotenoids, but little is known about the metabolic transformation of non provitamin A xanthophylls. The enzymatic oxidation of the secondary hydroxyl group leading to keto-carotenoids would occur as a common pathway of xanthophyll metabolism in mammals. This paper reviews the absorption and metabolism of xanthophylls by introducing recent advances in this field.

Absorption and metabolism of xanthophylls.

Science.gov (United States)

Kotake-Nara, Eiichi; Nagao, Akihiko

2011-01-01

Dietary carotenoids, especially xanthophylls, have attracted significant attention because of their characteristic biological activities, including anti-allergic, anti-cancer, and anti-obese actions. Although no less than forty carotenoids are ingested under usual dietary habits, only six carotenoids and their metabolites have been found in human tissues, suggesting selectivity in the intestinal absorption of carotenoids. Recently, facilitated diffusion in addition to simple diffusion has been reported to mediate the intestinal absorption of carotenoids in mammals. The selective absorption of carotenoids may be caused by uptake to the intestinal epithelia by the facilitated diffusion and an unknown excretion to intestinal lumen. It is well known that β-carotene can be metabolized to vitamin A after intestinal absorption of carotenoids, but little is known about the metabolic transformation of non provitamin A xanthophylls. The enzymatic oxidation of the secondary hydroxyl group leading to keto-carotenoids would occur as a common pathway of xanthophyll metabolism in mammals. This paper reviews the absorption and metabolism of xanthophylls by introducing recent advances in this field.

Improved intestinal absorption of a poorly water-soluble oral drug using mannitol microparticles containing a nanosolid drug dispersion.

Science.gov (United States)

Nishino, Yukiko; Kubota, Aya; Kanazawa, Takanori; Takashima, Yuuki; Ozeki, Tetsuya; Okada, Hiroaki

2012-11-01

A nozzle for a spray dryer that can prepare microparticles of water-soluble carriers containing various nanoparticles in a single step was previously developed in our laboratory. To enhance the solubility and intestinal absorption of poorly water-soluble drugs, we used probucol (PBL) as a poorly water-soluble drug, mannitol (MAN) as a water-soluble carrier for the microparticles, and EUDRAGIT (EUD) as a polymer vehicle for the solid dispersion. PBL-EUD-acetone-methanol and aqueous MAN solutions were simultaneously supplied through different liquid passages of the spray nozzle and dried together. PBL-EUD solid dispersion was nanoprecipitated in the MAN solution using an antisolvent mechanism and rapidly dried by surrounding it with MAN. PBL in the dispersion vehicle was amorphous and had higher physical stability according to powder X-ray diffraction and differential scanning calorimetry analysis. The bioavailability of PBL in PBL-EUD S-100-MAN microparticles after oral administration in rats was markedly higher (14- and 6.2-fold, respectively) than that of the original PBL powder and PBL-MAN microparticles. These results demonstrate that the composite microparticles containing a nanosized solid dispersion of a poorly water-soluble drug prepared using the spray nozzle developed by us should be useful to increase the solubility and bioavailability of drugs after oral administration. Copyright © 2012 Wiley Periodicals, Inc.

Facilitation of Drug Transport across the Blood-Brain Barrier with Ultrasound and Microbubbles.

Science.gov (United States)

Meairs, Stephen

2015-08-31

Medical treatment options for central nervous system (CNS) diseases are limited due to the inability of most therapeutic agents to penetrate the blood-brain barrier (BBB). Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This technique offers a unique non-invasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. If this method could be applied for a range of different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This article reviews both the merits and potential risks of this new approach. It assesses methods used to verify disruption of the BBB with MRI and examines the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Possible interactions of this novel delivery method with brain disease, as well as safety aspects of BBB disruption with ultrasound and microbubbles are addressed. Initial translational research for treatment of brain tumors and Alzheimer's disease is presented.

Expression Profile of Drug and Nutrient Absorption Related Genes in Madin-Darby Canine Kidney (MDCK Cells Grown under Differentiation Conditions

Directory of Open Access Journals (Sweden)

Balvinder S. Vig

2012-06-01

Full Text Available The expression levels of genes involved in drug and nutrient absorption were evaluated in the Madin-Darby Canine Kidney (MDCK in vitro drug absorption model. MDCK cells were grown on plastic surfaces (for 3 days or on Transwell^® membranes (for 3, 5, 7, and 9 days. The expression profile of genes including ABC transporters, SLC transporters, and cytochrome P450 (CYP enzymes was determined using the Affymetrix^® Canine GeneChip^®. Expression of genes whose probe sets passed a stringent confirmation process was examined. Expression of a few transporter (MDR1, PEPT1 and PEPT2 genes in MDCK cells was confirmed by RT-PCR. The overall gene expression profile was strongly influenced by the type of support the cells were grown on. After 3 days of growth, expression of 28% of the genes was statistically different (1.5-fold cutoff, p < 0.05 between the cells grown on plastic and Transwell^® membranes. When cells were differentiated on Transwell^® membranes, large changes in gene expression profile were observed during the early stages, which then stabilized after 5–7 days. Only a small number of genes encoding drug absorption related SLC, ABC, and CYP were detected in MDCK cells, and most of them exhibited low hybridization signals. Results from this study provide valuable reference information on endogenous gene expression in MDCK cells that could assist in design of drug-transporter and/or drug-enzyme interaction studies, and help interpret the contributions of various transporters and metabolic enzymes in studies with MDCK cells.

Investigation of the effect of solubility increase at the main absorption site on bioavailability of BCS class II drug (risperidone) using liquisolid technique.

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Khames, Ahmed

2017-11-01

BCS class II drugs usually suffer inadequate bioavailability as dissolution step is the absorption rate limiting step. In this work, the effect of solubility increase at the main absorption site for these drugs was investigated using risperidone as a drug model. Liquisolid technique was applied to prepare risperidone per-oral tablets of high dissolution rate at intestinal pH (6.8) using versatile nonionic surfactants of high solubilizing ability [Transcutol HP, Labrasol and Labrasol/Labrafil (1:1) mixture] as liquid vehicles at different drug concentrations (10-30%) and fixed (R). The prepared liquisolid tablets were fully evaluated and the dissolution rate at pH 6.8 was investigated. The formulae that showed significantly different release rate were selected and subjected to mathematical modeling using DE 25 , MDT and similarity factor (f2). Depending on mathematical modeling results, formula of higher dissolution rate was subjected to solid state characterization using differential scanning calorimetric (DSC), infrared spectroscopy (IR) and X-ray diffraction (XRD). Finally, the drug bioavailability was studied in comparison to conventional tablets in rabbits. Results showed that liquisolid tablet prepared using Labrasol/Labrafil (1:1) mixture as liquid vehicle containing 10% risperidone is a compatible formula with law drug crystallinity and higher dissolution rate (100% in 25 min). The drug bioavailability was significantly increased in comparison to the conventional tablets (1441.711 μg h/mL and 137.518 μg/mL in comparison to 321.011 μg h/mL and 38.673 μg/mL for AUC and Cp max , respectively). This led to the conclusion that liquisolid technique was efficiently improved drug solubility and solubility increase of BCS class II drugs at their main absorption site significantly increases their bioavailability.

A review of drug-facilitated sexual assault evidence: an Irish perspective.

LENUS (Irish Health Repository)

McBrierty, Dermot

2013-05-01

Drug-facilitated sexual assault (DFSA) is prevalent in Western society. There is a significant degree of confusion regarding the definition and prevalence of DFSA. It is a subject with medical, scientific and legal aspects. These facets are explored in this review through a detailed examination of published data. The legal issues are defined in the context of the Irish judicial system. Several key case-law studies are presented to aid in understanding unresolved difficulties that persist in this complex field of forensics. The aim of this paper is to aid individuals from disparate disciplines to increase their evidence base in the complex and evolving issue of DFSA.

In silico prediction of drug dissolution and absorption with variation in intestinal pH for BCS class II weak acid drugs: ibuprofen and ketoprofen.

Science.gov (United States)

Tsume, Yasuhiro; Langguth, Peter; Garcia-Arieta, Alfredo; Amidon, Gordon L

2012-10-01

The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS class III and BCS class II have been proposed, in particular, BCS class II weak acids. However, a discrepancy between the in vivo BE results and in vitro dissolution results for BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH of 6.0. Further the experimental dissolution of ibuprofen tablets in a low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol l (-1) /pH) was dramatically reduced compared with the dissolution in SIF (the average buffer capacity 12.6 mmol l (-1) /pH). Thus these predictions for the oral absorption of BCS class II acids indicate that the absorption patterns depend largely on the intestinal pH and buffer strength and must be considered carefully for a bioequivalence test. Simulation software may be a very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. Copyright © 2012 John Wiley & Sons, Ltd.

In Silico Prediction of Drug Dissolution and Absorption with variation in Intestinal pH for BCS Class II Weak Acid Drugs: Ibuprofen and Ketoprofen§

Science.gov (United States)

Tsume, Yasuhiro; Langguth, Peter; Garcia-Arieta, Alfredo; Amidon, Gordon L.

2012-01-01

The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS Class III and BCS class II have been proposed, particularly, BCS class II weak acids. However, a discrepancy between the in vivo- BE results and in vitro- dissolution results for a BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH=6.0. Further the experimental dissolution of ibuprofen tablets in the low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol L-1/pH) was dramatically reduced compared to the dissolution in SIF (the average buffer capacity 12.6 mmol L -1/pH). Thus these predictions for oral absorption of BCS class II acids indicate that the absorption patterns largely depend on the intestinal pH and buffer strength and must be carefully considered for a bioequivalence test. Simulation software may be very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. PMID:22815122

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.

A Comparative Study of Molecular Structure, pKa, Lipophilicity, Solubility, Absorption and Polar Surface Area of Some Antiplatelet Drugs

Directory of Open Access Journals (Sweden)

Milan Remko

2016-03-01

Full Text Available Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor and several thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p level of density functional theory. Computed dissociation constants show that the active metabolites of prodrugs (ticlopidine, clopidogrel and prasugrel and drugs elinogrel and cangrelor are completely ionized at pH 7.4. Both ticagrelor and its active metabolite are present at pH = 7.4 in neutral undissociated form. The thienopyridine prodrugs ticlopidine, clopidogrel and prasugrel are lipophilic and insoluble in water. Their lipophilicity is very high (about 2.5–3.5 logP values. The polar surface area, with regard to the structurally-heterogeneous character of these antiplatelet drugs, is from very large interval of values of 3–255 Å2. Thienopyridine prodrugs, like ticlopidine, clopidogrel and prasugrel, with the lowest polar surface area (PSA values, exhibit the largest absorption. A high value of polar surface area (PSA of cangrelor (255 Å2 results in substantial worsening of the absorption in comparison with thienopyridine drugs.

Facilitation of Drug Transport across the Blood–Brain Barrier with Ultrasound and Microbubbles

Directory of Open Access Journals (Sweden)

Stephen Meairs

2015-08-01

Full Text Available Medical treatment options for central nervous system (CNS diseases are limited due to the inability of most therapeutic agents to penetrate the blood–brain barrier (BBB. Although a variety of approaches have been investigated to open the BBB for facilitation of drug delivery, none has achieved clinical applicability. Mounting evidence suggests that ultrasound in combination with microbubbles might be useful for delivery of drugs to the brain through transient opening of the BBB. This technique offers a unique non-invasive avenue to deliver a wide range of drugs to the brain and promises to provide treatments for CNS disorders with the advantage of being able to target specific brain regions without unnecessary drug exposure. If this method could be applied for a range of different drugs, new CNS therapeutic strategies could emerge at an accelerated pace that is not currently possible in the field of drug discovery and development. This article reviews both the merits and potential risks of this new approach. It assesses methods used to verify disruption of the BBB with MRI and examines the results of studies aimed at elucidating the mechanisms of opening the BBB with ultrasound and microbubbles. Possible interactions of this novel delivery method with brain disease, as well as safety aspects of BBB disruption with ultrasound and microbubbles are addressed. Initial translational research for treatment of brain tumors and Alzheimer’s disease is presented.

Pharmacokinetic-Pharmacodynamic (PKPD) Analysis with Drug Discrimination.

Science.gov (United States)

Negus, S Stevens; Banks, Matthew L

2016-08-30

Discriminative stimulus and other drug effects are determined by the concentration of drug at its target receptor and by the pharmacodynamic consequences of drug-receptor interaction. For in vivo procedures such as drug discrimination, drug concentration at receptors in a given anatomical location (e.g., the brain) is determined both by the dose of drug administered and by pharmacokinetic processes of absorption, distribution, metabolism, and excretion that deliver drug to and from that anatomical location. Drug discrimination data are often analyzed by strategies of dose-effect analysis to determine parameters such as potency and efficacy. Pharmacokinetic-Pharmacodynamic (PKPD) analysis is an alternative to conventional dose-effect analysis, and it relates drug effects to a measure of drug concentration in a body compartment (e.g., venous blood) rather than to drug dose. PKPD analysis can yield insights on pharmacokinetic and pharmacodynamic determinants of drug action. PKPD analysis can also facilitate translational research by identifying species differences in pharmacokinetics and providing a basis for integrating these differences into interpretation of drug effects. Examples are discussed here to illustrate the application of PKPD analysis to the evaluation of drug effects in rhesus monkeys trained to discriminate cocaine from saline.

Facilitating a More Efficient Commercial Review Process for Pediatric Drugs and Biologics

Directory of Open Access Journals (Sweden)

Ryan D. Rykhus

2017-12-01

Full Text Available Over the past two decades, the biopharmaceutical industry has seen unprecedented expansion and innovation in concert with significant technological advancements. While the industry has experienced marked growth, the regulatory system in the United States still operates at a capacity much lower than the influx of new drug and biologic candidates. As a result, it has become standard for months or even years of waiting for commercial approval by the U.S. Food and Drug Administration. These regulatory delays have generated a system that stifles growth and innovation due to the exorbitant costs associated with awaiting approval from the nation’s sole regulatory agency. The recent re-emergence of diseases that impact pediatric demographics represents one particularly acute reason for developing a regulatory system that facilitates a more efficient commercial review process. Herein, we present a range of initiatives that could represent early steps toward alleviating the delays in approving life-saving therapeutics.

Pharmacy Student Facilitation of Reporting of Adverse Drug Reactions in a Hospital.

Science.gov (United States)

Wentzell, Jason; Nguyen, Tiffany; Bui, Stephanie; MacDonald, Erika

2017-01-01

Health Canada relies on health professionals to voluntarily report adverse reactions to the Canada Vigilance Program. Current rates of reporting adverse drug reactions (ADRs) are inadequate to detect important safety issues. To assess the impact of pharmacy student facilitation of ADR reporting by pharmacists at a tertiary care teaching hospital in Canada. The intervention of interest, implemented at one campus of the hospital, was facilitation of ADR reporting by pharmacy students. The students received training on how to submit ADR reports and presented information sessions on the topic to hospital pharmacists; the pharmacists were then encouraged to report ADRs to a designated student for formal reporting. Frequency of reporting by pharmacists at the intervention campus was compared with reporting at a control campus of the same hospital. Data were collected prospectively over a 6-month pilot period, starting in April 2015. During the pilot period, 27 ADR reports were submitted at the intervention campus, and 3 reports at the control campus. All student participants strongly agreed that they would recommend that responsibility for submitting ADR reports to the Canada Vigilance Program remain with pharmacy students during future rotations. Availability of a pharmacy student to facilitate reporting of ADRs may increase the frequency of ADR reporting and could alleviate pharmacist workload; this activity is also a potentially valuable learning experience for students.

In Vitro Characterization of the Biomimetic Properties of Poly(dimethylsiloxane) To Simulate Oral Drug Absorption.

Science.gov (United States)

Sinko, Patrick D; Gidley, David; Vallery, Richard; Lamoureux, Aaron; Amidon, Gordon L; Amidon, Gregory E

2017-12-04

The potential use of poly(dimethylsiloxane) (PDMS) as an in vitro biomimetic analogue of the passive drug absorption process in the human gastrointestinal tract (GI) is assessed. PDMS is biomimetic because of similarities in small molecule transport, such as mechanism, ionization selectivity, lipophilicity. Nine molecular probes are used to evaluate the transport pathways and properties used to predict human oral absorption rates. The transport pathways through PDMS (bulk/pore) are analogous to transcellular (TCDT) and paracellular (PCDT) drug transport pathways. PDMS PCDT is assessed using positronium annihilation lifetime spectroscopy (PALS) and partition experiments; TCDT using diffusion and partition experiments. PALS determined that PDMS pores were uniform (D ∼ 0.85 nm), isolated, and void volume was unaffected by drug accumulation after equilibrium partitioning. Therefore, there is no PCDT or convective flow through PDMS. A strong linear correlation exists between predicted octanol-water partition coefficients and PDMS partition coefficients (LogK PDMS = 0.736 × LogP O-W - 0.971, R 2 = 0.981). The pH-partition hypothesis is confirmed in PDMS using ibuprofen over pH 2-12. Diffusivity through PDMS is a function of lipophilicity and polar surface area K × D PDMS = 4.46 × 10 -8 × e 2.91×LogK PDMS (R 2 = 0.963) and [Formula: see text] (R 2 = 0.973). Varying the mass% of curing agent changed the lipophilicity and diffusivity (p < 0.02), but not practically (K × D = 2.23 × 10 -5 cm 2 s -1 vs 2.60 × 10 -5 cm 2 s -1 ), and does affect elastic modulus (3.2% = 0.3 MPa to 25% = 3.2 MPa).

Slow-light enhancement of Beer-Lambert-Bouguer absorption

DEFF Research Database (Denmark)

Mortensen, Asger; Xiao, Sanshui

2007-01-01

We theoretically show how slow light in an optofluidic environment facilitates enhanced light-matter interactions, by orders of magnitude. The proposed concept provides strong opportunities for improving existing miniaturized chemical absorbance cells for Beer-Lambert-Bouguer absorption measureme......We theoretically show how slow light in an optofluidic environment facilitates enhanced light-matter interactions, by orders of magnitude. The proposed concept provides strong opportunities for improving existing miniaturized chemical absorbance cells for Beer-Lambert-Bouguer absorption...

The impact of supersaturation level for oral absorption of BCS class IIb drugs, dipyridamole and ketoconazole, using in vivo predictive dissolution system: Gastrointestinal Simulator (GIS).

Science.gov (United States)

Tsume, Yasuhiro; Matsui, Kazuki; Searls, Amanda L; Takeuchi, Susumu; Amidon, Gregory E; Sun, Duxin; Amidon, Gordon L

2017-05-01

The development of formulations and the assessment of oral drug absorption for Biopharmaceutical Classification System (BCS) class IIb drugs is often a difficult issue due to the potential for supersaturation and precipitation in the gastrointestinal (GI) tract. The physiological environment in the GI tract largely influences in vivo drug dissolution rates of those drugs. Thus, those physiological factors should be incorporated into the in vitro system to better assess in vivo performance of BCS class IIb drugs. In order to predict oral bioperformance, an in vitro dissolution system with multiple compartments incorporating physiologically relevant factors would be expected to more accurately predict in vivo phenomena than a one-compartment dissolution system like USP Apparatus 2 because, for example, the pH change occurring in the human GI tract can be better replicated in a multi-compartmental platform. The Gastrointestinal Simulator (GIS) consists of three compartments, the gastric, duodenal and jejunal chambers, and is a practical in vitro dissolution apparatus to predict in vivo dissolution for oral dosage forms. This system can demonstrate supersaturation and precipitation and, therefore, has the potential to predict in vivo bioperformance of oral dosage forms where this phenomenon may occur. In this report, in vitro studies were performed with dipyridamole and ketoconazole to evaluate the precipitation rates and the relationship between the supersaturation levels and oral absorption of BCS class II weak base drugs. To evaluate the impact of observed supersaturation levels on oral absorption, a study utilizing the GIS in combination with mouse intestinal infusion was conducted. Supersaturation levels observed in the GIS enhanced dipyridamole and ketoconazole absorption in mouse, and a good correlation between their supersaturation levels and their concentration in plasma was observed. The GIS, therefore, appears to represent in vivo dissolution phenomena and

Erbium:YAG laser resurfacing increases skin permeability and the risk of excessive absorption of antibiotics and sunscreens: the influence of skin recovery on drug absorption.

Science.gov (United States)

Lee, Woan-Ruoh; Shen, Shing-Chuan; Al-Suwayeh, Saleh A; Li, Yi-Ching; Fang, Jia-You

2012-06-01

While laser skin resurfacing is expected to result in reduced barrier function and increased risk of drug absorption, the extent of the increment has not yet been systematically investigated. We aimed to establish the skin permeation profiles of tetracycline and sunscreens after exposure to the erbium:yttrium-aluminum-garnet (Er:YAG) laser during postoperative periods. Physiological and histopathological examinations were carried out for 5 days after laser treatment on nude mice. Percutaneous absorption of the permeants was determined by an in vitro Franz cell. Ablation depths varied in reaching the stratum corneum (10 μm, 2.5 J/cm²) to approach the epidermis (25 μm, 6.25 J/cm²) and upper dermis (40 μm, 10 J/cm²). Reepithelialization evaluated by transepidermal water loss was complete within 2-4 days and depended on the ablation depth. Epidermal hyperplasia was observed in the 40-μm-treated group. The laser was sufficient to disrupt the skin barrier and allow the transport of the permeants into and across the skin. The laser fluence was found to play an important role in modulating skin absorption. A 25-μm ablation depth increased tetracycline flux 84-fold. A much smaller enhancement (3.3-fold) was detected for tetracycline accumulation within the skin. The laser with different fluences produced enhancement of oxybenzone skin deposition of 3.4-6.4-fold relative to the untreated group. No penetration across the skin was shown regardless of whether titanium dioxide was applied to intact or laser-treated skin. However, laser resurfacing increased the skin deposition of titanium dioxide from 46 to 109-188 ng/g. Tetracycline absorption had recovered to the level of intact skin after 5 days, while more time was required for oxybenzone absorption. The in vivo skin accumulation and plasma concentration revealed that the laser could increase tetracycline absorption 2-3-fold. The experimental results indicated that clinicians should be cautious when determining the

Automated applications of sandwich-cultured hepatocytes in the evaluation of hepatic drug transport.

Science.gov (United States)

Perry, Cassandra H; Smith, William R; St Claire, Robert L; Brouwer, Kenneth R

2011-04-01

Predictions of the absorption, distribution, metabolism, excretion, and toxicity of compounds in pharmaceutical development are essential aspects of the drug discovery process. B-CLEAR is an in vitro system that uses sandwich-cultured hepatocytes to evaluate and predict in vivo hepatobiliary disposition (hepatic uptake, biliary excretion, and biliary clearance), transporter-based hepatic drug-drug interactions, and potential drug-induced hepatotoxicity. Automation of predictive technologies is an advantageous and preferred format in drug discovery. In this study, manual and automated studies are investigated and equivalence is demonstrated. In addition, automated applications using model probe substrates and inhibitors to assess the cholestatic potential of drugs and evaluate hepatic drug transport are examined. The successful automation of this technology provides a more reproducible and less labor-intensive approach, reducing potential operator error in complex studies and facilitating technology transfer.

Enabling the intestinal absorption of highly polar antiviral agents: ion-pair facilitated membrane permeation of zanamivir heptyl ester and guanidino oseltamivir.

Science.gov (United States)

Miller, Jonathan M; Dahan, Arik; Gupta, Deepak; Varghese, Sheeba; Amidon, Gordon L

2010-08-02

Antiviral drugs often suffer from poor intestinal permeability, preventing their delivery via the oral route. The goal of this work was to enhance the intestinal absorption of the low-permeability antiviral agents zanamivir heptyl ester (ZHE) and guanidino oseltamivir (GO) utilizing an ion-pairing approach, as a critical step toward making them oral drugs. The counterion 1-hydroxy-2-naphthoic acid (HNAP) was utilized to enhance the lipophilicity and permeability of the highly polar drugs. HNAP substantially increased the log P of the drugs by up to 3.7 log units. Binding constants (K(11(aq))) of 388 M(-1) for ZHE-HNAP and 2.91 M(-1) for GO-HNAP were obtained by applying a quasi-equilibrium transport model to double-reciprocal plots of apparent octanol-buffer distribution coefficients versus HNAP concentration. HNAP enhanced the apparent permeability (P(app)) of both compounds across Caco-2 cell monolayers in a concentration-dependent manner, as substantial P(app) (0.8-3.0 x 10(-6) cm/s) was observed in the presence of 6-24 mM HNAP, whereas no detectable transport was observed without counterion. Consistent with a quasi-equilibrium transport model, a linear relationship with slope near 1 was obtained from a log-log plot of Caco-2 P(app) versus HNAP concentration, supporting the ion-pair mechanism behind the permeability enhancement. In the rat jejunal perfusion assay, the addition of HNAP failed to increase the effective permeability (P(eff)) of GO. However, the rat jejunal permeability of ZHE was significantly enhanced by the addition of HNAP in a concentration-dependent manner, from essentially zero without HNAP to 4.0 x 10(-5) cm/s with 10 mM HNAP, matching the P(eff) of the high-permeability standard metoprolol. The success of ZHE-HNAP was explained by its >100-fold stronger K(11(aq)) versus GO-HNAP, making ZHE-HNAP less prone to dissociation and ion-exchange with competing endogenous anions and able to remain intact during membrane permeation. Overall, this

Evaluation of the use of Göttingen minipigs to predict food effects on the oral absorption of drugs in humans

DEFF Research Database (Denmark)

Christiansen, Martin Lau; Müllertz, Anette; Garmer, Mats

2015-01-01

This study investigated the oral absorption of drugs in minipigs to predict food effects in man. The protocol was based on a previously described model in dogs and further investigated the food source (i.e., US FDA breakfast or a nutritional drink) and food quantities. Two poorly soluble compounds...

A new concept of efficient therapeutic drug monitoring using the high-resolution continuum source absorption spectrometry and the surface enhanced Raman spectroscopy

Science.gov (United States)

Xing, Yanlong; Fuss, Harald; Lademann, Jürgen; Huang, Mao Dong; Becker-Ross, Helmut; Florek, Stefan; Patzelt, Alexa; Meinke, Martina C.; Jung, Sora; Esser, Norbert

2018-04-01

In this study, a new therapeutic drug monitoring approach has been tested based on the combination of CaF molecular absorption using high-resolution continuum source absorption spectrometry (HR-CSAS) and surface enhanced Raman spectroscopy (SERS). HR-CSAS with mini graphite tube was successfully tested for clinical therapeutic drug monitoring of the fluorine-containing drug capecitabine in sweat samples of cancer patients: It showed advantageous features of high selectivity (no interference from Cl), high sensitivity (characteristic mass of 0.1 ng at CaF 583.069 nm), low sample consumption (down to 30 nL) and fast measurement (no sample pretreatment and less than 1 min of responding time) in tracing the fluorine signal out of capecitabine. However, this technique has the disadvantage of the total loss of the drug's structure information after burning the sample at very high temperature. Therefore, a new concept of combining HR-CSAS with a non-destructive spectroscopic method (SERS) was proposed for the sensitive sensing and specific identification of capecitabine. We tested and succeed in obtaining the molecular characteristics of the metabolite of capecitabine (named 5-fluorouracil) by the non-destructive SERS technique. With the results shown in this work, it is demonstrated that the combined spectroscopic technique of HR-CSAS and SERS will be very useful in efficient therapeutic drug monitoring in the future.

Clinical Drug-Drug Pharmacokinetic Interaction Potential of Sucralfate with Other Drugs: Review and Perspectives.

Science.gov (United States)

Sulochana, Suresh P; Syed, Muzeeb; Chandrasekar, Devaraj V; Mullangi, Ramesh; Srinivas, Nuggehally R

2016-10-01

Sucralfate, a complex of aluminium hydroxide with sulfated sucrose, forms a strong gastrointestinal tract (GIT) mucosal barrier with excellent anti-ulcer property. Because sucralfate does not undergo any significant oral absorption, sucralfate resides in the GIT for a considerable length of time. The unabsorbed sucralfate may alter the pharmacokinetics of the oral drugs by impeding its absorption and reducing the oral bioavailability. Because of the increased use of sucralfate, it was important to provide a reappraisal of the published clinical drug-drug interaction studies of sucralfate with scores of drugs. This review covers several category of drugs such as non-steroidal anti-inflammatory drugs, fluoroquinolones, histamine H2-receptor blockers, macrolides, anti-fungals, anti-diabetics, salicylic acid derivatives, steroidal anti-inflammatory drugs and provides pharmacokinetic data summary along with study design, objectives and key remarks. While the loss of oral bioavailability was significant for the fluoroquinolone class, it generally varied for other classes of drugs, suggesting that impact of the co-administration of sucralfate is manageable in clinical situations. Given the technology advancement in formulation development, it may be in order feasible to develop appropriate formulation strategies to either avoid or minimize the absorption-related issues when co-administered with sucralfate. It is recommended that consideration of both in vitro and preclinical studies may be in order to gauge the level of interaction of a drug with sucralfate. Such data may aid in the development of appropriate strategies to navigate the co-administration of sucralfate with other drugs in this age of polypharmacy.

Systems Pharmacology in Small Molecular Drug Discovery

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Wei Zhou

2016-02-01

Full Text Available Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity, target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

MNC Knowledge Transfer, Subsidiary Absorptive Capacity and HRM

DEFF Research Database (Denmark)

Minbaeva, Dana; Pedersen, Torben; Björkman, Ingmar

2014-01-01

Based on a sample of 169 subsidiaries of multinational corporations (MNCs) operating in the USA, Russia, and Finland, this paper investigates the relationship between MNC subsidiary HRM practices, absorptive capacity and knowledge transfer. First, we examine the relationship between the application...... of specific HRM practices and the level of the absorptive capacity. Second, we suggest that absorptive capacity should be conceptualized as being comprised of both employees’ ability and motivation. Further, results indicate that both ability and motivation (absorptive capacity) are needed to facilitate...

Physiologically Based Pharmacokinetic and Absorption Modeling for Osmotic Pump Products.

Science.gov (United States)

Ni, Zhanglin; Talattof, Arjang; Fan, Jianghong; Tsakalozou, Eleftheria; Sharan, Satish; Sun, Dajun; Wen, Hong; Zhao, Liang; Zhang, Xinyuan

2017-07-01

Physiologically based pharmacokinetic (PBPK) and absorption modeling approaches were employed for oral extended-release (ER) drug products based on an osmotic drug delivery system (osmotic pumps). The purpose was to systemically evaluate the in vivo relevance of in vitro dissolution for this type of formulation. As expected, in vitro dissolution appeared to be generally predictive of in vivo PK profiles, because of the unique feature of this delivery system that the in vitro and in vivo release of osmotic pump drug products is less susceptible to surrounding environment in the gastrointestinal (GI) tract such as pH, hydrodynamic, and food effects. The present study considered BCS (Biopharmaceutics Classification System) class 1, 2, and 3 drug products with half-lives ranging from 2 to greater than 24 h. In some cases, the colonic absorption models needed to be adjusted to account for absorption in the colon. C max (maximum plasma concentration) and AUCt (area under the concentration curve) of the studied drug products were sensitive to changes in colon permeability and segmental GI transit times in a drug product-dependent manner. While improvement of the methodology is still warranted for more precise prediction (e.g., colonic absorption and dynamic movement in the GI tract), the results from the present study further emphasized the advantage of using PBPK modeling in addressing product-specific questions arising from regulatory review and drug development.

Pharmacokinetic aspects of the anti-epileptic drug substance vigabatrin

DEFF Research Database (Denmark)

Nøhr, Martha Kampp; Frølund, Sidsel; Holm, René

2014-01-01

are discussed in detail. Special focus is on the contribution of the proton-coupled amino acid transporter 1 (PAT1) for intestinal vigabatrin absorption. Furthermore, the review gives an overview of the pharmacokinetic parameters of vigabatrin across different species and drug-food and drug-drug interactions......Drug transporters in various tissues, such as intestine, kidney, liver and brain, are recognized as important mediators of absorption, distribution, metabolism and excretion of drug substances. This review gives a current status on the transporter(s) mediating the absorption, distribution......, metabolism and excretion properties of the anti-epileptic drug substance vigabatrin. For orally administered drugs, like vigabatrin, the absorption from the intestine is a prerequisite for the bioavailability. Therefore, transporter(s) involved in the intestinal absorption of vigabatrin in vitro and in vivo...

Risk assessment of excess drug and sunscreen absorption via skin with ablative fractional laser resurfacing : optimization of the applied dose for postoperative care.

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Chen, Wei-Yu; Fang, Chia-Lang; Al-Suwayeh, Saleh A; Yang, Hung-Hsu; Li, Yi-Ching; Fang, Jia-You

2013-09-01

The ablative fractional laser is a new modality used for surgical resurfacing. It is expected that laser treatment can generally deliver drugs into and across the skin, which is toxicologically relevant. The aim of this study was to establish skin absorption characteristics of antibiotics, sunscreens, and macromolecules via laser-treated skin and during postoperative periods. Nude mice were employed as the animal model. The skin received a single irradiation of a fractional CO2 laser, using fluences of 4-10 mJ with spot densities of 100-400 spots/cm(2). In vitro skin permeation using Franz cells was performed. Levels of skin water loss and erythema were evaluated, and histological examinations with staining by hematoxylin and eosin, cyclooxygenase-2, and claudin-1 were carried out. Significant signs of erythema, edema, and scaling of the skin treated with the fractional laser were evident. Inflammatory infiltration and a reduction in tight junctions were also observed. Laser treatment at 6 mJ increased tetracycline and tretinoin fluxes by 70- and 9-fold, respectively. A higher fluence resulted in a greater tetracycline flux, but lower skin deposition. On the other hand, tretinoin skin deposition increased following an increase in the laser fluence. The fractional laser exhibited a negligible effect on modulating oxybenzone absorption. Dextrans with molecular weights of 4 and 10 kDa showed increased fluxes from 0.05 to 11.05 and 38.54 μg/cm(2)/h, respectively. The optimized drug dose for skin treated with the fractional laser was 1/70-1/60 of the regular dose. The skin histology and drug absorption had recovered to a normal status within 2-3 days. Our findings provide the first report on risk assessment of excessive skin absorption after fractional laser resurfacing.

Impact of pharmaceutical cocrystals: the effects on drug pharmacokinetics.

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Shan, Ning; Perry, Miranda L; Weyna, David R; Zaworotko, Michael J

2014-09-01

Pharmaceutical cocrystallization has emerged in the past decade as a new strategy to enhance the clinical performance of orally administered drugs. A pharmaceutical cocrystal is a multi-component crystalline material in which the active pharmaceutical ingredient is in a stoichiometric ratio with a second compound that is generally a solid under ambient conditions. The resulting cocrystal exhibits different solid-state thermodynamics, leading to changes in physicochemical properties that offer the potential to significantly modify drug pharmacokinetics. The impact of cocrystallization upon drug pharmacokinetics has not yet been well delineated. Herein, we compile previously published data to address two salient questions: what effect does cocrystallization impart upon physicochemical properties of a drug substance and to what degree can those effects impact its pharmacokinetics. Cocrystals can impact various aspects of drug pharmacokinetics, including, but not limited to, drug absorption. The diversity of solid forms offered through cocrystallization can facilitate drastic changes in solubility and pharmacokinetics. Therefore, it is unsurprising that cocrystal screening is now a routine step in early-stage drug development. With the increasing recognition of pharmaceutical cocrystals from clinical, regulatory and legal perspectives, the systematic commercialization of cocrystal containing drug products is just a matter of time.

Absorption mechanism of three curcumin constituents through in situ intestinal perfusion method

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Y.-H. Wang

2017-09-01

Full Text Available This study aimed to investigate the absorption mechanism of three curcumin constituents in rat small intestines. Self-emulsification was used to solubilize the three curcumin constituents, and the rat in situ intestinal perfusion method was used to study factors on drug absorption, including drug mass concentration, absorption site, and the different types and concentrations of absorption inhibitors. Within the scope of experimental concentrations, three curcumin constituents were absorbed in rat small intestines through the active transport mechanism.

The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.

Science.gov (United States)

David, Dahlgren; Carl, Roos; Pernilla, Johansson; Christer, Tannergren; Anders, Lundqvist; Peter, Langguth; Markus, Sjöblom; Erik, Sjögren; Hans, Lennernäs

2018-05-11

Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients (CPEs), or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs/CPEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME/CPE effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME/CPE evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations. Copyright © 2018. Published by Elsevier B.V.

Intestinal absorption of the antiepileptic drug substance vigabatrin is altered by infant formula in vitro and in vivo

DEFF Research Database (Denmark)

Nielsen, Carsten Uhd

2014-01-01

Vigabatrin is an antiepileptic drug substance mainly used in pediatric treatment of infantile spasms. The main source of nutrition for infants is breast milk and/or infant formula. Our hypothesis was that infant formula may affect the intestinal absorption of vigabatrin. The aim was therefore...... to investigate the potential effect of coadministration of infant formula with vigabatrin on the oral absorption in vitro and in vivo. The effect of vigabatrin given with an infant formula on the oral uptake and transepithelial transport was investigated in vitro in Caco-2 cells. In vivo effects of infant...... formula and selected amino acids on the pharmacokinetic profile of vigabatrin was investigated after oral coadministration to male Sprague–Dawley rats using acetaminophen as a marker for gastric emptying. The presence of infant formula significantly reduced the uptake rate and permeability of vigabatrin...

Impaired drug absorption due to high stomach pH: a review of strategies for mitigation of such effect to enable pharmaceutical product development.

Science.gov (United States)

Mitra, Amitava; Kesisoglou, Filippos

2013-11-04

Published reports have clearly shown that weakly basic drugs which have low solubility at high pH could have impaired absorption in patients with high gastric pH thus leading to reduced and variable bioavailability. Since such reduction in exposure can lead to significant loss of efficacy, it is imperative to (1) understand the behavior of the compound as a function of stomach pH to inform of any risk of bioavailability loss in clinical studies and (2) develop a robust formulation which can provide adequate exposure in achlorhydric patients. In this review paper, we provide an overview of the factors that can cause high gastric pH in human, discuss clinical and preclinical pharmacokinetic data for weak bases under conditions of normal and high gastric pH, and give examples of formulation strategies to minimize or mitigate the reduced absorption of weakly basic drugs under high gastric pH conditions. It should be noted that the ability to overcome pH sensitivity issues is highly compound dependent and there are no obvious and general solutions to overcome such effect. Further, we discuss, along with several examples, the use of biopharmaceutical tools such as in vitro dissolution, absorption modeling, and gastric pH modified animal models to assess absorption risk of weak bases in high gastric pH and also the use of these tools to enable development of formulations to mitigate such effects.

21 CFR 862.2850 - Atomic absorption spectrophotometer for clinical use.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Atomic absorption spectrophotometer for clinical... Laboratory Instruments § 862.2850 Atomic absorption spectrophotometer for clinical use. (a) Identification. An atomic absorption spectrophotometer for clinical use is a device intended to identify and measure...

Mechanisms for oral absorption of poorly water-soluble compounds

DEFF Research Database (Denmark)

Lind, Marianne Ladegaard

Abstract A large part of the new drug candidates discovered by the pharmaceutical industry have poor solubility in aqueous media. The preferred route of drug administration is the oral route, but for these poorly water-soluble drug candidates the oral bioavailability can be low and variable. Often......, phospholipids) and exogenous surfactants used in pharmaceutical formulations on the oral absorption of poorly water-soluble drug substances. Three different models were used for this purpose. The first model was the in vitro Caco-2 cell model. Simulated intestinal fluids which did not decrease cellular...... products are important for the solubilization of poorly water-soluble drug substances and thus absorption. The second model used was the lipoprotein secreting Caco-2 cell model, which was used to simulate intestinal lymphatic transport in vitro. Various simulated intestinal fluids were composed...

Recent Advances in Delivery Systems and Therapeutics of Cinnarizine: A Poorly Water Soluble Drug with Absorption Window in Stomach

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Smita Raghuvanshi

2014-01-01

Full Text Available Low solubility causing low dissolution in gastrointestinal tract is the major problem for drugs meant for systemic action after oral administration, like cinnarizine. Pharmaceutical products of cinnarizine are commercialized globally as immediate release preparations presenting low absorption with low and erratic bioavailability. Approaches to enhance bioavailability are widely cited in the literature. An attempt has been made to review the bioavailability complications and clinical therapeutics of poorly water soluble drug: cinnarizine. The interest of writing this paper is to summarize the pharmacokinetic limitations of drug with special focus on strategies to improvise bioavailability along with effectiveness of novel dosage forms to circumvent the obstacle. The paper provides insight to the approaches to overcome low and erratic bioavailability of cinnarizine by cyclodextrin complexes and novel dosage forms: self-nanoemulsifying systems and buoyant microparticulates. Nanoformulations need to systematically explored in future, for their new clinical role in prophylaxis of migraine attacks in children. Clinical reports have affirmed the role of cinnarizine in migraine prophylaxis. Research needs to be dedicated to develop dosage forms for efficacious bioavailability and drug directly to brain.

Drug- and Alcohol-Facilitated, Incapacitated, and Forcible Rape in Relation to Mental Health among a National Sample of Women

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Zinzow, Heidi M.; Resnick, Heidi S.; Amstadter, Ananda B.; McCauley, Jenna L.; Ruggiero, Kenneth J.; Kilpatrick, Dean G.

2009-01-01

Objective Rape is a well-established risk factor for mental health disorders such as posttraumatic stress disorder (PTSD) and depression. However, most studies have focused on forcible rape tactics and have not distinguished these from tactics that involve drug or alcohol intoxication. Our aim was to examine correlates of PTSD and depression in a community sample of women, with particular emphasis on evaluating the unique effects of lifetime exposure to three specific rape tactics. Methods A nationally representative sample of 3,001 non-institutionalized, civilian, English or Spanish speaking women (aged 18–86 years) participated in a structured telephone interview by use of Computer-Assisted Telephone Interviewing technology. Results Multivariable models showed that history of drug or alcohol facilitated rape tactics (OR = 1.87, prape tactics (OR = 3.46, prape was associated with depression (OR = 3.65, prape tactics were associated with a number of factors that may have contributed to their stronger association with mental health outcomes, including force, injury, lower income, revictimization history, and labeling the event as rape. Conclusions Our results underscore the importance of using a behaviorally specific assessment of rape history, as rape tactic and multiple rape history differentially predicted psychopathology outcomes. The association between drug or alcohol facilitated rape tactics and PTSD suggests that these are important rape tactics to include in assessments and future studies. PMID:20100896

Evaluation of transporters in drug development: Current status and contemporary issues.

Science.gov (United States)

Lee, Sue-Chih; Arya, Vikram; Yang, Xinning; Volpe, Donna A; Zhang, Lei

2017-07-01

Transporters govern the access of molecules to cells or their exit from cells, thereby controlling the overall distribution of drugs to their intracellular site of action. Clinically relevant drug-drug interactions mediated by transporters are of increasing interest in drug development. Drug transporters, acting alone or in concert with drug metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism and excretion, thus affecting the pharmacokinetics and/or pharmacodynamics of a drug. The drug interaction guidance documents from regulatory agencies include various decision criteria that may be used to predict the need for in vivo assessment of transporter-mediated drug-drug interactions. Regulatory science research continues to assess the prediction performances of various criteria as well as to examine the strength and limitations of each prediction criterion to foster discussions related to harmonized decision criteria that may be used to facilitate global drug development. This review discusses the role of transporters in drug development with a focus on methodologies in assessing transporter-mediated drug-drug interactions, challenges in both in vitro and in vivo assessments of transporters, and emerging transporter research areas including biomarkers, assessment of tissue concentrations, and effect of diseases on transporters. Published by Elsevier B.V.

Cell-patterned glass spray for direct drug assay using mass spectrometry

International Nuclear Information System (INIS)

Wu, Jing; Wang, Shiqi; Chen, Qiushui; Jiang, Hao; Liang, Shuping; Lin, Jin-Ming

2015-01-01

In this work, the establishment of a glass spray mass spectrometry (GS-MS) platform for direct cell-based drug assay was described. Cell co-culture, drug-induced cell apoptosis, proliferation analysis and intracellular drug absorption measurement were performed simultaneously on this specifically designed platform. Two groups of co-cultured cells (NIH-3T3/HepG2 and HepG2/MCF-7) were cultivated and they showed high viability within 3 days. The biocompatibility of the platform facilitated the subsequent bioassays, in which, cyclophosphamide (CPA) and genistein were used as the model drugs. The distinctions of cell apoptosis and proliferation between the mono-cultured and co-cultured cells were clearly observed and well explained by in situ GS-MS measurements. A satisfactory linearity of the calibration curve between the relative MS intensity and CPA concentrations was obtained using stable isotope labeling method (y = 0.16545 + 0.0985x, R"2 = 0.9937). The variations in the quantity of absorbed drug were detected and the results were consistent with the concentration-dependence of cell apoptosis. All the results demonstrated that direct cell-based drug assay could be performed on the stable isotope labeling assisted GS-MS platform in a facile and quantitative manner. - Highlights: • A versatile glass spray mass spectrometry (GS-MS) platform for direct cell-based drug assay was developed in this paper. • It has characteristics of the atmospheric pressure ionization method. • It is multifunctional for cell co-culture, bioassays, qualitative and quantitative intracellular drug absorption measurement. • GS-MS has the potential to increase the use of mass spectrometry in biological analysis.

Chitosan Based Self-Assembled Nanoparticles in Drug Delivery

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Javier Pérez Quiñones

2018-02-01

Full Text Available Chitosan is a cationic polysaccharide that is usually obtained by alkaline deacetylation of chitin poly(N-acetylglucosamine. It is biocompatible, biodegradable, mucoadhesive, and non-toxic. These excellent biological properties make chitosan a good candidate for a platform in developing drug delivery systems having improved biodistribution, increased specificity and sensitivity, and reduced pharmacological toxicity. In particular, chitosan nanoparticles are found to be appropriate for non-invasive routes of drug administration: oral, nasal, pulmonary and ocular routes. These applications are facilitated by the absorption-enhancing effect of chitosan. Many procedures for obtaining chitosan nanoparticles have been proposed. Particularly, the introduction of hydrophobic moieties into chitosan molecules by grafting to generate a hydrophobic-hydrophilic balance promoting self-assembly is a current and appealing approach. The grafting agent can be a hydrophobic moiety forming micelles that can entrap lipophilic drugs or it can be the drug itself. Another suitable way to generate self-assembled chitosan nanoparticles is through the formation of polyelectrolyte complexes with polyanions. This paper reviews the main approaches for preparing chitosan nanoparticles by self-assembly through both procedures, and illustrates the state of the art of their application in drug delivery.

The role of social capital in the creation of organisational absorptive capacity

DEFF Research Database (Denmark)

Bergenholtz, Carsten

2010-01-01

Based on a double case-study, this paper discusses the role of social capital in the creation of organisational absorptive capacity. Bridging social capital makes it possible to acquire new knowledge whereas bonding social capital assists the exploitation of that knowledge. In addition, this study...... presents a concept of creative social capital to facilitate the transition from assimilation to transformation. Two action research cases present the generation of social interaction mechanisms that facilitate the move from potential absorptive capacity to realised absorptive capacity. In these cases...... the creative social capital is being concretised as a) group-based identity, and b) willingness to form a mutual goal....

A modified physiological BCS for prediction of intestinal absorption in drug discovery.

Science.gov (United States)

Zaki, Noha M; Artursson, Per; Bergström, Christel A S

2010-10-04

In this study, the influence of physiologically relevant media on the compound position in a biopharmaceutical classification system (BCS) which resembled the intestinal absorption was investigated. Both solubility and permeability limited compounds (n = 22) were included to analyze the importance of each of these on the final absorption. Solubility was determined in three different dissolution media, phosphate buffer pH 6.5 (PhB 6.5), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) at 37 °C, and permeability values were determined using the 2/4/A1 cell line. The solubility data and membrane permeability values were used for sorting the compounds into a BCS modified to reflect the fasted and fed state. Three of the seven compounds sorted as BCS II in PhB 6.5 (high permeability, low solubility) changed their position to BCS I when dissolved in FaSSIF and/or FeSSIF (high permeability, high solubility). These were low dosed (20 mg or less) lipophilic molecules displaying solvation limited solubility. In contrast, compounds having solid-state limited solubility had a minor increase in solubility when dissolved in FaSSIF and/or FeSSIF. Although further studies are needed to enable general cutoff values, our study indicates that low dosed BCS Class II compounds which have solubility normally restricted by poor solvation may behave as BCS Class I compounds in vivo. The large series of compounds investigated herein reveals the importance of investigating solubility and dissolution under physiologically relevant conditions in all stages of the drug discovery process to push suitable compounds forward, to select proper formulations, and to reduce the risk of food effects.

Glucose Absorption by the Bacillary Band of Trichuris muris.

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Tina V A Hansen

2016-09-01

Full Text Available A common characteristic of Trichuris spp. infections in humans and animals is the variable but low efficacy of single-dose benzimidazoles currently used in mass drug administration programmes against human trichuriasis. The bacillary band, a specialised morphological structure of Trichuris spp., as well as the unique partly intracellular habitat of adult Trichuris spp. may affect drug absorption and perhaps contribute to the low drug accumulation in the worm. However, the exact function of the bacillary band is still unknown.We studied the dependency of adult Trichuris muris on glucose and/or amino acids for survival in vitro and the absorptive function of the bacillary band. The viability of the worms was evaluated using a motility scale from 0 to 3, and the colorimetric assay Alamar Blue was utilised to measure the metabolic activity. The absorptive function of the bacillary band in living worms was explored using a fluorescent glucose analogue (6-NBDG and confocal microscopy. To study the absorptive function of the bacillary band in relation to 6-NBDG, the oral uptake was minimised or excluded by sealing the oral cavity with glue and agarose.Glucose had a positive effect on both the motility (p < 0.001 and metabolic activity (p < 0.001 of T. muris in vitro, whereas this was not the case for amino acids. The 6-NBDG was observed in the pores of the bacillary band and within the stichocytes of the living worms, independent of oral sealing.Trichuris muris is dependent on glucose for viability in vitro, and the bacillary band has an absorptive function in relation to 6-NBDG, which accumulates within the stichocytes. The absorptive function of the bacillary band calls for an exploration of its possible role in the uptake of anthelmintics, and as a potential anthelmintic target relevant for future drug development.

Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition.

Science.gov (United States)

Longest, P Worth; Hindle, Michael

2017-10-01

To predict the cellular-level epithelial absorbed dose from deposited inhaled corticosteroid (ICS) particles in a model of an expanding and contracting small airway segment for different particle forms. A computational fluid dynamics (CFD)-based model of drug dissolution, absorption and clearance occurring in the surface liquid of a representative small airway generation (G13) was developed and used to evaluate epithelial dose for the same deposited drug mass of conventional microparticles, nanoaggregates and a true nanoaerosol. The ICS medications considered were budesonide (BD) and fluticasone propionate (FP). Within G13, total epithelial absorption efficiency (AE) and dose uniformity (microdosimetry) were evaluated. Conventional microparticles resulted in very poor AE of FP (0.37%) and highly nonuniform epithelial absorption, such that <5% of cells received drug. Nanoaggregates improved AE of FP by a factor of 57-fold and improved dose delivery to reach approximately 40% of epithelial cells. True nanoaerosol resulted in near 100% AE for both drugs and more uniform drug delivery to all cells. Current ICS therapies are absorbed by respiratory epithelial cells in a highly nonuniform manner that may partially explain poor clinical performance in the small airways. Both nanoaggregates and nanoaerosols can significantly improve ICS absorption efficiency and uniformity.

Effect of food and acid-reducing agents on the absorption of oral targeted therapies in solid tumors

NARCIS (Netherlands)

Willemsen, A.E.C.A.B.; Lubberman, F.J.E.; Tol, J.; Gerritsen, W.R.; Herpen, C.M.L. van; Erp, N. van

2016-01-01

Oral targeted therapies represent an increasingly important group of drugs within modern oncology. With the shift from intravenously to orally administered drugs, drug absorption is a newly introduced factor in drug disposition. The process of absorption can have a large effect on inter- and

Transporter-Guided Delivery of Nanoparticles to Improve Drug Permeation across Cellular Barriers and Drug Exposure to Selective Cell Types

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Longfa Kou

2018-01-01

Full Text Available Targeted nano-drug delivery systems conjugated with specific ligands to target selective cell-surface receptors or transporters could enhance the efficacy of drug delivery and therapy. Transporters are expressed differentially on the cell-surface of different cell types, and also specific transporters are expressed at higher than normal levels in selective cell types under pathological conditions. They also play a key role in intestinal absorption, delivery via non-oral routes (e.g., pulmonary route and nasal route, and transfer across biological barriers (e.g., blood–brain barrier and blood–retinal barrier. As such, the cell-surface transporters represent ideal targets for nano-drug delivery systems to facilitate drug delivery to selective cell types under normal or pathological conditions and also to avoid off-target adverse side effects of the drugs. There is increasing evidence in recent years supporting the utility of cell-surface transporters in the field of nano-drug delivery to increase oral bioavailability, to improve transfer across the blood–brain barrier, and to enhance delivery of therapeutics in a cell-type selective manner in disease states. Here we provide a comprehensive review of recent advancements in this interesting and important area. We also highlight certain key aspects that need to be taken into account for optimal development of transporter-assisted nano-drug delivery systems.

In vivo evaluation of thiolated poly(acrylic acid) as a drug absorption modulator for MRP2 efflux pump substrates.

Science.gov (United States)

Greindl, Melanie; Föger, Florian; Hombach, Juliane; Bernkop-Schnürch, Andreas

2009-08-01

Recently, several polymers have been reported to modulate drug absorption by inhibition of intestinal efflux pumps such as multidrug resistance proteins (MRPs) and P-glycoprotein (P-gp). The aim of the present study was to evaluate the efficiency of thiolated poly(acrylic acid) (PAA-Cys) to act as a drug absorption modulator for MRP2 efflux pump substrates in vivo, using sulforhodamine 101 as representative MRP2 substrate. In vitro, the permeation-enhancing effect of unmodified PAA and PAA(250)-Cys(,) displaying 580 micromol free thiol groups per gram polymer, was evaluated by using freshly excised rat intestinal mucosa mounted in Ussing-type chambers. In comparison to that of the buffer control, the sulforhodamine 101 transport in the presence of 0.5% unmodified PAA(250) and 0.5% (w/v) PAA(250)-Cys was 1.3- and 4.0-fold improved, respectively. In vivo, sulforhodamine 101 solutions containing 4% (w/v) unmodified PAA(250) or 4% (w/v) thiolated PAA(250) were orally given to rats. The PAA(250)-Cys solution increased the area under the plasma concentration-time curve (AUC(0-12)) of sulforhodamine 101 3.8-fold in comparison to control and 2.2-fold in comparison to unmodified PAA(250). This in vivo study revealed that PAA(250)-Cys significantly increased the oral bioavailability of MRP2 substrate sulforhodamine 101.

Projecting ADME Behavior and Drug-Drug Interactions in Early Discovery and Development: Application of the Extended Clearance Classification System.

Science.gov (United States)

El-Kattan, Ayman F; Varma, Manthena V; Steyn, Stefan J; Scott, Dennis O; Maurer, Tristan S; Bergman, Arthur

2016-12-01

To assess the utility of Extended Clearance Classification System (ECCS) in understanding absorption, distribution, metabolism, and elimination (ADME) attributes and enabling victim drug-drug interaction (DDI) predictions. A database of 368 drugs with relevant ADME parameters, main metabolizing enzymes, uptake transporters, efflux transporters, and highest change in exposure (%AUC) in presence of inhibitors was developed using published literature. Drugs were characterized according to ECCS using ionization, molecular weight and estimated permeability. Analyses suggested that ECCS class 1A drugs are well absorbed and systemic clearance is determined by metabolism mediated by CYP2C, esterases, and UGTs. For class 1B drugs, oral absorption is high and the predominant clearance mechanism is hepatic uptake mediated by OATP transporters. High permeability neutral/basic drugs (class 2) showed high oral absorption, with metabolism mediated generally by CYP3A, CYP2D6 and UGTs as the predominant clearance mechanism. Class 3A/4 drugs showed moderate absorption with dominant renal clearance involving OAT/OCT2 transporters. Class 3B drugs showed low to moderate absorption with hepatic uptake (OATPs) and/or renal clearance as primary clearance mechanisms. The highest DDI risk is typically seen with class 2/1B/3B compounds manifested by inhibition of either CYP metabolism or active hepatic uptake. Class 2 showed a wider range in AUC change likely due to a variety of enzymes involved. DDI risk for class 3A/4 is small and associated with inhibition of renal transporters. ECCS provides a framework to project ADME profiles and further enables prediction of victim DDI liabilities in drug discovery and development.

FAF-Drugs2: free ADME/tox filtering tool to assist drug discovery and chemical biology projects.

Science.gov (United States)

Lagorce, David; Sperandio, Olivier; Galons, Hervé; Miteva, Maria A; Villoutreix, Bruno O

2008-09-24

Drug discovery and chemical biology are exceedingly complex and demanding enterprises. In recent years there are been increasing awareness about the importance of predicting/optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of small chemical compounds along the search process rather than at the final stages. Fast methods for evaluating ADMET properties of small molecules often involve applying a set of simple empirical rules (educated guesses) and as such, compound collections' property profiling can be performed in silico. Clearly, these rules cannot assess the full complexity of the human body but can provide valuable information and assist decision-making. This paper presents FAF-Drugs2, a free adaptable tool for ADMET filtering of electronic compound collections. FAF-Drugs2 is a command line utility program (e.g., written in Python) based on the open source chemistry toolkit OpenBabel, which performs various physicochemical calculations, identifies key functional groups, some toxic and unstable molecules/functional groups. In addition to filtered collections, FAF-Drugs2 can provide, via Gnuplot, several distribution diagrams of major physicochemical properties of the screened compound libraries. We have developed FAF-Drugs2 to facilitate compound collection preparation, prior to (or after) experimental screening or virtual screening computations. Users can select to apply various filtering thresholds and add rules as needed for a given project. As it stands, FAF-Drugs2 implements numerous filtering rules (23 physicochemical rules and 204 substructure searching rules) that can be easily tuned.

Challenges and strategies to facilitate formulation development of pediatric drug products: Safety qualification of excipients.

Science.gov (United States)

Buckley, Lorrene A; Salunke, Smita; Thompson, Karen; Baer, Gerri; Fegley, Darren; Turner, Mark A

2018-02-05

A public workshop entitled "Challenges and strategies to facilitate formulation development of pediatric drug products" focused on current status and gaps as well as recommendations for risk-based strategies to support the development of pediatric age-appropriate drug products. Representatives from industry, academia, and regulatory agencies discussed the issues within plenary, panel, and case-study breakout sessions. By enabling practical and meaningful discussion between scientists representing the diversity of involved disciplines (formulators, nonclinical scientists, clinicians, and regulators) and geographies (eg, US, EU), the Excipients Safety workshop session was successful in providing specific and key recommendations for defining paths forward. Leveraging orthogonal sources of data (eg. food industry, agro science), collaborative data sharing, and increased awareness of the existing sources such as the Safety and Toxicity of Excipients for Paediatrics (STEP) database will be important to address the gap in excipients knowledge needed for risk assessment. The importance of defining risk-based approaches to safety assessments for excipients vital to pediatric formulations was emphasized, as was the need for meaningful stakeholder (eg, patient, caregiver) engagement. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug facilitated sexual assault: detection and stability of benzodiazepines in spiked drinks using gas chromatography-mass spectrometry.

Directory of Open Access Journals (Sweden)

Lata Gautam

Full Text Available Benzodiazepines are detected in a significant number of drug facilitated sexual assaults (DFSA. Whilst blood and urine from the victim are routinely analysed, due to the delay in reporting DFSA cases and the short half lives of most of these drugs in blood and urine, drug detection in such samples is problematic. Consideration of the drinks involved and analysis for drugs may start to address this. Here we have reconstructed the 'spiking' of three benzodiazepines (diazepam, flunitrazepam and temazepam into five drinks, an alcopop (flavoured alcoholic drink, a beer, a white wine, a spirit, and a fruit based non-alcoholic drink (J2O chosen as representative of those drinks commonly used by women in 16-24 year old age group. Using a validated GC-MS method for the simultaneous detection of these drugs in the drinks we have studied the storage stability of the benzodiazepines under two different storage conditions, uncontrolled room temperature and refrigerator (4°C over a 25 day period. All drugs could be detected in all beverages over this time period. Diazepam was found to be stable in all of the beverages, except the J2O, under both storage conditions. Flunitrazepam and temazepam were found not to be stable but were detectable (97% loss of temazepam and 39% loss of flunitrazepam from J2O. The recommendations from this study are that there should be a policy change and that drinks thought to be involved in DFSA cases should be collected and analysed wherever possible to support other evidence types.

Drug-mineral interactions

International Nuclear Information System (INIS)

Kramer, L.

1986-01-01

The effect of drugs such as glucocorticoids and thyroid extract on calcium metabolism is unknown. However, several other medications affect the excretion and intestinal absorption of calcium. A controlled study was carried out to investigate these aspects. Urinary calcium was determined for 3 months during the long-term intake of the antituberculous drug isoniazid (INH) and of the antibiotic tetracycline. The effect of the diuretics furosemide and hydrochlorothiazide, of several aluminum-containing antacids, of thyroid extract and of corticosteroids was also studied. Metabolic balances of calcium, phosphorus, magnesium and zinc were determined, as well as the intestinal absorption of calcium using Ca 47. Plasma levels, urinary and fecal excretions of Ca 47 were determined. All drugs tested increased urinary calcium except for the diuretic hydrochlorothiazide. Regarding the effect of corticosteroids: the intestinal absorption of calcium was unchanged after the short-term use and was very high after long-term use. The studies have shown that several commonly used drugs induce an increase in urinary calcium excretion which may contribute to calcium loss, if this increase persists for prolonged periods of time. Urinary excretions of phosphorus, magnesium and zinc increased in some of the studies

Prediction of Human Intestinal Absorption of Compounds Using Artificial Intelligence Techniques.

Science.gov (United States)

Kumar, Rajnish; Sharma, Anju; Siddiqui, Mohammed Haris; Tiwari, Rajesh Kumar

2017-01-01

Information about Pharmacokinetics of compounds is an essential component of drug design and development. Modeling the pharmacokinetic properties require identification of the factors effecting absorption, distribution, metabolism and excretion of compounds. There have been continuous attempts in the prediction of intestinal absorption of compounds using various Artificial intelligence methods in the effort to reduce the attrition rate of drug candidates entering to preclinical and clinical trials. Currently, there are large numbers of individual predictive models available for absorption using machine learning approaches. Six Artificial intelligence methods namely, Support vector machine, k- nearest neighbor, Probabilistic neural network, Artificial neural network, Partial least square and Linear discriminant analysis were used for prediction of absorption of compounds. Prediction accuracy of Support vector machine, k- nearest neighbor, Probabilistic neural network, Artificial neural network, Partial least square and Linear discriminant analysis for prediction of intestinal absorption of compounds was found to be 91.54%, 88.33%, 84.30%, 86.51%, 79.07% and 80.08% respectively. Comparative analysis of all the six prediction models suggested that Support vector machine with Radial basis function based kernel is comparatively better for binary classification of compounds using human intestinal absorption and may be useful at preliminary stages of drug design and development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A facile nanoaggregation strategy for oral delivery of hydrophobic drugs by utilizing acid-base neutralization reactions

International Nuclear Information System (INIS)

Chen Huabing; Wan Jiangling; Wang Yirui; Mou Dongsheng; Liu Hongbin; Xu Huibi; Yang Xiangliang

2008-01-01

Nanonization strategies have been used to enhance the oral availability of numerous drugs that are poorly soluble in water. Exploring a facile nanonization strategy with highly practical potential is an attractive focus. Here, we report a novel facile nanoaggregation strategy for constructing drug nanoparticles of poorly soluble drugs with pH-dependent solubility by utilizing acid-base neutralization in aqueous solution, thus facilitating the exploration of nanonization in oral delivery for general applicability. We demonstrate that hydrophobic itraconazole dissolved in acid solution formed a growing core and aggregated into nanoparticles in the presence of stabilizers. The nanoparticles, with an average diameter of 279.3 nm and polydispersity index of 0.116, showed a higher dissolution rate when compared with the marketed formulation; the average dissolution was about 91.3%. The in vivo pharmacokinetic studies revealed that the nanoparticles had a rapid absorption and enhanced oral availability. The diet state also showed insignificant impact on the absorption of itraconazole from nanoparticles. This nanoaggregation strategy is a promising nanonization method with a facile process and avoidance of toxic organic solvents for oral delivery of poorly soluble drugs with pH-dependent solubility and reveals a highly practical potential in the pharmaceutical and chemical industries

Understanding the Oral Mucosal Absorption and Resulting Clinical Pharmacokinetics of Asenapine

NARCIS (Netherlands)

Bartlett, Jeremy A.; Maarschalk, Kees van der Voort

2012-01-01

Absorption of drugs from the oral cavity into the mucosal tissues is typically a fast event. Dissolved drugs partition into the mucosal membranes and within minutes will reach equilibrium with drug in solution in the oral cavity. However, this does not always equate to rapid drug appearance in the

ORAL COLON TARGETED DRUG DELIVERY SYSTEM: A REVIEW ON CURRENT AND NOVEL PERSPECTIVES

OpenAIRE

Asija Rajesh; Chaudhari Bharat; Asija Sangeeta

2012-01-01

Small intestine is mostly the site for drug absorption but in some cases the drug needs to be targeted to colon due to some factors like local colonic disease, degradation related conditions, delayed release of drugs, systemic delivery of protein and peptide drugs etc. Colon targeted drug delivery is important and relatively new concept for the absorption of drugs because it offers almost neutral pH and long residence time, thereby increasing the drug absorption. Colon has proved to be a site...

Updates on drug-target network; facilitating polypharmacology and data integration by growth of DrugBank database.

Science.gov (United States)

Barneh, Farnaz; Jafari, Mohieddin; Mirzaie, Mehdi

2016-11-01

Network pharmacology elucidates the relationship between drugs and targets. As the identified targets for each drug increases, the corresponding drug-target network (DTN) evolves from solely reflection of the pharmaceutical industry trend to a portrait of polypharmacology. The aim of this study was to evaluate the potentials of DrugBank database in advancing systems pharmacology. We constructed and analyzed DTN from drugs and targets associations in the DrugBank 4.0 database. Our results showed that in bipartite DTN, increased ratio of identified targets for drugs augmented density and connectivity of drugs and targets and decreased modular structure. To clear up the details in the network structure, the DTNs were projected into two networks namely, drug similarity network (DSN) and target similarity network (TSN). In DSN, various classes of Food and Drug Administration-approved drugs with distinct therapeutic categories were linked together based on shared targets. Projected TSN also showed complexity because of promiscuity of the drugs. By including investigational drugs that are currently being tested in clinical trials, the networks manifested more connectivity and pictured the upcoming pharmacological space in the future years. Diverse biological processes and protein-protein interactions were manipulated by new drugs, which can extend possible target combinations. We conclude that network-based organization of DrugBank 4.0 data not only reveals the potential for repurposing of existing drugs, also allows generating novel predictions about drugs off-targets, drug-drug interactions and their side effects. Our results also encourage further effort for high-throughput identification of targets to build networks that can be integrated into disease networks. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides.

Science.gov (United States)

Holm, René; Porter, Christopher J H; Edwards, Glenn A; Müllertz, Anette; Kristensen, Henning G; Charman, William N

2003-09-01

The potential for lipidic self-microemulsifying drug delivery systems (SMEDDS) containing triglycerides with a defined structure, where the different fatty acids on the glycerol backbone exhibit different metabolic fate, to improve the lymphatic transport and the portal absorption of a poorly water-soluble drug, halofantrine, were investigated in fasted lymph cannulated canines. Two different structured triglycerides were incorporated into the SMEDDS; 1,3-dioctanoyl-2-linoleyl-sn-glycerol (C8:0-C18:2-C8:0) (MLM) and 1,3-dilinoyl-2-octanoyl-sn-glycerol (C18:2-C8:0-C18:2) (LML). A previously optimised SMEDDS formulation for halofantrine, comprising of triglyceride, Cremophor EL, Maisine 35-1 and ethanol was selected for bioavailability assessment. The extent of lymphatic transport via the thoracic duct was 17.9% of the dose for the animals dosed with the MLM SMEDDS and 27.4% for LML. Also the plasma availability was affected by the triglyceride incorporated into the multi-component delivery system and availabilities of 56.9% (MLM) and 37.2% (LML) were found. These data indicate that the pharmaceutical scientist can use the structure of the lipid to affect the relative contribution of the two absorption pathways. The MLM formulation produced a total bioavailability of 74.9%, which is higher than the total absorption previously observed after post-prandial administration. This could indicate the utility of disperse lipid-base formulations based on structured triglycerides for the oral delivery of halofantrine, and potentially other lipophilic drugs.

Barriers and facilitators to disease-modifying antirheumatic drug use in patients with inflammatory rheumatic diseases: a qualitative theory-based study.

Science.gov (United States)

Voshaar, Marieke; Vriezekolk, Johanna; van Dulmen, Sandra; van den Bemt, Bart; van de Laar, Mart

2016-10-21

Although disease-modifying anti-rheumatic drugs (DMARDs) are the cornerstone of treatment for inflammatory rheumatic diseases, medication adherence to DMARDs is often suboptimal. Effective interventions to improve adherence to DMARDs are lacking, and new targets are needed to improve adherence. The aim of the present study was to explore patients' barriers and facilitators of optimal DMARD use. These factors might be used as targets for adherence interventions. In a mixed method study design, patients (n = 120) with inflammatory arthritis (IA) completed a questionnaire based on an existing adapted Theoretical Domains Framework (TDF) to identify facilitators and barriers of DMARD use. A subgroup of these patients (n = 21) participated in focus groups to provide insights into their facilitators and barriers. The answers to the questionnaires and responses of the focus groups were thematically coded by three researchers independently and subsequently categorized. The barriers and facilitators that were reported by IA patients presented large inter-individual variations. The identified barriers and facilitators could be captured in the following domains based on an adapted TDF: (i) knowledge, (ii) emotions, (iii) attention, memory, and decision processes, (iv) social influences, (v) beliefs about capability, (vi) beliefs about consequences, (vii) motivation and goals, (viii) goal conflict, (ix) environmental context and resources, and (x) skills. Patients with IA have a variety of barriers and facilitators with regard to their DMARD use. All of these barriers and facilitators could be categorized into adapted domains of the TDF. Interventions that address individual facilitators and barriers, based on capability, opportunity, and motivation, are needed to develop strategies for medication adherence that are tailored to individual patient needs.

Use of a standard meal to study iron absorption in humans

International Nuclear Information System (INIS)

Reddy, M.B.; Cook, J.D.

1994-01-01

Iron absorption varies widely between subjects and groups of subjects because of differences in iron status which markedly influence iron assimilation from the gastrointestinal tract. A small dose of isotopically labelled inorganic iron termed the reference dose (3 mg iron as FeSO 4 ) has been used extensively during the past two decades to standardize food iron absorption in human subjects and thereby eliminate the effect of differences in iron status. Recent studies from this laboratory have shown that because of the high variability of absorption from the reference dose, nonheme iron absorption from a standardized meal provides a more reliable means of standardizing absorption from regional diets. We therefore performed initial studies with a rice based meal but we found a relatively high variation in absorption from 2.0 to 4.7% that presumably reflects differences in the phytate content of rice fours. We then undertook the evaluation of meals prepared with farina, a wheat product that is available in most regions of the world. In six different studies from a farina based meal, iron absorption ranged from 3.4 to 6.5%. Nonheme iron absorption from the farina meal when evaluated in separate laboratories extensively engaged in human studies of iron absorption, ranged from 5.1 to 10.8% but when related to the FeSO 4 dose, a more consistent ratio between 0.21 to 0.26 was observed with the exception of one laboratory where a very low absorption of 1.1.% was observed. Percentage absorption from the farina based meal decreased when the iron content of the meal was increased and showed the expected facilitation of absorption when increasing amounts of ascorbic acid were added. By reducing variability and measuring iron absorption from food rather than inorganic iron, we believe that the use of this standard meal will facilitate comparison of iron absorption data obtained in laboratories throughout the world. 4 refs, 2 tabs

Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Effects of Nasal Spray Suspension Particle Size and Properties.

Science.gov (United States)

Rygg, Alex; Hindle, Michael; Longest, P Worth

2016-04-01

The objective of this study was to use a recently developed nasal dissolution, absorption, and clearance (DAC) model to evaluate the extent to which suspended drug particle size influences nasal epithelial drug absorption for a spray product. Computational fluid dynamics (CFD) simulations of mucociliary clearance and drug dissolution were used to calculate total and microscale epithelial absorption of drug delivered with a nasal spray pump. Ranges of suspended particle sizes, drug solubilities, and partition coefficients were evaluated. Considering mometasone furoate as an example, suspended drug particle sizes in the range of 1-5 μm did not affect the total nasal epithelial uptake. However, the microscale absorption of suspended drug particles with low solubilities was affected by particle size and this controlled the extent to which the drug penetrated into the distal nasal regions. The nasal-DAC model was demonstrated to be a useful tool in determining the nasal exposure of spray formulations with different drug particle sizes and solubilities. Furthermore, the model illustrated a new strategy for topical nasal drug delivery in which drug particle size is selected to increase the region of epithelial surface exposure using mucociliary clearance while minimizing the drug dose exiting the nasopharynx.

FAF-Drugs2: Free ADME/tox filtering tool to assist drug discovery and chemical biology projects

Directory of Open Access Journals (Sweden)

Miteva Maria A

2008-09-01

Full Text Available Abstract Background Drug discovery and chemical biology are exceedingly complex and demanding enterprises. In recent years there are been increasing awareness about the importance of predicting/optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET properties of small chemical compounds along the search process rather than at the final stages. Fast methods for evaluating ADMET properties of small molecules often involve applying a set of simple empirical rules (educated guesses and as such, compound collections' property profiling can be performed in silico. Clearly, these rules cannot assess the full complexity of the human body but can provide valuable information and assist decision-making. Results This paper presents FAF-Drugs2, a free adaptable tool for ADMET filtering of electronic compound collections. FAF-Drugs2 is a command line utility program (e.g., written in Python based on the open source chemistry toolkit OpenBabel, which performs various physicochemical calculations, identifies key functional groups, some toxic and unstable molecules/functional groups. In addition to filtered collections, FAF-Drugs2 can provide, via Gnuplot, several distribution diagrams of major physicochemical properties of the screened compound libraries. Conclusion We have developed FAF-Drugs2 to facilitate compound collection preparation, prior to (or after experimental screening or virtual screening computations. Users can select to apply various filtering thresholds and add rules as needed for a given project. As it stands, FAF-Drugs2 implements numerous filtering rules (23 physicochemical rules and 204 substructure searching rules that can be easily tuned.

Absorption and Metabolism of Xanthophylls

OpenAIRE

Kotake-Nara, Eiichi; Nagao, Akihiko

2011-01-01

Dietary carotenoids, especially xanthophylls, have attracted significant attention because of their characteristic biological activities, including anti-allergic, anti-cancer, and anti-obese actions. Although no less than forty carotenoids are ingested under usual dietary habits, only six carotenoids and their metabolites have been found in human tissues, suggesting selectivity in the intestinal absorption of carotenoids. Recently, facilitated diffusion in addition to simple diffusion has bee...

Cyanobacteria: photosynthetic factories combining biodiversity, radiation resistance, and genetics to facilitate drug discovery.

Science.gov (United States)

Cassier-Chauvat, Corinne; Dive, Vincent; Chauvat, Franck

2017-02-01

Cyanobacteria are ancient, abundant, and widely diverse photosynthetic prokaryotes, which are viewed as promising cell factories for the ecologically responsible production of chemicals. Natural cyanobacteria synthesize a vast array of biologically active (secondary) metabolites with great potential for human health, while a few genetic models can be engineered for the (low level) production of biofuels. Recently, genome sequencing and mining has revealed that natural cyanobacteria have the capacity to produce many more secondary metabolites than have been characterized. The corresponding panoply of enzymes (polyketide synthases and non-ribosomal peptide synthases) of interest for synthetic biology can still be increased through gene manipulations with the tools available for the few genetically manipulable strains. In this review, we propose to exploit the metabolic diversity and radiation resistance of cyanobacteria, and when required the genetics of model strains, for the production and radioactive ( 14 C) labeling of bioactive products, in order to facilitate the screening for new drugs.

Nasal Delivery of High Molecular Weight Drugs

Directory of Open Access Journals (Sweden)

Erdal Cevher

2009-09-01

Full Text Available Nasal drug delivery may be used for either local or systemic effects. Low molecular weight drugs with are rapidly absorbed through nasal mucosa. The main reasons for this are the high permeability, fairly wide absorption area, porous and thin endothelial basement membrane of the nasal epithelium. Despite the many advantages of the nasal route, limitations such as the high molecular weight (HMW of drugs may impede drug absorption through the nasal mucosa. Recent studies have focused particularly on the nasal application of HMW therapeutic agents such as peptide-protein drugs and vaccines intended for systemic effects. Due to their hydrophilic structure, the nasal bioavailability of peptide and protein drugs is normally less than 1%. Besides their weak mucosal membrane permeability and enzymatic degradation in nasal mucosa, these drugs are rapidly cleared from the nasal cavity after administration because of mucociliary clearance. There are many approaches for increasing the residence time of drug formulations in the nasal cavity resulting in enhanced drug absorption. In this review article, nasal route and transport mechanisms across the nasal mucosa will be briefly presented. In the second part, current studies regarding the nasal application of macromolecular drugs and vaccines with nanoand micro-particulate carrier systems will be summarised.

Enhancement of in-vitro drug dissolution of ketoconazole for its optimal in-vivo absorption using Nanoparticles and Solid Dispersion forms of the drug

Science.gov (United States)

Syed, Mohammed Irfan

was modified to include 0.02%, 0.05% and 0.1% sodium lauryl sulfate. Here, after 2 hours, the amount of drug dissolved was calculated to be 10% from controls, 21% from solid dispersion and 36% from nanoparticles in SIF with 0.02% SLS. Drug release was 20% from controls, 41% from solid dispersion and 52% from nanoparticle formulation in SIF with 0.05% SLS. Whereas amount of drug released in SIF with 0.1% SLS showed 21% from the control, 62% from solid dispersion and 85% from Nanoparticles respectively. This data supports that the ketoconazole Nanoparticles and its solid-dispersion exhibit many fold increase in dissolution of the drug, which could lead to a less variable and enhanced in-vivo drug absorption profiles. In addition, the data from the Physical Characterization (DSC, XRD and FTIR) supports that there were no interaction within the ingredients occurred in Nanoparticles and solid-dispersion formulations of the drug sample. Wet Bead Milling and Hot Melt methods proved useful in developing the Nanoparticles and solid dispersion form of ketoconazole. Results from particle size analysis were in correlation with data obtained from Scanning electron Microscopy and size of the nanoparticles was below 100nm. The dissolution studies with the modified simulated intestinal fluid (SIF) exhibited several fold increase in the dissolution of the drug compared to the pure drug powder and the commercial products used as the control. Also, the results from the physical characterization studies clearly support the stability of ketoconazole in both of these formulations.

Slow-light enhancement of Beer-Lambert-Bouguer absorption

OpenAIRE

Mortensen, Niels Asger; Xiao, Sanshui

2007-01-01

We theoretically show how slow light in an optofluidic environment facilitates enhanced light-matter interactions, by orders of magnitude. The proposed concept provides strong opportunities for improving existing miniaturized chemical absorbance cells for Beer-Lambert-Bouguer absorption measurements widely employed in analytical chemistry.

Transdermic absorption of Melagenina II

International Nuclear Information System (INIS)

Hernandez Gonzalez, I.; Martinez Lopez, B.; Ruiz Pena, M.; Caso Pena, R.

1997-01-01

The transdermic absorption of Melagenina II (MII) was evaluated. MII was a labelled with 125I by the yodogen method and purified by column chromatography with Sephadex LH-20 in ethanol: water (7:3). In vitro absorption of ( 125I ) - MII thought human skin was carried out in Keshary-Chien modified diffusion cells. Tape stripping method was applied after 24 hours to evaluate the accumulated activity in dermis and epidermis. In vivo assays were performed in Sprague Dawley rats to analyze absorption of MII until 24 hours after a single application and for five days a low penetrability of the drug while in vivo there were not found blood levels significantly greater than zero , nevertheless and important amount of radioactivity was found in feces and urine. The activity was concentrated mainly in the application site in both models

Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides

DEFF Research Database (Denmark)

Holm, René; Porter, Christopher J H; Edwards, Glenn A

2003-01-01

The potential for lipidic self-microemulsifying drug delivery systems (SMEDDS) containing triglycerides with a defined structure, where the different fatty acids on the glycerol backbone exhibit different metabolic fate, to improve the lymphatic transport and the portal absorption of a poorly water......-soluble drug, halofantrine, were investigated in fasted lymph cannulated canines. Two different structured triglycerides were incorporated into the SMEDDS; 1,3-dioctanoyl-2-linoleyl-sn-glycerol (C8:0-C18:2-C8:0) (MLM) and 1,3-dilinoyl-2-octanoyl-sn-glycerol (C18:2-C8:0-C18:2) (LML). A previously optimised...... availability was affected by the triglyceride incorporated into the multi-component delivery system and availabilities of 56.9% (MLM) and 37.2% (LML) were found. These data indicate that the pharmaceutical scientist can use the structure of the lipid to affect the relative contribution of the two absorption...

Micro-segmental hair analysis for proving drug-facilitated crimes: Evidence that a victim ingested a sleeping aid, diphenhydramine, on a specific day.

Science.gov (United States)

Kuwayama, Kenji; Nariai, Maika; Miyaguchi, Hajime; Iwata, Yuko T; Kanamori, Tatsuyuki; Tsujikawa, Kenji; Yamamuro, Tadashi; Segawa, Hiroki; Abe, Hiroko; Iwase, Hirotaro; Inoue, Hiroyuki

2018-07-01

Sleeping aids are often abused in the commission of drug-facilitated crimes. Generally, there is little evidence that a victim ingested a spiked drink unknowingly because the unconscious victim cannot report the situation to the police immediately after the crime occurred. Although conventional segmental hair analysis can estimate the number of months since a targeted drug was ingested, this analysis cannot determine the specific day of ingestion. We recently developed a method of micro-segmental hair analysis using internal temporal markers (ITMs) to estimate the day of drug ingestion. This method was based on volunteer ingestion of ITMs to determine a timescale within individual hair strands, by segmenting a single hair strand at 0.4-mm intervals, corresponding to daily hair growth. This study assessed the ability of this method to estimate the day of ingestion of an over-the-counter sleeping aid, diphenhydramine, which can be easily abused. To model ingestion of a diphenhydramine-spiked drink unknowingly, each subject ingested a dose of diphenhydramine, followed by ingestion of two doses of the ITM, chlorpheniramine, 14days apart. Several hair strands were collected from each subject's scalp several weeks after the second ITM ingestion. Diphenhydramine and ITM were detected at specific regions within individual hair strands. The day of diphenhydramine ingestion was estimated from the distances between the regions and the days of ITM ingestion. The error between estimated and actual ingestion day ranged from -0.1 to 1.9days regardless of subjects and hair collection times. The total time required for micro-segmental analysis of 96 hair segments (hair length: 3.84cm) was approximately 2days and the cost was almost the same as in general drug analysis. This procedure may be applicable to the investigation of crimes facilitated by various drugs. Copyright © 2018 Elsevier B.V. All rights reserved.

Modulation of intestinal absorption of calcium

Energy Technology Data Exchange (ETDEWEB)

Fournier, P; Dupuis, Y [Ecole Pratique des Hautes Etudes, 75 - Paris (France); Paris-11 Univ., 92 - Chatenay-Malabry (France))

1975-01-01

Absorption of ingested calcium (2ml of a 10mM CaCl/sub 2/ solution + /sup 45/Ca) by the adult rat was shown to be facilitated by the simultaneous ingestion of an active carbohydrate, L-arabinose. As the carbohydrate concentration is increased from 10 to 200mM, the absorption of calcium is maximised at a level corresponding to about twice the control absorption level. A similar doubling of calcium absorption is obtained when a 100mM concentration of any one of a number of other carbohydrates is ingested simultaneously with a 10mM CaCl/sub 2/ solution. Conversely, the simultaneous ingestion of increasing doses (10 to 100mM) of phosphate (NaH/sub 2/PO/sub 4/) with a 10mM CaCl/sub 2/ solution results in decreased /sup 45/Ca absorption and retention by the adult rat. The maximum inhibition of calcium absorption by phosphate is independent of the concentration of the ingested calcium solution (from 5 to 50mM CaCl/sub 2/). The simultaneous ingestion of CaCl/sub 2/ (10mM) with lactose and sodium phosphate (50 and 10mM respectively) shows that the activation effect of lactose upon /sup 45/Ca absorption may be partly dissimulated by the presence of phosphate. These various observations indicate that, within a large concentration range (2 to 50mM CaCl/sub 2/) calcium absorption appears to be a precisely modulated diffusion process. Calcium absorption varies (between minimum and maximum levels) as a function of the state of saturation by the activators (carbohydrates) and inhibitors (phosphate) of the calcium transport system.

Assessment of absorption of four lignan constituents of JingNing ...

African Journals Online (AJOL)

Purpose: To study small intestinal absorption of schisadrol A, schisandrol B, schizandrin A and schisandrin B in JingNing particles using in situ single-pass intestinal perfusion (SPIP). Methods: Absorption rate constant (Ka) and apparent permeability (Papp) of the drugs at different concentrations in various parts of rat small ...

Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery

Science.gov (United States)

Wu, Shih-Ying; Fix, Samantha M.; Arena, Christopher B.; Chen, Cherry C.; Zheng, Wenlan; Olumolade, Oluyemi O.; Papadopoulou, Virginie; Novell, Anthony; Dayton, Paul A.; Konofagou, Elisa E.

2018-02-01

Focused ultrasound with nanodroplets could facilitate localized drug delivery after vaporization with potentially improved in vivo stability, drug payload, and minimal interference outside of the focal zone compared with microbubbles. While the feasibility of blood-brain barrier (BBB) opening using nanodroplets has been previously reported, characterization of the associated delivery has not been achieved. It was hypothesized that the outcome of drug delivery was associated with the droplet’s sensitivity to acoustic energy, and can be modulated with the boiling point of the liquid core. Therefore, in this study, octafluoropropane (OFP) and decafluorobutane (DFB) nanodroplets were used both in vitro for assessing their relative vaporization efficiency with high-speed microscopy, and in vivo for delivering molecules with a size relevant to proteins (40 kDa dextran) to the murine brain. It was found that at low pressures (300-450 kPa), OFP droplets vaporized into a greater number of microbubbles compared to DFB droplets at higher pressures (750-900 kPa) in the in vitro study. In the in vivo study, successful delivery was achieved with OFP droplets at 300 kPa and 450 kPa without evidence of cavitation damage using ¼ dosage, compared to DFB droplets at 900 kPa where histology indicated tissue damage due to inertial cavitation. In conclusion, the vaporization efficiency of nanodroplets positively impacted the amount of molecules delivered to the brain. The OFP droplets due to the higher vaporization efficiency served as better acoustic agents to deliver large molecules efficiently to the brain compared with the DFB droplets.

Nasal Absorption of Macromolecules from Powder Formulations and Effects of Sodium Carboxymethyl Cellulose on Their Absorption.

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Akiko Tanaka

Full Text Available The nasal absorption of macromolecules from powder formulations and the effect of sodium carboxymethyl cellulose (CMC-Na as a pharmaceutical excipient on their absorption were studied. Model macromolecules were fluorescein isothiocyanate-labeled dextran (average molecular weight of 4.4kDa, FD4 and insulin. The plasma concentration of FD4 after application of the powder containing 50% starch (control was higher than that after application of the solution, and the absorption from 50% starch powder was enhanced by the substitution of starch with CMC-Na. The fractional absorption of FD4 after administration of the CMC-Na powder formulation was 30% and 40% higher than that after administration from the solution and the starch powder, respectively. The nasal absorption of insulin from the powder and the effect of CMC-Na were similar with those of FD4. The effective absorption of FD4 and insulin after application of powder with CMC-Na could be due to the increase in the nasal residence of FD4 and insulin. No damage in the nasal mucosa or dysfunction of the mucociliary clearance was observed after application of the drug powder and CMC-Na. The present findings indicate that nasal delivery of powder formulations with the addition of CMC-Na as an excipient is a promising approach for improving the nasal absorption of macromolecules.

Peptide- and saccharide-conjugated dendrimers for targeted drug delivery: a concise review

Science.gov (United States)

Liu, Jie; Gray, Warren D.; Davis, Michael E.; Luo, Ying

2012-01-01

Dendrimers comprise a category of branched materials with diverse functions that can be constructed with defined architectural and chemical structures. When decorated with bioactive ligands made of peptides and saccharides through peripheral chemical groups, dendrimer conjugates are turned into nanomaterials possessing attractive binding properties with the cognate receptors. At the cellular level, bioactive dendrimer conjugates can interact with cells with avidity and selectivity, and this function has particularly stimulated interests in investigating the targeting potential of dendrimer materials for the design of drug delivery systems. In addition, bioactive dendrimer conjugates have so far been studied for their versatile capabilities to enhance stability, solubility and absorption of various types of therapeutics. This review presents a brief discussion on three aspects of the recent studies to use peptide- and saccharide-conjugated dendrimers for drug delivery: (i) synthesis methods, (ii) cell- and tissue-targeting properties and (iii) applications of conjugated dendrimers in drug delivery nanodevices. With more studies to elucidate the structure–function relationship of ligand–dendrimer conjugates in transporting drugs, the conjugated dendrimers hold promise to facilitate targeted delivery and improve drug efficacy for discovery and development of modern pharmaceutics. PMID:23741608

Studies on the percutaneous absorption of 14C-labelled Flurbiprofen, 3

International Nuclear Information System (INIS)

Nagao, Soshichi; Sakai, Takeo; Hayakawa, Toru

1983-01-01

Whole body autoradiography was carried out to clarify and compare the distribution of 14 C-labelled Flurbiprofen which was applied to the skin as an ointment in rats and guinea-pigs. Both in rats and guinea-pigs almost the same autoradiogram was gained. The radioactivity was strongest at the skin area inspite of the time elapse, showing that the drug was fixed in the site of skin applied. In other parts of the body, however, it was small except the kidney and intestine. It seemed that the absorption of the drug was a little although the migration of the drug into the blood circulation as fast at the beginning as was shown in pigs previously. A storonger radioactivity in the kidney and intestine might indicate that a main pathway of excretion of this drug was through those two organs. Absorption, distribution and excretion of the drug were not different between rats and guinea-pigs, similar to those observed in pigs. (author)

Terahertz absorption spectra of commonly used antimalarial drugs

Science.gov (United States)

Bawuah, Prince; Zeitler, J. Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik

2018-06-01

Terahertz (THz) spectra from the pure forms [i.e. the active pharmaceutical ingredients (APIs)] of four commonly used antimalarial drugs are reported. The well-defined spectral fingerprints obtained for these APIs in the spectral range of 0.1 THz-3 THz show the sensitivity of the THz time-domain spectroscopic (THz-TDS) method for screening antimalarial drugs. For identification purpose, two commercially available antimalarial tablets were detected. Clear spectral fingerprints of the APIs in the antimalarial tablets were obtained even amidst the several types of excipients present in the tablets. This observation further proves the high sensitivity of the THz techniques in tracking the presence or absence of API in a pharmaceutical tablet. We envisage that the spectral data obtained for these drugs can contribute to a spectroscopic database in the far infrared spectral region and hence support the modelling of THz sensing to differentiate between genuine and counterfeit antimalarial tablets.

Terahertz absorption spectra of commonly used antimalarial drugs

Science.gov (United States)

Bawuah, Prince; Zeitler, J. Axel; Ketolainen, Jarkko; Peiponen, Kai-Erik

2018-03-01

Terahertz (THz) spectra from the pure forms [i.e. the active pharmaceutical ingredients (APIs)] of four commonly used antimalarial drugs are reported. The well-defined spectral fingerprints obtained for these APIs in the spectral range of 0.1 THz-3 THz show the sensitivity of the THz time-domain spectroscopic (THz-TDS) method for screening antimalarial drugs. For identification purpose, two commercially available antimalarial tablets were detected. Clear spectral fingerprints of the APIs in the antimalarial tablets were obtained even amidst the several types of excipients present in the tablets. This observation further proves the high sensitivity of the THz techniques in tracking the presence or absence of API in a pharmaceutical tablet. We envisage that the spectral data obtained for these drugs can contribute to a spectroscopic database in the far infrared spectral region and hence support the modelling of THz sensing to differentiate between genuine and counterfeit antimalarial tablets.

Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

NARCIS (Netherlands)

Kip, Anke E; Schellens, Jan H M; Beijnen, Jos H; Dorlo, Thomas P C

This review describes the pharmacokinetic properties of the systemically administered antileishmanial drugs pentavalent antimony, paromomycin, pentamidine, miltefosine and amphotericin B (AMB), including their absorption, distribution, metabolism and excretion and potential drug-drug interactions.

Drug Facilitated Sexual Assault and That the Problems in Turkey

Directory of Open Access Journals (Sweden)

Nabi Kantarcı

2012-10-01

Full Text Available The assailants of sexuel assault to serve this purpose to the victims of many different drug can use. These drugs can be applied together with alcohol, soft drinks, water and other drinks can be given together. Most of these drugs tasteless and odorless. In a few minutes after ingestion chemical effect of drugs can start. Victims the conscious reduction and limitation of the physical move occur. Drug drinking from the pass the time until impact memory loss can occur. For this purpose the main benzodiazepines (Diazepam, flunitrazepam, lorazepam, etc., hypnotics (Zopiclone, zolpidem, anesthetics (Gama-hydroxybutyrate, ketamine, amphetamines (Metylendioxymetamphetamine=ecstasy, opiats (Cocaine, cannabis=marihuana and alcohols such as ethanol substances used. However in study frequently encountered in the literature; cocaine, cannabis, metylendioxymetamphetamine, zolpidem, ketamine hydrochloride, zopiclone, gamma hydroxybutirate, diazepam, flunitrazepam and the effects of these substances after oral ingestion were evaluated and the approach to victims.

Predicting transporter-mediated drug interactions: Commentary on: "Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin and rosuvastatin" and "Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A".

Science.gov (United States)

Zhang, L; Sparreboom, A

2017-04-01

Transporters, expressed in various tissues, govern the absorption, distribution, metabolism, and excretion of drugs, and consequently their inherent safety and efficacy profiles. Drugs may interact with a transporter as a substrate and/or an inhibitor. Understanding transporter-mediated drug-drug interactions (DDIs), in addition to enzyme-mediated DDIs, is an integral part of risk assessment in drug development and regulatory review because the concomitant use of more than one medication in patients is common. © 2016 ASCPT.

Delayed absorption of many (paracetamol, aspirin, other NSAIDs and zolmitriptan) but not all (sumatriptan, rizatriptan) drugs during migraine attacks and most likely normal gastric emptying outside attacks. A review

DEFF Research Database (Denmark)

Tfelt-Hansen, Peer Carsten

2017-01-01

Background In most pharmacokinetic studies, the oral absorption of drugs is impaired during migraine attacks but exceptions occur. A study on gastric emptying using gastric scintigraphy indicated that gastric stasis also occurs interictally in migraine. These studies were reviewed critically. Res...

High-throughput liquid-absorption air-sampling apparatus and methods

Science.gov (United States)

Zaromb, Solomon

2000-01-01

A portable high-throughput liquid-absorption air sampler [PHTLAAS] has an asymmetric air inlet through which air is drawn upward by a small and light-weight centrifugal fan driven by a direct current motor that can be powered by a battery. The air inlet is so configured as to impart both rotational and downward components of motion to the sampled air near said inlet. The PHTLAAS comprises a glass tube of relatively small size through which air passes at a high rate in a swirling, highly turbulent motion, which facilitates rapid transfer of vapors and particulates to a liquid film covering the inner walls of the tube. The pressure drop through the glass tube is 20% for vapors or airborne particulates in the 2-3.mu. range and >50% for particles larger than 4.mu.. In conjunction with various analyzers, the PHTLAAS can serve to monitor a variety of hazardous or illicit airborne substances, such as lead-containing particulates, tritiated water vapor, biological aerosols, or traces of concealed drugs or explosives.

High-throughput liquid-absorption air-sampling apparatus and methods

International Nuclear Information System (INIS)

2000-01-01

A portable high-throughput liquid-absorption air sampler [PHTLAAS] has an asymmetric air inlet through which air is drawn upward by a small and light-weight centrifugal fan driven by a direct current motor that can be powered by a battery. The air inlet is so configured as to impart both rotational and downward components of motion to the sampled air near said inlet. The PHTLAAS comprises a glass tube of relatively small size through which air passes at a high rate in a swirling, highly turbulent motion, which facilitates rapid transfer of vapors and particulates to a liquid film covering the inner walls of the tube. The pressure drop through the glass tube is 20% for vapors or airborne particulates in the 2--3 microns range and > 50% for particles larger than 4 microns. In conjunction with various analyzers, the PHTLAAS can serve to monitor a variety of hazardous or illicit airborne substances, such as lead-containing particulates, tritiated water vapor, biological aerosols, or traces of concealed drugs or explosives

Erbium-yttrium-aluminum-garnet laser irradiation ameliorates skin permeation and follicular delivery of antialopecia drugs.

Science.gov (United States)

Lee, Woan-Ruoh; Shen, Shing-Chuan; Aljuffali, Ibrahim A; Li, Yi-Ching; Fang, Jia-You

2014-11-01

Alopecia usually cannot be cured because of the available drug therapy being unsatisfactory. To improve the efficiency of treatment, erbium-yttrium-aluminum-garnet (Er-YAG) laser treatment was conducted to facilitate skin permeation of antialopecia drugs such as minoxidil (MXD), diphencyprone (DPCP), and peptide. In vitro and in vivo percutaneous absorption experiments were carried out by using nude mouse skin and porcine skin as permeation barriers. Fluorescence and confocal microscopies were used to visualize distribution of permeants within the skin. Laser ablation at a depth of 6 and 10 μm enhanced MXD skin accumulation twofold to ninefold depending on the skin barriers selected. DPCP absorption showed less enhancement by laser irradiation as compared with MXD. An ablation depth of 10 μm could increase the peptide flux from zero to 4.99 and 0.33 μg cm(-2) h(-1) for nude mouse skin and porcine skin, respectively. The laser treatment also promoted drug uptake in the hair follicles, with DPCP demonstrating the greatest enhancement (sixfold compared with the control). The imaging of skin examined by microscopies provided evidence of follicular and intercellular delivery assisted by the Er-YAG laser. Besides the ablative effect of removing the stratum corneum, the laser may interact with sebum to break up the barrier function, increasing the skin delivery of antialopecia drugs. The minimally invasive, well-controlled approach of laser-mediated drug permeation offers a potential way to treat alopecia. This study's findings provide the basis for the first report on laser-assisted delivery of antialopecia drugs. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Slowing down with resonance absorption

International Nuclear Information System (INIS)

Moura Neto, C. de; Nair, R.P.K.

1979-08-01

The presence of heavy nuclei in nuclear reactors, in significant concentrations, facilitates the appearance of absorption resonances. For the moderation in the presence of absorbers an exact solution of the integral equations is possible by numerical methods. Approximated solutions for separated resonances in function of the practical width, (NR and NRIM approximations) are discussed in this paper. The method is generalized, presenting the solution by an intermediate approximation, in the definition of the resonance integral. (Author) [pt

Polymeric nanoparticles developed by vitamin E-modified aliphatic polycarbonate polymer to promote oral absorption of oleanolic acid

Directory of Open Access Journals (Sweden)

Wenjuan Zhang

2017-11-01

Full Text Available Oleanolic acid (OA exhibited good pharmacological activities in the clinical treatment of hypoglycemia, immune regulation, acute jaundice and chronic toxic hepatitis. However, the oral delivery of OA is greatly limited by its inferior water solubility and poor intestinal mucosa permeability. Herein, we developed a novel polymeric nanoparticle (NP delivery system based on vitamin E modified aliphatic polycarbonate (mPEG-PCC-VE to facilitate oral absorption of OA. OA encapsulated mPEG-PCC-VE NPs (OA/mPEG-PCC-VE NPs showed uniform particle size of about 170 nm with high drug loading capability (8.9%. Furthermore, the polymeric mPEG-PCC-VE NPs, with good colloidal stability and pH-sensitive drug release characteristics, significantly enhanced the in vitro dissolution of OA in the alkaline medium. The in situ single pass intestinal perfusion (SPIP studies performed on rats demonstrated that the OA/mPEG-PCC-VE NPs showed significantly improved permeability in the whole intestinal tract when compared to OA solution, especially for duodenum and colon. As a result, the in vivo pharmacokinetics study indicated that the bioavailability of OA/mPEG-PCC-VE NPs showed 1.5-fold higher than commercially available OA tablets. These results suggest that mPEG-PCC-VE NPs are a promising platform to facilitate the oral delivery of OA.

Investigation of clinical pharmacokinetic variability of an opioid antagonist through physiologically based absorption modeling.

Science.gov (United States)

Ding, Xuan; He, Minxia; Kulkarni, Rajesh; Patel, Nita; Zhang, Xiaoyu

2013-08-01

Identifying the source of inter- and/or intrasubject variability in pharmacokinetics (PK) provides fundamental information in understanding the pharmacokinetics-pharmacodynamics relationship of a drug and project its efficacy and safety in clinical populations. This identification process can be challenging given that a large number of potential causes could lead to PK variability. Here we present an integrated approach of physiologically based absorption modeling to investigate the root cause of unexpectedly high PK variability of a Phase I clinical trial drug. LY2196044 exhibited high intersubject variability in the absorption phase of plasma concentration-time profiles in humans. This could not be explained by in vitro measurements of drug properties and excellent bioavailability with low variability observed in preclinical species. GastroPlus™ modeling suggested that the compound's optimal solubility and permeability characteristics would enable rapid and complete absorption in preclinical species and in humans. However, simulations of human plasma concentration-time profiles indicated that despite sufficient solubility and rapid dissolution of LY2196044 in humans, permeability and/or transit in the gastrointestinal (GI) tract may have been negatively affected. It was concluded that clinical PK variability was potentially due to the drug's antagonism on opioid receptors that affected its transit and absorption in the GI tract. Copyright © 2013 Wiley Periodicals, Inc.

[Drugs in pregnancy].

Science.gov (United States)

Danchev, N; Astrug, A; Tsankova, V; Nikolova, I

2006-01-01

The use of drugs in pregnancy is being discussed. The influence of different factors, both physiological and drug related (physicochemical characteristics, dose, duration of pharmacotherapy) on the processes of absorption, distribution, protein binding, metabolism and excretion are reviewed. The up-to-date classification of the drugs in relation to their effects on the fetus is presented. Special emphasize is given to drugs (antibiotics, cardio-vascular, psychotropic etc.) used for the treatment of acute and chronic conditions in the course of pregnancy. Drugs used for symptoms like pain, high temperature and constipation are also reviewed. Recommendations for the use of safer drugs in pregnancy are given. Drugs with proven teratogenic effects are presented.

Impact of concentration and rate of intraluminal drug delivery on absorption and gut wall metabolism of verapamil in humans.

Science.gov (United States)

Glaeser, Hartmut; Drescher, Siegfried; Hofmann, Ute; Heinkele, Georg; Somogyi, Andrew A; Eichelbaum, Michel; Fromm, Martin F

2004-09-01

In humans gut wall metabolism can be quantitatively as important as hepatic drug metabolism in limiting the systemic exposure to drugs after oral administration. However, it has been proposed that the role of gut wall metabolism might be overemphasized, because high luminal drug concentrations would lead to a saturation of gut wall metabolism. Therefore we investigated the impact of concentration and rate of intraluminal drug delivery on absorption (F(abs)) and gastrointestinal extraction (E(GI)) of a luminally administered cytochrome P450 (CYP) 3A4 substrate (verapamil) using a multilumen perfusion catheter in combination with a stable isotope technique. Two 20-cm-long, adjacent jejunal segments were isolated with the multilumen perfusion catheter in 7 subjects. In this study 80 mg of unlabeled verapamil (d0-verapamil 15 min) was infused into one segment over a 15-minute period, 80 mg of 3-fold deuterated verapamil (d3-verapamil 240 min) was administered over a 240-minute period into the other segment, and simultaneously, 5 mg of 7-fold deuterated verapamil (d7-verapamil) was injected intravenously over a 15-minute period. The rate of intraluminal drug delivery had only a modest effect on bioavailability of the verapamil isotopes (after correction for F abs ) (F/F abs d3-verapamil 240 min versus d0-verapamil 15 min, 0.24 +/- 0.10 versus 0.20 +/- 0.09; P d3-verapamil 240 min was 0.50 +/- 0.18 compared with 0.59 +/- 0.14 for d0 -verapamil 15 min ( P d0-verapamil 15 min ) correlated strongly with E GI (d3-verapamil 240 min ) (r = 0.94, P d0-verapamil 15 min /d3-verapamil 240 min (r = 0.62, P =.03). Substantial gut wall metabolism of verapamil occurs in humans and can be predicted from ex vivo data by use of shed enterocytes. The different intraluminal concentrations and rates of intraluminal drug delivery did not lead to a pronounced saturation of intestinal drug metabolism.

Rectal drug administration: clinical pharmacokinetic considerations.

Science.gov (United States)

de Boer, A G; Moolenaar, F; de Leede, L G; Breimer, D D

1982-01-01

The human rectum represents a body cavity in which drugs can be easily introduced and retained and from which absorption is well possible. There are important therapeutic reasons why it is sometimes preferable to give a drug rectally rather than orally, e.g. in cases of nausea and vomiting. Drawbacks of rectal drug administration include the interruption of absorption by defaecation and lack of patient acceptability. The mechanism of drug absorption from the rectum is probably no different to that in the upper part of the gastrointestinal tract, despite the fact that the physiological circumstances (e.g. pH, fluid content) differ substantially, Absorption from aqueous and alcoholic solutions may occur very rapidly, which has proved to be of considerable therapeutic value in the rapid suppression of acute convulsive attacks by diazepam (e.g. in children), but absorption from suppositories is generally slower and very much dependent on the nature of the suppository base, the use of surfactants or other additives, particle size of the active ingredient, etc. There is some evidence that hepatic first-pass elimination of high clearance drugs is partially avoided after rectal administration, e.g. lignocaine. This can be explained by the rectal venous blood supply: the upper part is connected with the portal system, whereas the lower part is directly connected with the systemic circulation. Plasma concentration data following rectal administration of representatives of several classes of drugs are reviewed: anticonvulsants, non-narcotic analgesics and non-steroidal anti-inflammatory agents, hypnosedatives and anaesthetics, strong analgesics, theophylline and derivatives, corticosteroids, antibacterial agents, thiazinamium, promethazine, hyoscine-N-butyl-bromide, streptokinase, progesterone, ergotamine tartrate and levodopa. Only limited number of cases has it been adequately shown that the rectal route of administration gives plasma concentrations which are comparable to

Characterization of particulate drug delivery systems for oral delivery of Peptide and protein drugs.

Science.gov (United States)

Christophersen, Philip Carsten; Fano, Mathias; Saaby, Lasse; Yang, Mingshi; Nielsen, Hanne Mørck; Mu, Huiling

2015-01-01

Oral drug delivery is a preferred route because of good patient compliance. However, most peptide/ protein drugs are delivered via parenteral routes because of the absorption barriers in the gastrointestinal (GI) tract such as enzymatic degradation by proteases and low permeability acrossthe biological membranes. To overcome these barriers, different formulation strategies for oral delivery of biomacromolecules have been proposed, including lipid based formulations and polymer-based particulate drug delivery systems (DDS). The aim of this review is to summarize the existing knowledge about oral delivery of peptide/protein drugs and to provide an overview of formulationand characterization strategies. For a better understanding of the challenges in oral delivery of peptide/protein drugs, the composition of GI fluids and the digestion processes of different kinds of excipients in the GI tract are summarized. Additionally, the paper provides an overview of recent studies on characterization of solid drug carriers for peptide/protein drugs, drug distribution in particles, drug release and stability in simulated GI fluids, as well as the absorption of peptide/protein drugs in cell-based models. The use of biorelevant media when applicable can increase the knowledge about the quality of DDS for oral protein delivery. Hopefully, the knowledge provided in this review will aid the establishment of improved biorelevant models capable of forecasting the performance of particulate DDS for oral peptide/protein delivery.

Assessment of veterinary drugs in plants using pharmacokinetic approaches: The absorption, distribution and elimination of tetracycline and sulfamethoxazole in ephemeral vegetables

Science.gov (United States)

Chen, Hui-Ru; Rairat, Tirawat; Loh, Shih-Hurng; Wu, Yu-Chieh; Vickroy, Thomas W.

2017-01-01

The present study was carried out to demonstrate novel use of pharmacokinetic approaches to characterize drug behaviors/movements in the vegetables with implications to food safety. The absorption, distribution, metabolism and most importantly, the elimination of tetracycline (TC) and sulfamethoxazole (SMX) in edible plants Brassica rapa chinensis and Ipomoea aquatica grown hydroponically were demonstrated and studied using non-compartmental pharmacokinetic analysis. The results revealed drug-dependent and vegetable-dependent pharmacokinetic differences and indicated that ephemeral vegetables could have high capacity accumulating antibiotics (up to 160 μg g-1 for TC and 38 μg g-1 for SMX) within hours. TC concentration in the root (Cmax) could reach 11 times higher than that in the cultivation fluid and 3–28 times higher than the petioles/stems. Based on the volume of distribution (Vss), SMX was 3–6 times more extensively distributed than TC. Both antibiotics showed evident, albeit slow elimination phase with elimination half-lives ranging from 22 to 88 hours. For the first time drug elimination through the roots of a plant was demonstrated, and by viewing the root as a central compartment and continuous infusion without a loading dose as drug administration mode, it is possible to pharmacokinetically monitor the movement of antibiotics and their fate in the vegetables with more detailed information not previously available. Phyto-pharmacokinetic could be a new area worth developing new models for the assessment of veterinary drugs in edible plants. PMID:28797073

The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class III immediate-release drugs predicted by computer simulation.

Science.gov (United States)

Tsume, Yasuhiro; Amidon, Gordon L

2010-08-02

The Biopharmaceutical Classification System (BCS) guidance issued by the FDA allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release (IR) solid oral dosage forms only for BCS class I drugs. However, a number of drugs within BCS class III have been proposed to be eligible for biowaivers. The World Health Organization (WHO) has shortened the requisite dissolution time of BCS class III drugs on their Essential Medicine List (EML) from 30 to 15 min for extended biowaivers; however, the impact of the shorter dissolution time on AUC(0-inf) and C(max) is unknown. The objectives of this investigation were to assess the ability of gastrointestinal simulation software to predict the oral absorption of the BCS class I drugs propranolol and metoprolol and the BCS class III drugs cimetidine, atenolol, and amoxicillin, and to perform in silico bioequivalence studies to assess the feasibility of extending biowaivers to BCS class III drugs. The drug absorption from the gastrointestinal tract was predicted using physicochemical and pharmacokinetic properties of test drugs provided by GastroPlus (version 6.0). Virtual trials with a 200 mL dose volume at different drug release rates (T(85%) = 15 to 180 min) were performed to predict the oral absorption (C(max) and AUC(0-inf)) of the above drugs. Both BCS class I drugs satisfied bioequivalence with regard to the release rates up to 120 min. The results with BCS class III drugs demonstrated bioequivalence using the prolonged release rate, T(85%) = 45 or 60 min, indicating that the dissolution standard for bioequivalence is dependent on the intestinal membrane permeability and permeability profile throughout the gastrointestinal tract. The results of GastroPlus simulations indicate that the dissolution rate of BCS class III drugs could be prolonged to the point where dissolution, rather than permeability, would control the overall absorption. For BCS class III drugs with intestinal absorption patterns

DRUG-INTERACTIONS WITH QUINOLONE ANTIBACTERIALS

NARCIS (Netherlands)

BROUWERS, JRBJ

1992-01-01

The quinolone antibacterials are prone to many interactions with other drugs. Quinolone absorption is markedly reduced with antacids containing aluminium, magnesium and/or calcium and therapeutic failure may result. Other metallic ion-containing drugs, such as sucralfate, iron salts, and zinc salts,

Near-infrared free carrier absorption in heavily doped silicon

International Nuclear Information System (INIS)

Baker-Finch, Simeon C.; McIntosh, Keith R.; Yan, Di; Fong, Kean Chern; Kho, Teng C.

2014-01-01

Free carrier absorption in heavily doped silicon can have a significant impact on devices operating in the infrared. In the near infrared, the free carrier absorption process can compete with band to band absorption processes, thereby reducing the number of available photons to optoelectronic devices such as solar cells. In this work, we fabricate 18 heavily doped regions by phosphorus and boron diffusion into planar polished silicon wafers; the simple sample structure facilitates accurate and precise measurement of the free carrier absorptance. We measure and model reflectance and transmittance dispersion to arrive at a parameterisation for the free carrier absorption coefficient that applies in the wavelength range between 1000 and 1500 nm, and the range of dopant densities between ∼10 18 and 3 × 10 20  cm −3 . Our measurements indicate that previously published parameterisations underestimate the free carrier absorptance in phosphorus diffusions. On the other hand, published parameterisations are generally consistent with our measurements and model for boron diffusions. Our new model is the first to be assigned uncertainty and is well-suited to routine device analysis

Lipid-based formulations for oral administration of poorly water-soluble drugs

DEFF Research Database (Denmark)

Mu, Huiling; Holm, René; Müllertz, Anette

2013-01-01

Lipid-based drug delivery systems have shown great potentials in oral delivery of poorly water-soluble drugs, primarily for lipophilic drugs, with several successfully marketed products. Pre-dissolving drugs in lipids, surfactants, or mixtures of lipids and surfactants omits the dissolving....../dissolution step, which is a potential rate limiting factor for oral absorption of poorly water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form has a pronounced effect...

Advancement in integrin facilitated drug delivery.

Science.gov (United States)

Arosio, Daniela; Casagrande, Cesare

2016-02-01

The research of integrin-targeted anticancer agents has recorded important advancements in ingenious design of delivery systems, based either on the prodrug approach, or on nanoparticle carriers, but for now, none of these has reached a clinical stage of development. Past work in this area has been extensively reviewed by us and others. Thus, the purpose and scope of the present review is to survey the advancement reported in the last 3years, with focus on innovative delivery systems that appear to afford openings for future developments. These systems exploit the labelling with conventional and novel integrin ligands for targeting the interface of cancer cells and of endothelial cells involved in cancer angiogenesis, with the proteins of the extracellular matrix, in the circulation, in tissues, and in tumour stroma, as the site of progression and metastatic evolution of the disease. Furthermore, these systems implement the expertise in the development of nanomedicines to the purpose of achieving preferential biodistribution and uptake in cancer tissues, internalisation in cancer cells, and release of the transported drugs at intracellular sites. The assessment of the value of controlling these factors, and their combination, for future developments requires support of biological testing in appropriate mechanistic models, but also imperatively demand confirmation in therapeutically relevant in vivo models for biodistribution, efficacy, and lack of off-target effects. Thus, among many studies, we have tried to point out the results supported by relevant in vivo studies, and we have emphasised in specific sections those addressing the medical needs of drug delivery to brain tumours, as well as the delivery of oligonucleotides modulating gene-dependent pathological mechanism. The latter could constitute the basis of a promising third branch in the therapeutic armamentarium against cancer, in addition to antibody-based agents and to cytotoxic agents. Copyright © 2015

Studies on effective atomic numbers for photon energy absorption and electron density of some narcotic drugs in the energy range 1 keV-20 MeV

Science.gov (United States)

Gounhalli, Shivraj G.; Shantappa, Anil; Hanagodimath, S. M.

2013-04-01

Effective atomic numbers for photon energy absorption ZPEA,eff, photon interaction ZPI,eff and for electron density Nel, have been calculated by a direct method in the photon-energy region from 1 keV to 20 MeV for narcotic drugs, such as Heroin (H), Cocaine (CO), Caffeine (CA), Tetrahydrocannabinol (THC), Cannabinol (CBD), Tetrahydrocannabivarin (THCV). The ZPEA,eff, ZPI,eff and Nel values have been found to change with energy and composition of the narcotic drugs. The energy dependence ZPEA,eff, ZPI,eff and Nel is shown graphically. The maximum difference between the values of ZPEA,eff, and ZPI,eff occurs at 30 keV and the significant difference of 2 to 33% for the energy region 5-100 keV for all drugs. The reason for these differences is discussed.

Profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets using gastrointestinal simulation technology.

Science.gov (United States)

Wu, Chunnuan; Sun, Le; Sun, Jin; Yang, Yajun; Ren, Congcong; Ai, Xiaoyu; Lian, He; He, Zhonggui

2013-09-10

The aim of the present study was to correlate in vitro properties of drug formulation to its in vivo performance, and to elucidate the deciding properties of oral absorption. Gastrointestinal simulation technology (GST) was used to simulate the in vivo plasma concentration-time curve and was implemented by GastroPlus™ software. Lansoprazole, a typical BCS class II drug, was chosen as a model drug. Firstly, physicochemical and pharmacokinetic parameters of lansoprazole were determined or collected from literature to construct the model. Validation of the developed model was performed by comparison of the predicted and the experimental plasma concentration data. We found that the predicted curve was in a good agreement with the experimental data. Then, parameter sensitivity analysis (PSA) was performed to find the key parameters of oral absorption. The absorption was particularly sensitive to dose, solubility and particle size for lansoprazole enteric-coated tablets. With a single dose of 30 mg and the solubility of 0.04 mg/ml, the absorption was complete. A good absorption could be achieved with lansoprazole particle radius down to about 25 μm. In summary, GST is a useful tool for profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets and guiding the formulation optimization. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Interaction of Drug or Food with Drug Transporters in Intestine and Liver.

Science.gov (United States)

Nakanishi, Takeo; Tamai, Ikumi

2015-01-01

Oral bioavailability (F) is determined as fraction of the drug dose absorbed through the gastrointestinal membranes (Fa), the unmetabolized fraction of the absorbed dose that passes through the gut into the portal blood (Fg), and the hepatic first pass availability (Fh), namely F is expressed as the product of Fa, Fg and Fh (F = Fa.Fg.Fh). Current evidence suggests that transporter proteins play a role in intestinal absorption and hepatobiliary clearance of drugs. Among those transporters, this review will focus on PEPT1 and OATP2B1 as influx transporter and p-glycoprotein (P-gp) and BCRP as efflux transporter in intestinal epithelial cells, and on OATP1B1 and 1B3 as influx transporter and MRP2 as efflux transporter in hepatocytes, respectively, because drug-drug (DDI) and -food (DFI) interactions on these transporter are considered to affect bioavailability of their substrate drugs. DDI and DFI may reduce systemic exposure to drug by blocking influx transporters in intestine, but increase it by modulating influx and efflux transporters in liver and efflux transporters in intestines. Namely, drug disposition and efficacy are likely affected by DDI and DFI, resulting in treatment failures or increase in adverse effect. Therefore, it is of significantly importance to understand precise mechanism of DDI and DFI. This review will present information about transporter-based DDI and DFI in the processes of intestinal absorption and hepatic clearance of drugs, and discuss about their clinical implication.

Absorption-desorption of drugs in porous polymers obtained by plasma; Absorcion-desorcion de farmacos en polimeros porosos obtenidos por plasma

Energy Technology Data Exchange (ETDEWEB)

Gonzalez T, M.

2016-07-01

A study about drug absorption and release in plasma polymers is presented in this work, these materials can be used as implants in the human body. In these applications the polymer should be biocompatible and/or biodegradable. Poly pyrroles and poly allylamine s synthesized by plasma have amine groups in their structure which makes them biocompatible with potential as drug carriers. In this function, the polymers were lyophilized to induce pores where the drug can be hosted. Drug-polymer mixtures with 1:10 ratio were prepared. The mixture morphology was studied by Scanning Electron Microscopy while their chemical structure was studied by Infrared Spectroscopy and X-ray Photoelectron Spectroscopy. Two models were studied to assess drug release, dynamic and static, in two solutions: water and Krebs Ringer (Kr) using the UV characteristic absorbance of each drug. In the static model release, 5 mg of the mixture were placed in 10 ml of solution. In the dynamic model, the release was performed with 5 mg of the mixture in 10 ml of solution, 1.5 ml of release medium was removed for UV analysis and replaced with an equal volume of fresh medium. The results indicate that the morphology of the polymers was modified with the lyophilization, in Poly pyrrole pores were induced with diameter in the range of 0.7 to 19 μm, while in Polyallyl amine the surface changed from smooth to rough. Drugs were absorbed in Poly pyrrole by filling the pores first and then coating the polymer with a drug layer. In Poly allylamine the drugs adhered to the polymer surface. Analyzing the atomic orbitals of the mixtures, it was found that the drugs interacted with the polymer. The most affected orbital was S2p, whose separation between 1/2 and 3/2 sub orbitals increased from 0.9 eV in Dapsone and Heparin to 4 eV in the mixtures, where the oxidation state changed from valence 6 to 6 and 2 in the mixtures. This suggests physicochemical interaction between drug and polymer. The drugs were released

Absorptive capacity and smart companies

Directory of Open Access Journals (Sweden)

Patricia Moro González

2014-12-01

.Originality/value: This paper presents a novel integration of various concepts: the concept of absorptive capacity from academic research and strategic consulting associated with the tools of information management. This allows us to develop better management practices by obtaining profit from these investments and facilitating the creation of intelligence inside organizations.

Effective photons in weakly absorptive dielectric media and the Beer–Lambert–Bouguer law

International Nuclear Information System (INIS)

Judge, A C; Brownless, J S; Martijn de Sterke, C; Bhat, N A R; Sipe, J E; Steel, M J

2014-01-01

We derive effective photon modes that facilitate an intuitive and convenient picture of photon dynamics in a structured Kramers–Kronig dielectric in the limit of weak absorption. Each mode is associated with a mode field distribution that includes the effects of both material and structural dispersion, and an effective line-width that determines the temporal decay rate of the photon. These results are then applied to obtain an expression for the Beer–Lambert–Bouguer law absorption coefficient for unidirectional propagation in structured media consisting of dispersive, weakly absorptive dielectric materials

Dynamics of water absorption through superabsorbent polymer

Science.gov (United States)

Chang, Sooyoung; Kim, Wonjung

2017-11-01

Superabsorbent polymers (SAPs) consist of hydrophilic cross-linked polymer networks that can absorb and retain a great amount of water relative to their own mass, so that they are widely used for disposable diapers and holding soil moisture in agriculture. SAPs are typically available in the form of submillimeter-sized particles, and the water absorption is driven by capillary flows between particles as well as diffusion that entail swelling. Although the control of water absorption of SAPs is important in engineering applications, but the dynamics of water absorption in SAP particles has not been fully understood. We examine the dynamics of the water absorption of sodium polyacrylate, one of the most common SAP. We experimentally measured the water absorption of sodium polyacrylate particles in one-dimensional confined channel. The water flows through the particles were analyzed by capillarity dominant at the early stage and by diffusion involving volume expansion critical at a later stage. The results provide a quantitative basis of the hydrodynamic analysis of the water flow through SAP particles from a macroscopic point of view, facilitating the prediction of water uptake of SAPs in hygienic and agricultural applications. This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIP) (No.2015R1A2A2A04006181).

Future of the transdermal drug delivery market--have we barely touched the surface?

Science.gov (United States)

Watkinson, Adam C; Kearney, Mary-Carmel; Quinn, Helen L; Courtenay, Aaron J; Donnelly, Ryan F

2016-01-01

Transdermal drug delivery is the movement of drugs across the skin for absorption into the systemic circulation. Transfer of the drug can occur via passive or active means; passive transdermal products do not disrupt the stratum corneum to facilitate delivery whereas active technologies do. Due to the very specific physicochemical properties necessary for successful passive transdermal drug delivery, this sector of the pharmaceutical industry is relatively small. There are many well-documented benefits of this delivery route however, and as a result there is great interest in increasing the number of therapeutic substances that can be delivered transdermally. This review discusses the various transdermal products that are currently/have been marketed, and the paths that led to their success, or lack of. Both passive and active transdermal technologies are considered with the advantages and limitations of each highlighted. In addition to marketed products, technologies that are in the investigative stages by various pharmaceutical companies are reviewed. Passive transdermal drug delivery has made limited progress in recent years, however with the ongoing intense research into active technologies, there is great potential for growth within the transdermal delivery market. A number of active technologies have already been translated into marketed products, with other platforms including microneedles, rapidly progressing towards commercialisation.

Corneal and conjunctival drug permeability: Systematic comparison and pharmacokinetic impact in the eye.

Science.gov (United States)

Ramsay, Eva; Del Amo, Eva M; Toropainen, Elisa; Tengvall-Unadike, Unni; Ranta, Veli-Pekka; Urtti, Arto; Ruponen, Marika

2018-07-01

On the surface of the eye, both the cornea and conjunctiva are restricting ocular absorption of topically applied drugs, but barrier contributions of these two membranes have not been systemically compared. Herein, we studied permeability of 32 small molecular drug compounds across an isolated porcine cornea and built a quantitative structure-property relationship (QSPR) model for the permeability. Corneal drug permeability (data obtained for 25 drug molecules) showed a 52-fold range in permeability (0.09-4.70 × 10 -6  cm/s) and the most important molecular descriptors in predicting the permeability were hydrogen bond donor, polar surface area and halogen ratio. Corneal permeability values were compared to their conjunctival drug permeability values. Ocular drug bioavailability and systemic absorption via conjunctiva were predicted for this drug set with pharmacokinetic calculations. Drug bioavailability in the aqueous humour was simulated to be drug across the conjunctiva to the blood circulation restricts significantly ocular drug bioavailability and, therefore, ocular absorption does not increase proportionally with the increasing corneal drug permeability. Copyright © 2018 Elsevier B.V. All rights reserved.

Drug-drug interactions of antifungal agents and implications for patient care.

Science.gov (United States)

Gubbins, Paul O; Amsden, Jarrett R

2005-10-01

Drug interactions in the gastrointestinal tract, liver and kidneys result from alterations in pH, ionic complexation, and interference with membrane transport proteins and enzymatic processes involved in intestinal absorption, enteric and hepatic metabolism, renal filtration and excretion. Azole antifungals can be involved in drug interactions at all the sites, by one or more of the above mechanisms. Consequently, azoles interact with a vast array of compounds. Drug-drug interactions associated with amphotericin B formulations are predictable and result from the renal toxicity and electrolyte disturbances associated with these compounds. The echinocandins are unknown cytochrome P450 substrates and to date are relatively devoid of significant drug-drug interactions. This article reviews drug interactions involving antifungal agents that affect other agents and implications for patient care are highlighted.

Self-Assembled Core-Shell-Type Lipid-Polymer Hybrid Nanoparticles: Intracellular Trafficking and Relevance for Oral Absorption.

Science.gov (United States)

Li, Qiuxia; Xia, Dengning; Tao, Jinsong; Shen, Aijun; He, Yuan; Gan, Yong; Wang, Chi

2017-10-01

Lipid-polymer hybrid nanoparticles (NPs) are advantageous for drug delivery. However, their intracellular trafficking mechanism and relevance for oral drug absorption are poorly understood. In this study, self-assembled core-shell lipid-polymer hybrid NPs made of poly(lactic-co-glycolic acid) (PLGA) and various lipids were developed to study their differing intracellular trafficking in intestinal epithelial cells and their relevance for oral absorption of a model drug saquinavir (SQV). Our results demonstrated that the endocytosis and exocytosis of hybrid NPs could be changed by varying the kind of lipid. A glyceride mixture (hybrid NPs-1) decreased endocytosis but increased exocytosis in Caco-2 cells, whereas the phospholipid (E200) (hybrid NPs-2) decreased endocytosis but exocytosis was unaffected as compared with PLGA nanoparticles. The transport of hybrid NPs-1 in cells involved various pathways, including caveolae/lipid raft-dependent endocytosis, and clathrin-mediated endocytosis and macropinocytosis, which was different from the other groups of NPs that involved only caveolae/lipid raft-dependent endocytosis. Compared with that of the reference formulation (nanoemulsion), the oral absorption of SQV-loaded hybrid NPs in rats was poor, probably due to the limited drug release and transcytosis of NPs across the intestinal epithelium. In conclusion, the intracellular processing of hybrid NPs in intestinal epithelia can be altered by adding lipids to the NP. However, it appears unfavorable to use PLGA-based NPs to improve oral absorption of SQV compared with nanoemulsion. Our findings will be essential in the development of polymer-based NPs for the oral delivery of drugs with the purpose of improving their oral absorption. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Organizational forms and knowledge absorption

Directory of Open Access Journals (Sweden)

Radovanović Nikola

2016-01-01

Full Text Available Managing the entire portion of knowledge in an organization is a challenging task. At the organizational level, there can be enormous quantities of unknown, poorly valued or inefficiently applied knowledge. This is normally followed with the underdeveloped potential or inability of organizations to absorb knowledge from external sources. Facilitation of the efficient internal flow of knowledge within the established communication network may positively affect organizational capacity to absorb or identify, share and subsequently apply knowledge to commercial ends. Based on the evidences that the adoption of different organizational forms affects knowledge flows within an organization, this research analyzed the relationship between common organizational forms and absorptive capacity of organizations. In this paper, we test the hypothesis stating that the organizational structure affects knowledge absorption and exploitation in the organization. The methodology included quantitative and qualitative research method based on a questionnaire, while the data has been statistically analyzed and the hypothesis has been tested with the use of cross-tabulation and chi-square tests. The findings suggest that the type of organizational form affects knowledge absorption capacity and that having a less formalized and more flexible structure in an organization increases absorbing and exploiting opportunities of potentially valuable knowledge.

High-throughput liquid-absorption air-sampling apparatus and methods

Energy Technology Data Exchange (ETDEWEB)

NONE

2000-07-11

A portable high-throughput liquid-absorption air sampler [PHTLAAS] has an asymmetric air inlet through which air is drawn upward by a small and light-weight centrifugal fan driven by a direct current motor that can be powered by a battery. The air inlet is so configured as to impart both rotational and downward components of motion to the sampled air near said inlet. The PHTLAAS comprises a glass tube of relatively small size through which air passes at a high rate in a swirling, highly turbulent motion, which facilitates rapid transfer of vapors and particulates to a liquid film covering the inner walls of the tube. The pressure drop through the glass tube is < 10 cm of water, usually < 5 cm of water. The sampler's collection efficiency is usually > 20% for vapors or airborne particulates in the 2--3 microns range and > 50% for particles larger than 4 microns. In conjunction with various analyzers, the PHTLAAS can serve to monitor a variety of hazardous or illicit airborne substances, such as lead-containing particulates, tritiated water vapor, biological aerosols, or traces of concealed drugs or explosives.

Pickering emulsions stabilized by biodegradable block copolymer micelles for controlled topical drug delivery.

Science.gov (United States)

Laredj-Bourezg, Faiza; Bolzinger, Marie-Alexandrine; Pelletier, Jocelyne; Chevalier, Yves

2017-10-05

Surfactant-free biocompatible and biodegradable Pickering emulsions were investigated as vehicles for skin delivery of hydrophobic drugs. O/w emulsions of medium-chain triglyceride (MCT) oil droplets loaded with all-trans retinol as a model hydrophobic drug were stabilized by block copolymer nanoparticles: either poly(lactide)-block-poly(ethylene glycol) (PLA-b-PEG) or poly(caprolactone)-block-poly(ethylene glycol) (PCL-b-PEG). Those innovative emulsions were prepared using two different processes allowing drug loading either inside oil droplets or inside both oil droplets and non-adsorbed block copolymer nanoparticles. Skin absorption of retinol was investigated in vitro on pig skin biopsies using the Franz cell method. Supplementary experiments by confocal fluorescence microscopy allowed the visualization of skin absorption of the Nile Red dye on histological sections. Retinol and Nile Red absorption experiments showed the large accumulation of hydrophobic drugs in the stratum corneum for the Pickering emulsions compared to the surfactant-based emulsion and an oil solution. Loading drug inside both oil droplets and block copolymer nanoparticles enhanced again skin absorption of drugs, which was ascribed to the supplementary contribution of free block copolymer nanoparticles loaded with drug. Such effect allowed tuning drug delivery to skin over a wide range by means of a suitable selection of either the formulation or the drug loading process. Copyright © 2017 Elsevier B.V. All rights reserved.

Investigating the correlation between in vivo absorption and in vitro release of fenofibrate from lipid matrix particles in biorelevant medium.

Science.gov (United States)

Borkar, Nrupa; Xia, Dengning; Holm, René; Gan, Yong; Müllertz, Anette; Yang, Mingshi; Mu, Huiling

2014-01-23

Lipid matrix particles (LMP) may be used as better carriers for poorly water-soluble drugs than liquid lipid carriers because of reduced drug mobilization in the formulations. However, the digestion process of solid lipid particles and their effect on the absorption of poorly water-soluble drugs are not fully understood. This study aimed at investigating the effect of particle size of LMP on drug release in vitro as well as absorption in vivo in order to get a better understanding on the effect of degradation of lipid particles on drug solubilisation and absorption. Fenofibrate, a model poorly water-soluble drug, was incorporated into LMP in this study using probe ultrasound sonication. The resultant LMP were characterised in terms of particle size, size distribution, zeta potential, entrapment efficiency, in vitro lipolysis and in vivo absorption in rat model. LMP of three different particle sizes i.e. approximately 100 nm, 400 nm, and 10 μm (microparticles) were produced with high entrapment efficiencies. The in vitro lipolysis study showed that the recovery of fenofibrate in the aqueous phase for 100 nm and 400 nm LMP was significantly higher (pmicroparticles>control. In summary, the present study demonstrated the particle size dependence of bioavailability of fenofibrate loaded LMP in rat model which correlates well with the in vitro drug release performed in the biorelevant medium. Copyright © 2013 Elsevier B.V. All rights reserved.

Skin absorption through atopic dermatitis skin

DEFF Research Database (Denmark)

Halling-Overgaard, A-S; Kezic, S; Jakasa, I

2017-01-01

Patients with atopic dermatitis have skin barrier impairment in both lesional and non-lesional skin. They are typically exposed to emollients daily and topical anti-inflammatory medicaments intermittently, hereby increasing the risk of developing contact allergy and systemic exposed to chemicals...... ingredients found in these topical preparations. We systematically searched for studies that investigated skin absorption of various penetrants, including medicaments, in atopic dermatitis patients, but also animals with experimentally induced dermatitis. We identified 40 articles, i.e. 11 human studies...... examining model penetrants, 26 human studies examining atopic dermatitis drugs and 3 animal studies. We conclude that atopic dermatitis patients have nearly two-fold increased skin absorption when compared to healthy controls. There is a need for well-designed epidemiological and dermato...

Iron absorption studies

International Nuclear Information System (INIS)

Ekenved, G.

1976-01-01

The main objective of the present work was to study iron absorption from different iron preparations in different types of subjects and under varying therapeutic conditions. The studies were performed with different radioiron isotope techniques and with a serum iron technique. The preparations used were solutions of ferrous sulphate and rapidly-disintegrating tablets containing ferrous sulphate, ferrous fumarate and ferrous carbonate and a slow-release ferrous sulphate tablet of an insoluble matrix type (Duroferon Durules). The serum iron method was evaluated and good correlation was found between the serum iron response and the total amount of iron absorbed after an oral dose of iron given in solution or in tablet form. New technique for studying the in-vivo release properties of tablets was presented. Iron tablets labelled with a radio-isotope were given to healthy subjects. The decline of the radioactivity in the tablets was followed by a profile scanning technique applied to different types of iron tablets. The release of iron from the two types of tablets was shown to be slower in vivo than in vitro. It was found that co-administration of antacids and iron tablets led to a marked reduction in the iron absorption and that these drugs should not be administered sumultaneously. A standardized meal markedly decreased the absorbability of iron from iron tablets. The influence of the meal was more marked with rapidly-disintegrating than with slow-release ferrous sulphate tablets. The absorption from rapidly-disintegrating and slow-release ferrous sulphate tablets was compared under practical clinical conditions during an extended treatment period. The studies were performed in healthy subjects, blood donors and patients with iron deficiency anaemia and it was found that the absorption of iron from the slow-release tablets was significantly better than from the rapidly-disintegrating tablets in all three groups of subjects. (author)

Fitness-compensatory mutations facilitate the spread of drug ...

Indian Academy of Sciences (India)

Charissa C. Naidoo

2017-08-19

Aug 19, 2017 ... Cells were seeded at 2×105 cells/mL in 24-well cell culture plates (Porvair). Infection ..... the intermediary metabolism and respiration group, and conserved hypotheticals ... cellular growth in F15/LAM4/KZN strains. Mycobacte- .... drugs and is thought to occur as a result of metabolic shut- down (Gomez and ...

New Insights into Drug Absorption from Oil Depots

NARCIS (Netherlands)

Kalicharan, R.W.

2017-01-01

Sustained delivery formulations are used in order to prolong the pharmacological activity of a drug. A commonly used parenteral sustained delivery formulation is an oil depot which consists of a solution of lipophilic molecules in a vegetable oil. These are normally administered either

Differentiation of illicit drugs with THz time-domain spectroscopy

International Nuclear Information System (INIS)

Liu Guifeng; Ma Shihua; Ji Te; Zhao Hongwei; Wang Wenfeng

2010-01-01

The tera hertz time-domain spectroscopy (THz-TDS) was used for sensing and identifying illicit drugs. The absorption spectra of seven illicit drug samples(morphine and its hydrochloride, cocaine hydrochloride, codeine phosphate, papaverine hydrochloride, pethidine hydrochloride, and thebaine) were studied by THz-TDS at 0.3-2.0 THz at room temperature. The geometric structure and vibration frequencies of morphine were calculated by density functional theory. The four absorption features were dominated by intra-/inter-molecular collective or lattice vibration modes. Each illicit drug has a distinct signature in its THz spectra. The results indicate that the THz-TDS can be used to identify and discriminate illicit drugs by their characteristic fingerprints. (authors)

Confusing the drug facts on one nonprescription drug label with those on another: The Drug Facts Label as a text schema

Directory of Open Access Journals (Sweden)

Michael P Ryan

2016-04-01

Full Text Available The Drug Facts Label is designed to guide consumers in comparing nonprescription drugs. Undergraduates studied and recalled drug facts for three analgesic or non-analgesic labels using Drug Facts Label headings as retrieval cues. They then studied and recalled drug facts from an aspirin label. Aspirin recall was greater when the prior labels were analgesics, but prior-label intrusion errors were also greater. These two effects were associated with the number of prior drug labels on which facilitating and interfering drug facts appeared. Using the Drug Facts Label schema to read drug labels can both enhance and degrade the recall of nonprescription drug facts.

Multi-drug resistance (MDR1 gene and P-glycoprotein influence on pharmacokinetic and pharmacodymanic of therapeutic drugs

Directory of Open Access Journals (Sweden)

Linardi Renata Lehn

2006-01-01

Full Text Available (MDR1 gene expressed in tumor cells and also in several normal tissues, such as intestine, liver, kidney, blood-brain barrier, spinal cord, and placenta. P-gp has been identified in mice, rat, bovine, monkey, rodents, and human beings and has been receiving a particular clinical relevance because this protein expression limits brain access and intestinal absorption of many drugs. This protein plays a role as a protective barrier against a wide variety of substrates, avoiding drug entry into the central nervous system. P-glycoprotein also interferes with drug bioavailability and disposition, including absorption, distribution, metabolization, and excretion, influencing pharmacokinetic and pharmacodynamic of drugs. Modulation of P-gp may help the efficacy of treatment of several diseases and can explain some adverse central nervous system effects induced by drugs after intravenous administration and the poor response of oral administration in patients. Alteration in P-gp expression or function has been associated with several diseases susceptibility in humans and animals. Furthermore, additional studies relating MDR1 and P-gp expression has an important clinical implication also in terms of treatment efficacy.

Prenatal exposure to ethanol during late gestation facilitates operant self-administration of the drug in 5-day-old rats.

Science.gov (United States)

Miranda-Morales, Roberto Sebastián; Nizhnikov, Michael E; Spear, Norman E

2014-02-01

Prenatal ethanol exposure modifies postnatal affinity to the drug, increasing the probability of ethanol use and abuse. The present study tested developing rats (5-day-old) in a novel operant technique to assess the degree of ethanol self-administration as a result of prenatal exposure to low ethanol doses during late gestation. On a single occasion during each of gestational days 17-20, pregnant rats were intragastrically administered ethanol 1 g/kg, or water (vehicle). On postnatal day 5, pups were tested on a novel operant conditioning procedure in which they learned to touch a sensor to obtain 0.1% saccharin, 3% ethanol, or 5% ethanol. Immediately after a 15-min training session, a 6-min extinction session was given in which operant behavior had no consequence. Pups were positioned on a smooth surface and had access to a touch-sensitive sensor. Physical contact with the sensor activated an infusion pump, which served to deliver an intraoral solution as reinforcement (Paired group). A Yoked control animal evaluated at the same time received the reinforcer when its corresponding Paired pup touched the sensor. Operant behavior to gain access to 3% ethanol was facilitated by prenatal exposure to ethanol during late gestation. In contrast, operant learning reflecting ethanol reinforcement did not occur in control animals prenatally exposed to water only. Similarly, saccharin reinforcement was not affected by prenatal ethanol exposure. These results suggest that in 5-day-old rats, prenatal exposure to a low ethanol dose facilitates operant learning reinforced by intraoral administration of a low-concentration ethanol solution. This emphasizes the importance of intrauterine experiences with ethanol in later susceptibility to drug reinforcement. The present operant conditioning technique represents an alternative tool to assess self-administration and seeking behavior during early stages of development. Published by Elsevier Inc.

Self-double-emulsifying drug delivery system (SDEDDS): a new way for oral delivery of drugs with high solubility and low permeability.

Science.gov (United States)

Qi, Xiaole; Wang, Lishuang; Zhu, Jiabi; Hu, Zhenyi; Zhang, Jie

2011-05-16

Water-in-oil-in-water (w/o/w) double emulsions are potential for enhancing oral bioavailability of drugs with high solubility and low permeability, but their industrial application is limited due to the instability. Herein, we developed a novel formulation, self-double-emulsifying drug delivery systems (SDEDDS) by formulating mixtures of hydrophilic surfactants and water-in-oil (w/o) emulsions, which were easier to be stable through formulations optimization. SDEDDS can spontaneously emulsify to water-in-oil-in-water (w/o/w) double emulsions in the mixed aqueous gastrointestinal environment, with drugs encapsulated in the internal water phase of the double emulsions. We employed SDEDDS to improve the oral absorption of pidotimod, a peptide-like drug with high solubility and low permeability. The optimized pidotimod-SDEDDS were found to be stable up to 6 months under 25°C. Plasma concentration-time profiles from pharmacokinetic studies in rats dosed with SDEDDS showed 2.56-fold (p<0.05) increased absorption of pidotimod, compared to the pidotimod solution. Histopathologic studies confirmed that SDEDDS exerted absorption promoting effect without serious local damages. These studies demonstrate that SDEDDS may be a promising strategy for peroral delivery of peptide and peptidomimetic drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

Early pharmaceutical profiling to predict oral drug absorption

DEFF Research Database (Denmark)

Bergström, Christel A S; Holm, René; Jørgensen, Søren Astrup

2014-01-01

Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmac......Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary...... and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties...

Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole.

Science.gov (United States)

Chin, T W; Loeb, M; Fong, I W

1995-08-01

Absorption of ketoconazole is impaired in patients with achlorhydria. The purpose of this study was to determine the effectiveness of a palatable acidic beverage (Coca-Cola Classic, pH 2.5) in improving the absorption of ketoconazole in the presence of drug-induced achlorhydria. A prospective, randomized, three-way crossover design with a 1-week wash-out period between each treatment was employed. Nine healthy nonsmoking, nonobese volunteers between 22 and 41 years old were studied. Each subject was randomized to receive three treatments: (A) ketoconazole 200-mg tablet with water (control), (B) omeprazole (60 mg) followed by ketoconazole (200 mg) taken with water, and (C) omeprazole (60 mg) followed by ketoconazole (200 mg) taken with 240 ml of Coca-Cola Classic. The pH values of gastric aspirates were checked after omeprazole was administered to confirm attainment of a pH of > 6. Multiple serum samples were obtained for measurements of ketoconazole concentrations by high-pressure liquid chromatography. The mean area under the ketoconazole concentration-time curve from zero to infinity for the control treatment (17.9 +/- 13.1 mg.h/liter) was significantly greater than that for treatment B (3.5 +/- 5.1 mg.h/liter; 16.6% +/- 15.0% of control). The mean peak concentration was highest for the control treatment (4.1 +/- 1.9 micrograms/ml), for which the mean peak concentration showed a significant increase over that for treatment B. The absorption of ketoconazole was reduced in the presence of omeprazole-induced achlorhydria. However, drug absorption was significantly increased, to approximately 65% of the mean for the control treatment, when the drug was taken with an acidic beverage, such as Coca-Cola.

Drug-permeability and transporter assays in Caco-2 and MDCK cell lines.

Science.gov (United States)

Volpe, Donna A

2011-12-01

The human colon adenocarcinoma Caco-2 and Madin-Darby canine kidney epithelial cell lines provide in vitro tools to assess a drug's permeability and transporter interactions during discovery and development. The cells, when cultured on semiporous filters, form confluent monolayers that model the intestinal epithelial barrier for permeability, transporter and drug-interaction assays. The applications of these assays in pharmaceutical research include qualitative prediction and ranking of absorption, determining mechanism(s) of permeability, formulation effects on drug permeability, and the potential for transporter-mediated drug-drug interactions. This review focuses on recent examples of Caco-2 and Madin-Darby canine kidney cells assays for drug permeability including transfected and knock-down cells, miniaturization and automation, and assay combinations to better understand and predict intestinal drug absorption.

Influence of drug load and physical form of cinnarizine in new SNEDDS dosing regimens

DEFF Research Database (Denmark)

Siqueira, Scheyla D V S; Müllertz, Anette; Gräeser, Kirsten

2017-01-01

The aim of this work was to evaluate the influence of drug load and physical form of cinnarizine (CIN) in self-nanoemulsifying drug delivery systems (SNEDDS) on absorption in rats. Further, the predictivity of the dynamic in vitro lipolysis model was evaluated. The following dosing regimens were......, compared to the aqueous suspension. Since the drug level in the aqueous phase is traditionally considered as the fraction available for absorption, a lack of in vitro-in vivo relation was observed. This study revealed that the physical form of CIN in the current SNEDDS does not affect CIN absorption...

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.

Controlled drug release from cross-linked κ-carrageenan/hyaluronic acid membranes.

Science.gov (United States)

El-Aassar, M R; El Fawal, G F; Kamoun, Elbadawy A; Fouda, Moustafa M G

2015-01-01

In this work, hydrogel membrane composed of; kappa carrageenan (κC) and hyaluronic acid (HA) crosslinked with epichlorohydrine is produced. The optimum condition has been established based on their water absorption properties. Tensile strength (TS) and elongation (E%) for the formed films are evaluated. The obtained films were characterized by FTIR, scanning electron microscopy (SEM) and thermal analysis. All membranes were loaded with l-carnosine as a drug model. The swelling properties and kinetics of the release of the model drug from the crosslinked hydrogel membrane were monitored in buffer medium at 37°C. The equilibrium swelling of films showed fair dependency on the high presence of HA in the hydrogel. Moreover, the cumulative release profile increased significantly and ranged from 28% to 93%, as HA increases. SEM explored that, the porosity increased by increasing HA content; consequently, drug release into the pores and channels of the membranes is facilitated. In addition, water uptake % increased as well. A slight change in TS occurred by increasing the HA% to κC, while the highest value of strain for κC membrane was 498.38% by using 3% HA. The thermal stability of the κC/HA was higher than that of HA. Copyright © 2015 Elsevier B.V. All rights reserved.

Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: Report of an FDA Public Workshop.

Science.gov (United States)

Zhang, X; Duan, J; Kesisoglou, F; Novakovic, J; Amidon, G L; Jamei, M; Lukacova, V; Eissing, T; Tsakalozou, E; Zhao, L; Lionberger, R

2017-08-01

On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled "Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation." The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole-body framework. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Exploring the Barriers to and Facilitators of Using Evidence-Based Drugs in the Secondary Prevention of Cardiovascular Diseases: Findings From a Multistakeholder, Qualitative Analysis.

Science.gov (United States)

Miller, Victoria; Nambiar, Lavanya; Saxena, Malvika; Leong, Darryl; Banerjee, Amitava; Werba, José Pablo; Faria Neto, Jose Rocha; Quinto, Katherine Curi; Moniruzzaman, Mohammed; Khandelwal, Shweta

2018-03-01

Health-system barriers and facilitators associated with cardiovascular medication adherence have seldom been studied, particularly in low- and middle-income countries where uptake rates are poorest. This study sought to explore the major obstacles and facilitators to the use of evidence-supported medications for secondary prevention of cardiovascular disease using qualitative analysis in 2 diverse countries across multiple levels of their health care systems. A qualitative descriptive study approach was implemented in Hamilton, Ontario, Canada, and Delhi, India. A purposeful sample (n = 69) of 23 patients, 10 physicians, 2 nurse practitioners, 5 Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homoeopathy physicians, 11 pharmacists, 3 nurses, 4 hospital administrators, 1 social worker, 3 nongovernmental organization workers, 2 pharmaceutical company representatives, and 5 policy makers participated in interviews in Hamilton, Ontario, Canada (n = 21), and Delhi, India (n = 48). All interviews were digitally recorded and transcribed followed by directed content analysis to summarize and categorize the interviews. Themes that emerged across the stakeholder groups included: medication counseling; monitoring adherence; medication availability; medication affordability and drug coverage; time restrictions; and task shifting. The depth of verbal medication counseling provided varied substantially between countries, with prescribers in India unable to convey relevant information about drug treatments due to time constraint and high patient load. Canadian patients reported drug affordability as a common issue and very few patients were familiar with government subsidized drug programs. In India, patients purchased medications out-of-pocket from private, community pharmacies to avoid long commutes, lost wages, and unavailability of medications from hospitals formularies. Task shifting medication-refilling and titration to nonphysician health workers was

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...

Drugs and the Brain: An Introduction to Neuropharmacology. Pamphlet Series.

Science.gov (United States)

Brick, John

The thousands of different drugs on the market can be separated into two categories: drugs that affect behavior, called psychoactive drugs, and drugs that do not affect behavior. Drugs get into the body by mouth, inhalation into the lungs, by injection into a vein, muscle or under the skin, and by absorption through mucous membranes. Regardless of…

Pectin-based colon-specific drug delivery

OpenAIRE

Shailendra Shukla; Deepak Jain; Kavita Verma; Shiddarth Verma

2011-01-01

Colon-specific drug delivery have a great importance in the delivery of drugs for the treatment of local colonic, as well as systemic diseases like Crohn′s disease, ulcerative colitis, colorectal cancer, amoebiasis, asthma, arthritis and inflammation which can be achieved by targeted delivery of drug to colon. Specific systemic absorption in the colon gave interesting possibilities for the delivery of protein and peptides. It contains relatively less proteolytic enzyme activities in the colon...

In vivo analysis of supersaturation/precipitation/absorption behavior after oral administration of pioglitazone hydrochloride salt; determinant site of oral absorption.

Science.gov (United States)

Tanaka, Yusuke; Sugihara, Masahisa; Kawakami, Ayaka; Imai, So; Itou, Takafumi; Murase, Hirokazu; Saiki, Kazunori; Kasaoka, Satoshi; Yoshikawa, Hiroshi

2017-08-30

The purpose of this study was to evaluate in vivo supersaturation/precipitation/absorption behavior in the gastrointestinal (GI) tract based on the luminal concentration-time profiles after oral administration of pioglitazone (PG, a highly permeable lipophilic base) and its hydrochloride salt (PG-HCl) to rats. In the in vitro precipitation experiment in the classic closed system, while the supersaturation was stable in the simulated gastric condition, PG drastically precipitated in the simulated intestinal condition, particularly at a higher initial degree of supersaturation. Nonetheless, a drastic and moderate improvement in absorption was observed in vivo at a low and high dose of PG-HCl, respectively. Analysis based on the luminal concentration of PG after oral administration of PG-HCl at a low dose revealed that most of the dissolved PG emptied from the stomach was rapidly absorbed before its precipitation in the duodenum. At a high dose of PG-HCl, PG partly precipitated in the duodenum but was absorbed to some extent. Therefore, the extent of the absorption was mainly dependent on the duodenal precipitation behavior. Furthermore, a higher-than expected absorption after oral administration of PG-HCl from in vitro precipitation study may be due to the absorption process in the small intestine, which suppresses the precipitation by removal of the drug. This study successfully clarify the impact of the absorption process on the supersaturation/precipitation/absorption behavior and key absorption site for a salt formulation of a highly permeable lipophilic base based on the direct observation of in vivo luminal concentration. Our findings may be beneficial in developing an ideal physiologically based pharmacokinetic model and in vitro predictive dissolution tools and/or translating the in silico and in vitro data to the in vivo outcome. Copyright © 2017 Elsevier B.V. All rights reserved.

Facilitating functional annotation of chicken microarray data

Directory of Open Access Journals (Sweden)

Gresham Cathy R

2009-10-01

Full Text Available Abstract Background Modeling results from chicken microarray studies is challenging for researchers due to little functional annotation associated with these arrays. The Affymetrix GenChip chicken genome array, one of the biggest arrays that serve as a key research tool for the study of chicken functional genomics, is among the few arrays that link gene products to Gene Ontology (GO. However the GO annotation data presented by Affymetrix is incomplete, for example, they do not show references linked to manually annotated functions. In addition, there is no tool that facilitates microarray researchers to directly retrieve functional annotations for their datasets from the annotated arrays. This costs researchers amount of time in searching multiple GO databases for functional information. Results We have improved the breadth of functional annotations of the gene products associated with probesets on the Affymetrix chicken genome array by 45% and the quality of annotation by 14%. We have also identified the most significant diseases and disorders, different types of genes, and known drug targets represented on Affymetrix chicken genome array. To facilitate functional annotation of other arrays and microarray experimental datasets we developed an Array GO Mapper (AGOM tool to help researchers to quickly retrieve corresponding functional information for their dataset. Conclusion Results from this study will directly facilitate annotation of other chicken arrays and microarray experimental datasets. Researchers will be able to quickly model their microarray dataset into more reliable biological functional information by using AGOM tool. The disease, disorders, gene types and drug targets revealed in the study will allow researchers to learn more about how genes function in complex biological systems and may lead to new drug discovery and development of therapies. The GO annotation data generated will be available for public use via AgBase website and

Balancing Absorptive Capacity and Inbound Open Innovation for Sustained Innovative Performance

DEFF Research Database (Denmark)

Bongsun, Kim; Kim, Eonsoo; Foss, Nicolai Juul

2016-01-01

How can a firm develop new ideas and turn them into profitable innovations on a sustained basis? We address this fundamental issue in a novel way by developing an integrative framework of absorptive capacity (AC) and inbound open innovation that is rooted in the attention-based view of the firm. We...... specifically address why a balance between open and closed innovation is important from the perspective of absorptive capacity, and show how it may be brought about. Pursuing either open or closed inbound innovation alone may result in an imbalance between potential AC and realized AC as well as inward......-looking AC and outward-looking AC, which will hinder innovative performance.We argue that practicing open and closed inbound innovation repeatedly and alternately by switching organizational attentions, and thus developing the associated AC, can facilitate balancing absorptive capacity and lead to innovative...

Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption

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Patel, Chirag; Douard, Veronique; Yu, Shiyan; Gao, Nan; Ferraris, Ronaldo P.

2015-01-01

Dietary fructose that is linked to metabolic abnormalities can up-regulate its own absorption, but the underlying regulatory mechanisms are not known. We hypothesized that glucose transporter (GLUT) protein, member 5 (GLUT5) is the primary fructose transporter and that fructose absorption via GLUT5, metabolism via ketohexokinase (KHK), as well as GLUT5 trafficking to the apical membrane via the Ras-related protein-in-brain 11 (Rab11)a-dependent endosomes are each required for regulation. Introducing fructose but not lysine and glucose solutions into the lumen increased by 2- to 10-fold the heterogeneous nuclear RNA, mRNA, protein, and activity levels of GLUT5 in adult wild-type mice consuming chow. Levels of GLUT5 were >100-fold that of candidate apical fructose transporters GLUTs 7, 8, and 12 whose expression, and that of GLUT 2 and the sodium-dependent glucose transporter protein 1 (SGLT1), was not regulated by luminal fructose. GLUT5-knockout (KO) mice exhibited no facilitative fructose transport and no compensatory increases in activity and expression of SGLT1 and other GLUTs. Fructose could not up-regulate GLUT5 in GLUT5-KO, KHK-KO, and intestinal epithelial cell-specific Rab11a-KO mice. The fructose-specific metabolite glyceraldehyde did not increase GLUT5 expression. GLUT5 is the primary transporter responsible for facilitative absorption of fructose, and its regulation specifically requires fructose uptake and metabolism and normal GLUT5 trafficking to the apical membrane.—Patel, C., Douard, V., Yu, S., Gao, N., Ferraris, R. P. Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption. PMID:26071406

Indolealkylamines: biotransformations and potential drug-drug interactions.

Science.gov (United States)

Yu, Ai-Ming

2008-06-01

Indolealkylamine (IAA) drugs are 5-hydroxytryptamine (5-HT or serotonin) analogs that mainly act on the serotonin system. Some IAAs are clinically utilized for antimigraine therapy, whereas other substances are notable as drugs of abuse. In the clinical evaluation of antimigraine triptan drugs, studies on their biotransformations and pharmacokinetics would facilitate the understanding and prevention of unwanted drug-drug interactions (DDIs). A stable, principal metabolite of an IAA drug of abuse could serve as a useful biomarker in assessing intoxication of the IAA substance. Studies on the metabolism of IAA drugs of abuse including lysergic acid amides, tryptamine derivatives and beta-carbolines are therefore emerging. An important role for polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of IAA drugs of abuse has been revealed by recent studies, suggesting that variations in IAA metabolism, pharmaco- or toxicokinetics and dynamics can arise from distinct CYP2D6 status, and CYP2D6 polymorphism may represent an additional risk factor in the use of these IAA drugs. Furthermore, DDIs with IAA agents could occur additively at the pharmaco/toxicokinetic and dynamic levels, leading to severe or even fatal serotonin toxicity. In this review, the metabolism and potential DDIs of these therapeutic and abused IAA drugs are described.

Effect of aspirin on the pharmacokinetics and absorption of panax notoginseng saponins.

Science.gov (United States)

Tian, Zhihao; Pang, Huanhuan; Zhang, Qiang; Du, Shouying; Lu, Yang; Zhang, Lin; Bai, Jie; Li, Pengyue; Li, Danqi; Zhao, Mengdi; Chen, Xiaonan

2018-02-01

Panax notoginseng saponins, a traditional Chinese medicine extraction, and aspirin are both widely used to treat cerebral infarction in China. Good results in clinical practice have been achieved, when Panax notoginseng saponins was taken together with aspirin. To investigate the interaction of the two drugs in vivo, the concentration of notoginsenoside R 1 , ginsenoside Rg 1 , Rb 1 , Re and Rd. in blood were simultaneously measured by UPLC/MS/MS. Sample preparation was carried out by the protein precipitation technique with an internal standard saikosaponin A standard. The separation of six components was achieved by using an ACQUITY UPLC ®BEH C18 column (1.7μm 2.1×100mm) by gradient elution using water (containing 0.2% formic acid) and acetonitrile (containing 0.2% formic acid) as the mobile phase at a flow rate of 0.2mL/min. The pharmacokinetic parameters were determined using non-compartmental analysis. The transport of notoginsenoside R 1 , ginsenoside Rg 1 , Rb 1 , Re and Rd. in MDCK -MDR1 cell monolayer was also used to verify the conclusion of pharmacokinetic drug-drug interaction and study the mechanism of drug interaction. The concentrations of the five components increased in a certain extent when the two drugs administered together in rats. The values of apparent permeability coefficients were significantly increased when the two drugs were used together. Aspirin and salicylic acid could destroy the tight junction protein and open the intercellular space to increase the absorption of Panax notoginseng saponins. Pharmacokinetic drug-drug interaction in vivo existed between Panax notoginseng saponins and aspirin. The drug-drug interaction mainly occurred in the process of absorption. Copyright © 2018 Elsevier B.V. All rights reserved.

Colloidal drug delivery system: amplify the ocular delivery.

Science.gov (United States)

Ali, Javed; Fazil, Mohd; Qumbar, Mohd; Khan, Nazia; Ali, Asgar

2016-01-01

The ocular perceivers are the most voluntarily accessible organs in terms of location in the body, yet drug distribution to these tissues is one of the most intriguing and challenging endeavors and problematic to the pharmaceutical scientist. The most of ocular diseases are treated with topical application of conventional formulation, i.e. solutions, suspensions and ointment. Typically on installation of these conventional formulations, only <5% of the applied dose penetrates the cornea and reaches intraocular tissues, while a major fraction of the instilled dose is wastage due to the presence of many ocular barriers like external barriers, rapid loss of the instilled solution from the precorneal area and nasolacrimal drainage system. Systemic absorption caused systemic side effects varying from mild to life-threatening events. The main objective of this review is to explore the role of colloidal delivery of drug to minimize the drawbacks associated with them. This review provides an insight into the various constraints associated with ocular drug delivery, summarizes recent findings and applications of colloidal delivery systems, i.e. nanoparticles, nanosuspensions, liposomes, niosomes, dendrimers and contact lenses containing nanoparticles have the capacity to distribute ocular drugs to categorical target sites and hold promise to revolutionize the therapy of many ocular perceiver diseases and minimized the circumscription of conventional delivery. Form the basis of literature review, it has been found that the novel delivery system have greater impact to maximize ocular drug absorption, and minimize systemic absorption and side effects.

Combining in vitro and in silico methods for better prediction of surfactant effects on the absorption of poorly water soluble drugs-a fenofibrate case example.

Science.gov (United States)

Berthelsen, Ragna; Sjögren, Erik; Jacobsen, Jette; Kristensen, Jakob; Holm, René; Abrahamsson, Bertil; Müllertz, Anette

2014-10-01

The aim of this study was to develop a sensitive and discriminative in vitro-in silico model able to simulate the in vivo performance of three fenofibrate immediate release formulations containing different surfactants. In addition, the study was designed to investigate the effect of dissolution volume when predicting the oral bioavailability of the formulations. In vitro dissolution studies were carried out using the USP apparatus 2 or a mini paddle assembly, containing 1000 mL or 100mL fasted state biorelevant medium, respectively. In silico simulations of small intestinal absorption were performed using the GI-Sim absorption model. All simulation runs were performed twice adopting either a total small intestinal volume of 533 mL or 105 mL, in order to examine the implication of free luminal water volumes for the in silico predictions. For the tested formulations, the use of a small biorelevant dissolution volume was critical for in vitro-in silico prediction of drug absorption. Good predictions, demonstrating rank order in vivo-in vitro-in silico correlations for Cmax, were obtained with in silico predictions utilizing a 105 mL estimate for the human intestinal water content combined with solubility and dissolution data performed in a mini paddle apparatus with 100mL fasted state simulated media. Copyright © 2014. Published by Elsevier B.V.

Active intestinal drug absorption and the solubility-permeability interplay.

Science.gov (United States)

Porat, Daniel; Dahan, Arik

2018-02-15

The solubility-permeability interplay deals with the question: what is the concomitant effect on the drug's apparent permeability when increasing the apparent solubility with a solubility-enabling formulation? The solubility and the permeability are closely related, exhibit certain interplay between them, and ongoing research throughout the past decade shows that treating the one irrespectively of the other may be insufficient. The aim of this article is to provide an overview of the current knowledge on the solubility-permeability interplay when using solubility-enabling formulations for oral lipophilic drugs, highlighting active permeability aspects. A solubility-enabling formulation may affect the permeability in opposite directions; the passive permeability may decrease as a result of the apparent solubility increase, according to the solubility-permeability tradeoff, but at the same time, certain components of the formulation may inhibit/saturate efflux transporters (when relevant), resulting in significant apparent permeability increase. In these cases, excipients with both solubilizing and e.g. P-gp inhibitory properties may lead to concomitant increase of both the solubility and the permeability. Intelligent development of such formulation will account for the simultaneous effects of the excipients' nature/concentrations on the two arms composing the overall permeability: the passive and the active arms. Overall, thorough mechanistic understanding of the various factors involved in the solubility-permeability interplay may allow developing better solubility-enabling formulations, thereby exploiting the advantages analyzed in this article, offering oral delivery solution even for BCS class IV drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Mucoadhesive microspheres: a promising tool in drug delivery.

Science.gov (United States)

Patil, Sanjay B; Sawant, Krutika K

2008-10-01

Mucoadhesive polymers have recently gained interest among pharmaceutical scientists as a means of improving drug delivery by promoting the residence time and contact time of the dosage form with the mucous membranes. Mucoadhesion is the process whereby synthetic and natural polymers adhere to mucosal surfaces in the body. If these materials are then incorporated into pharmaceutical formulations, drug absorption by mucosal cells may be enhanced or the drug will be released at the site for an extended period of time. Microspheres, in general, have the potential to be used for targeted and controlled release drug delivery; however, coupling of mucoadhesive properties to microspheres has additional advantages like, a much more intimate contact with the mucus layer, efficient absorption and enhanced bioavailability of the drugs due to a high surface to volume ratio. The present review describes the potential applications of mucoadhesive microspheres as a novel carrier system to improve drug delivery by various routes of administration like buccal, oral, nasal, ocular, vaginal and rectal, either for systemic or for local effects. The mucoadhesive polymers, methods of preparation of microspheres and their in vitro and in vivo evaluation are also described.

Fat digestion and absorption in spice-pretreated rats.

Science.gov (United States)

Prakash, Usha N S; Srinivasan, Krishnapura

2012-02-01

A few common spices are known to stimulate secretion of bile with higher amount of bile acids which play a major role in digestion and absorption of dietary lipids. It would be appropriate to verify if these spices enable efficient digestion and absorption during high-fat intake. In this context, dietary ginger (0.05%), piperine (0.02%), capsaicin (0.015%), and curcumin (0.5%) were examined for their influence on bile secretion, digestive enzymes of pancreas and absorption of dietary fat in high-fat (30%) fed Wistar rats for 8 weeks. These spices enhanced the activity of pancreatic lipase, amylase, trypsin and chymotrypsin by 22-57%, 32-51%, 63-81% and 12-38%, respectively. Dietary intake of spices along with high-fat enhanced fat absorption. These dietary spices increased bile secretion with higher bile acid content. Stimulation of lipid mobilisation from adipose tissue was suggested by the decrease in perirenal adipose tissue weight by dietary capsaicin and piperine. This was also accompanied by prevention of the accumulation of triglyceride in liver and serum in high-fat fed rats. Activities of key lipogenic enzymes in liver were reduced which was accompanied by an increased activity of hormone-sensitive lipase. Thus, dietary ginger and other spice compounds enhance fat digestion and absorption in high-fat fed situation through enhanced secretion of bile salts and a stimulation of the activity pancreatic lipase. At the same time, the energy expenditure is facilitated by these spices to prevent the accumulation of absorbed fat. Copyright © 2011 Society of Chemical Industry.

Promises of Machine Learning Approaches in Prediction of Absorption of Compounds.

Science.gov (United States)

Kumar, Rajnish; Sharma, Anju; Siddiqui, Mohammed Haris; Tiwari, Rajesh Kumar

2018-01-01

The Machine Learning (ML) is one of the fastest developing techniques in the prediction and evaluation of important pharmacokinetic properties such as absorption, distribution, metabolism and excretion. The availability of a large number of robust validation techniques for prediction models devoted to pharmacokinetics has significantly enhanced the trust and authenticity in ML approaches. There is a series of prediction models generated and used for rapid screening of compounds on the basis of absorption in last one decade. Prediction of absorption of compounds using ML models has great potential across the pharmaceutical industry as a non-animal alternative to predict absorption. However, these prediction models still have to go far ahead to develop the confidence similar to conventional experimental methods for estimation of drug absorption. Some of the general concerns are selection of appropriate ML methods and validation techniques in addition to selecting relevant descriptors and authentic data sets for the generation of prediction models. The current review explores published models of ML for the prediction of absorption using physicochemical properties as descriptors and their important conclusions. In addition, some critical challenges in acceptance of ML models for absorption are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Evaluation of an oral carrier system in rats: bioavailability and gastrointestinal absorption properties of curcumin encapsulated PBCA nanoparticles

Energy Technology Data Exchange (ETDEWEB)

Sun Min; Zhao Lixia; Guo Chenyu; Cao Fengliang; Chen Huanlei; Zhao Liyan; Tan Qi; Zhu Xiuqing; Zhu Fanping; Ding Tingting; Zhai Yingjie; Zhai Guangxi, E-mail: professorzhai@yeah.net [Shandong University, Department of Pharmaceutics, College of Pharmacy (China)

2012-02-15

A new oral delivery system, polybutylcyanoacrylate nanoparticles (PBCNs), was introduced to improve the oral bioavailability of curcumin (CUR), a poorly soluble drug. The formulation was optimized by orthogonal design and the optimal PBCNs loading CUR exhibited a spherical shape under transmission electron microscopy with a range of 40-400 nm. Physicochemical state of CUR in PBCN was investigated by X-ray diffraction and the possible structure changes occurring in CUR after conjugating with polybutylcyanoacrylate were studied with FTIR. The results indicated that CUR in PBCN was in a non-crystalline state and CUR was encapsulated in PBCN without chemical reaction. The oral pharmacokinetic study was conducted in rats and the relative bioavailability of CUR encapsulated PBCNs to the crude CUR was more than 800%. The in situ absorption experiment in rat intestine indicated the absorption was first order with passive diffusion mechanism. The absorption results in various segments of intestine showed that the main absorption sites were ileum and colon. It can be concluded that PBCNs as an oral carrier can significantly improve the oral absorption of a poorly soluble drug.

Evaluation of an oral carrier system in rats: bioavailability and gastrointestinal absorption properties of curcumin encapsulated PBCA nanoparticles

International Nuclear Information System (INIS)

Sun Min; Zhao Lixia; Guo Chenyu; Cao Fengliang; Chen Huanlei; Zhao Liyan; Tan Qi; Zhu Xiuqing; Zhu Fanping; Ding Tingting; Zhai Yingjie; Zhai Guangxi

2012-01-01

A new oral delivery system, polybutylcyanoacrylate nanoparticles (PBCNs), was introduced to improve the oral bioavailability of curcumin (CUR), a poorly soluble drug. The formulation was optimized by orthogonal design and the optimal PBCNs loading CUR exhibited a spherical shape under transmission electron microscopy with a range of 40–400 nm. Physicochemical state of CUR in PBCN was investigated by X-ray diffraction and the possible structure changes occurring in CUR after conjugating with polybutylcyanoacrylate were studied with FTIR. The results indicated that CUR in PBCN was in a non-crystalline state and CUR was encapsulated in PBCN without chemical reaction. The oral pharmacokinetic study was conducted in rats and the relative bioavailability of CUR encapsulated PBCNs to the crude CUR was more than 800%. The in situ absorption experiment in rat intestine indicated the absorption was first order with passive diffusion mechanism. The absorption results in various segments of intestine showed that the main absorption sites were ileum and colon. It can be concluded that PBCNs as an oral carrier can significantly improve the oral absorption of a poorly soluble drug.

Evaluation of an oral carrier system in rats: bioavailability and gastrointestinal absorption properties of curcumin encapsulated PBCA nanoparticles

Science.gov (United States)

Sun, Min; Zhao, Lixia; Guo, Chenyu; Cao, Fengliang; Chen, Huanlei; Zhao, Liyan; Tan, Qi; Zhu, Xiuqing; Zhu, Fanping; Ding, Tingting; Zhai, Yingjie; Zhai, Guangxi

2012-02-01

A new oral delivery system, polybutylcyanoacrylate nanoparticles (PBCNs), was introduced to improve the oral bioavailability of curcumin (CUR), a poorly soluble drug. The formulation was optimized by orthogonal design and the optimal PBCNs loading CUR exhibited a spherical shape under transmission electron microscopy with a range of 40-400 nm. Physicochemical state of CUR in PBCN was investigated by X-ray diffraction and the possible structure changes occurring in CUR after conjugating with polybutylcyanoacrylate were studied with FTIR. The results indicated that CUR in PBCN was in a non-crystalline state and CUR was encapsulated in PBCN without chemical reaction. The oral pharmacokinetic study was conducted in rats and the relative bioavailability of CUR encapsulated PBCNs to the crude CUR was more than 800%. The in situ absorption experiment in rat intestine indicated the absorption was first order with passive diffusion mechanism. The absorption results in various segments of intestine showed that the main absorption sites were ileum and colon. It can be concluded that PBCNs as an oral carrier can significantly improve the oral absorption of a poorly soluble drug.

Flow analysis-hydride generation-gas phase derivative molecular absorption spectrophotometric determination of antimony in antileishmanial drugs

Directory of Open Access Journals (Sweden)

Máximo Gallignani

2009-01-01

Full Text Available In the present work, the development of a method based on the coupling of flow analysis (FA, hydride generation (HG, and derivative molecular absorption spectrophotometry (D-EAM in gas phase (GP, is described in order to determine total antimony in antileishmanial products. Second derivative order (D²224nm of the absorption spectrum (190 - 300 nm is utilized as measurement criterion. Each one of the parameters involved in the development of the proposed method was examined and optimized. The utilization of the EAM in GP as detection system in a continuous mode instead of atomic absorption spectrometry represents the great potential of the analytic proposal.

Microemulsions based transdermal drug delivery systems.

Science.gov (United States)

Vadlamudi, Harini C; Narendran, Hyndavi; Nagaswaram, Tejeswari; Yaga, Gowri; Thanniru, Jyotsna; Yalavarthi, Prasanna R

2014-01-01

Since the discovery of microemulsions by Jack H Schulman, there has been huge progress made in applying microemulsion systems in plethora of research and industrial process. Microemulsions are optically isotropic systems consisting of water, oil and amphiphile. These systems are beneficial due to their thermodynamic stability, optical clarity, ease of preparation, higher diffusion and absorption rates. Moreover, it has been reported that the ingredients of microemulsion can effectively overcome the diffusion barrier and penetrate through the stratum corneum of the skin. Hence it becomes promising for both transdermal and dermal drug delivery. However, low viscosity of microemulsion restrains its applicability in pharmaceutical industry. To overcome the above drawback, the low viscous microemulsions were added to viscous gel bases to potentiate its applications as topical drug delivery systems so that various drug related toxic effects and erratic drug absorption can be avoided. The present review deals with the microemulsions, various techniques involved in the development of organic nanoparticles. The review emphasized on microemulsion based systems such as hydrogels and organogels. The physicochemical characteristics, mechanical properties, rheological and stability principles involved in microemulsion based viscous gels were also explored.

Microcontainers - an oral drug delivery system for poorly soluble drugs

DEFF Research Database (Denmark)

Nielsen, Line Hagner; Petersen, Ritika Singh; Marizza, Paolo

In oral delivery, it can sometimes be necessary to employ drug delivery systems to achieve targeted delivery to the intestine. Microcontainers are polymeric, cylindrical devices in the micrometer size range (Figure 1), and are suggested as a promising oral drug delivery system [1],[2]. The purpose...... of these studies was to fabricate microcontainers in either SU-8 or biodegradable poly-L-lactic acid (PLLA), and fill the microcontainers with poorly soluble drugs. Furthermore, the application of the microcontainers as an oral drug delivery system was investigated in terms of release, in situ intestinal perfusion...... medium at pH 6.5 was observed. In situ intestinal perfusions were performed in rats of the Eudragit-coated ASSF-filled microcontainers and compared to a furosemide solution. At the end of the study, the small intestine was harvested from the rat and imaged under a light microscope. The absorption rate...

Annette Bunge: developing the principles in percutaneous absorption using chemical engineering principles.

Science.gov (United States)

Stinchcomb, A L

2013-01-01

Annette Bunge and her research group have had the central theme of mathematically modeling the dermal absorption process. Most of the research focus has been on estimating dermal absorption for the purpose of risk assessment, for exposure scenarios in the environment and in the occupational setting. Her work is the basis for the United States Environmental Protection Agency's estimations for dermal absorption from contaminated water. It is also the basis of the dermal absorption estimates used in determining if chemicals should be assigned a 'skin notation' for potential systemic toxicity following occupational skin exposure. The work is truly translational in that it started with mathematical theory, is validated with preclinical and human experiments, and then is used in guidelines to protect human health. Her valued research has also extended into the topical drug bioavailability and bioequivalence assessment field.

[Study on lead absorption in pumpkin by atomic absorption spectrophotometry].

Science.gov (United States)

Li, Zhen-Xia; Sun, Yong-Dong; Chen, Bi-Hua; Li, Xin-Zheng

2008-07-01

A study was carried out on the characteristic of lead absorption in pumpkin via atomic absorption spectrophotometer. The results showed that lead absorption amount in pumpkin increased with time, but the absorption rate decreased with time; And the lead absorption amount reached the peak in pH 7. Lead and cadmium have similar characteristic of absorption in pumpkin.

Characterization of particulate drug delivery systems for oral delivery of Peptide and protein drugs

DEFF Research Database (Denmark)

Christophersen, Philip Carsten; Fano, Mathias; Saaby, Lasse

2015-01-01

Oral drug delivery is a preferred route because of good patient compliance. However, most peptide/ protein drugs are delivered via parenteral routes because of the absorption barriers in the gastrointestinal (GI) tract such as enzymatic degradation by proteases and low permeability acrossthe...... delivery of peptide/protein drugs and to provide an overview of formulationand characterization strategies. For a better understanding of the challenges in oral delivery of peptide/protein drugs, the composition of GI fluids and the digestion processes of different kinds of excipients in the GI tract...... biological membranes. To overcome these barriers, different formulation strategies for oral delivery of biomacromolecules have been proposed, including lipid based formulations and polymer-based particulate drug delivery systems (DDS). The aim of this review is to summarize the existing knowledge about oral...

Emerging integrated nanoclay-facilitated drug delivery system for papillary thyroid cancer therapy

Science.gov (United States)

Zhang, Yi; Long, Mei; Huang, Peng; Yang, Huaming; Chang, Shi; Hu, Yuehua; Tang, Aidong; Mao, Linfeng

2016-09-01

Nanoclay can be incorporated into emerging dual functional drug delivery systems (DDSs) to promote efficiency in drug delivery and reduce the toxicity of doxorubicin (DOX) used for thyroid cancer treatment. This paper reports the expansion of the basal spacing of kaolinite nanoclay was expanded from 0.72 nm to 0.85 nm, which could provide sufficiently spacious site for hosting doxorubicin molecules and controlling the diffusion rate. A targeted design for papillary thyroid cancer cells was achieved by introducing KI, which is consumed by the sodium-iodide symporter (NIS). As indicated by MTT assays, confocal laser scanning microscopy and bio-TEM observations, methoxy-intercalated kaolinite (KaolinMeOH) exhibited negligible cytotoxicity against papillary thyroid cancer cells. By contrast, DOX-KaolinMeOH showed dose-dependent therapeutic effects in vitro, and KI@DOX-KaolinMeOH was found to act as a powerful targeted therapeutic drug. Furthermore, active and passive targeting strategies played a role in the accumulation of the drug molecules, as verified by an in vivo bio-distribution analysis.

Quantification of the fluorine containing drug 5-fluorouracil in cancer cells by GaF molecular absorption via high-resolution continuum source molecular absorption spectrometry

International Nuclear Information System (INIS)

Krüger, Magnus; Huang, Mao-Dong; Becker-Roß, Helmut; Florek, Stefan; Ott, Ingo; Gust, Ronald

2012-01-01

The development of high-resolution continuum source molecular absorption spectrometry made the quantification of fluorine feasible by measuring the molecular absorption as gallium monofluoride (GaF). Using this new technique, we developed on the example of 5-fluorouracil (5-FU) a graphite furnace method to quantify fluorine in organic molecules. The effect of 5-FU on the generation of the diatomic GaF molecule was investigated. The experimental conditions such as gallium nitrate amount, temperature program, interfering anions (represented as corresponding acids) and calibration for the determination of 5-FU in standard solution and in cellular matrix samples were investigated and optimized. The sample matrix showed no effect on the sensitivity of GaF molecular absorption. A simple calibration curve using an inorganic sodium fluoride solution can conveniently be used for the calibration. The described method is sensitive and the achievable limit of detection is 0.23 ng of 5-FU. In order to establish the concept of “fluorine as a probe in medicinal chemistry” an exemplary application was selected, in which the developed method was successfully demonstrated by performing cellular uptake studies of the 5-FU in human colon carcinoma cells. - Highlights: ► Development of HR-CS MAS for quantification of fluorine bound to organic molecules ► Measuring as molecular absorption of gallium monofluoride ► Quantification of organic-bound fluorine in biological material ► The concept of “fluorine as a probe in medicinal chemistry” could be established

Indolealkylamines: Biotransformations and Potential Drug–Drug Interactions

OpenAIRE

Yu, Ai-Ming

2008-01-01

Indolealkylamine (IAA) drugs are 5-hydroxytryptamine (5-HT or serotonin) analogs that mainly act on the serotonin system. Some IAAs are clinically utilized for antimigraine therapy, whereas other substances are notable as drugs of abuse. In the clinical evaluation of antimigraine triptan drugs, studies on their biotransformations and pharmacokinetics would facilitate the understanding and prevention of unwanted drug–drug interactions (DDIs). A stable, principal metabolite of an IAA drug of ab...

Drug metabolism and pharmacokinetic diversity of ranunculaceae medicinal compounds.

Science.gov (United States)

Hao, Da-Cheng; Ge, Guang-Bo; Xiao, Pei-Gen; Wang, Ping; Yang, Ling

2015-01-01

The wide-reaching distributed angiosperm family Ranunculaceae has approximately 2200 species in around 60 genera. Chemical components of this family include several representative groups: benzylisoquinoline alkaloid (BIA), ranunculin, triterpenoid saponin and diterpene alkaloid, etc. Their extensive clinical utility has been validated by traditional uses of thousands of years and current evidence-based medicine studies. Drug metabolism and pharmacokinetic (DMPK) studies of plant-based natural products are an indispensable part of comprehensive medicinal plant exploration, which could facilitate conservation and sustainable utilization of Ranunculaceae pharmaceutical resources, as well as new chemical entity development with improved DMPK parameters. However, DMPK characteristics of Ranunculaceaederived medicinal compounds have not been summarized. Black cohosh (Cimicifuga) and goldenseal (Hydrastis) raise concerns of herbdrug interaction. DMPK studies of other Ranunculaceae genera, e.g., Nigella, Delphinium, Aconitum, Trollius, and Coptis, are also rapidly increasing and becoming more and more clinically relevant. In this contribution, we highlight the up-to-date awareness, as well as the challenges around the DMPK-related issues in optimization of drug development and clinical practice of Ranunculaceae compounds. Herb-herb interaction of Ranunculaceae herb-containing traditional Chinese medicine (TCM) formula could significantly influence the in vivo pharmacokinetic behavior of compounds thereof, which may partially explain the complicated therapeutic mechanism of TCM formula. Although progress has been made on revealing the absorption, distribution, metabolism, excretion and toxicity (ADME/T) of Ranunculaceae compounds, there is a lack of DMPK studies of traditional medicinal genera Aquilegia, Thalictrum and Clematis. Fluorescent probe compounds could be promising substrate, inhibitor and/or inducer in future DMPK studies of Ranunculaceae compounds. A better

Application of three-dimensional printing for colon targeted drug delivery systems.

Science.gov (United States)

Charbe, Nitin B; McCarron, Paul A; Lane, Majella E; Tambuwala, Murtaza M

2017-01-01

Orally administered solid dosage forms currently dominate over all other dosage forms and routes of administrations. However, human gastrointestinal tract (GIT) poses a number of obstacles to delivery of the drugs to the site of interest and absorption in the GIT. Pharmaceutical scientists worldwide have been interested in colon drug delivery for several decades, not only for the delivery of the drugs for the treatment of colonic diseases such as ulcerative colitis and colon cancer but also for delivery of therapeutic proteins and peptides for systemic absorption. Despite extensive research in the area of colon targeted drug delivery, we have not been able to come up with an effective way of delivering drugs to the colon. The current tablets designed for colon drug release depend on either pH-dependent or time-delayed release formulations. During ulcerative colitis the gastric transit time and colon pH-levels is constantly changing depending on whether the patient is having a relapse or under remission. Hence, the current drug delivery system to the colon is based on one-size-fits-all. Fails to effectively deliver the drugs locally to the colon for colonic diseases and delivery of therapeutic proteins and peptides for systemic absorption from the colon. Hence, to overcome the current issues associated with colon drug delivery, we need to provide the patients with personalized tablets which are specifically designed to match the individual's gastric transit time depending on the disease state. Three-dimensional (3D) printing (3DP) technology is getting cheaper by the day and bespoke manufacturing of 3D-printed tablets could provide the solutions in the form of personalized colon drug delivery system. This review provides a bird's eye view of applications and current advances in pharmaceutical 3DP with emphasis on the development of colon targeted drug delivery systems.

Poly(amido amine) dendrimers as absorption enhancers for oral delivery of camptothecin.

Science.gov (United States)

Sadekar, S; Thiagarajan, G; Bartlett, K; Hubbard, D; Ray, A; McGill, L D; Ghandehari, H

2013-11-01

Oral delivery of camptothecin has a treatment advantage but is limited by low bioavailability and gastrointestinal toxicity. Poly(amido amine) or PAMAM dendrimers have shown promise as intestinal penetration enhancers, drug solubilizers and drug carriers for oral delivery in vitro and in situ. There have been very limited studies in vivo to evaluate PAMAM dendrimers for oral drug delivery. In this study, camptothecin (5 mg/kg) was formulated and co-delivered with cationic, amine-terminated PAMAM dendrimer generation 4.0 (G4.0) (100 and 300 mg/kg) and anionic, carboxylate-terminated PAMAM generation 3.5 (G3.5) (300 and 1000 mg/kg) in CD-1 mice. Camptothecin associated to a higher extent with G4.0 than G3.5 in the formulation, attributed to an electrostatic interaction on the surface of G4.0. Both PAMAM G4.0 and G3.5 increased camptothecin solubilization in simulated gastric fluid and caused a 2-3 fold increase in oral absorption of camptothecin when delivered at 2 h. PAMAM G4.0 and G3.5 did not increase mannitol transport suggesting that the oral absorption of camptothecin was not due to tight junction modulation. Histologic observations of the epithelial layer of small intestinal segments of the gastrointestinal tract (GIT) at 4 h post dosing supported no evidence of toxicity at the evaluated doses of PAMAM dendrimers. This study demonstrates that both cationic (G.4) and anionic (G3.5) PAMAM dendrimers were effective in enhancing the oral absorption of camptothecin. Results suggest that drug inclusion in PAMAM interior controlled solubilization in simulated gastric and intestinal fluids, and increased oral bioavailability. Copyright © 2013 Elsevier B.V. All rights reserved.

Soluble polymer conjugates for drug delivery.

Science.gov (United States)

Minko, Tamara

2005-01-01

The use of water-soluble polymeric conjugates as drug carriers offers several possible advantages. These advantages include: (1) improved drug pharmacokinetics; (2) decreased toxicity to healthy organs; (3) possible facilitation of accumulation and preferential uptake by targeted cells; (4) programmed profile of drug release. In this review, we will consider the main types of useful polymeric conjugates and their role and effectiveness as carriers in drug delivery systems.: © 2005 Elsevier Ltd . All rights reserved.

Bile salts and their importance for drug absorption

DEFF Research Database (Denmark)

Holm, René; Müllertz, Anette; Mu, Huiling

2013-01-01

Bile salts are present in the intestines of humans as well as the animals used during the development of pharmaceutical products. This review provides a short introduction into the physical chemical properties of bile salts, a description of the bile concentration and composition of bile...... in different animal species and an overview of the literature investigating the influence of bile salts on the in vivo performance of different compounds and drug formulations. Generally, there is a positive effect on bioavailability when bile is present in the gastro-intestinal tract, independent...

Emerging Frontiers in Drug Delivery.

Science.gov (United States)

Tibbitt, Mark W; Dahlman, James E; Langer, Robert

2016-01-27

Medicine relies on the use of pharmacologically active agents (drugs) to manage and treat disease. However, drugs are not inherently effective; the benefit of a drug is directly related to the manner by which it is administered or delivered. Drug delivery can affect drug pharmacokinetics, absorption, distribution, metabolism, duration of therapeutic effect, excretion, and toxicity. As new therapeutics (e.g., biologics) are being developed, there is an accompanying need for improved chemistries and materials to deliver them to the target site in the body, at a therapeutic concentration, and for the required period of time. In this Perspective, we provide an historical overview of drug delivery and controlled release followed by highlights of four emerging areas in the field of drug delivery: systemic RNA delivery, drug delivery for localized therapy, oral drug delivery systems, and biologic drug delivery systems. In each case, we present the barriers to effective drug delivery as well as chemical and materials advances that are enabling the field to overcome these hurdles for clinical impact.

Prediction of intestinal absorption and blood-brain barrier penetration by computational methods.

Science.gov (United States)

Clark, D E

2001-09-01

This review surveys the computational methods that have been developed with the aim of identifying drug candidates likely to fail later on the road to market. The specifications for such computational methods are outlined, including factors such as speed, interpretability, robustness and accuracy. Then, computational filters aimed at predicting "drug-likeness" in a general sense are discussed before methods for the prediction of more specific properties--intestinal absorption and blood-brain barrier penetration--are reviewed. Directions for future research are discussed and, in concluding, the impact of these methods on the drug discovery process, both now and in the future, is briefly considered.

Rapid screening and identification of illicit drugs by IR absorption spectroscopy and gas chromatography

Science.gov (United States)

Mengali, Sandro; Liberatore, Nicola; Luciani, Domenico; Viola, Roberto; Cardinali, Gian Carlo; Elmi, Ivan; Poggi, Antonella; Zampolli, Stefano; Biavardi, Elisa; Dalcanale, Enrico; Bonadio, Federica; Delemont, Olivier; Esseiva, Pierre; Romolo, Francesco S.

2013-01-01

Analytical instruments based on InfraRed Absorption Spectroscopy (IRAS) and Gas Chromatography (GC) are today available only as bench-top instrumentation for forensic labs and bulk analysis. Within the 'DIRAC' project funded by the European Commission, we are developing an advanced portable sensor, that combines miniaturized GC as its key chemical separation tool, and IRAS in a Hollow Fiber (HF) as its key analytical tool, to detect and recognize illicit drugs and key precursors, as bulk and as traces. The HF-IRAS module essentially consists of a broadly tunable External Cavity (EC) Quantum Cascade Laser (QCL), thermo-electrically cooled MCT detectors, and an infrared hollow fiber at controlled temperature. The hollow fiber works as a miniaturized gas cell, that can be connected to the output of the GC column with minimal dead volumes. Indeed, the module has been coupled to GC columns of different internal diameter and stationary phase, and with a Vapour Phase Pre-concentrator (VPC) that selectively traps target chemicals from the air. The presentation will report the results of tests made with amphetamines and precursors, as pure substances, mixtures, and solutions. It will show that the sensor is capable of analyzing all the chemicals of interest, with limits of detection ranging from a few nanograms to about 100-200 ng. Furthermore, it is suitable to deal with vapours directly trapped from the headspace of a vessel, and with salts treated in a basic solution. When coupled to FAST GC columns, the module can analyze multi-components mixes in less than 5 minutes.

Photon buildup factors of some chemotherapy drugs.

Science.gov (United States)

Kavaz, Esra; Ahmadishadbad, Nader; Özdemir, Yüksel

2015-02-01

Everyday more and more people are diagnosed with some form of cancer. Some are treatable with chemotherapy alone, while others need radiotherapy and occasionally surgery. Recently, concurrent administration of chemotherapy and radiotherapy has been increasingly used in cancer treatment, leading to improvements in survival as well as quality of life. Accordingly, interaction of chemotherapy drugs with radiation will be meaningful to examine. In the present study, gamma ray energy absorption and exposure of buildup factors were computed using the five-parameter geometric progression (G-P) fitting formula for some chemotherapy drugs in the energy range 0.015-15 MeV, and for penetration depths up to 40 mean free path (mfp). The generated energy absorption (EABF) and exposure buildup factors (EBF) of chemotherapy drugs have been studied as a function of penetration depth and incident photon energy. The significant variations in EABF and EBF for chemotherapy drugs have been observed at the moderate energy region. It has been concluded that the buildup of photons is less in azathioprine and is more in vinblastine compared with other drugs. Buildup factors investigated in the present work could be useful in radiation dosimetry and therapy. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Up-regulation of abscisic acid signaling pathway facilitates aphid xylem absorption and osmoregulation under drought stress.

Science.gov (United States)

Guo, Huijuan; Sun, Yucheng; Peng, Xinhong; Wang, Qinyang; Harris, Marvin; Ge, Feng

2016-02-01

The activation of the abscisic acid (ABA) signaling pathway reduces water loss from plants challenged by drought stress. The effect of drought-induced ABA signaling on the defense and nutrition allocation of plants is largely unknown. We postulated that these changes can affect herbivorous insects. We studied the effects of drought on different feeding stages of pea aphids in the wild-type A17 of Medicago truncatula and ABA signaling pathway mutant sta-1. We examined the impact of drought on plant water status, induced plant defense signaling via the abscisic acid (ABA), jasmonic acid (JA), and salicylic acid (SA) pathways, and on the host nutritional quality in terms of leaf free amino acid content. During the penetration phase of aphid feeding, drought decreased epidermis/mesophyll resistance but increased mesophyll/phloem resistance of A17 but not sta-1 plants. Quantification of transcripts associated with ABA, JA and SA signaling indicated that the drought-induced up-regulation of ABA signaling decreased the SA-dependent defense but increased the JA-dependent defense in A17 plants. During the phloem-feeding phase, drought had little effect on the amino acid concentrations and the associated aphid phloem-feeding parameters in both plant genotypes. In the xylem absorption stage, drought decreased xylem absorption time of aphids in both genotypes because of decreased water potential. Nevertheless, the activation of the ABA signaling pathway increased water-use efficiency of A17 plants by decreasing the stomatal aperture and transpiration rate. In contrast, the water potential of sta-1 plants (unable to close stomata) was too low to support xylem absorption activity of aphids; the aphids on sta-1 plants had the highest hemolymph osmolarity and lowest abundance under drought conditions. Taken together this study illustrates the significance of cross-talk between biotic-abiotic signaling pathways in plant-aphid interaction, and reveals the mechanisms leading to alter

CD36 mediates both cellular uptake of very long chain fatty acids and their intestinal absorption in mice.

Science.gov (United States)

Drover, Victor A; Nguyen, David V; Bastie, Claire C; Darlington, Yolanda F; Abumrad, Nada A; Pessin, Jeffrey E; London, Erwin; Sahoo, Daisy; Phillips, Michael C

2008-05-09

The intestine has an extraordinary capacity for fatty acid (FA) absorption. Numerous candidates for a protein-mediated mechanism of dietary FA absorption have been proposed, but firm evidence for this process has remained elusive. Here we show that the scavenger receptor CD36 is required both for the uptake of very long chain FAs (VLCFAs) in cultured cells and the absorption of dietary VLCFAs in mice. We found that the fraction of CD36-dependent saturated fatty acid association/absorption in these model systems is proportional to the FA chain length and specific for fatty acids and fatty alcohols containing very long saturated acyl chains. Moreover, intestinal VLCFA absorption is completely abolished in CD36-null mice fed a high fat diet, illustrating that the predominant mechanism for VLCFA absorption is CD36-dependent. Together, these findings represent the first direct evidence for protein-facilitated FA absorption in the intestine and identify a novel therapeutic target for the treatment of diseases characterized by elevated VLCFA levels.

Mechanistic understanding of the effect of PPIs and acidic carbonated beverages on the oral absorption of itraconazole based on absorption modeling with appropriate in vitro data.

Science.gov (United States)

Fotaki, Nikoletta; Klein, Sandra

2013-11-04

Proton pump inhibitors (PPIs) are potent gastric acid suppressing agents and are among the most widely sold drugs in the world. However, even though these antisecretory agents are regarded as safe, they can alter the pharmacokinetics of coadministered drugs. Due to the suppression of gastric acid secretion, they can significantly alter the intragastric pH conditions and are thus likely to affect the bioavailability of coadministered drugs requiring an acidic gastric environment for dissolution and subsequent absorption. Among these drugs can be found itraconazole, a poorly soluble triazole-type antifungal compound. Based on observations reported in the literature, gastric pH alterations due to the coadministration of PPIs or acidic beverages can significantly decrease (PPI) or increase (e.g., Coca-Cola) the bioavailability of this compound. In the present work we estimated the fraction of itraconazole that can be absorbed (fabs) from Sporanox capsules or an itraconazole-HBenBCD complex formulation after oral administration with and without coadministration of a PPI or an acidic (carbonated) beverage. For this purpose, the sensitivity of the two formulations toward the impact of various gastric variations (pH, volume, and emptying rate) as they can result from such administration conditions was studied using solubility and dissolution experiments and a physiologically based absorption model. Simulating coadministration of the two formulations with a PPI resulted in a significant (∼ 10-fold) decrease in itraconazole fabs, indicating the pH to be essential for in vivo dissolution and subsequent absorption. The fabs of itraconazole after coadministration of an acidic beverage (Coca-Cola) was far lower than the fabs obtained for itraconazole alone and did not support the observations reported in the literature. These results clearly indicate that in contrast to PPIs, which seem to affect itraconazole bioavailability mainly via intragastric pH changes, coadministered

A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin.

Science.gov (United States)

Shukla, Mahendra; Jaiswal, Swati; Sharma, Abhisheak; Srivastava, Pradeep Kumar; Arya, Abhishek; Dwivedi, Anil Kumar; Lal, Jawahar

2017-05-01

Curcumin, the golden spice from Indian saffron, has shown chemoprotective action against many types of cancer including breast cancer. However, poor oral bioavailability is the major hurdle in its clinical application. In the recent years, self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising tool to improve the oral absorption and enhancing the bioavailability of poorly water-soluble drugs. In this context, complexation with lipid carriers like phospholipid has also shown the tremendous potential to improve the solubility and therapeutic efficacy of certain drugs with poor oral bioavailability. In the present investigation, a systematic combination of both the approaches is utilized to prepare the phospholipid complex of curcumin and facilitate its incorporation into SNEDDS. The combined use of both the approaches has been explored for the first time to enhance the oral bioavailability and in turn increase the anticancer activity of curcumin. As evident from the pharmacokinetic studies and in situ single pass intestinal perfusion studies in Sprague-Dawley rats, the optimized SNEDDS of curcumin-phospholipid complex has shown enhanced oral absorption and bioavailability of curcumin. The cytotoxicity study in metastatic breast carcinoma cell line has shown the enhancement of cytotoxic action by 38.7%. The primary tumor growth reduction by 58.9% as compared with the control group in 4T1 tumor-bearing BALB/c mice further supported the theory of enhancement of anticancer activity of curcumin in SNEDDS. The developed formulation can be a potential and safe carrier for the oral delivery of curcumin.

Quantification of the fluorine containing drug 5-fluorouracil in cancer cells by GaF molecular absorption via high-resolution continuum source molecular absorption spectrometry

Energy Technology Data Exchange (ETDEWEB)

Krueger, Magnus [Freie Universitaet Berlin, Institut fuer Pharmazie, Pharmazeutische Chemie, Koenigin-Luise-Str. 2-4, 14195 Berlin (Germany); Huang, Mao-Dong; Becker-Ross, Helmut; Florek, Stefan [Leibniz Institut fuer Analytische Wissenschaften, ISAS-e.V., Department Berlin, Albert-Einstein-Str. 9, 12489 Berlin (Germany); Ott, Ingo [Technische Universitaet Carolo Wilhelmina zu Braunschweig, Institut fuer Medizinische und Pharmazeutische Chemie, Beethovenstr. 55, 38106 Braunschweig (Germany); Gust, Ronald, E-mail: ronald.gust@uibk.ac.at [Universitaet Innsbruck, Institut fuer Pharmazie, Pharmazeutische Chemie, Innrain 80/82, 6020 Innsbruck (Austria)

2012-03-15

The development of high-resolution continuum source molecular absorption spectrometry made the quantification of fluorine feasible by measuring the molecular absorption as gallium monofluoride (GaF). Using this new technique, we developed on the example of 5-fluorouracil (5-FU) a graphite furnace method to quantify fluorine in organic molecules. The effect of 5-FU on the generation of the diatomic GaF molecule was investigated. The experimental conditions such as gallium nitrate amount, temperature program, interfering anions (represented as corresponding acids) and calibration for the determination of 5-FU in standard solution and in cellular matrix samples were investigated and optimized. The sample matrix showed no effect on the sensitivity of GaF molecular absorption. A simple calibration curve using an inorganic sodium fluoride solution can conveniently be used for the calibration. The described method is sensitive and the achievable limit of detection is 0.23 ng of 5-FU. In order to establish the concept of 'fluorine as a probe in medicinal chemistry' an exemplary application was selected, in which the developed method was successfully demonstrated by performing cellular uptake studies of the 5-FU in human colon carcinoma cells. - Highlights: Black-Right-Pointing-Pointer Development of HR-CS MAS for quantification of fluorine bound to organic molecules Black-Right-Pointing-Pointer Measuring as molecular absorption of gallium monofluoride Black-Right-Pointing-Pointer Quantification of organic-bound fluorine in biological material Black-Right-Pointing-Pointer The concept of 'fluorine as a probe in medicinal chemistry' could be established.

Kinetics of drug release from ointments: Role of transient-boundary layer.

Science.gov (United States)

Xu, Xiaoming; Al-Ghabeish, Manar; Krishnaiah, Yellela S R; Rahman, Ziyaur; Khan, Mansoor A

2015-10-15

In the current work, an in vitro release testing method suitable for ointment formulations was developed using acyclovir as a model drug. Release studies were carried out using enhancer cells on acyclovir ointments prepared with oleaginous, absorption, and water-soluble bases. Kinetics and mechanism of drug release was found to be highly dependent on the type of ointment bases. In oleaginous bases, drug release followed a unique logarithmic-time dependent profile; in both absorption and water-soluble bases, drug release exhibited linearity with respect to square root of time (Higuchi model) albeit differences in the overall release profile. To help understand the underlying cause of logarithmic-time dependency of drug release, a novel transient-boundary hypothesis was proposed, verified, and compared to Higuchi theory. Furthermore, impact of drug solubility (under various pH conditions) and temperature on drug release were assessed. Additionally, conditions under which deviations from logarithmic-time drug release kinetics occur were determined using in situ UV fiber-optics. Overall, the results suggest that for oleaginous ointments containing dispersed drug particles, kinetics and mechanism of drug release is controlled by expansion of transient boundary layer, and drug release increases linearly with respect to logarithmic time. Published by Elsevier B.V.

Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions.

Science.gov (United States)

Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

2012-09-04

In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane's biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug 5-aza-2'-deoxycytidine (decitabine) significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.

Investigating the correlation between in vivo absorption and in vitro release of fenofibrate from lipid matrix particles in biorelevant medium

DEFF Research Database (Denmark)

Borkar, Nrupa Nitin; Xia, Dengning; Holm, René

2014-01-01

Lipid matrix particles (LMP) may be used as better carriers for poorly water-soluble drugs than liquid lipid carriers because of reduced drug mobilization in the formulations. However, the digestion process of solid lipid particles and their effect on the absorption of poorly water-soluble drugs......-soluble drug, was incorporated into LMP in this study using probe ultrasound sonication. The resultant LMP were characterised in terms of particle size, size distribution, zeta potential, entrapment efficiency, in vitro lipolysis and in vivo absorption in rat model. LMP of three different particle sizes i.......e. approximately 100 nm, 400 nm, and 10 μm (microparticles) were produced with high entrapment efficiencies. The in vitro lipolysis study showed that the recovery of fenofibrate in the aqueous phase for 100 nm and 400 nm LMP was significantly higher (p

Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs.

Science.gov (United States)

Dahan, Arik; Amidon, Gordon L

2009-01-01

The purpose of this study was to investigate the role of P-gp efflux in the in vivo intestinal absorption process of BCS class III P-gp substrates, i.e. high-solubility low-permeability drugs. The in vivo permeability of two H (2)-antagonists, cimetidine and famotidine, was determined by the single-pass intestinal perfusion model in different regions of the rat small intestine, in the presence or absence of the P-gp inhibitor verapamil. The apical to basolateral (AP-BL) and the BL-AP transport of the compounds in the presence or absence of various efflux transporters inhibitors (verapamil, erythromycin, quinidine, MK-571 and fumitremorgin C) was investigated across Caco-2 cell monolayers. P-gp expression levels in the different intestinal segments were confirmed by immunoblotting. Cimetidine and famotidine exhibited segmental dependent permeability through the gut wall, with decreased P(eff) in the distal ileum in comparison to the proximal regions of the intestine. Coperfusion of verapamil with the drugs significantly increased the permeability in the ileum, while no significant change in the jejunal permeability was observed. Both drugs exhibited significantly greater BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion. Concentration dependent decrease of this secretion was obtained by the P-gp inhibitors verapamil, erythromycin and quinidine, while no effect was evident by the MRP2 inhibitor MK-571 and the BCRP inhibitor FTC, indicating that P-gp is the transporter mediates the intestinal efflux of cimetidine and famotidine. P-gp levels throughout the intestine were inversely related to the in vivo permeability of the drugs from the different segments. The data demonstrate that for these high-solubility low-permeability P-gp substrates, P-gp limits in vivo intestinal absorption in the distal segments of the small intestine; however P-gp plays a minimal role in the proximal intestinal segments due to significant lower P-gp expression levels

Signalling possible drug-drug interactions in a spontaneous reporting system : delay of withdrawal bleeding during concomitant use of oral contraceptives and itraconazole

NARCIS (Netherlands)

Van Puijenbroek, E P; Egberts, A C; Meyboom, R H; Leufkens, H G

AIMS: In spontaneous adverse drug reaction reporting systems, there is a growing need for methods facilitating the automated detection of signals concerning possible adverse drug reactions. In addition, special attention is needed for the detection of adverse drug reactions resulting from possible

Artificial Lipid Membrane Permeability Method for Predicting Intestinal Drug Transport: Probing the Determining Step in the Oral Absorption of Sulfadiazine; Influence of the Formation of Binary and Ternary Complexes with Cyclodextrins.

Science.gov (United States)

Delrivo, Alicia; Aloisio, Carolina; Longhi, Marcela R; Granero, Gladys

2018-04-01

We propose an in vitro permeability assay by using a modified lipid membrane to predict the in vivo intestinal passive permeability of drugs. Two conditions were tested, one with a gradient pH (pH 5.5 donor/pH 7.4 receptor) and the other with an iso-pH 7.4. The predictability of the method was established by correlating the obtained apparent intestinal permeability coefficients (P app ) and the oral dose fraction absorbed in humans (f a ) of 16 drugs with different absorption properties. The P app values correlated well with the absorption rates under the two conditions, and the method showed high predictability and good reproducibility. On the other hand, with this method, we successfully predicted the transport characteristics of oral sulfadiazine (SDZ). Also, the tradeoff between the increase in the solubility of SDZ by its complex formation with cyclodextrins and/or aminoacids and its oral permeability was assessed. Results suggest that SDZ is transported through the gastrointestinal epithelium by passive diffusion in a pH-dependent manner. These results support the classification of SDZ as a high/low borderline permeability compound and are in agreement with the Biopharmaceutics Classification Systems (BCS). This conclusion is consistent with the in vivo pharmacokinetic properties of SDZ.

Fructose and related food carbohydrates. Sources, intake, absorption, and clinical implications

DEFF Research Database (Denmark)

Rumessen, J J

1992-01-01

It is possible to point out subjects consuming considerable quantities of fructose and sorbitol, and the intake seems to be increasing both from added and natural sources. Studies of the absorption of fructose in animals are inconsistent, and the mechanisms of fructose uptake seem to vary...... in accordance with the species. In most species fructose absorption takes place by a specific carrier (facilitated transport), but it may be active in the rat. In vitro studies of human intestine are very scarce; there is no evidence of active intestinal fructose transport in the human intestine. By means...... interest. Fructans are not absorbed in the small intestine but are strongly fermented in the large bowel. Fructans may be of potential benefit for large-bowel function and blood glucose regulation....

Quantification of the fluorine containing drug 5-fluorouracil in cancer cells by GaF molecular absorption via high-resolution continuum source molecular absorption spectrometry

Science.gov (United States)

Krüger, Magnus; Huang, Mao-Dong; Becker-Roß, Helmut; Florek, Stefan; Ott, Ingo; Gust, Ronald

The development of high-resolution continuum source molecular absorption spectrometry made the quantification of fluorine feasible by measuring the molecular absorption as gallium monofluoride (GaF). Using this new technique, we developed on the example of 5-fluorouracil (5-FU) a graphite furnace method to quantify fluorine in organic molecules. The effect of 5-FU on the generation of the diatomic GaF molecule was investigated. The experimental conditions such as gallium nitrate amount, temperature program, interfering anions (represented as corresponding acids) and calibration for the determination of 5-FU in standard solution and in cellular matrix samples were investigated and optimized. The sample matrix showed no effect on the sensitivity of GaF molecular absorption. A simple calibration curve using an inorganic sodium fluoride solution can conveniently be used for the calibration. The described method is sensitive and the achievable limit of detection is 0.23 ng of 5-FU. In order to establish the concept of "fluorine as a probe in medicinal chemistry" an exemplary application was selected, in which the developed method was successfully demonstrated by performing cellular uptake studies of the 5-FU in human colon carcinoma cells.

Influence of 2,3-dimercaptosuccinic acid on gastrointestinal lead absorption and whole-body lead retention

International Nuclear Information System (INIS)

Kapoor, S.C.; Wielopolski, L.; Graziano, J.H.; LoIacono, N.J.

1989-01-01

2,3-Dimercaptosuccinic acid (DMSA) is a new orally active heavy metal chelator for the treatment of childhood Pb intoxication on an outpatient basis. The influence of DMSA, as well as other chelating agents, on gastrointestinal 203Pb absorption and whole-body 203 Pb retention was examined. Groups of Sprague-Dawley rats (230-260 g) were gavaged with a solution containing approximately 25 mg/kg Pb [as Pb(NO 3 )2] plus 15 microCi 203 Pb. Some groups were then immediately given 0.11 mmol/kg of either DMSA, CaNa2EDTA, D-penicillamine, or BAL by oral gavage, while other groups received the same drugs by ip injection. Control groups received solutions of the drug vehicles po or ip. Whole-body Pb retention and gastrointestinal Pb absorption (whole body retention + urinary Pb excretion) were significantly decreased in rats that received DMSA po. This finding implies that the use of DMSA to treat childhood lead intoxication on an outpatient basis is not associated with a risk for increased Pb absorption

Herb-drug interactions.

Science.gov (United States)

Fugh-Berman, A

2000-01-08

Concurrent use of herbs may mimic, magnify, or oppose the effect of drugs. Plausible cases of herb-drug interactions include: bleeding when warfarin is combined with ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis), or danshen (Salvia miltiorrhiza); mild serotonin syndrome in patients who mix St John's wort (Hypericum perforatum) with serotonin-reuptake inhibitors; decreased bioavailability of digoxin, theophylline, cyclosporin, and phenprocoumon when these drugs are combined with St John's wort; induction of mania in depressed patients who mix antidepressants and Panax ginseng; exacerbation of extrapyramidal effects with neuroleptic drugs and betel nut (Areca catechu); increased risk of hypertension when tricyclic antidepressants are combined with yohimbine (Pausinystalia yohimbe); potentiation of oral and topical corticosteroids by liquorice (Glycyrrhiza glabra); decreased blood concentrations of prednisolone when taken with the Chinese herbal product xaio chai hu tang (sho-salko-to); and decreased concentrations of phenytoin when combined with the Ayurvedic syrup shankhapushpi. Anthranoid-containing plants (including senna [Cassia senna] and cascara [Rhamnus purshiana]) and soluble fibres (including guar gum and psyllium) can decrease the absorption of drugs. Many reports of herb-drug interactions are sketchy and lack laboratory analysis of suspect preparations. Health-care practitioners should caution patients against mixing herbs and pharmaceutical drugs.

The Combination of GIS and Biphasic to Better Predict In Vivo Dissolution of BCS Class IIb Drugs, Ketoconazole and Raloxifene.

Science.gov (United States)

Tsume, Yasuhiro; Igawa, Naoto; Drelich, Adam J; Amidon, Gregory E; Amidon, Gordon L

2018-01-01

The formulation developments and the in vivo assessment of Biopharmaceutical Classification System (BCS) class II drugs are challenging due to their low solubility and high permeability in the human gastrointestinal (GI) tract. Since the GI environment influences the drug dissolution of BCS class II drugs, the human GI characteristics should be incorporated into the in vitro dissolution system to predict bioperformance of BCS class II drugs. An absorptive compartment may be important in dissolution apparatus for BCS class II drugs, especially for bases (BCS IIb) because of high permeability, precipitation, and supersaturation. Thus, the in vitro dissolution system with an absorptive compartment may help predicting the in vivo phenomena of BCS class II drugs better than compendial dissolution apparatuses. In this study, an absorptive compartment (a biphasic device) was introduced to a gastrointestinal simulator. This addition was evaluated if this in vitro system could improve the prediction of in vivo dissolution for BCS class IIb drugs, ketoconazole and raloxifene, and subsequent absorption. The gastrointestinal simulator is a practical in vivo predictive tool and exhibited an improved in vivo prediction utilizing the biphasic format and thus a better tool for evaluating the bioperformance of BCS class IIb drugs than compendial apparatuses. Copyright © 2018. Published by Elsevier Inc.

Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs.

Science.gov (United States)

Tian, Ye; Mao, Shirui

2012-06-01

Many amphiphilic copolymers have recently been synthesized as novel promising micellar carriers for the delivery of poorly water-soluble anticancer drugs. Studies on the formulation and oral delivery of such micelles have demonstrated their efficacy in enhancing drug uptake and absorption, and exhibit prolonged circulation time in vitro and in vivo. In this review, literature on hydrophobic modifications of several hydrophilic polymers, including polyethylene glycol, chitosan, hyaluronic acid, pluronic and tocopheryl polyethylene glycol succinate, is summarized. Parameters influencing the properties of polymeric micelles for oral chemotherapy are discussed and strategies to overcome main barriers for polymeric micelles peroral absorption are proposed. During the design of polymeric micelles for peroral chemotherapy, selecting or synthesizing copolymers with good compatibility with the drug is an effective strategy to increase drug loading and encapsulation efficiency. Stability of the micelles can be improved in different ways. It is recommended to take permeability, mucoadhesion, sustained release, and P-glycoprotein inhibition into consideration during copolymer preparation or to consider adding some excipients in the formulation. Furthermore, both the copolymer structure and drug loading methods should be controlled in order to get micelles with appropriate particle size for better absorption.

Dexmedetomidine infusion to facilitate opioid detoxification and withdrawal in a patient with chronic opioid abuse

Directory of Open Access Journals (Sweden)

Surjya Prasad Upadhyay

2011-01-01

Full Text Available Many patients are admitted to the intensive care unit (ICU for acute intoxication, serious complication of overdose, or withdrawal symptoms of illicit drugs. An acute withdrawal of drugs with addiction potential is associated with a sympathetic overactivity leading to marked psychomimetic disturbances. Acute intoxication or withdrawal of such drugs is often associated with life-threatening complications which require ICU admission and necessitate prolonged sedative analgesic medications, weaning from which is often complicated by withdrawal and other psychomimetic symptoms. Dexmedetomidine, an alpha-2 (α2 agonist, has been used successfully to facilitate withdrawal and detoxification of various drugs and also to control delirium in ICU patients. Herein, we report a case of a chronic opioid abuse (heroin patient admitted with acute overdose complications leading to a prolonged ICU course requiring sedative-analgesic medication; the drug withdrawal-related symptoms further complicated the weaning process. Dexmedetomidine infusion was successfully used as a sedative-analgesic to control the withdrawal-related psychomimetic symptoms and to facilitate smooth detoxification and weaning from opioid and other sedatives.

Studies on the percutaneous absorption of /sup 14/C-labelled Flurbiprofen, 3. Whole body autoradiography of rats and guinea-pigs

Energy Technology Data Exchange (ETDEWEB)

Nagao, Soshichi; Sakai, Takeo; Hayakawa, Toru (Nihon Univ., Tokyo. Coll. of Agriculture and Veterinary Medicine)

1983-03-01

Whole body autoradiography was carried out to clarify and compare the distribution of /sup 14/C-labelled Flurbiprofen which was applied to the skin as an ointment in rats and guinea-pigs. Both in rats and guinea-pigs almost the same autoradiogram was gained. The radioactivity was strongest at the skin area inspite of the time elapse, showing that the drug was fixed in the site of skin applied. In other parts of the body, however, it was small except the kidney and intestine. It seemed that the absorption of the drug was a little although the migration of the drug into the blood circulation is fast at the beginning as was shown in pigs previously. A stronger radioactivity in the kidney and intestine might indicate that a main pathway of excretion of this drug was through those two organs. Absorption, distribution and excretion of the drug were not different between rats and guinea-pigs, similar to those observed in pigs.

Specificity of drug transport mediated by CaMDR1: a major facilitator ...

Indian Academy of Sciences (India)

Unknown

CaMDR1 encodes a major facilitator superfamily (MFS) protein in Candida albicans whose expression has been linked to .... by plaque assay and the integration of CaMDR1 at the ... with recombinant virus, vAcCaMDR1 and cells infected.

[The percutaneous absorption of diclofenac].

Science.gov (United States)

Riess, W; Schmid, K; Botta, L; Kobayashi, K; Moppert, J; Schneider, W; Sioufi, A; Strusberg, A; Tomasi, M

1986-07-01

The percutaneous absorption of diclofenac diethylammonium 1.16% (w/w) in a combination of emulsion cream and gel (Voltaren Emulgel) and of diclofenac sodium 1% (w/w) in a cream formulation (Voltaren cream) was investigated in guinea-pig, rabbit and man. The percutaneous absorption of diclofenac sodium in guinea-pig was 3 to 6% of the dose when the cream formulation in doses of 320, 100 or 40 mg was applied on 10 cm2 of occluded skin and left in place for 6 h. The transdermal delivery of 14C-labelled diclofenac yielded plateau plasma concentrations of radiotracer from 1.5 h after application until removal of the residual cream. Subsequently the steady state drug depots in the skin and muscle tissue were depleted promptly. During daily administration the steady state levels in the muscle tissue in proximity to the application site were about 3 times higher than in distant muscle tissue. By topical application on knee joints of rabbits diclofenac penetrated into the patellar ligament, the adipose corpus and the synovial fluid. In man the percutaneous absorption was 6% of the dose when the Emulgel formulation was spread by 5 mg/cm2 and left for 12 h on non-occluded skin. The pattern of metabolites of diclofenac in human urine was the same after topical and oral administration. In man, upon daily topical administration of 3 times 2.5 g cream formulation (10 mg/cm2) the diclofenac steady state plasma levels were 20 to 40 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic transporter drug-drug interactions: an evaluation of approaches and methodologies.

Science.gov (United States)

Williamson, Beth; Riley, Robert J

2017-12-01

Drug-drug interactions (DDIs) continue to account for 5% of hospital admissions and therefore remain a major regulatory concern. Effective, quantitative prediction of DDIs will reduce unexpected clinical findings and encourage projects to frontload DDI investigations rather than concentrating on risk management ('manage the baggage') later in drug development. A key challenge in DDI prediction is the discrepancies between reported models. Areas covered: The current synopsis focuses on four recent influential publications on hepatic drug transporter DDIs using static models that tackle interactions with individual transporters and in combination with other drug transporters and metabolising enzymes. These models vary in their assumptions (including input parameters), transparency, reproducibility and complexity. In this review, these facets are compared and contrasted with recommendations made as to their application. Expert opinion: Over the past decade, static models have evolved from simple [I]/k i models to incorporate victim and perpetrator disposition mechanisms including the absorption rate constant, the fraction of the drug metabolised/eliminated and/or clearance concepts. Nonetheless, models that comprise additional parameters and complexity do not necessarily out-perform simpler models with fewer inputs. Further, consideration of the property space to exploit some drug target classes has also highlighted the fine balance required between frontloading and back-loading studies to design out or 'manage the baggage'.

Facilitation as a teaching strategy : experiences of facilitators

Directory of Open Access Journals (Sweden)

E Lekalakala-Mokgele

2006-09-01

Full Text Available Changes in nursing education involve the move from traditional teaching approaches that are teacher-centred to facilitation, a student centred approach. The studentcentred approach is based on a philosophy of teaching and learning that puts the learner on centre-stage. The aim of this study was to identify the challenges of facilitators of learning using facilitation as a teaching method and recommend strategies for their (facilitators development and support. A qualitative, explorative and contextual design was used. Four (4 universities in South Africa which utilize facilitation as a teaching/ learning process were identified and the facilitators were selected to be the sample of the study. The main question posed during in-depth group interviews was: How do you experience facilitation as a teaching/learning method?. Facilitators indicated different experiences and emotions when they first had to facilitate learning. All of them indicated that it was difficult to facilitate at the beginning as they were trained to lecture and that no format for facilitation was available. They experienced frustrations and anxieties as a result. The lack of knowledge of facilitation instilled fear in them. However they indicated that facilitation had many benefits for them and for the students. Amongst the ones mentioned were personal and professional growth. Challenges mentioned were the fear that they waste time and that they do not cover the content. It is therefore important that facilitation be included in the training of nurse educators.

Recent Advancement and Technological Aspects of Pulsatile Drug Delivery System - A Laconic Review.

Science.gov (United States)

Pandit, Vinay; Kumar, Ajay; Ashawat, Mahendra S; Verma, Chander P; Kumar, Pravin

2017-01-01

Pulsatile drug delivery system (PDDS) shows potential significance in the field of drug delivery to release the maximum amount of drug at a definite site and at specific time. PDDS are mainly time controlled delivery devices having a definite pause period for drug release, which is not affected by acidity, alkalinity, motility and enzymes present in the gastrointestinal tract. Pulsatile medication possess the potential to deliver the drugs in the therapy of diseases where drug dose is essential during sleep, drugs having greater first pass metabolism and absorption at precise location in digestive tract. The review article, discuss the general concepts, marketed formulations and patents or any other recent advancement in pulsatile release technology. It also highlights on diseases requiring therapy by pulsatile release, various researches on herbal pulsatile formulations and quality control aspects of PDDS. Pulsatile medication possess the potential to deliver the drugs in the therapy of diseases where drug dose is essential during sleep, drugs having greater first pass metabolism and absorption at precise location in digestive tract. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Natural products to improve quality of life targeting for colon drug delivery.

Science.gov (United States)

Kim, Hyunjo

2012-03-01

The colon is largely being investigated as a site for administration of protein and peptides, which are degraded by digestive enzymes in the upper GIT. Also for local diseases of the colon such as inflammatory bowel disease, colorectal cancer and ameobiasis, drug administration to the site of action can not only reduce the dose to be administered, but also decrease the side effects. Inflammatory Bowel Disease (IBD) such as Ulcerative colitis and Crohn's disease are characterized by chronic intestinal inflammation. Intestinal bacteria initiate the activation of intestinal inflammatory processes, which are mediated by pro-inflammatory cytokines and chemokine. Increased chemokine expression has also been observed in epithelial cells, endothelial cells, and smooth muscle cells. Future trials of specific agents capable of inhibiting chemokine synthesis and secretion or blocking chemokine-chemokine receptor interaction will be important to study in patients with ulcerative colitis and Crohn's disease. Many important bioactive compounds have been discovered from natural sources using bioactivity directed fractionation and isolation (BDFl) Continuing discovery has also been facilitated by the recent development of new bioassay methods. These bioactive compounds are mostly plant secondary metabolites, and many naturally occurring pure compounds have become medicines, dietary supplements, and other useful commercial products. The present review includes various approaches investigated for colon drug delivery and their site specificity. To achieve successful colonic delivery, a drug needs to be protected from absorption and the environment of the upper gastrointestinal tract and then be abruptly released into the proximal colon, which is considered the optimum site for colon targeted delivery of drugs.

Impact of Pharmacist Facilitated Discharge Medication Reconciliation

Directory of Open Access Journals (Sweden)

Todd M. Super

2014-07-01

Full Text Available Preventable adverse drug events occur frequently at transitions in care and are a problem for many patients following hospital discharge. Many of these problems can be attributed to poor medication reconciliation. The purpose of this study was to assess the impact that direct pharmacist involvement in the discharge medication reconciliation process had on medication discrepancies, patient outcomes, and satisfaction. A cohort study of 70 patients was designed to assess the impact of pharmacist facilitated discharge medication reconciliation at a 204-bed community hospital in Battle Creek, Michigan, USA. Discharge summaries were analyzed to compare patients who received standard discharge without pharmacist involvement to those having pharmacist involvement. The total number of discrepancies in the group without pharmacist involvement was significantly higher than that of the pharmacist facilitated group.

DenguePredict: An Integrated Drug Repositioning Approach towards Drug Discovery for Dengue.

Science.gov (United States)

Wang, QuanQiu; Xu, Rong

2015-01-01

Dengue is a viral disease of expanding global incidence without cures. Here we present a drug repositioning system (DenguePredict) leveraging upon a unique drug treatment database and vast amounts of disease- and drug-related data. We first constructed a large-scale genetic disease network with enriched dengue genetics data curated from biomedical literature. We applied a network-based ranking algorithm to find dengue-related diseases from the disease network. We then developed a novel algorithm to prioritize FDA-approved drugs from dengue-related diseases to treat dengue. When tested in a de-novo validation setting, DenguePredict found the only two drugs tested in clinical trials for treating dengue and ranked them highly: chloroquine ranked at top 0.96% and ivermectin at top 22.75%. We showed that drugs targeting immune systems and arachidonic acid metabolism-related apoptotic pathways might represent innovative drugs to treat dengue. In summary, DenguePredict, by combining comprehensive disease- and drug-related data and novel algorithms, may greatly facilitate drug discovery for dengue.

Self-microemulsifying drug delivery system for improved oral bioavailability of dipyridamole: preparation and evaluation.

Science.gov (United States)

Guo, Feng; Zhong, Haijun; He, Jing; Xie, Baogang; Liu, Fen; Xu, Helin; Liu, Minmin; Xu, Chunlian

2011-07-01

Dipyridamole shows poor and variable bioavailability after oral administration due to pHdependent solubility, low biomembrane permeability as well as being a substrate of P-glycoprotein. In order to improve the oral absorption of dipyridamole, a self-microemulsifying drug delivery system (SMEDDS) for dipyridamole was prepared and evaluated in vitro and in vivo. The optimum formulation was 18% oleic acid, 12% Labrafac lipophile WL 1349, 42% Solutol HS 15 and 28% isopropyl alcohol. It was found that the performance of self-microemulsification with the combination of oleic acid and Labrafac lipophile WL 1349 increased compared with just one oil. The results obtained from an in vitro dissolution assay indicated that dipyridamole in SMEDDS dissolved rapidly and completely in pH 6.8 aqueous media, while the commercial drug tablet was less soluble. An oral bioavailability study in rats showed that dipyridamole in the SMEDDS formulation had a 2.06-fold increased absorption compared with the simple drug suspension. It was evident that SMEDDS may be an effective approach to improve the oral absorption for drugs having pH-dependent solubility.

Orally active-targeted drug delivery systems for proteins and peptides.

Science.gov (United States)

Li, Xiuying; Yu, Miaorong; Fan, Weiwei; Gan, Yong; Hovgaard, Lars; Yang, Mingshi

2014-09-01

In the past decade, extensive efforts have been devoted to designing 'active targeted' drug delivery systems (ATDDS) to improve oral absorption of proteins and peptides. Such ATDDS enhance cellular internalization and permeability of proteins and peptides via molecular recognition processes such as ligand-receptor or antigen-antibody interaction, and thus enhance drug absorption. This review focuses on recent advances with orally ATDDS, including ligand-protein conjugates, recombinant ligand-protein fusion proteins and ligand-modified carriers. In addition to traditional intestinal active transport systems of substrates and their corresponding receptors, transporters and carriers, new targets such as intercellular adhesion molecule-1 and β-integrin are also discussed. ATDDS can improve oral absorption of proteins and peptides. However, currently, no clinical studies on ATDDS for proteins and peptides are underway, perhaps due to the complexity and limited knowledge of transport mechanisms. Therefore, more research is warranted to optimize ATDDS efficiency.

Energy-Looping Nanoparticles: Harnessing Excited-State Absorption for Deep-Tissue Imaging.

Science.gov (United States)

Levy, Elizabeth S; Tajon, Cheryl A; Bischof, Thomas S; Iafrati, Jillian; Fernandez-Bravo, Angel; Garfield, David J; Chamanzar, Maysamreza; Maharbiz, Michel M; Sohal, Vikaas S; Schuck, P James; Cohen, Bruce E; Chan, Emory M

2016-09-27

Near infrared (NIR) microscopy enables noninvasive imaging in tissue, particularly in the NIR-II spectral range (1000-1400 nm) where attenuation due to tissue scattering and absorption is minimized. Lanthanide-doped upconverting nanocrystals are promising deep-tissue imaging probes due to their photostable emission in the visible and NIR, but these materials are not efficiently excited at NIR-II wavelengths due to the dearth of lanthanide ground-state absorption transitions in this window. Here, we develop a class of lanthanide-doped imaging probes that harness an energy-looping mechanism that facilitates excitation at NIR-II wavelengths, such as 1064 nm, that are resonant with excited-state absorption transitions but not ground-state absorption. Using computational methods and combinatorial screening, we have identified Tm(3+)-doped NaYF4 nanoparticles as efficient looping systems that emit at 800 nm under continuous-wave excitation at 1064 nm. Using this benign excitation with standard confocal microscopy, energy-looping nanoparticles (ELNPs) are imaged in cultured mammalian cells and through brain tissue without autofluorescence. The 1 mm imaging depths and 2 μm feature sizes are comparable to those demonstrated by state-of-the-art multiphoton techniques, illustrating that ELNPs are a promising class of NIR probes for high-fidelity visualization in cells and tissue.

The application of skin metabolomics in the context of transdermal drug delivery.

Science.gov (United States)

Li, Jinling; Xu, Weitong; Liang, Yibiao; Wang, Hui

2017-04-01

Metabolomics is a powerful emerging tool for the identification of biomarkers and the exploration of metabolic pathways in a high-throughput manner. As an administration site for percutaneous absorption, the skin has a variety of metabolic enzymes, except other than hepar. However, technologies to fully detect dermal metabolites remain lacking. Skin metabolomics studies have mainly focused on the regulation of dermal metabolites by drugs or on the metabolism of drugs themselves. Skin metabolomics techniques include collection and preparation of skin samples, data collection, data processing and analysis. Furthermore, studying dermal metabolic effects via metabolomics can provide novel explanations for the pathogenesis of some dermatoses and unique insights for designing targeted prodrugs, promoting drug absorption and controlling drug concentration. This paper reviews current progress in the field of skin metabolomics, with a specific focus on dermal drug delivery systems and dermatosis. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Self-Micro Emulsifying Drug Delivery Systems: a Strategy to Improve Oral Bioavailability

Directory of Open Access Journals (Sweden)

Vijay K. Sharma

Full Text Available Aim: Oral route has always been the favorite route of drug administration in many diseases and till today it is the first way investigated in the development of new dosage forms. The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility, thereby pose problems in their formulation. For the therapeutic delivery of lipophilic active moieties (BCS class II drugs, lipid based formulations are inviting increasing attention. Methods: To that aim, from the web sites of PubMed, HCAplus, Thomson, and Registry were used as the main sources to perform the search for the most significant research articles published on the subject. The information was then carefully analyzed, highlighting the most important results in the formulation and development of self-micro emulsifying drug delivery systems as well as its therapeutic activity. Results: Self-emulsifying drug delivery system (SMEDDS has gained more attention due to enhanced oral bio-availability enabling reduction in dose, more consistent temporal profiles of drug absorption, selective targeting of drug(s toward specific absorption window in GIT, and protection of drug(s from the unreceptive environment in gut. Conclusions: This article gives a complete overview of SMEDDS as a promising approach to effectively deal with the problem of poorly soluble molecules.

NSLS [National Synchrotron Light Source] X-19A beamline performance for x-ray absorption measurements

International Nuclear Information System (INIS)

Yang, C.Y.; Penner-Hahn, J.E.; Stefan, P.M.

1989-01-01

Characterization of the X-19A beamline at the National Synchrotron Light Source (NSLS) is described. The beamline is designed for high resolution x-ray absorption spectroscopy over a wide energy range. All of the beamline optical components are compatible with ultrahigh vacuum (UHV) operation. This permits measurements to be made in a window-less mode, thereby facilitating lower energy (<4 KeV) studies. To upgrade the beamline performance, several possible improvements in instrumentation and practice are discussed to increase photon statistics with an optimum energy resolution, while decreasing the harmonic contamination and noise level. A special effort has been made to improve the stability and UHV compatibility of the monochromator system. Initial x-ray absorption results demonstrate the capabilities of this beamline for x-ray absorption studies of low Z elements (e.g. S) in highly dilute systems. The future use of this beamline for carrying out various x-ray absorption experiments is presented. 10 refs., 4 figs

Drug metabolism and ageing.

Science.gov (United States)

Wynne, Hilary

2005-06-01

Older people are major consumers of drugs and because of this, as well as co-morbidity and age-related changes in pharmacokinetics and pharmacodynamics, are at risk of associated adverse drug reactions. While age does not alter drug absorption in a clinically significant way, and age-related changes in volume of drug distribution and protein binding are not of concern in chronic therapy, reduction in hepatic drug clearance is clinically important. Liver blood flow falls by about 35% between young adulthood and old age, and liver size by about 24-35% over the same period. First-pass metabolism of oral drugs avidly cleared by the liver and clearance of capacity-limited hepatically metabolized drugs fall in parallel with the fall in liver size, and clearance of drugs with a high hepatic extraction ratio falls in parallel with the fall in hepatic blood flow. In normal ageing, in general, activity of the cytochrome P450 enzymes is preserved, although a decline in frail older people has been noted, as well as in association with liver disease, cancer, trauma, sepsis, critical illness and renal failure. As the contribution of age, co-morbidity and concurrent drug therapy to altered drug clearance is impossible to predict in an individual older patient, it is wise to start any drug at a low dose and increase this slowly, monitoring carefully for beneficial and adverse effects.

MALDI imaging facilitates new topical drug development process by determining quantitative skin distribution profiles.

Science.gov (United States)

Bonnel, David; Legouffe, Raphaël; Eriksson, André H; Mortensen, Rasmus W; Pamelard, Fabien; Stauber, Jonathan; Nielsen, Kim T

2018-04-01

Generation of skin distribution profiles and reliable determination of drug molecule concentration in the target region are crucial during the development process of topical products for treatment of skin diseases like psoriasis and atopic dermatitis. Imaging techniques like mass spectrometric imaging (MSI) offer sufficient spatial resolution to generate meaningful distribution profiles of a drug molecule across a skin section. In this study, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to generate quantitative skin distribution profiles based on tissue extinction coefficient (TEC) determinations of four different molecules in cross sections of human skin explants after topical administration. The four drug molecules: roflumilast, tofacitinib, ruxolitinib, and LEO 29102 have different physicochemical properties. In addition, tofacitinib was administrated in two different formulations. The study reveals that with MALDI-MSI, we were able to observe differences in penetration profiles for both the four drug molecules and the two formulations and thereby demonstrate its applicability as a screening tool when developing a topical drug product. Furthermore, the study reveals that the sensitivity of the MALDI-MSI techniques appears to be inversely correlated to the drug molecules' ability to bind to the surrounding tissues, which can be estimated by their Log D values. Graphical abstract.

Pepsi® or Coke®? Influence of acid on dasatinib absorption.

Science.gov (United States)

Knoebel, Randall W; Larson, Richard A

2018-03-01

Dasatinib is a second generation ABL kinase inhibitor used in the management of chronic myeloid leukemia or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Dasatinib's bioavailability is highly dependent on gastric pH. When proton-pump inhibitors (PPIs) are co-administered with dasatinib, absorption is significantly reduced. Cola intake at the time of drug administration has been demonstrated to lead to relevant increases in the bioavailability for other acid labile drugs during PPI treatment. This manuscript reviews the relevant literature supporting a strategy of temporarily lowering the gastric pH with a carbonated beverage at the time of drug administration. The use of cola provides an easy to implement way to significantly improve dasatinib bioavailability, especially during concomitant use of a PPI.

Exciplex formation and electroluminescent absorption in ultraviolet organic light-emitting diodes

International Nuclear Information System (INIS)

Zhang Qi; Zhang Hao; Xu Tao; Wei Bin; Zhang Xiao-Wen

2015-01-01

We investigated the formation of exciplex and electroluminescent absorption in ultraviolet organic light-emitting diodes (UV OLEDs) using different heterojunction structures. It is found that an energy barrier of over 0.3 eV between the emissive layer (EML) and adjacent transport layer facilitates exciplex formation. The electron blocking layer effectively confines electrons in the EML, which contributes to pure UV emission and enhances efficiency. The change in EML thickness generates tunable UV emission from 376 nm to 406 nm. In addition, the UV emission excites low-energy organic function layers and produces photoluminescent emission. In UV OLED, avoiding the exciplex formation and averting light absorption can effectively improve the purity and efficiency. A maximum external quantum efficiency of 1.2% with a UV emission peak of 376 nm is realized. (paper)

78 FR 48691 - Food and Drug Administration Patient Network Annual Meeting; Demystifying Food and Drug...

Science.gov (United States)

2013-08-09

... 240-316-3200 ext. 207. If you need special accommodations due to a disability, please specify those... impact the drug development and review paradigm. Though several programs exist that facilitate patient...

Adaptation and evolution of drug-resistant Mycobacterium tuberculosis

NARCIS (Netherlands)

Bergval, I.L.

2013-01-01

Many studies have been conducted on drug resistance and the evolution of Mycobacterium tuberculosis. Notwithstanding, many molecular mechanisms facilitating the emergence, adaptation and spread of drug-resistant tuberculosis have yet to be discovered. This thesis reports studies of the adaptive

Nasal Inserts for Drug Delivery: An Overview

African Journals Online (AJOL)

In this review, the benefits, limitations and absorption mechanisms of the nasal route, as well ... molecules including peptide and proteins for ... (Mw) drugs, rapid and fast onset of action due to ... while the former act by disrupting the nasal.

Radiotracer investigation of the cold-vapour atomic absorption method of analysis for trace mercury

International Nuclear Information System (INIS)

Stuart, D.C.

1978-01-01

Because of certain problems found in application of the atomic absorption method for trace analysis of mercury, a careful check of the procedures used was undertaken, with radiotracer mercury to facilitate the investigation. The results obtained, in conjunction with those of sample ashing procedures, indicate that the method is less straightforward than its simplicity suggests. (Auth.)

Polymeric Micelles, a Promising Drug Delivery System to Enhance Bioavailability of Poorly Water-Soluble Drugs

Directory of Open Access Journals (Sweden)

Wei Xu

2013-01-01

Full Text Available Oral administration is the most commonly used and readily accepted form of drug delivery; however, it is find that many drugs are difficult to attain enough bioavailability when administered via this route. Polymeric micelles (PMs can overcome some limitations of the oral delivery acting as carriers able to enhance drug absorption, by providing (1 protection of the loaded drug from the harsh environment of the GI tract, (2 release of the drug in a controlled manner at target sites, (3 prolongation of the residence time in the gut by mucoadhesion, and (4 inhibition of efflux pumps to improve the drug accumulation. To explain the mechanisms for enhancement of oral bioavailability, we discussed the special stability of PMs, the controlled release properties of pH-sensitive PMs, the prolongation of residence time with mucoadhesive PMs, and the P-gp inhibitors commonly used in PMs, respectively. The primary purpose of this paper is to illustrate the potential of PMs for delivery of poorly water-soluble drugs with bioavailability being well maintained.

Drugs as instruments: a new framework for non-addictive psychoactive drug use.

Science.gov (United States)

Müller, Christian P; Schumann, Gunter

2011-12-01

Most people who are regular consumers of psychoactive drugs are not drug addicts, nor will they ever become addicts. In neurobiological theories, non-addictive drug consumption is acknowledged only as a "necessary" prerequisite for addiction, but not as a stable and widespread behavior in its own right. This target article proposes a new neurobiological framework theory for non-addictive psychoactive drug consumption, introducing the concept of "drug instrumentalization." Psychoactive drugs are consumed for their effects on mental states. Humans are able to learn that mental states can be changed on purpose by drugs, in order to facilitate other, non-drug-related behaviors. We discuss specific "instrumentalization goals" and outline neurobiological mechanisms of how major classes of psychoactive drugs change mental states and serve non-drug-related behaviors. We argue that drug instrumentalization behavior may provide a functional adaptation to modern environments based on a historical selection for learning mechanisms that allow the dynamic modification of consummatory behavior. It is assumed that in order to effectively instrumentalize psychoactive drugs, the establishment of and retrieval from a drug memory is required. Here, we propose a new classification of different drug memory subtypes and discuss how they interact during drug instrumentalization learning and retrieval. Understanding the everyday utility and the learning mechanisms of non-addictive psychotropic drug use may help to prevent abuse and the transition to drug addiction in the future.

Kidney-on-a-Chip: a New Technology for Predicting Drug Efficacy, Interactions, and Drug-induced Nephrotoxicity.

Science.gov (United States)

Lee, Jeonghwan; Kim, Sejoong

2018-03-08

The kidneys play a pivotal role in most drug-removal processes and are important when evaluating drug safety. Kidney dysfunction resulting from various drugs is an important issue in clinical practice and during the drug development process. Traditional in vivo animal experiments are limited with respect to evaluating drug efficacy and nephrotoxicity due to discrepancies in drug pharmacokinetics and pharmacodynamics between humans and animals, and static cell culture experiments cannot fully reflect the actual microphysiological environment in humans. A kidney-on-a-chip is a microfluidic device that allows the culture of living renal cells in 3-dimensional channels and mimics the human microphysiological environment, thus simulating the actual drug filtering, absorption, and secretion process.. In this review, we discuss recent developments in microfluidic culturing technique and describe current and future kidney-on-a-chip applications. We focus on pharmacological interactions and drug-induced nephrotoxicity, and additionally discuss the development of multi-organ chips and their possible applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Potential drug – nanosensor conjugates: Raman, infrared absorption, surface – enhanced Raman, and density functional theory investigations of indolic molecules

Energy Technology Data Exchange (ETDEWEB)

Pięta, Ewa, E-mail: Ewa.Pieta@ifj.edu.pl [Institute of Nuclear Physics, Polish Academy of Sciences, PL-31342 Krakow (Poland); Paluszkiewicz, Czesława [Institute of Nuclear Physics, Polish Academy of Sciences, PL-31342 Krakow (Poland); Oćwieja, Magdalena [J. Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, PL-30239 Krakow (Poland); Kwiatek, Wojciech M. [Institute of Nuclear Physics, Polish Academy of Sciences, PL-31342 Krakow (Poland)

2017-05-15

Highlights: • Molecular fragments involved in the adsorption process were determined. • Formation of hydrogen bonds with the negatively charged gold substrates was observed. • Indole moiety strongly interacts with gold nanosensors. • The synthesized sensors are characterized by high stability and reproducibility. • Chemical mechanism plays a crucial role in the enhancement of the Raman signal. - Abstract: An extremely important aspect of planning cancer treatment is not only the drug efficiency but also a number of challenges associated with the side effects and control of this process. That is why it is worth paying attention to the promising potential of the gold nanoparticles combined with a compound treated as a potential drug. This work presents Raman (RS), infrared absorption (IR) and surface–enhanced Raman scattering (SERS) spectroscopic investigations of N–acetyl–5–methoxytryptamine (melatonin) and α–methyl–DL–tryptophan, regarding as anti breast cancer agents. The experimental spectroscopic analysis was supported by the quantum-chemical calculations based on the B3LYP hybrid density functional theory (DFT) at the B3LYP 6–311G(d,p) level of theory. The studied compounds were adsorbed onto two colloidal gold nanosensors synthesized by a chemical reduction method using sodium borohydride (SB) and trisodium citrate (TC), respectively. Its morphology characteristics were obtained using transmission electron microscopy (TEM). It has been suggested that the NH moiety from the aromatic ring, a well-known proton donor, causes the formation of hydrogen bonds with the negatively charged gold surface.

Common drug-drug interactions in antifungal treatments for superficial fungal infections.

Science.gov (United States)

Gupta, Aditya K; Versteeg, Sarah G; Shear, Neil H

2018-04-01

Antifungal agents can be co-administered alongside several other medications for a variety of reasons such as the presence of comorbidities. Pharmacodynamic interactions such as synergistic and antagonistic interactions could be the result of co-administered medications. Pharmacokinetic interactions could also transpire through the inhibition of metabolizing enzymes and drug transport systems, altering the absorption, metabolism and excretion of co-administered medications. Both pharmacodynamic and pharmacokinetic interactions can result in hospitalization due to serious adverse effects associated with antifungal agents, lower therapeutic doses required to achieve desired antifungal activity, and prevent antifungal resistance. Areas covered: The objective of this review is to summarize pharmacodynamic and pharmacokinetic interactions associated with common antifungal agents used to treat superficial fungal infections. Pharmacodynamic and pharmacokinetic interactions that impact the therapeutic effects of antifungal agents and drugs that are influenced by the presence of antifungal agents was the context to which these antifungal agents were addressed. Expert opinion: The potential for drug-drug interactions is minimal for topical antifungals as opposed to oral antifungals as they have minimal exposure to other co-administered medications. Developing non-lipophilic antifungals that have unique metabolizing pathways and are topical applied are suggested properties that could help limit drug-drug interactions associated with future treatments.

Acoustically sticky topographic metasurfaces for underwater sound absorption.

Science.gov (United States)

Lee, Hunki; Jung, Myungki; Kim, Minsoo; Shin, Ryung; Kang, Shinill; Ohm, Won-Suk; Kim, Yong Tae

2018-03-01

A class of metasurfaces for underwater sound absorption, based on a design principle that maximizes thermoviscous loss, is presented. When a sound meets a solid surface, it leaves a footprint in the form of thermoviscous boundary layers in which energy loss takes place. Considered to be a nuisance, this acoustic to vorticity/entropy mode conversion and the subsequent loss are often ignored in the existing designs of acoustic metamaterials and metasurfaces. The metasurface created is made of a series of topographic meta-atoms, i.e., intaglios and reliefs engraved directly on the solid object to be concealed. The metasurface is acoustically sticky in that it rather facilitates the conversion of the incident sound to vorticity and entropy modes, hence the thermoviscous loss, leading to the desired anechoic property. A prototype metasurface machined on a brass object is tested for its anechoicity, and shows a multitude of absorption peaks as large as unity in the 2-5 MHz range. Computations also indicate that a topographic metasurface is robust to hydrostatic pressure variation, a quality much sought-after in underwater applications.

Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine

DEFF Research Database (Denmark)

Tfelt-Hansen, Peer; Ågesen, Frederik Nybye; Pavbro, Agniezka

2017-01-01

In this review, we evaluate the variability in the pharmacokinetics of 11 drugs with established prophylactic effects in migraine to facilitate 'personalized medicine' with these drugs. PubMed was searched for 'single-dose' and 'steady-state' pharmacokinetic studies of these 11 drugs. The maximum...

The effects of cyclodextrins on drug release from fatty suppository bases : II. In vivo observations

NARCIS (Netherlands)

Frijlink, H.W.; Eissens, Anko; Schoonen, Adelbert; Lerk, C.F.

The effects of cyclodextrin complexation on the absorption of drugs from fatty suppositories was evaluated in human volunteers. Three model drugs: diazepam, ibuprofen and prednisolone were used. When diazepam was complexed with γ-cyclcodextrin the drug release from the fatty suppositories was

A tale of two citizens: a State Attorney General and a hematologist facilitate translation of research into US Food and Drug Administration actions--a SONAR report.

Science.gov (United States)

Chen, Brian; Restaino, John; Norris, LeAnn; Xirasagar, Sudha; Qureshi, Zaina P; McKoy, June M; Lopez, Isaac S; Trenery, Alyssa; Murday, Alanna; Kahn, Adam; Mattison, Donald R; Ray, Paul; Sartor, Oliver; Bennett, Charles L

2012-11-01

Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizen petition filed to address these thalidomide safety issues. Case study. The AG petitioned the FDA requesting thalidomide-related safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved. New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon.

Mechanistic understanding of time-dependent oral absorption based on gastric motor activity in humans.

Science.gov (United States)

Higaki, Kazutaka; Choe, Sally Y; Löbenberg, Raimar; Welage, Lynda S; Amidon, Gordon L

2008-09-01

The relationship of gastric motor activity and gastric emptying of 0.7 mm caffeine pellets with their absorption was investigated in the fed state in healthy human subjects by simultaneous monitoring of antral motility and plasma concentrations. A kinetic model for gastric emptying-dependent absorption yielded multiple phases of gastric emptying and rate constants (k(g)) with large inter-individual differences and large variability in onset of gastric emptying (50-175 min). The model suggests that 50% of the dose is emptied in 1-2h and over 90% emptied by 3.5h following dosing, in all subjects. The maximum values of k(g) (k(g)(max)) were much greater than those reported for emptying of liquids in the fasted state and were comparable to k(g) values in the late Phase II/III of the migrating motor complex (MMC). The model described the observed irregular absorption rate-time and plasma concentration-time profiles adequately but not in detail. The model was more successful at simulating double-peak phenomena in absorption rate profiles and onset of caffeine absorption. The results suggest that gastric emptying regulates drug absorption of small particles in the fed state. Further, estimates of k(a) derived using the time-dependent absorption model were closer to the intrinsic absorption rate constant for caffeine.

Chitosan and its derivatives for application in mucoadhesive drug delivery systems

OpenAIRE

Ways, Twana Mohammed M.; Lau, Wing Man; Khutoryanskiy, Vitaliy V.

2018-01-01

Mucoadhesive drug delivery systems are desirable as they can increase the residence time of drugs at the site of absorption/action, provide sustained drug release and minimize the degradation of drugs in various body sites. Chitosan is a cationic polysaccharide that exhibits mucoadhesive properties and it has been widely used in the design of mucoadhesive dosage forms. However, its limited mucoadhesive strength and limited water-solubility at neutral and basic pHs are considered as two major ...

Chitosan and Its Derivatives for Application in Mucoadhesive Drug Delivery Systems

OpenAIRE

Twana Mohammed M. Ways; Wing Man Lau; Vitaliy V. Khutoryanskiy

2018-01-01

Mucoadhesive drug delivery systems are desirable as they can increase the residence time of drugs at the site of absorption/action, provide sustained drug release and minimize the degradation of drugs in various body sites. Chitosan is a cationic polysaccharide that exhibits mucoadhesive properties and it has been widely used in the design of mucoadhesive dosage forms. However, its limited mucoadhesive strength and limited water-solubility at neutral and basic pHs are considered as two major ...

The Effect of Soya bean ( Glycine max ) on Pefloxacin Absorption in ...

African Journals Online (AJOL)

The study was to investigate the effect of soya bean on the absorption of pefloxacin when given by oral route in rats. The first group of animals feeding on standard pellet feeds was given pefloxacin (8 mg/kg, p.o), while the second and third groups were also given the drug at the same dosage level but were fed with 50 ...

Oral pharmacokinetics of the acidic drugs, diclofenac and sulfamonomethoxine in male Shiba goats.

Science.gov (United States)

Elbadawy, Mohamed; Sakiyama, Takara; Abohatab, Rania; Sasaki, Kazuaki; Shimoda, Minoru

2015-01-01

In the present study, we examined the oral pharmacokinetics of the acidic drugs, diclofenac (DF) and sulfamonomethoxine (SMM), which have different physicochemical properties, in Shiba goats. DF and SMM were intravenously and orally administered to 5 male goats using a crossover design. The T(max) of DF and SMM were reached 1.5 and 5.6 hr after they have been orally administered, respectively, and this was followed by their slow elimination. The elimination of both drugs was markedly faster after being intravenously rather than orally administered, which indicated flip-flop phenomena after the oral administration. The mean absorption times (MATs) of DF and SMM were 6 and 15 hr, respectively. This slow absorption may have been due to slow gastric emptying in goats. The large difference observed in MATs between DF and SMM may have been because DF, which is more lipophilic than SMM, was partly absorbed from the forestomach. Therefore, these results suggest that the absorption of highly lipophilic drugs from the forestomach may be markedly high in Shiba goats. In case of drugs whose elimination is quite fast, their efficacies may appear from the early stage after oral administration even in ruminants, because elimination rate is the determinant factor of T(max) in flip-flop phenomena. Such drugs may be used orally even in ruminants.

The contribution of the in-vivo fate of an oil depot to drug absorption

NARCIS (Netherlands)

Kalicharan, R. W.; Oussoren, C; Schot, Peter; Rijk, de, E.; Vromans, H.

2017-01-01

Sustained release of lipophilic compounds can be achieved with oil depots. These parenteral formulations are generally injected in the vastus lateralis and deltoid muscle. It is known that the absorption rate differs between these two muscles. The reason for this is not fully understood. The aim of

Absorption studies

International Nuclear Information System (INIS)

Ganatra, R.D.

1992-01-01

Absorption studies were once quite popular but hardly anyone does them these days. It is easier to estimate the blood level of the nutrient directly by radioimmunoassay (RIA). However, the information obtained by estimating the blood levels of the nutrients is not the same that can be obtained from the absorption studies. Absorption studies are primarily done to find out whether some of the essential nutrients are absorbed from the gut or not and if they are absorbed, to determine how much is being absorbed. In the advanced countries, these tests were mostly done to detect pernicious anaemia where vitamin B 12 is not absorbed because of the lack of the intrinsic factor in the stomach. In the tropical countries, ''malabsorption syndrome'' is quire common. In this condition, several nutrients like fat, folic acid and vitamin B 12 are not absorbed. It is possible to study absorption of these nutrients by radioisotopic absorption studies

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.

Strategies to facilitate integrated care for people with alcohol and other drug problems: a systematic review.

Science.gov (United States)

Savic, Michael; Best, David; Manning, Victoria; Lubman, Dan I

2017-04-07

There is a growing body of research highlighting the potential benefits of integrated care as a way of addressing the needs of people with alcohol and other drug (AOD) problems, given the broad range of other issues clients often experience. However, there has been little academic attention on the strategies that treatment systems, agencies and clinicians could implement to facilitate integrated care. We synthesised the existing evidence on strategies to improve integrated care in an AOD treatment context by conducting a systematic review of the literature. We searched major academic databases for peer-reviewed articles that evaluated strategies that contribute to integrated care in an AOD context between 1990 and 2014. Over 2600 articles were identified, of which 14 met the study inclusion criteria of reporting on an empirical study to evaluate the implementation of integrated care strategies. The types of strategies utilised in included articles were then synthesised. We identified a number of interconnected strategies at the funding, organisational, service delivery and clinical levels. Ensuring that integrated care is included within service specifications of commissioning bodies and is adequately funded was found to be critical in effective integration. Cultivating positive inter-agency relationships underpinned and enabled the implementation of most strategies identified. Staff training in identifying and responding to needs beyond clinicians' primary area of expertise was considered important at a service level. However, some studies highlight the need to move beyond discrete training events and towards longer term coaching-type activities focussed on implementation and capacity building. Sharing of client information (subject to informed consent) was critical for most integrated care strategies. Case-management was found to be a particularly good approach to responding to the needs of clients with multiple and complex needs. At the clinical level, screening

Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment‐Based Drug Design Facilitated by Dynamic Combinatorial Chemistry

Science.gov (United States)

Mondal, Milon; Radeva, Nedyalka; Fanlo‐Virgós, Hugo; Otto, Sijbren; Klebe, Gerhard

2016-01-01

Abstract Fragment‐based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit‐identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X‐ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis‐acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240‐fold improvement in potency compared to the parent hits. Subsequent X‐ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit‐identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit‐to‐lead optimization. PMID:27400756

Advances in buccal drug delivery.

Science.gov (United States)

Birudaraj, Raj; Mahalingam, Ravichandran; Li, Xiaoling; Jasti, Bhaskara R

2005-01-01

The buccal route offers an attractive alternative for systemic drug delivery of drugs because of better patient compliance, ease of dosage form removal in emergencies, robustness, and good accessibility. Use of buccal mucosa for drug absorption was first attempted by Sobrero in 1847, and since then much research was done to deliver drugs through this route. Today, research is more focused on the development of suitable delivery devices, permeation enhancement, and buccal delivery of drugs that undergo a first-pass effect, such as cardiovascular drugs, analgesics, and peptides. In addition, studies have been conducted on the development of controlled or slow release delivery systems for systemic and local therapy of diseases in the oral cavity. In this review, the anatomy and physiology of buccal mucosa, followed by discussion of recent literature on the buccal permeation enhancement, and pathways of enhancement for various molecules are detailed. In addition, bioadhesion theories from historic perspective and current status are discussed. The various dosage forms on the market and in different stages of development are also reviewed.

Improved Intranasal Retentivity and Transnasal Absorption Enhancement by PEGylated Poly-l-ornithine

Directory of Open Access Journals (Sweden)

Yusuke Kamiya

2018-01-01

Full Text Available We reported that the introduction of polyethylene glycol (PEG to poly-l-ornithine (PLO, which is an homopolymeric basic amino acid having absorption-enhancement ability, prolonged retention time in an in vitro inclined plate test, probably due to an increase in viscosity caused by PEGylation. The aim of the present study is to investigate whether the introduction of PEG chains to PLO improves intranasal retention and transnasal absorption in vivo. We performed intranasal administration experiments using PLO and PEG-PLO with a model drug, fluorescein isothiocyanate dextran (FD-4, in rats under closed and open systems. In the open system, transition of plasma FD-4 concentration after co-administration with unmodified PLO was low, and the area under the plasma concentration-time curve (AUC decreased to about 60% of that in the closed system. In contrast, the AUC after co-administration with PEG-PLO in the open system was about 90% of that in the closed system, and the transition of plasma FD-4 concentration and FD-4 absorption profile were similar to those of the closed system. These findings indicate that introducing PEG chains to homopolymeric basic amino acids (HPBAAs is a very useful method for developing a functional absorption enhancer that can exhibit an efficient in vivo absorption-enhancing effect.

Variational finite element method to study the absorption rate of drug ...

African Journals Online (AJOL)

M.A. Khanday

2014-11-25

Nov 25, 2014 ... ematical transport models describing the release of drug from various delivery systems and ... numerical simulations to describe the pharmacokinetics of ... studied the diffusion of heat and mass in biological tissues particularly ...

Biodegradable microcontainers as an oral drug delivery system for poorly soluble drugs

DEFF Research Database (Denmark)

Nielsen, Line Hagner; Nagstrup, Johan; Keller, Stephan Sylvest

2013-01-01

PURPOSE: To fabricate microcontainers in biodegradable polylactic acid (PLLA) polymer films using hot embossing, and investigate the application of fabricated microcontainers as an oral drug delivery system for a poorly soluble drug. METHODS: For fabrication of the PLLA microcontainers, a film...... (produced by spray drying) using a simplified version of a screen printing technique. An enteric-resistant lid of Eudragit L-100 was subsequently spray coated onto the cavity of the microcontainers. Release of amorphous furosemide salt from the coated microcontainers was investigated using a μ-Diss profiler...... release from microcontainers in gastric medium, and facilitated an immediate release in the intestinal medium. The fabricated microcontainers therefore show considerable future potential as oral drug delivery systems....

Absorption heat pumps

International Nuclear Information System (INIS)

Formigoni, C.

1998-01-01

A brief description of the difference between a compression and an absorption heat pump is made, and the reasons why absorption systems have spread lately are given. Studies and projects recently started in the field of absorption heat pumps, as well as criteria usually followed in project development are described. An outline (performance targets, basic components) of a project on a water/air absorption heat pump, running on natural gas or LPG, is given. The project was developed by the Robur Group as an evolution of a water absorption refrigerator operating with a water/ammonia solution, which has been on the market for a long time and recently innovated. Finally, a list of the main energy and cost advantages deriving from the use of absorption heat pumps is made [it

Magnetic Nanoparticle Facilitated Drug Delivery for Cancer Therapy with Targeted and Image-Guided Approaches.

Science.gov (United States)

Huang, Jing; Li, Yuancheng; Orza, Anamaria; Lu, Qiong; Guo, Peng; Wang, Liya; Yang, Lily; Mao, Hui

2016-06-14

With rapid advances in nanomedicine, magnetic nanoparticles (MNPs) have emerged as a promising theranostic tool in biomedical applications, including diagnostic imaging, drug delivery and novel therapeutics. Significant preclinical and clinical research has explored their functionalization, targeted delivery, controllable drug release and image-guided capabilities. To further develop MNPs for theranostic applications and clinical translation in the future, we attempt to provide an overview of the recent advances in the development and application of MNPs for drug delivery, specifically focusing on the topics concerning the importance of biomarker targeting for personalized therapy and the unique magnetic and contrast-enhancing properties of theranostic MNPs that enable image-guided delivery. The common strategies and considerations to produce theranostic MNPs and incorporate payload drugs into MNP carriers are described. The notable examples are presented to demonstrate the advantages of MNPs in specific targeting and delivering under image guidance. Furthermore, current understanding of delivery mechanisms and challenges to achieve efficient therapeutic efficacy or diagnostic capability using MNP-based nanomedicine are discussed.

Variational finite element method to study the absorption rate of drug ...

African Journals Online (AJOL)

M.A. Khanday

2014-11-25

Nov 25, 2014 ... Abstract Background: The delivery of drugs through dermal layers known as transdermal ... number of factors which includes the physio-co-chemical prop- ..... 9. Kumari B, Adlakha N. One dimensional model to study the effect.

Enhanced oral absorption and therapeutic effect of acetylpuerarin based on D-α-tocopheryl polyethylene glycol 1000 succinate nanoemulsions

Directory of Open Access Journals (Sweden)

Sun DQ

2014-07-01

Full Text Available Deqing Sun,1,2 Xinbing Wei,1 Xia Xue,2 Zengjun Fang,3 Manru Ren,1 Haiyan Lou,1 Xiumei Zhang11Department of Pharmacology, School of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Pharmacy, 3Department of Clinical Pharmacology, Second Hospital of Shandong University, Jinan, People’s Republic of ChinaBackground: Acetylpuerarin (AP, because of its lower water solubility, shows poor absorption that hinders its therapeutic application. Thus, the aim of this study was to prepare nanoemulsions for AP, enhance its oral bioavailability, and thus improve the therapeutic effect.Methods: The nanoemulsions stabilized by D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS were prepared by high-pressure homogenization and characterized in terms of particle size, drug loading, morphology, and in vitro drug release. A lipid digestion model was used to predict in vivo drug solubilization in the gastrointestinal environment. The pharmacokinetics of AP formulations were performed in rats; meanwhile, a chylomicron flow-blocking rat model was used to evaluate the lymphatic drug transport. Moreover, the therapeutic effects of AP nanoemulsions on the model of focal cerebral ischemia-reperfusion for brain injury were also assessed.Results: The nanoemulsions with a droplet size of 150 nm were well stabilized by TPGS and showed a high loading capacity for AP. In the digestion model, the distribution of AP in aqueous phase/pellet phase was about 90%/10% for nanoemulsions and 5%/95% for oil solution, indicating that the drug encapsulated in nanoemulsions would present in solubilized form after transportation into the gastrointestinal tract, whereas drug precipitation would occur as the oil solution was orally administered. The area under the curve value of AP nanoemulsions was 5.76±0.56 µg·hour·mL-1, or was about 2.6 and 1.7 times as great as that of suspension and oil solution, respectively, indicating enhanced drug

Protein-Based Drug-Delivery Materials

Directory of Open Access Journals (Sweden)

Dave Jao

2017-05-01

Full Text Available There is a pressing need for long-term, controlled drug release for sustained treatment of chronic or persistent medical conditions and diseases. Guided drug delivery is difficult because therapeutic compounds need to survive numerous transport barriers and binding targets throughout the body. Nanoscale protein-based polymers are increasingly used for drug and vaccine delivery to cross these biological barriers and through blood circulation to their molecular site of action. Protein-based polymers compared to synthetic polymers have the advantages of good biocompatibility, biodegradability, environmental sustainability, cost effectiveness and availability. This review addresses the sources of protein-based polymers, compares the similarity and differences, and highlights characteristic properties and functionality of these protein materials for sustained and controlled drug release. Targeted drug delivery using highly functional multicomponent protein composites to guide active drugs to the site of interest will also be discussed. A systematical elucidation of drug-delivery efficiency in the case of molecular weight, particle size, shape, morphology, and porosity of materials will then be demonstrated to achieve increased drug absorption. Finally, several important biomedical applications of protein-based materials with drug-delivery function—including bone healing, antibiotic release, wound healing, and corneal regeneration, as well as diabetes, neuroinflammation and cancer treatments—are summarized at the end of this review.

Drug quantification in turbid media by fluorescence imaging combined with light-absorption correction using white Monte Carlo simulations

DEFF Research Database (Denmark)

Xie, Haiyan; Liu, Haichun; Svenmarker, Pontus

2011-01-01

Accurate quantification of photosensitizers is in many cases a critical issue in photodynamic therapy. As a noninvasive and sensitive tool, fluorescence imaging has attracted particular interest for quantification in pre-clinical research. However, due to the absorption of excitation and emission...... in vivo by the fluorescence imaging technique. In this paper we present a novel approach to compensate for the light absorption in homogeneous turbid media both for the excitation and emission light, utilizing time-resolved fluorescence white Monte Carlo simulations combined with the Beer-Lambert law......-absorption correction and absolute fluorophore concentrations. These results suggest that the technique potentially provides the means to quantify the fluorophore concentration from fluorescence images. © 2011 Society of Photo-Optical Instrumentation Engineers (SPIE)....

Drug dosing in chronic kidney disease.

Science.gov (United States)

Gabardi, Steven; Abramson, Stuart

2005-05-01

Patients with chronic kidney disease (CKD) are at high risk for adverse drug reactions and drug-drug interactions. Drug dosing in these patients often proves to be a difficult task. Renal dysfunction-induced changes in human pathophysiology regularly results may alter medication pharmacodynamics and handling. Several pharmacokinetic parameters are adversely affected by CKD, secondary to a reduced oral absorption and glomerular filtration; altered tubular secretion; and reabsorption and changes in intestinal, hepatic, and renal metabolism. In general, drug dosing can be accomplished by multiple methods; however, the most common recommendations are often to reduce the dose or expand the dosing interval, or use both methods simultaneously. Some medications need to be avoided all together in CKD either because of lack of efficacy or increased risk of toxicity. Nevertheless, specific recommendations are available for dosing of certain medications and are an important resource, because most are based on clinical or pharmacokinetic trials.

Quasar Absorption Studies

Science.gov (United States)

Mushotzky, Richard (Technical Monitor); Elvis, Martin

2004-01-01

The aim of the proposal is to investigate the absorption properties of a sample of inter-mediate redshift quasars. The main goals of the project are: Measure the redshift and the column density of the X-ray absorbers; test the correlation between absorption and redshift suggested by ROSAT and ASCA data; constrain the absorber ionization status and metallicity; constrain the absorber dust content and composition through the comparison between the amount of X-ray absorption and optical dust extinction. Unanticipated low energy cut-offs where discovered in ROSAT spectra of quasars and confirmed by ASCA, BeppoSAX and Chandra. In most cases it was not possible to constrain adequately the redshift of the absorber from the X-ray data alone. Two possibilities remain open: a) absorption at the quasar redshift; and b) intervening absorption. The evidences in favour of intrinsic absorption are all indirect. Sensitive XMM observations can discriminate between these different scenarios. If the absorption is at the quasar redshift we can study whether the quasar environment evolves with the Cosmic time.

Self-Nanoemulsifying Drug Delivery Systems Based on Melon Oil ...

African Journals Online (AJOL)

Erah

Tropical Journal of Pharmaceutical Research June 2011; 10 (3): 299-307 ... membrane (the major pathway for absorption of drugs) ... [7,8] and a more reproducible plasma level - ... Proximate analysis ..... ionic surfactant-vegetable oil mixture.

Evidence of D-phenylglycine as delivering tool for improving L-dopa absorption.

Science.gov (United States)

Wang, Chun-Li; Fan, Yang-Bin; Lu, Hsiao-Hwa; Tsai, Tung-Hu; Tsai, Ming-Cheng; Wang, Hui-Po

2010-09-06

L-dopa has been used for Parkinson's disease management for a long time. However, its wide variety in the rate and the extent of absorption remained challenge in designing suitable therapeutic regime. We report here a design of using D-phenylglycine to guard L-dopa for better absorption in the intestine via intestinal peptide transporter I (PepT1). D-phenylglycine was chemically attached on L-dopa to form D-phenylglycine-L-dopa as a dipeptide prodrug of L-dopa. The cross-membrane transport of this dipeptide and L-dopa via PepT1 was compared in brush-boarder membrane vesicle (BBMV) prepared from rat intestine. The intestinal absorption was compared by in situ jejunal perfusion in rats. The pharmacokinetics after i.v. and p.o. administration of both compounds were also compared in Wistar rats. The striatal dopamine released after i.v. administration of D-phenylglycine-L-dopa was collected by brain microdialysis and monitored by HPLC. Anti-Parkinsonism effect was determined by counting the rotation of 6-OHDA-treated unilateral striatal lesioned rats elicited rotation with (+)-methamphetamine (MA). The BBMV uptake of D-phenylglycine-L-dopa was inhibited by Gly-Pro, Gly-Phe and cephradine, the typical PepT1 substrates, but not by amino acids Phe or L-dopa. The cross-membrane permeability (Pm*) determined in rat jejunal perfusion of D-phenylglycine-L-dopa was higher than that of L-dopa (2.58 ± 0.14 vs. 0.94 ± 0.10). The oral bioavailability of D-phenylglycine-L-dopa was 31.7 times higher than that of L-dopa in rats. A sustained releasing profile of striatal dopamine was demonstrated after i. v. injection of D-phenylglycine-L-dopa (50 mg/kg), indicated that D-phenylglycine-L-dopa might be a prodrug of dopamine. D-phenylglycine-L-dopa was more efficient than L-dopa in lowering the rotation of unilateral striatal lesioned rats (19.1 ± 1.7% vs. 9.9 ± 1.4%). The BBMV uptake studies indicated that D-phenylglycine facilitated the transport of L-dopa through the intestinal

Evidence of d-phenylglycine as delivering tool for improving l-dopa absorption

Directory of Open Access Journals (Sweden)

Wang Chun-Li

2010-09-01

-phenylglycine facilitated the transport of l-dopa through the intestinal PepT1 transporter. The higher jejunal permeability and the improved systemic bioavailability of d-phenylglycine-l-dopa in comparison to that of l-dopa suggested that d-phenylglycine is an effective delivery tool for improving the oral absorption of drugs like l-dopa with unsatisfactory pharmacokinetics. The gradual release of dopamine in brain striatum rendered this dipeptide as a potential dopamine sustained-releasing prodrug.

Consensus hologram QSAR modeling for the prediction of human intestinal absorption.

Science.gov (United States)

Moda, Tiago L; Andricopulo, Adriano D

2012-04-15

Consistent in silico models for ADME properties are useful tools in early drug discovery. Here, we report the hologram QSAR modeling of human intestinal absorption using a dataset of 638 compounds with experimental data associated. The final validated models are consistent and robust for the consensus prediction of this important pharmacokinetic property and are suitable for virtual screening applications. Copyright © 2012 Elsevier Ltd. All rights reserved.

In vitro efficacy and release study with anti-inflammatory drugs incorporated in adhesive transdermal drug delivery systems.

Science.gov (United States)

Meyer, Stefanie; Peters, Nils; Mann, Tobias; Wolber, Rainer; Pörtner, Ralf; Nierle, Jens

2014-04-01

The topical application of two different anti-inflammatory extracts incorporated in adhesive transdermal drug delivery systems (TDDSs) was investigated. Therefore, anti-inflammatory properties and percutaneous absorption behavior of adhesive TDDSs were characterized in vitro conducting experiments with a dermatologically relevant human skin model. Anti-inflammatory efficacy against UV irradiation of both TDDSs was determined in vitro with EpiDerm™. The reduction of the release of proinflammatory cytokines by topically applied TDDSs was compared with the reduction during the presence of the specific cyclooxygenase inhibitor diclofenac in the culture medium. A similar anti-inflammatory efficacy of the topically applied TDDSs in comparison with the use of diclofenac in the culture medium should be achieved. Furthermore, percutaneous absorption in efficacy tests was compared with percutaneous absorption in diffusion studies with porcine cadaver skin. Both the topically applied TDDSs showed a significant anti-inflammatory activity. Permeation coefficients through the stratum corneum and the epidermis gained from the release studies on porcine cadaver skin (Magnolia: 2.23·10(-5) cm/h, licorice: 4.68·10(-6) cm/h) were approximately five times lower than the permeation coefficients obtained with the EpiDerm™ skin model (Magnolia: 9.48·10(-5) cm/h, licorice: 24.0·10(-6) cm/h). Therefore, an adjustment of drug doses during experiments with the EpiDerm™ skin model because of weaker skin barrier properties should be considered.

A further component analysis for illicit drugs mixtures with THz-TDS

Science.gov (United States)

Xiong, Wei; Shen, Jingling; He, Ting; Pan, Rui

2009-07-01

A new method for quantitative analysis of mixtures of illicit drugs with THz time domain spectroscopy was proposed and verified experimentally. In traditional method we need fingerprints of all the pure chemical components. In practical as only the objective components in a mixture and their absorption features are known, it is necessary and important to present a more practical technique for the detection and identification. Our new method of quantitatively inspect of the mixtures of illicit drugs is developed by using derivative spectrum. In this method, the ratio of objective components in a mixture can be obtained on the assumption that all objective components in the mixture and their absorption features are known but the unknown components are not needed. Then methamphetamine and flour, a illicit drug and a common adulterant, were selected for our experiment. The experimental result verified the effectiveness of the method, which suggested that it could be an effective method for quantitative identification of illicit drugs. This THz spectroscopy technique is great significant in the real-world applications of illicit drugs quantitative analysis. It could be an effective method in the field of security and pharmaceuticals inspection.

A Tale of Two Citizens: A State Attorney General and a Hematologist Facilitate Translation of Research Into US Food and Drug Administration Actions—A SONAR Report

Science.gov (United States)

Chen, Brian; Restaino, John; Norris, LeAnn; Xirasagar, Sudha; Qureshi, Zaina P.; McKoy, June M.; Lopez, Isaac S.; Trenery, Alyssa; Murday, Alanna; Kahn, Adam; Mattison, Donald R.; Ray, Paul; Sartor, Oliver; Bennett, Charles L.

2012-01-01

Purpose: Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizen petition filed to address these thalidomide safety issues. Methods: Case study. Results: The AG petitioned the FDA requesting thalidomide-related safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved. Conclusion: New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon. PMID:23598851

Drug release, preclinical and clinical pharmacokinetics relationships of alginate pellets prepared by melt technology.

Science.gov (United States)

Bose, Anirbandeep; Harjoh, Nurulaini; Pal, Tapan Kumar; Dan, Shubhasis; Wong, Tin Wui

2016-01-01

Alginate pellets prepared by the aqueous agglomeration technique experience fast drug dissolution due to the porous pre-formed calcium alginate microstructure. This study investigated in vitro drug release, preclinical and clinical pharmacokinetics relationships of intestinal-specific calcium acetate-alginate pellets against calcium-free and calcium carbonate-alginate pellets. Alginate pellets were prepared by solvent-free melt pelletization instead of aqueous agglomeration technique using chlorpheniramine maleate as model drug. A fast in situ calcium acetate dissolution in pellets resulted in rapid pellet breakup, soluble Ca(2+) crosslinking of alginate fragments and drug dissolution retardation at pH 1.2, which were not found in other pellet types. The preclinical drug absorption rate was lower with calcium acetate loaded than calcium-free alginate pellets. In human subjects, however, the extent and the rate of drug absorption were higher from calcium acetate-loaded pellets than calcium-free alginate pellets. The fine, dispersible and weakly gastric mucoadhesive calcium alginate pellets underwent fast human gastrointestinal transit. They released the drug at a greater rate than calcium-free pellets in the intestine, thereby promoting drug bioavailability. Calcium acetate was required as a disintegrant more than as a crosslinking agent clinically to promote pellet fragmentation, fast gastrointestinal transit and drug release in intestinal medium, and intestinal-specific drug bioavailability.

Atomic-absorption determination of tantalum and niobium in ore concentrates

International Nuclear Information System (INIS)

Elinson, S.V.; Korovin, Yu.I.; Kuchumov, V.A.

1975-01-01

A flame atom-absorption method was developed for determining tantalum and niobium at their level greater than 5% in Ta-Nb ore concentrates. Flame was produced by a nitrous oxide-acetylene mixture. The optimal composition of a buffer (3 mg/ml) of iron was determined by the method of factorial planning of the experiment and steep ascention by gradient. The optimizing parameter in factorial planning was obtained from the difference of optical densities of Ta and Nb, by taking the average value for two solutions which had dissimilar total composition and which imitated the real composition of the ore concentrates, i.e., the value of (ΔD/Dsub(av))sub(Ta) or (ΔD/Dsub(av))sub(Nb). The optimization of analytical conditions corresponded to the condition (ΔD/Dsub(av))→ 0, which indicated that the chosen optimizing parameter also facilitated the attainment of maximum D values. The variation coefficient in the determination of Ta and Nb was respectively 0.8 and 1.4%. There was a good agreement between the results obtained in Ta analysis by the atom-absorption and the extraction-gravimetric methods, and in Nb analysis by the atom-absorption, differential spectrophotometric and x-ray fluorescence methods

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.

Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.

Science.gov (United States)

Kang, S; Brange, J; Burch, A; Vølund, A; Owens, D R

1991-11-01

To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans. Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting. The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and

Transcutaneous drug delivery by liposomes using fractional laser technology.

Science.gov (United States)

Fujimoto, Takahiro; Wang, Jian; Baba, Kazuki; Oki, Yuka; Hiruta, Yuki; Ito, Masayuki; Ito, Shinobu; Kanazawa, Hideko

2017-07-01

Transdermal delivery of hydrophilic peptides remains a challenge due to their poor cellular uptake and transdermal penetration. We hypothesize that combination of a CO 2 fractional laser to enhance percutaneous absorption and liposomes as transdermal carriers would improve skin penetration of hydrophilic drugs. NA. Liposomes were prepared using membrane fusion lipid dioleoylphosphatidylethanolamine, and used to deliver 5-carboxyfluorescein (CF) and fluorescein isothiocyanate-conjugated ovalbumin (OVA-FITC) as model hydrophilic peptide drugs. Liposome size was estimated by dynamic light scattering. Liposome uptake into murine macrophage cells and penetration or permeation into Yucatan micropig skin after irradiation by CO 2 fractional laser at varying energy levels (laser power and exposure duration) were investigated using Franz cell and fluorescence microscopy. Oxidative damage to the irradiated mouse skin was assessed by electron spin resonance. Size of CF and OVA-FITC encapsulated liposomes was 324 ± 75 nm. Cellular uptake of OVA-FITC delivered by liposomes was 10-fold higher (1,370 relative fluorescence units, RFU) than delivered in solution form (130 RFU). Fractional laser irradiation increased skin permeation rate of CF liposomes (0-10%) and OVA-FITC liposomes (4-40%) in a dose-dependent manner. Although peeling off the stratum corneum facilitated CF liposome penetration at low energy levels (2.69-3.29 J/cm 2 ; 10-20 W for 500 μs), drug permeation was similar (7-8%) in peeled or untreated skin at higher laser energy levels (6.06 J/cm 2 ; 20 W for 1,500 μs). FITC penetrated deeper in the skin after laser irradiation. However, OH, O2-, and VC reactive oxygen species were generated upon irradiation of the skin with a fractional CO 2 laser. Increasing laser power and irradiation, time increased liposome uptake by cells and penetration of peptide drugs across the skin in a dose-dependent manner. High-energy CO 2 fractional laser overcomes the

Nanostructured lipid carriers versus microemulsions for delivery of the poorly water-soluble drug luteolin.

Science.gov (United States)

Liu, Ying; Wang, Lan; Zhao, Yiqing; He, Man; Zhang, Xin; Niu, Mengmeng; Feng, Nianping

2014-12-10

Nanostructured lipid carriers and microemulsions effectively deliver poorly water-soluble drugs. However, few studies have investigated their ability and difference in improving drug bioavailability, especially the factors contributed to the difference. Thus, this study was aimed at investigating their efficiency in bioavailability enhancement based on studying two key processes that occur in NLC and ME during traverse along the intestinal tract: the solubilization process and the intestinal permeability process. The nanostructured lipid carriers and microemulsions had the same composition except that the former were prepared with solid lipids and the latter with liquid lipids; both were evaluated for particle size and zeta potential. Transmission electron microscopy, differential scanning calorimetry, and X-ray diffraction were performed to characterize their properties. Furthermore, in vitro drug release, in situ intestinal absorption, and in vitro lipolysis were studied. The bioavailability of luteolin delivered using nanostructured lipid carriers in rats was compared with that delivered using microemulsions and suspensions. The in vitro analysis revealed different release mechanisms for luteolin in nanostructured lipid carriers and microemulsions, although the in situ intestinal absorption was similar. The in vitro lipolysis data indicated that digestion speed and extent were higher for microemulsions than for nanostructured lipid carriers, and that more of the former partitioned to the aqueous phase. The in vivo bioavailability analysis in rats indicated that the oral absorption and bioavailability of luteolin delivered using nanostructured lipid carriers and microemulsions were higher than those of luteolin suspensions. Nanostructured lipid carriers and microemulsions improved luteolin's oral bioavailability in rats. The rapid lipid digestion and much more drug solubilized available for absorption in microemulsions may contribute to better absorption and

Smart Polymers in Nasal Drug Delivery.

Science.gov (United States)

Chonkar, Ankita; Nayak, Usha; Udupa, N

2015-01-01

Nasal drug delivery has now been recognized as a promising route for drug delivery due to its capability of transporting a drug to systemic circulation and central nervous system. Though nasal mucosa offers improved bioavailability and quick onset of action of the drug, main disadvantage associated with nasal drug delivery is mucocilliary clearance due to which drug particles get cleared from the nose before complete absorption through nasal mucosa. Therefore, mucoadhesive polymeric approach can be successfully used to enhance the retention of the drug on nasal mucosal surface. Here, some of the aspects of the stimuli responsive polymers have been discussed which possess liquid state at the room temperature and in response to nasal temperature, pH and ions present in mucous, can undergo in situ gelation in nasal cavity. In this review, several temperature responsive, pH responsive and ion responsive polymers used in nasal delivery, their gelling mechanisms have been discussed. Smart polymers not only able to enhance the retention of the drug in nasal cavity but also provide controlled release, ease of administration, enhanced permeation of the drug and protection of the drug from mucosal enzymes. Thus smart polymeric approach can be effectively used for nasal delivery of peptide drugs, central nervous system dugs and hormones.

Polarization control of intermediate state absorption in resonance-mediated multi-photon absorption process

International Nuclear Information System (INIS)

Xu, Shuwu; Yao, Yunhua; Jia, Tianqing; Ding, Jingxin; Zhang, Shian; Sun, Zhenrong; Huang, Yunxia

2015-01-01

We theoretically and experimentally demonstrate the control of the intermediate state absorption in an (n + m) resonance-mediated multi-photon absorption process by the polarization-modulated femtosecond laser pulse. An analytical solution of the intermediate state absorption in a resonance-mediated multi-photon absorption process is obtained based on the time-dependent perturbation theory. Our theoretical results show that the control efficiency of the intermediate state absorption by the polarization modulation is independent of the laser intensity when the transition from the intermediate state to the final state is coupled by the single-photon absorption, but will be affected by the laser intensity when this transition is coupled by the non-resonant multi-photon absorption. These theoretical results are experimentally confirmed via a two-photon fluorescence control in (2 + 1) resonance-mediated three-photon absorption of Coumarin 480 dye and a single-photon fluorescence control in (1 + 2) resonance-mediated three-photon absorption of IR 125 dye. (paper)

Calcium absorption and achlorhydria

International Nuclear Information System (INIS)

Recker, R.R.

1985-01-01

Defective absorption of calcium has been thought to exist in patients with achlorhydria. The author compared absorption of calcium in its carbonate form with that in a pH-adjusted citrate form in a group of 11 fasting patients with achlorhydria and in 9 fasting normal subjects. Fractional calcium absorption was measured by a modified double-isotope procedure with 0.25 g of calcium used as the carrier. Mean calcium absorption (+/- S.D.) in the patients with achlorhydria was 0.452 +/- 0.125 for citrate and 0.042 +/- 0.021 for carbonate (P less than 0.0001). Fractional calcium absorption in the normal subjects was 0.243 +/- 0.049 for citrate and 0.225 +/- 0.108 for carbonate (not significant). Absorption of calcium from carbonate in patients with achlorhydria was significantly lower than in the normal subjects and was lower than absorption from citrate in either group; absorption from citrate in those with achlorhydria was significantly higher than in the normal subjects, as well as higher than absorption from carbonate in either group. Administration of calcium carbonate as part of a normal breakfast resulted in completely normal absorption in the achlorhydric subjects. These results indicate that calcium absorption from carbonate is impaired in achlorhydria under fasting conditions. Since achlorhydria is common in older persons, calcium carbonate may not be the ideal dietary supplement

Biochemistry of drugs. XXVII

International Nuclear Information System (INIS)

Raz, K.; Smolik, S.; Vinarova, M.; Janda, J.; Franc, Z.

1979-01-01

The erythro- and threoform of p-hydroxynorephedrine belong to the group of drugs affecting the course of hypertensive disease. For pharmacological studies both forms were labelled with 3 H radionuclide on the benzene ring. 90% of radioactivity was concentrated in the ortho positions with regard to the hydroxyl, 10% in the meta position. After the administration of the labelled drug to rats, rapid absorption occurs and radioactivity is eliminated from the organism, especially in the urine. Three radioactive substances were found in the urine of experimental animals. A substance with properties corresponding to those of the administered drug prevailed. The highest levels of radioactivity in the tissues were found after intravenous administration as early as after 5 minutes after administration, 15 minutes after subcutaneous administration. It was found that p-hydroxynorephedrine significantly restricted the detainment of labelled noradrenaline-7- 3 H in the tissues of premedicated animals. (author)

An Exploration of the Calcium-Binding Mode of Egg White Peptide, Asp-His-Thr-Lys-Glu, and In Vitro Calcium Absorption Studies of Peptide-Calcium Complex.

Science.gov (United States)

Sun, Na; Jin, Ziqi; Li, Dongmei; Yin, Hongjie; Lin, Songyi

2017-11-08

The binding mode between the pentapeptide (DHTKE) from egg white hydrolysates and calcium ions was elucidated upon its structural and thermodynamics characteristics. The present study demonstrated that the DHTKE peptide could spontaneously bind calcium with a 1:1 stoichiometry, and that the calcium-binding site corresponded to the carboxyl oxygen, amino nitrogen, and imidazole nitrogen atoms of the DHTKE peptide. Moreover, the effect of the DHTKE-calcium complex on improving the calcium absorption was investigated in vitro using Caco-2 cells. Results showed that the DHTKE-calcium complex could facilitate the calcium influx into the cytosol and further improve calcium absorption across Caco-2 cell monolayers by more than 7 times when compared to calcium-free control. This study facilitates the understanding about the binding mechanism between peptides and calcium ions as well as suggests a potential application of egg white peptides as nutraceuticals to improve calcium absorption.

Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications.

Science.gov (United States)

Singh, Bhupinder; Bandopadhyay, Shantanu; Kapil, Rishi; Singh, Ramandeep; Katare, O

2009-01-01

Self-emulsifying drug delivery systems (SEDDS) possess unparalleled potential in improving oral bioavailability of poorly water-soluble drugs. Following their oral administration, these systems rapidly disperse in gastrointestinal fluids, yielding micro- or nanoemulsions containing the solubilized drug. Owing to its miniscule globule size, the micro/nanoemulsifed drug can easily be absorbed through lymphatic pathways, bypassing the hepatic first-pass effect. We present an exhaustive and updated account of numerous literature reports and patents on diverse types of self-emulsifying drug formulations, with emphasis on their formulation, characterization, and systematic optimization strategies. Recent advancements in various methodologies employed to characterize their globule size and shape, ability to encapsulate the drug, gastrointestinal and thermodynamic stability, rheological characteristics, and so forth, are discussed comprehensively to guide the formula-tor in preparing an effective and robust SEDDS formulation. Also, this exhaustive review offers an explicit discussion on vital applications of the SEDDS in bioavailability enhancement of various drugs, outlining an overview on myriad in vitro, in situ, and ex vivo techniques to assess the absorption and/ or permeation potential of drugs incorporated in the SEDDS in animal and cell line models, and the subsequent absorption pathways followed by them. In short, the current article furnishes an updated compilation of wide-ranging information on all the requisite vistas of the self-emulsifying formulations, thus paving the way for accelerated progress into the SEDDS application in pharmaceutical research.

Transport mechanisms at the pulmonary mucosa: implications for drug delivery.

Science.gov (United States)

Nickel, Sabrina; Clerkin, Caoimhe G; Selo, Mohammed Ali; Ehrhardt, Carsten

2016-01-01

Over the past years, a significant number of papers have substantiated earlier findings proposing a role for drug transporter proteins in pulmonary drug disposition. Whilst the majority of reports present data from in vitro models, a growing number of publications advance the field by introducing sophisticated ex vivo and in vivo techniques. In a few cases, evidence from clinical studies in human volunteers is complementing the picture. In this review, recent advances in pulmonary drug transporter research are critically evaluated. Transporter expression data in tissues and cell-based in vitro models is summarized and information on transport activity assessed. Novel techniques allowing for better quantification of transporter-related effects following pulmonary delivery are also described. Different tissue and cell populations of the lung have distinct transporter expression patterns. Whether these patterns are affected by disease, gender and smoking habits requires further clarification. Transporters have been found to have an impact on drug absorption processes, at least in vitro. Recent ex vivo experiments using isolated, perfused lung models, however, suggest that mainly efflux pumps have significant effects on absorption into the pulmonary circulation. Whether these rodent-based ex vivo models predict the human situation is basis for further research.

Relationships Between Integration and Drug Use Among Deported Migrants in Tijuana, Mexico.

Science.gov (United States)

Horyniak, Danielle; Pinedo, Miguel; Burgos, Jose Luis; Ojeda, Victoria D

2017-10-01

Deported migrants face numerous challenges which may elevate their risk for drug use. We examined relationships between integration and drug use among deported migrants in Tijuana, Mexico. A cross-sectional survey conducted at a free health clinic included 255 deported Mexican-born migrants residing in Tijuana ≥6 months. Multivariable logistic regression examined associations between variables across four integration domains (public participation, social connections, macro-level facilitators and foundations) and recent (past 6-month) drug use. The prevalence of recent drug use was 46 %. Having sought work in Tijuana in the past 6 months, greater household affluence, lifetime history of incarceration in both US and Mexico, and lacking health insurance were independently associated with recent drug use. Policies that support access to employment, adequate housing and healthcare in Mexico, particularly for justice-involved deportees, may facilitate successful integration and reduce potential stressors that may contribute to drug use.

Review on absorption technology with emphasis on small capacity absorption machines

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Labus Jerko M.

2013-01-01

Full Text Available The aim of this paper is to review the past achievements in the field of absorption systems, their potential and possible directions for future development. Various types of absorption systems and research on working fluids are discussed in detail. Among various applications, solar cooling and combined cooling, heating and power (CCHP are identified as two most promising applications for further development of absorption machines. Under the same framework, special attention is given to the small capacity absorption machines and their current status at the market. Although this technology looks promising, it is still in development and many issues are open. With respect to that fact, this paper covers all the relevant aspects for further development of small capacity absorption machines.

New insights into the molecular mechanism of intestinal fatty acid absorption.

Science.gov (United States)

Wang, Tony Y; Liu, Min; Portincasa, Piero; Wang, David Q-H

2013-11-01

Dietary fat is one of the most important energy sources of all the nutrients. Fatty acids, stored as triacylglycerols (also called triglycerides) in the body, are an important reservoir of stored energy and derived primarily from animal fats and vegetable oils. Although the molecular mechanisms for the transport of water-insoluble amphipathic fatty acids across cell membranes have been debated for many years, it is now believed that the dominant means for intestinal fatty acid uptake is via membrane-associated fatty acid-binding proteins, that is, fatty acid transporters on the apical membrane of enterocytes. These findings indicate that intestinal fatty acid absorption is a multistep process that is regulated by multiple genes at the enterocyte level, and intestinal fatty acid absorption efficiency could be determined by factors influencing intraluminal fatty acid molecules across the brush border membrane of enterocytes. To facilitate research on intestinal, hepatic and plasma triacylglycerol metabolism, it is imperative to establish standard protocols for precisely and accurately measuring the efficiency of intestinal fatty acid absorption in humans and animal models. In this review, we will discuss the chemical structure and nomenclature of fatty acids and summarize recent progress in investigating the molecular mechanisms underlying the intestinal absorption of fatty acids, with a particular emphasis on the physical chemistry of intestinal lipids and the molecular physiology of intestinal fatty acid transporters. A better understanding of the molecular mechanism of intestinal fatty acid absorption should lead to novel approaches to the treatment and the prevention of fatty acid-related metabolic diseases that are prevalent worldwide. © 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

Paracetamol as a Post Prandial Marker for Gastric Emptying, A Food-Drug Interaction on Absorption.

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R Bartholomé

Full Text Available The use of paracetamol as tool to determine gastric emptying was evaluated in a cross over study. Twelve healthy volunteers were included and each of them consumed two low and two high caloric meals. Paracetamol was mixed with a liquid meal and administered by a nasogastric feeding tube. The post prandial paracetamol plasma concentration time curve in all participants and the paracetamol concentration in the stomach content in six participants were determined. It was found that after paracetamol has left the stomach, based on analysis of the stomach content, there was still a substantial rise in the plasma paracetamol concentration time curve. Moreover, the difference in gastric emptying between high and low caloric meals was missed using the plasma paracetamol concentration time curve. The latter curves indicate that (i part of the paracetamol may leave the stomach much quicker than the meal and (ii part of the paracetamol may be relatively slowly absorbed in the duodenum. This can be explained by the partition of the homogenous paracetamol-meal mixture in the stomach in an aqueous phase and a solid bolus. The aqueous phase leaves the stomach quickly and the paracetamol in this phase is quickly absorbed in the duodenum, giving rise to the relatively steep increase of the paracetamol concentration in the plasma. The bolus leaves the stomach relatively slowly, and encapsulation by the bolus results in relatively slow uptake of paracetamol from the bolus in the duodenum. These findings implicate that paracetamol is not an accurate post prandial marker for gastric emptying. The paracetamol concentration time curve rather illustrates the food-drug interaction on absorption, which is not only governed by gastric emptying.ClinicalTrials.gov NCT01335503 Nederlands Trial Register NTR2780.

Drug target ontology to classify and integrate drug discovery data.

Science.gov (United States)

Lin, Yu; Mehta, Saurabh; Küçük-McGinty, Hande; Turner, John Paul; Vidovic, Dusica; Forlin, Michele; Koleti, Amar; Nguyen, Dac-Trung; Jensen, Lars Juhl; Guha, Rajarshi; Mathias, Stephen L; Ursu, Oleg; Stathias, Vasileios; Duan, Jianbin; Nabizadeh, Nooshin; Chung, Caty; Mader, Christopher; Visser, Ubbo; Yang, Jeremy J; Bologa, Cristian G; Oprea, Tudor I; Schürer, Stephan C

2017-11-09

One of the most successful approaches to develop new small molecule therapeutics has been to start from a validated druggable protein target. However, only a small subset of potentially druggable targets has attracted significant research and development resources. The Illuminating the Druggable Genome (IDG) project develops resources to catalyze the development of likely targetable, yet currently understudied prospective drug targets. A central component of the IDG program is a comprehensive knowledge resource of the druggable genome. As part of that effort, we have developed a framework to integrate, navigate, and analyze drug discovery data based on formalized and standardized classifications and annotations of druggable protein targets, the Drug Target Ontology (DTO). DTO was constructed by extensive curation and consolidation of various resources. DTO classifies the four major drug target protein families, GPCRs, kinases, ion channels and nuclear receptors, based on phylogenecity, function, target development level, disease association, tissue expression, chemical ligand and substrate characteristics, and target-family specific characteristics. The formal ontology was built using a new software tool to auto-generate most axioms from a database while supporting manual knowledge acquisition. A modular, hierarchical implementation facilitate ontology development and maintenance and makes use of various external ontologies, thus integrating the DTO into the ecosystem of biomedical ontologies. As a formal OWL-DL ontology, DTO contains asserted and inferred axioms. Modeling data from the Library of Integrated Network-based Cellular Signatures (LINCS) program illustrates the potential of DTO for contextual data integration and nuanced definition of important drug target characteristics. DTO has been implemented in the IDG user interface Portal, Pharos and the TIN-X explorer of protein target disease relationships. DTO was built based on the need for a formal semantic

Modeling the absorption spectrum of the permanganate ion in vacuum and in aqueous solution

DEFF Research Database (Denmark)

Olsen, Jógvan Magnus Haugaard; Hedegård, Erik Donovan

2017-01-01

The absorption spectrum of the MnO4(-) ion has been a test-bed for quantum-chemical methods over the last decades. Its correct description requires highly-correlated multiconfigurational methods, which are incompatible with the inclusion of finite-temperature and solvent effects due to their high...... by employing the polarizable embedding (PE) model combined with a range-separated complete active space short-range density functional theory method (CAS-srDFT). Finite-temperature effects are taken into account by averaging over structures obtained from ab initio molecular dynamics simulations. The explicit...... treatment of finite-temperature and solvent effects facilitates the interpretation of the bands in the low-energy region of the MnO4(-) absorption spectrum, whose assignment has been elusive....

Decreased absorption of midazolam in the stomach due to low pH induced by co-administration of Banha-sasim-tang

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Jun Hyeon Jo

2016-08-01

Full Text Available Objectives Banha-sasim-tang (BST, which consists of seven different herbs, is one of the most popular herbal formulae for treating gastrointestinal disorders in Eastern Asia. The commonly used herbal medicine is often co-administered with other therapeutic drugs, which raises the possibility of herb–drug interactions and may modify the clinical safety profile of therapeutic drugs. Methods We investigated the potential herb–drug interactions between BST extract and midazolam (MDZ in mice. The area under the plasma concentration-time curve (AUC of MDZ and 1ʹ-hydroxymidazolam (1ʹ-OH-MDZ was evaluated for both oral and intraperitoneal administration of MDZ, following oral administration of BST (0.5 and 1 g/kg. Results It was found that the AUC of MDZ and 1ʹ-OH-MDZ was lower in case of oral administration of MDZ. Administration of BST extract was not associated with hepatic cytochrome P450 activity. BST extract induced a strong reduction in pH and it has been reported that oral mucosal absorption of MDZ is lower at low pH. The decreased absorption rate of MDZ might be caused by the ingredients of BST and may not be related to other factors such as increased excretion of MDZ by P-glycoprotein. Conclusions The altered pharmacokinetics of midazolam caused by co-administration with BST in vivo could be attributed to a decrease in pH and subsequent reduction of MDZ absorption rate.

Transdermic absorption of Melagenina II; Evaluacion de la absorcion transdermica de la Melagenina II

Energy Technology Data Exchange (ETDEWEB)

Hernandez Gonzalez, I; Martinez Lopez, B; Ruiz Pena, M; Caso Pena, R [Centro de Isotopos, La Habana (Cuba)

1998-12-31

The transdermic absorption of Melagenina II (MII) was evaluated. MII was a labelled with {sup 125I} by the yodogen method and purified by column chromatography with Sephadex LH-20 in ethanol: water (7:3). In vitro absorption of ({sup 125I}) - MII thought human skin was carried out in Keshary-Chien modified diffusion cells. Tape stripping method was applied after 24 hours to evaluate the accumulated activity in dermis and epidermis. In vivo assays were performed in Sprague Dawley rats to analyze absorption of MII until 24 hours after a single application and for five days a low penetrability of the drug while in vivo there were not found blood levels significantly greater than zero , nevertheless and important amount of radioactivity was found in feces and urine. The activity was concentrated mainly in the application site in both models

Intestinal absorption of water-soluble vitamins in health and disease.

Science.gov (United States)

Said, Hamid M

2011-08-01

Our knowledge of the mechanisms and regulation of intestinal absorption of water-soluble vitamins under normal physiological conditions, and of the factors/conditions that affect and interfere with theses processes has been significantly expanded in recent years as a result of the availability of a host of valuable molecular/cellular tools. Although structurally and functionally unrelated, the water-soluble vitamins share the feature of being essential for normal cellular functions, growth and development, and that their deficiency leads to a variety of clinical abnormalities that range from anaemia to growth retardation and neurological disorders. Humans cannot synthesize water-soluble vitamins (with the exception of some endogenous synthesis of niacin) and must obtain these micronutrients from exogenous sources. Thus body homoeostasis of these micronutrients depends on their normal absorption in the intestine. Interference with absorption, which occurs in a variety of conditions (e.g. congenital defects in the digestive or absorptive system, intestinal disease/resection, drug interaction and chronic alcohol use), leads to the development of deficiency (and sub-optimal status) and results in clinical abnormalities. It is well established now that intestinal absorption of the water-soluble vitamins ascorbate, biotin, folate, niacin, pantothenic acid, pyridoxine, riboflavin and thiamin is via specific carrier-mediated processes. These processes are regulated by a variety of factors and conditions, and the regulation involves transcriptional and/or post-transcriptional mechanisms. Also well recognized now is the fact that the large intestine possesses specific and efficient uptake systems to absorb a number of water-soluble vitamins that are synthesized by the normal microflora. This source may contribute to total body vitamin nutrition, and especially towards the cellular nutrition and health of the local colonocytes. The present review aims to outline our current

Buccal Mucosa as A Route for Systemic Drug Delivery: A Review

OpenAIRE

Dhaval A. Pate; M. R. Pate; K. R. Pate; N. M. Pate

2012-01-01

Within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery. The mucosa has a rich blood supply and it is relatively permeable. It is the objective of this article to review buccal drug delivery by discussing the structure and environment of the oral mucosa and the experimental methods used in assessing buccal drug permeation/absorption. Buccal dosage forms will also be reviewed with an emphasis on bioadhesive polymeric based deliv...

Buccal mucosa as a route for systemic drug delivery: a review.

Science.gov (United States)

Shojaei, A H

1998-01-01

Within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery. The mucosa has a rich blood supply and it is relatively permeable. It is the objective of this article to review buccal drug delivery by discussing the structure and environment of the oral mucosa and the experimental methods used in assessing buccal drug permeation/absorption. Buccal dosage forms will also be reviewed with an emphasis on bioadhesive polymeric based delivery systems

The current status of community drug testing via the analysis of drugs and drug metabolites in sewage

Directory of Open Access Journals (Sweden)

Malcolm J. Reid

2011-12-01

Full Text Available Over the past few years the analysis of drug residues in sewage has been promoted as a means of estimating the level of drug use in communities. Measured drug residue concentrations in the sewage are used to determine the load (total mass of the drug being used by the entire community. Knowledge of the size or population of the community then allows for the calculation of drug-use relative to population (typically drug-mass/day/1000 inhabitants which facilitates comparisons between differing communities or populations. Studies have been performed in many European countries, including Norway, as well as in the US and Australia. The approach has successfully estimated the use of cocaine, amphetamine, methamphetamine, MDMA, cannabis, nicotine and alcohol. The analysis of biomarkers of drug use in sewage has great potential to support and complement existing techniques for estimating levels of drug use, and as such has been identified as a promising development by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA; www.emcdda.europa.eu/wastewater-analysis. The approach is not without its challenges, and ongoing collaboration across Europe aims at agreeing upon best-practice and harmonising the methods being used. In Norway development is being performed through the NFR RUSMIDDEL funded DrugMon (www.niva.no/drugmon project that has led to the development of many new techniques, significantly improved our understanding of the uncertainties associated with the approach and allowed the coordination of Europe wide collaboration which has included all important intercalibration exercises. Application of the technique can provide evidence-based and real-time estimates of collective drug use with the resulting data used to improve the much needed estimates of drug use and dependency.

Pharmacokinetics of drugs in cachectic patients: a systematic review.

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Katja Trobec

Full Text Available Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients.

Prediction of Human Pharmacokinetic Profile After Transdermal Drug Application Using Excised Human Skin.

Science.gov (United States)

Yamamoto, Syunsuke; Karashima, Masatoshi; Arai, Yuta; Tohyama, Kimio; Amano, Nobuyuki

2017-09-01

Although several mathematical models have been reported for the estimation of human plasma concentration profiles of drug substances after dermal application, the successful cases that can predict human pharmacokinetic profiles are limited. Therefore, the aim of this study is to investigate the prediction of human plasma concentrations after dermal application using in vitro permeation parameters obtained from excised human skin. The in vitro skin permeability of 7 marketed drug products was evaluated. The plasma concentration-time profiles of the drug substances in humans after their dermal application were simulated using compartment models and the clinical pharmacokinetic parameters. The transdermal process was simulated using the in vitro skin permeation rate and lag time assuming a zero-order absorption. These simulated plasma concentration profiles were compared with the clinical data. The result revealed that the steady-state plasma concentration of diclofenac and the maximum concentrations of nicotine, bisoprolol, rivastigmine, and lidocaine after topical application were within 2-fold of the clinical data. Furthermore, the simulated concentration profiles of bisoprolol, nicotine, and rivastigmine reproduced the decrease in absorption due to drug depletion from the formulation. In conclusion, this simple compartment model using in vitro human skin permeation parameters as zero-order absorption predicted the human plasma concentrations accurately. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A Review

Science.gov (United States)

Vadlamudi, Manoj Kumar; Dhanaraj, Sangeetha

2017-11-01

Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability using Hypromellose acetate succinate, Cyclodextrin, Povidone, Copovidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Crospovidone, Starch, Dimethylacetamide, Polyethylene glycol, Sodium lauryl sulfate, Polysorbate, Poloxamer. Mesoporous silica and so on. This review deliberates about the excipients significance on bioavailability enhancement of drug products in a single platform along with pragmatically proved applications so that user can able to select the right excipients as per the molecule.

Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.

Science.gov (United States)

Mondal, Milon; Radeva, Nedyalka; Fanlo-Virgós, Hugo; Otto, Sijbren; Klebe, Gerhard; Hirsch, Anna K H

2016-08-01

Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

[Recent knowledge about intestinal absorption and cleavage of carotenoids].

Science.gov (United States)

Borel, P; Drai, J; Faure, H; Fayol, V; Galabert, C; Laromiguière, M; Le Moël, G

2005-01-01

Our knowledge about intestinal absorption and cleavage of carotenoids has rapidly grown during the last years. New facts about carotenoid absorption have emerged while some controversies about cleavage are close to end. The knowledge of the absorption and conversion processes is indispensable to understand and interpret the perturbations that can occur in the metabolism of carotenoids and vitamin A. Recently, it has been shown that the absorption of certain carotenoids is not passive - as believed for a long time - but is a facilitated process that requires, at least for lutein, the class B-type 1 scavenger receptor (SR-B1). Various epidemiological and clinical studies have shown wide variations in carotenoid absorption from one subject to another, such differences are now explained by the structure of the concerned carotenoid, by the nature of the food that is absorbed with the carotenoid, by diverse exogenous factors like the intake of medicines or interfering components, by diet factors, by genetic factors, and by the nutritional status of the subject. Recently, the precise mechanism of beta-carotene cleavage by betabeta-carotene 15,15' monooxygenase (EC 1.14.99.36) - formerly called beta-carotene 15,15' dioxygenase (ex EC 1.13.11.21) - has been discovered, and a second enzyme which cleaves asymmetrically the beta-carotene molecule has been found. beta-carotene 15,15' monooxygenase only acts on the 15,15' bond, thus forming two molecules of retinal from one molecule of beta-carotene by central cleavage. Even though the betabeta-carotene 15,15' monooxygenase is much more active on the beta-carotene molecule, a study has shown that it can act on all carotenoids. Searchers now agree that other enzymes that can catalyse an eccentric cleavage of carotenoids probably exist, but under physiological conditions the betabeta-carotene 15,15' monooxygenase is by far the most active, and it is mainly effective in the small bowel mucosa and in the liver. However the

Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones.

Science.gov (United States)

Anker, Justin J; Carroll, Marilyn E

2011-01-01

Human and animal research indicates the presence of sex differences in drug abuse. These data suggest that females, compared to males, are more vulnerable to key phases of the addiction process that mark transitions in drug use such as initiation, drug bingeing, and relapse. Recent data indicate that the female gonadal hormone estrogen may facilitate drug abuse in women. For example, phases of the menstrual cycle when estrogen levels are high are associated with enhanced positive subjective measures following cocaine and amphetamine administration in women. Furthermore, in animal research, the administration of estrogen increases drug taking and facilitates the acquisition, escalation, and reinstatement of cocaine-seeking behavior. Neurobiological data suggest that estrogen may facilitate drug taking by interacting with reward- and stress-related systems. This chapter discusses sex differences in and hormonal effects on drug-seeking behaviors in animal models of drug abuse. The neurobiological basis of these differences and effects are also discussed.

Affordable orphan drugs: a role for not-for-profit organizations.

Science.gov (United States)

Davies, Elin H; Fulton, Emma; Brook, Daniel; Hughes, Dyfrig A

2017-07-01

The success of the Regulation on Orphan Medicinal Products in the European Union is evidenced by the 127 orphan drugs that have had market authorization since 2000. However, the incentives aimed at stimulating research and development have had the unintended consequence of increasing drug cost, resulting in many orphan drugs not being cost-effective. Orphan drugs command an increasing share of the pharmaceutical market and account for a disproportionate amount of healthcare expenditure. Orphan drug ownership by socially motivated, not-for-profit organizations may facilitate access to more affordable orphan drugs, for the benefit of patients and healthcare systems alike. This study aims to describe opportunities for such organizations to become orphan drug Market Authorization Holders. We reviewed data on the ownership of EMA designated and approved orphan drugs, identified funding opportunities and business models for not-for-profit organizations, and summarised relevant legal and policy documents concerning intellectual property rights and drug regulation. Using repurposed drugs as a paradigm, this narrative review navigates the regulatory hurdles, describes the legal context and identifies funding opportunities, in a bid to facilitate and encourage not-for-profit organizations to lead on the development of affordable orphan drugs. Although the regulatory steps required to obtain an MA for an orphan drug are numerous and challenging, they are not insurmountable and can be achieved by not-for-profit organizations that are socially motivated to reduce the costs of orphan drugs to the payers of healthcare. Opportunities for orphan drug development resulting in affordable products lie mainly with repurposed drugs. © 2017 The British Pharmacological Society.

Computational Amphiphilic Materials for Drug Delivery

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Naresh eThota

2015-10-01

Full Text Available Amphiphilic materials can assemble into a wide variety of morphologies and have emerged as a novel class of candidates for drug delivery. Along with a large number of experiments reported, computational studies have been also conducted in this field. At an atomistic/molecular level, computations can facilitate quantitative understanding of experimental observations and secure fundamental interpretation of underlying phenomena. This review summarizes the recent computational efforts on amphiphilic copolymers and peptides for drug delivery. Atom-resolution and time-resolved insights are provided from bottom-up to microscopically elucidate the mechanisms of drug loading/release, which are indispensable in the rational screening and design of new amphiphiles for high-efficacy drug delivery.

Facilitation of extinction of operant behaviour in C57Bl/6 mice by chlordiazepoxide and D-cycloserine.

Science.gov (United States)

Leslie, Julian C; Norwood, Kelly; Kennedy, Paul J; Begley, Michael; Shaw, David

2012-09-01

Effects on the extinction of GABAergic drug, chlordiazepoxide (CDP), and glutamatergic drug, D: -cycloserine (DCS), in C57BL/6 mice were compared. Following a palatability test (Experiment 1), Experiments 2-6 involved food-reinforced lever press training followed by extinction sessions at 1- or 4-day intervals. The effects of drugs were examined. Experiment 7 involved a two-lever task. CDP did not affect food palatability (Experiment 1), but facilitated extinction when administered prior to extinction sessions via intracerebral (Experiment 2) or peripheral administration at 1-day (Experiments 3-7) or 4-day intervals (Experiment 6). Reducing the amount of training prior to extinction reduced the delay in the effect of CDP typically seen, and CDP had a larger effect in early sessions on mice that had received less training (Experiment 3). There was some evidence that CDP could be blocked by flumazenil (Experiment 4), and CDP withdrawal reversed extinction facilitation (Experiments 5 and 7). With 4-day intervals, DCS administered immediately following extinction sessions, or pre-session CDP, facilitated extinction with 48-trial sessions (experiment 6B). With six-trial sessions, the co-administration of post-session DCS enhanced facilitation produced by pre-session CDP (experiment 6A). Finally, CDP facilitated extinction in a dose-related fashion following training on a two-lever food-reinforced task (Experiment 7). The findings are consistent with the hypotheses that two neurotransmitter systems have different roles in operant extinction and that glutamatergic systems are involved in extinction learning and GABAergic systems involved in the expression of that learning. This parallels findings with extinction following Pavlovian conditioning, which has been more extensively investigated.

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

OpenAIRE

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 insigh...

Engineering design and molecular dynamics of mucoadhesive drug delivery systems as targeting agents.

Science.gov (United States)

Serra, Laura; Doménech, Josep; Peppas, Nicholas A

2009-03-01

The goal of this critical review is to provide a critical analysis of the chain dynamics responsible for the action of micro- and nanoparticles of mucoadhesive biomaterials. The objective of using bioadhesive controlled drug delivery devices is to prolong their residence at a specific site of delivery, thus enhancing the drug absorption process. These mucoadhesive devices can protect the drug during the absorption process in addition to protecting it on its route to the delivery site. The major emphasis of recent research on mucoadhesive biomaterials has been on the use of adhesion promoters, which would enhance the adhesion between synthetic polymers and mucus. The use of adhesion promoters such as linear or tethered polymer chains is a natural result of the diffusional characteristics of adhesion. Mucoadhesion depends largely on the structure of the synthetic polymer gels used in controlled release applications.

Exciplex formation and electroluminescent absorption in ultraviolet organic light-emitting diodes

Science.gov (United States)

Zhang, Qi; Zhang, Hao; Zhang, Xiao-Wen; Xu, Tao; Wei, Bin

2015-02-01

We investigated the formation of exciplex and electroluminescent absorption in ultraviolet organic light-emitting diodes (UV OLEDs) using different heterojunction structures. It is found that an energy barrier of over 0.3 eV between the emissive layer (EML) and adjacent transport layer facilitates exciplex formation. The electron blocking layer effectively confines electrons in the EML, which contributes to pure UV emission and enhances efficiency. The change in EML thickness generates tunable UV emission from 376 nm to 406 nm. In addition, the UV emission excites low-energy organic function layers and produces photoluminescent emission. In UV OLED, avoiding the exciplex formation and averting light absorption can effectively improve the purity and efficiency. A maximum external quantum efficiency of 1.2% with a UV emission peak of 376 nm is realized. Project supported by the National Natural Science Foundation of China (Grant Nos. 61136003 and 61275041) and the Guangxi Provincial Natural Science Foundation, China (Grant No. 2012GXNSFBA053168).

Enhancement of absorption and bioavailability of echinacoside by verapamil or clove oil

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Shen JY

2015-08-01

Full Text Available Jin-Yang Shen,1,* Xiao-Lin Yang,2,* Zhong-Lin Yang,1 Jun-Ping Kou,1 Fei Li11State Key Laboratory of Natural Medicines, China Pharmaceutical University, 2Key Laboratory of Pharmaceutical and Biological Marine Resources Research and Development of Jiangsu Province, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China*These authors contributed equally to this workPurpose: This present study investigated the absorption kinetics of echinacoside (ECH in situ and in vitro and its oral bioavailability in rats. Additional aim was to find an agent(s to promote ECH absorption and oral bioavailability among two efflux proteins and three absorption promoters.Methods: ECH absorption behaviors were investigated by everted gut sac model in vitro and single-pass intestinal perfusion model in situ. Pharmacokinetics study was performed to investigate the influences of verapamil and clove oil on ECH bioavailability in vivo. All samples were measured at different time intervals by high performance liquid chromatography.Results: The results showed that the effective permeability coefficient (Peff and apparent permeability coefficient of ECH were 0.83×10-6–3.23×10-6 cm/s and 2.99×10-6–9.86×10-6 cm/s, respectively. The Peff among duodenum, jejunum, and ileum were not statistically different, but they were higher than colon (P<0.01, which demonstrated that intestinal ECH absorption was poor and site dependent. Additionally, verapamil and clove oil significantly increased the jejunal Peff of ECH both in situ and in vitro. Moreover, the bioavailability of ECH in combination with verapamil and clove oil were increased by 1.37-fold (P<0.05 and 2.36-fold (P<0.001, respectively, when compared to ECH group. Overall, verapamil and clove oil facilitated ECH absorption and oral bioavailability.Conclusion: The absorption and bioavailability of ECH were enhanced by verapamil and clove oil, respectively, both in vitro and in vivo. Consequently

The effect of BAY o 2752 on bile acid absorption and cholesterol esterification

International Nuclear Information System (INIS)

Harnett, K.M.

1988-01-01

BAY o 2752 [N,N-(1,11-undecandiyl)bis(2,3-dihydro-2-methyl-1H-indole-1-carboxamide)] has been demonstrated to inhibit intestinal cholesterol absorption in rats. Studies were carried out on male Wistar rats to determine if this drug alters intestinal bile acid absorption or cholesterol esterification by acyl CoA: cholesterol acyltransferase (ACAT) or cholesterol ester hydrolase (CEH). BAY o 2752 did not affect intestinal absorption of taurocholic acid (TC) from ileal segments perfused in vivo with a tragacanth suspension in phosphate buffer containing NaCl, TC, and 24- 14 C-TC as determined by the excretory rate of radioactivity in bile. BAY o 2752 also did not affect the uptake of TC into ileal everted sacs incubated in stirred, gassed Krebs-Ringer bicarbonate buffer with 1 mM TC, 24- 14 C-TC and 3 H-inulin. BAY o 2752 also did not bind TC; TG, in a filtrate of the above solutions remained at 92-98% of control

The effect of BAY o 2752 on bile acid absorption and cholesterol esterification

Energy Technology Data Exchange (ETDEWEB)

Harnett, K.M.

1988-01-01

BAY o 2752 (N,N-(1,11-undecandiyl)bis(2,3-dihydro-2-methyl-1H-indole-1-carboxamide)) has been demonstrated to inhibit intestinal cholesterol absorption in rats. Studies were carried out on male Wistar rats to determine if this drug alters intestinal bile acid absorption or cholesterol esterification by acyl CoA: cholesterol acyltransferase (ACAT) or cholesterol ester hydrolase (CEH). BAY o 2752 did not affect intestinal absorption of taurocholic acid (TC) from ileal segments perfused in vivo with a tragacanth suspension in phosphate buffer containing NaCl, TC, and 24-{sup 14}C-TC as determined by the excretory rate of radioactivity in bile. BAY o 2752 also did not affect the uptake of TC into ileal everted sacs incubated in stirred, gassed Krebs-Ringer bicarbonate buffer with 1 mM TC, 24-{sup 14}C-TC and {sup 3}H-inulin. BAY o 2752 also did not bind TC; TG, in a filtrate of the above solutions remained at 92-98% of control.

Supersaturation induced by Itraconazole/Soluplus® micelles provided high GI absorption in vivo

Directory of Open Access Journals (Sweden)

Yue Zhong

2016-04-01

Full Text Available To investigate the effect of supersaturation induced by micelle formation during dissolution on the bioavailability of itraconazole (ITZ/Soluplus® solid dispersion. Solid dispersions prepared by hot melt extrusion (HME were compressed into tablets directly with other excipients. Dissolution behavior of ITZ tablets was studied by dissolution testing and the morphology of micelles in dissolution media was studied using transmission electron microscopy (TEM. Drug transferring from stomach into intestine was simulated to obtain a supersaturated drug solution. Bioavailability studies were performed on the ITZ tablets and Sporanox® in beagle dogs. The morphology of micelles in the dissolution media was observed to be spherical in shape, with an average size smaller than 100 nm. The supersaturated solutions formed by Soluplus® micelles were stable and no precipitation took place over a period of 180 min. Compared with Sporanox®, ITZ tablets exhibited a 2.50-fold increase in the AUC(0–96 of ITZ and a 1.95-fold increase in its active metabolite hydroxyitraconazole (OH-ITZ in the plasma of beagle dogs. The results obtained provided clear evidence that not only the increase in the dissolution rate in the stomach, but also the supersaturation produced by micelles in the small intestine may be of great assistance in the successful development of poorly water-soluble drugs. The micelles formed by Soluplus® enwrapped the molecular ITZ inside the core which promoted the amount of free drug in the intestinal cavity and carried ITZ through the aqueous boundary layer (ABL, resulting in high absorption by passive transportation across biological membranes. The uptake of intact micelles through pinocytosis together with the inhibition of P-glycoprotein-mediated drug efflux in intestinal epithelia contributed to the absorption of ITZ in the gastrointestinal tract. These results indicate that HME with Soluplus®, which can induce supersaturation by micelle

Co-treatment with grapefruit juice inhibits while chronic administration activates intestinal P-glycoprotein-mediated drug efflux.

Science.gov (United States)

Panchagnula, R; Bansal, T; Varma, M V S; Kaul, C L

2005-12-01

P-Glycoprotein (P-gp) mediated efflux is recognized as a significant biochemical barrier affecting oral absorption for a number of drugs. Various conflicting reports have been published regarding the effects of grapefruit juice (GFJ) on P-gp-mediated drug efflux, in which GFJ has been shown both to inhibit and activate it. Hence, the present study adopted a two-way approach, involving both co-treatment and chronic administration. Bi-directional transport of paclitaxel (PCL) was carried out in the absence and presence of GFJ extract, in rat everted ileum sac. Further, the effect of chronic administration of GFJ to rats was characterized by permeability studies with indinavir (INDI). Co-treatment of GFJ extract at 100% concentration reduced the asymmetric transport of PCL (efflux ratio = 20.8) by increasing absorptive (A --> B) transport by 921% and reducing secretory (B --> A) transport by 41%. Further, GFJ showed a concentration dependent effect on PCL permeability. Imipramine, a passive permeability marker with absorptive permeability of 15.33 +/- 4.26 x 10(-6) cm/s showed no asymmetric transport and also no significant (P extract inhibited P-gp-mediated efflux in co-treatment, whereas chronic administration led to increased levels of P-gp expression, thus having a profound effect on intestinal absorption and GFJ-drug interactions in vivo.

Thermodynamic performance optimization of the absorption-generation process in an absorption refrigeration cycle

International Nuclear Information System (INIS)

Chen, Yi; Han, Wei; Jin, Hongguang

2016-01-01

Highlights: • This paper proposes a new thermal compressor model with boost pressure ratio. • The proposed model is an effective way to optimize the absorption-generation process. • Boost pressure ratio is a key parameter in the proposed thermal compressor model. • The optimum boost pressure ratios for two typical refrigeration systems are obtained. - Abstract: The absorption refrigeration cycle is a basic cycle that establishes the systems for utilizing mid-low temperature heat sources. A new thermal compressor model with a key parameter of boost pressure ratio is proposed to optimize the absorption-generation process. The ultimate generation pressure and boost pressure ratio are used to represent the potential and operating conditions of the thermal compressor, respectively. Using the proposed thermal compressor model, the operation mechanism and requirements of the absorption refrigeration system and absorption-compression refrigeration system are elucidated. Furthermore, the two typical heat conversion systems are optimized based on the thermal compressor model. The optimum boost pressure ratios of the absorption refrigeration system and the absorption-compression refrigeration system are 0.5 and 0.75, respectively. For the absorption refrigeration system, the optimum generation temperature is 125.31 °C at the cooling water temperature of 30 °C, which is obtained by simple thermodynamic calculation. The optimized thermodynamic performance of the absorption-compression refrigeration system is 16.7% higher than that of the conventional absorption refrigeration system when the generation temperature is 100 °C. The thermal compressor model proposed in this paper is an effective method for simplifying the optimization of the thermodynamic systems involving an absorption-generation process.

Inkjet Printing of Drug-Loaded Mesoporous Silica Nanoparticles—A Platform for Drug Development

Directory of Open Access Journals (Sweden)

Henrika Wickström

2017-11-01

Full Text Available Mesoporous silica nanoparticles (MSNs have shown great potential in improving drug delivery of poorly water soluble (BCS class II, IV and poorly permeable (BCS class III, IV drugs, as well as facilitating successful delivery of unstable compounds. The nanoparticle technology would allow improved treatment by reducing adverse reactions of currently approved drugs and possibly reintroducing previously discarded compounds from the drug development pipeline. This study aims to highlight important aspects in mesoporous silica nanoparticle (MSN ink formulation development for digital inkjet printing technology and to advice on choosing a method (2D/3D for nanoparticle print deposit characterization. The results show that both unfunctionalized and polyethyeleneimine (PEI surface functionalized MSNs, as well as drug-free and drug-loaded MSN–PEI suspensions, can be successfully inkjet-printed. Furthermore, the model BCS class IV drug remained incorporated in the MSNs and the suspension remained physically stable during the processing time and steps. This proof-of-concept study suggests that inkjet printing technology would be a flexible deposition method of pharmaceutical MSN suspensions to generate patterns according to predefined designs. The concept could be utilized as a versatile drug screening platform in the future due to the possibility of accurately depositing controlled volumes of MSN suspensions on various materials.

Inkjet Printing of Drug-Loaded Mesoporous Silica Nanoparticles-A Platform for Drug Development.

Science.gov (United States)

Wickström, Henrika; Hilgert, Ellen; Nyman, Johan O; Desai, Diti; Şen Karaman, Didem; de Beer, Thomas; Sandler, Niklas; Rosenholm, Jessica M

2017-11-21

Mesoporous silica nanoparticles (MSNs) have shown great potential in improving drug delivery of poorly water soluble (BCS class II, IV) and poorly permeable (BCS class III, IV) drugs, as well as facilitating successful delivery of unstable compounds. The nanoparticle technology would allow improved treatment by reducing adverse reactions of currently approved drugs and possibly reintroducing previously discarded compounds from the drug development pipeline. This study aims to highlight important aspects in mesoporous silica nanoparticle (MSN) ink formulation development for digital inkjet printing technology and to advice on choosing a method (2D/3D) for nanoparticle print deposit characterization. The results show that both unfunctionalized and polyethyeleneimine (PEI) surface functionalized MSNs, as well as drug-free and drug-loaded MSN-PEI suspensions, can be successfully inkjet-printed. Furthermore, the model BCS class IV drug remained incorporated in the MSNs and the suspension remained physically stable during the processing time and steps. This proof-of-concept study suggests that inkjet printing technology would be a flexible deposition method of pharmaceutical MSN suspensions to generate patterns according to predefined designs. The concept could be utilized as a versatile drug screening platform in the future due to the possibility of accurately depositing controlled volumes of MSN suspensions on various materials.

Profiling online recreational/prescription drugs' customers and overview of drug vending virtual marketplaces.

Science.gov (United States)

Orsolini, Laura; Francesconi, Giulia; Papanti, Duccio; Giorgetti, Arianna; Schifano, Fabrizio

2015-07-01

Internet and social networking sites play a significant role in the marketing and distribution of recreational/prescription drugs without restrictions. We aimed here at reviewing data relating to the profile of the online drug customer and at describing drug vending websites. The PubMed, Google Scholar, and Scopus databases were searched here in order to elicit data on the socio-demographic characteristics of the recreational marketplaces/online pharmacies' customers and the determinants relating to online drug purchasing activities. Typical online recreational drugs' customers seem to be Caucasian, men, in their 20s, highly educated, and using the web to impact as minimally as possible on their existing work/professional status. Conversely, people without any health insurance seemed to look at the web as a source of more affordable prescription medicines. Drug vending websites are typically presented here with a "no prescription required" approach, together with aggressive marketing strategies. The online availability of recreational/prescriptions drugs remains a public health concern. A more precise understanding of online vending sites' customers may well facilitate the drafting and implementation of proper prevention campaigns aimed at counteracting the increasing levels of online drug acquisition and hence intake activities. Copyright © 2015 John Wiley & Sons, Ltd.

Membrane Transporters: Structure, Function and Targets for Drug Design

Science.gov (United States)

Ravna, Aina W.; Sager, Georg; Dahl, Svein G.; Sylte, Ingebrigt

Current therapeutic drugs act on four main types of molecular targets: enzymes, receptors, ion channels and transporters, among which a major part (60-70%) are membrane proteins. This review discusses the molecular structures and potential impact of membrane transporter proteins on new drug discovery. The three-dimensional (3D) molecular structure of a protein contains information about the active site and possible ligand binding, and about evolutionary relationships within the protein family. Transporters have a recognition site for a particular substrate, which may be used as a target for drugs inhibiting the transporter or acting as a false substrate. Three groups of transporters have particular interest as drug targets: the major facilitator superfamily, which includes almost 4000 different proteins transporting sugars, polyols, drugs, neurotransmitters, metabolites, amino acids, peptides, organic and inorganic anions and many other substrates; the ATP-binding cassette superfamily, which plays an important role in multidrug resistance in cancer chemotherapy; and the neurotransmitter:sodium symporter family, which includes the molecular targets for some of the most widely used psychotropic drugs. Recent technical advances have increased the number of known 3D structures of membrane transporters, and demonstrated that they form a divergent group of proteins with large conformational flexibility which facilitates transport of the substrate.

Increasing efficacy and reducing systemic absorption of brimonidine tartrate ophthalmic gels in rabbits.

Science.gov (United States)

Pang, Xiaochen; Li, Jiawei; Pi, Jiaxin; Qi, Dongli; Guo, Pan; Li, Nan; Wu, Yumei; Liu, Zhidong

2018-03-01

Systemic absorption of ocularly administered Brimonidine Tartrate has been reported to give rise to several side-effects. Hence, it has become crucial to develop a delivery system that could increase efficacy and reduce systemic absorption. Therefore, the present work aims to develop Brimonidine Tartrate gels with different concentrations (0.05%, 0.1%, and 0.2% w/v, respectively) using Carbopol 974 P and HPMC E4M, and compare the therapeutic efficacy and systemic absorption with that of eye drop (0.2%, w/v) by UPLC-MS/MS. The result of histological analysis did not show any morphological or structural changes after the administration of formulations. In vitro residence time studies demonstrated that the gels exhibited a better precorneal residence time as compared with the eye drop. The gels with lower concentrations of the drug (0.05% and 0.1%, w/v) could significantly decrease intraocular pressure (IOP) in both normal and water-loaded rabbits as compared to the eye drop. Finally, the values of the ratio of AUC (0→∞) in comparison to eye drop showed the gels with lower concentrations of Brimonidine Tartrate could decrease the systemic absorption. From the result, it can be concluded the 0.1% ophthalmic gel has a potential to improve therapeutic efficacy and reduce the potential toxicity caused by systemic absorption.

Drugs in sport.

Science.gov (United States)

McGrath, J C; Cowan, D A

2008-06-01

This themed issue of the British Journal of Pharmacology has been compiled and edited by Ian McGrath, Regius Professor of Physiology at University of Glasgow and David Cowan, Director of the Drug Control Centre at King's College London. It contains 11 articles covering the mechanisms of action of the major groups of drugs used illicitly in sport. The articles, written by experts in how drugs work, set out where drugs can or cannot affect sporting performance, how this relates to their legitimate medicinal use, their other detrimental effects and how they can be detected. Publication coincides with Olympic year, when sport is highlighted in the public mind and much speculation is made concerning the use of drugs. The articles provide a framework of expert, accurate knowledge to inform and facilitate these debates and to help to overcome the ill-informed and dangerous anecdotal information by which sports men and women are persuaded to misuse drugs in the mistaken belief that this will improve their performance without present or future ill effects. A unique article is included by the Spedding brothers, Mike with a long career in drug discovery and Charlie, the 1984 Los Angeles Olympic Marathon Bronze Medallist and still the English National Marathon record holder. From their unique experience, they describe the insidious and unfair way that drug-assisted performance undermines the ethos of sport and endangers the vital place of sport in maintaining the health of the population.

Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A.

Science.gov (United States)

Prueksaritanont, T; Tatosian, D A; Chu, X; Railkar, R; Evers, R; Chavez-Eng, C; Lutz, R; Zeng, W; Yabut, J; Chan, G H; Cai, X; Latham, A H; Hehman, J; Stypinski, D; Brejda, J; Zhou, C; Thornton, B; Bateman, K P; Fraser, I; Stoch, S A

2017-04-01

A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics.

The potential of immobilized artificial membrane chromatography to predict human oral absorption.

Science.gov (United States)

Tsopelas, Fotios; Vallianatou, Theodosia; Tsantili-Kakoulidou, Anna

2016-01-01

The potential of immobilized artificial membrane (IAM) chromatography to estimate human oral absorption (%HOA) was investigated. For this purpose, retention indices on IAM stationary phases reported previously by our group or measured by other authors under similar conditions were used to model %HOA data, compiled from literature sources. Considering the pH gradient in gastrointestinal tract, the highest logkw(IAM) values were considered, obtained either at pH7.4 or 5.5, defined as logkw(IAM)(best). Non linear models were established upon introduction of additional parameters and after exclusion of drugs which are substrates either to efflux or uptake transporters. The best model included Abraham's hydrogen-bond acidity parameter, molecular weight as well as the positively and negatively charged molecular fractions. For reasons of comparison between IAM chromatography and traditional lipophilicity, corresponding models were derived by replacing IAM retention factors with octanol-water distribution coefficients (logD). An overexpression of electrostatic interactions with phosphate anions was observed in the case of IAM retention as expressed by the negative contribution of the positively charged fraction F(+). The same parameter is statistically significant also in the logD model, but with a positive sign, indicating the attraction of basic drugs in the negatively charged inner membrane. To validate the obtained models a blind test set of 22 structurally diverse drugs was used, whose logkw(IAM)(best) values were determined and analyzed in the present study under similar conditions. IAM retention factors were further compared with MDCK cell lines permeability data taken from literature for a set of validation drugs. The overexpression of electrostatic interactions with phosphate anions on IAM surface was also evident in respect to MDCK permeability. In contrast to the clear classification between drugs with high and poor (or intermediate) absorption provided by MDCK

Patient centric drug product design in modern drug delivery as an opportunity to increase safety and effectiveness.

Science.gov (United States)

Stegemann, Sven

2018-06-01

The advances in drug delivery technologies have enabled pharmaceutical scientists to deliver a drug through various administration routes and optimize the drug release and absorption. The wide range of drug delivery systems and dosage forms represent a toolbox of technology for the development of pharmaceutical drug products but might also be a source of medication errors and nonadherence. Patient centric drug product development is being suggested as an important factor to increase therapeutic outcomes. Areas covered: Patients have impaired health and potentially disabilities and they are not medical or pharmaceutical experts but are requested to manage complex therapeutic regimens. As such the application of technology should also serve to reduce complexity, build on patients' intuition and ease of use. Patients form distinct populations based on the targeted disease, disease cluster or age group with specific characteristics or therapeutic contexts. Expert opinion: Establishing a target product and patient profile is essential to guide drug product design development. Including the targeted patient populations in the process is a prerequisite to achieve patient-centric pharmaceutical drug product design. Addressing the needs early on in the product design process, will create more universal design, avoiding the necessity for multiple product presentations to cover the different patient populations.

Calcium absorption

International Nuclear Information System (INIS)

Carlmark, B.; Reizenstein, P.; Dudley, R.A.

1976-01-01

The methods most commonly used to measure the absorption and retention of orally administered calcium are reviewed. Nearly all make use of calcium radioisotopes. The magnitude of calcium absorption and retention depends upon the chemical form and amount of calcium administered, and the clinical and nutritional status of the subject; these influences are briefly surveyed. (author)

Particulate absorption properties in the Red Sea from hyperspectral particulate absorption spectra

KAUST Repository

Tiwari, Surya Prakash

2018-03-16

This paper aims to describe the variability of particulate absorption properties using a unique hyperspectral dataset collected in the Red Sea as part of the TARA Oceans expedition. The absorption contributions by phytoplankton (aph) and non-algal particles (aNAP) to the total particulate absorption coefficients are determined using a numerical decomposition method (NDM). The NDM is validated by comparing the NDM derived values of aph and aNAP with simulated values of aph and aNAP are found to be in excellent agreement for the selected wavelengths (i.e., 443, 490, 555, and 676nm) with high correlation coefficient (R2), low root mean square error (RMSE), mean relative error (MRE), and with a slope close to unity. Further analyses showed that the total particulate absorption coefficients (i.e., ap(443)average = 0.01995m−1) were dominated by phytoplankton absorption (i.e., aph(443)average = 0.01743m−1) with a smaller contribution by non-algal particles absorption (i.e., aNAP(443)average = 0.002524m−1). The chlorophyll a is computed using the absorption based Line Height Method (LHM). The derived chlorophyll-specific absorption ((a⁎ph = aph(λ)/ChlLH)) showed more variability in the blue part of spectrum as compared to the red part of spectrum representative of the package effect and changes in pigment composition. A new parametrization proposed also enabled the reconstruction of a⁎ph(λ) for the Red Sea. Comparison of derived spectral constants with the spectral constants of existing models showed that our study A(λ) values are consistent with the existing values, despite there is a divergence with the B(λ) values. This study provides valuable information derived from the particulate absorption properties and its spectral variability and this would help us to determine the relationship between the phytoplankton absorption coefficients and chlorophyll a and its host of variables for the Red Sea.

Easily Dispersible NiFe2O4/RGO Composite for Microwave Absorption Properties in the X-Band

Science.gov (United States)

Bateer, Buhe; Zhang, Jianjao; Zhang, Hongchen; Zhang, Xiaochen; Wang, Chunyan; Qi, Haiqun

2018-01-01

Composites with good dispersion and excellent microwave absorption properties have important applications. Therefore, an easily dispersible NiFe2O4/reduced graphene oxide (RGO) composite has been prepared conveniently through a simple hydrothermal method. Highly crystalline, small size (about 7 nm) monodispersed NiFe2O4 nanoparticles (NPs) are evenly distributed on the surface of RGO. The microwave absorbability revealed that the NiFe2O4/RGO composite exhibits excellent microwave absorption properties in the X-band (8-12 GHz), and the minimum reflection loss of the NiFe2O4/RGO composite is -27.7 dB at 9.2 GHz. The NiFe2O4/RGO composite has good dispersibility in nonpolar solvent, which facilitates the preparation of stable commercial microwave absorbing coatings. It can be a promising candidate for lightweight microwave absorption materials in many application fields.

Drug detection in breath: non-invasive assessment of illicit or pharmaceutical drugs.

Science.gov (United States)

Trefz, Phillip; Kamysek, Svend; Fuchs, Patricia; Sukul, Pritam; Schubert, Jochen K; Miekisch, Wolfram

2017-03-20

Breath analysis not only holds great potential for the development of new non-invasive diagnostic methods, but also for the identification and follow up of drug levels in breath. This is of interest for both, forensic and medical science. On the one hand, the detection of drugs of abuse in exhaled breath-similar to the well-known breath alcohol tests-would be highly desirable as an alternative to blood or urine analysis in situations such as police controls for drugged driving. The non-invasive detection of drugs and their metabolites is thus of great interest in forensic science, especially since marijuana is becoming legalized in certain parts of the US and the EU. The detection and monitoring of medical drugs in exhaled breath without the need of drawing blood samples on the other hand, is of high relevance in the clinical environment. This could facilitate a more precise medication and enable therapy control without any burden to the patient. Furthermore, it could be a step towards personalized medicine. This review gives an overview of the current state of drug detection in breath, including both volatile and non-volatile substances. The review is divided into two sections. The first section deals with qualitative detection of drugs (drugs of abuse), while the second is related to quantitative drug detection (medical drugs). Chances and limitations are discussed for both aspects. The detection of the intravenous anesthetic propofol is presented as a detailed example that demonstrates the potential, requirements, pitfalls and limitations of therapeutic drug monitoring by means of breath analysis.

Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements.

Science.gov (United States)

Sprouse, Alyssa A; van Breemen, Richard B

2016-02-01

The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but underinvestigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport, and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, phase 1 clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport, and metabolism. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Development of novel, 384-well high-throughput assay panels for human drug transporters: drug interaction and safety assessment in support of discovery research.

Science.gov (United States)

Tang, Huaping; Shen, Ding Ren; Han, Yong-Hae; Kong, Yan; Balimane, Praveen; Marino, Anthony; Gao, Mian; Wu, Sophie; Xie, Dianlin; Soars, Matthew G; O'Connell, Jonathan C; Rodrigues, A David; Zhang, Litao; Cvijic, Mary Ellen

2013-10-01

Transporter proteins are known to play a critical role in affecting the overall absorption, distribution, metabolism, and excretion characteristics of drug candidates. In addition to efflux transporters (P-gp, BCRP, MRP2, etc.) that limit absorption, there has been a renewed interest in influx transporters at the renal (OATs, OCTs) and hepatic (OATPs, BSEP, NTCP, etc.) organ level that can cause significant clinical drug-drug interactions (DDIs). Several of these transporters are also critical for hepatobiliary disposition of bilirubin and bile acid/salts, and their inhibition is directly implicated in hepatic toxicities. Regulatory agencies took action to address transporter-mediated DDI with the goal of ensuring drug safety in the clinic and on the market. To meet regulatory requirements, advanced bioassay technology and automation solutions were implemented for high-throughput transporter screening to provide structure-activity relationship within lead optimization. To enhance capacity, several functional assay formats were miniaturized to 384-well throughput including novel fluorescence-based uptake and efflux inhibition assays using high-content image analysis as well as cell-based radioactive uptake and vesicle-based efflux inhibition assays. This high-throughput capability enabled a paradigm shift from studying transporter-related issues in the development space to identifying and dialing out these concerns early on in discovery for enhanced mechanism-based efficacy while circumventing DDIs and transporter toxicities.

U.S. Food and Drug Administration drug approval: slow advances in obstetric care in the United States.

Science.gov (United States)

Wing, Deborah A; Powers, Barbara; Hickok, Durlin

2010-04-01

The process for drug approval in the United States is complex and time-consuming. There are comparatively few drugs with U.S. Food and Drug Administration (FDA)-approved indications for obstetric use in this country at this time; however, several are under development. We review the process for drug approval and recount the approval histories of obstetric drugs reviewed in the recent past. We also outline the current status of two progestational agents that are under development. For a variety of reasons, including a small market compared with others such as cardiology or oncology, and the potential of being drawn into medical-legal litigation, sponsors are disinclined to pursue drug development for obstetric purposes in this country. We compare the procedures for review and approval of drugs in the United States with those in Europe, and note that recent changes within the FDA may result in not only more drugs being approved but also changes in labeling of already approved drugs. Special programs to facilitate drug development and reforms to modernize the process and improve safety are discussed. These may result in changes in labeling of already approved drugs. Obstacles such as funding and liability are also discussed.

Effect of Coating Solvent Ratio on the Drug Release Lag Time of ...

African Journals Online (AJOL)

Erah

Research Article ... Lag Time of Coated Theophylline Osmotic Tablets ... Key words: Coating solvent, Drug release, Lag time, Osmotic tablet, HPMC, .... following composition (w/w): theophylline ... tablets was measured by UV absorption.

Vitamin A absorption

International Nuclear Information System (INIS)

Baker, S.J.

1976-01-01

Investigation of the absorption of vitamin A and related substances is complicated by the multiplicity of forms in which they occur in the diet and by the possibility that they may be subject to different mechanisms of absorption. Present knowledge of these mechanisms is inadequate, especially in the case of carotenoids. Numerous tests of absorption have been developed. The most common has been the biochemical measurement of the rise in plasma vitamin A after an oral dose of retinol or retinyl ester, but standardization is inadequate. Radioisotope tests based upon assay of serum or faecal activity following oral administration of tritiated vitamin A derivaties hold considerable promise, but again standardization is inadequate. From investigations hitherto performed it is known that absorption of vitamin A is influenced by several diseases, although as yet the consistency of results and the correlation with other tests of intestinal function have often been poor. However, the test of vitamin A absorption is nevertheless of clinical importance as a specialized measure of intestinal function. (author)

D-xylose absorption

Science.gov (United States)

... this page: //medlineplus.gov/ency/article/003606.htm D-xylose absorption To use the sharing features on this page, please enable JavaScript. D-xylose absorption is a laboratory test to determine ...

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.

Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

Science.gov (United States)

Wargo, A.R.; Huijben, S.; De Roode, J. C.; Shepherd, J.; Read, A.F.

2007-01-01

Malaria infections frequently consist of mixtures of drug-resistant and drug-sensitive parasites. If crowding occurs, where clonal population densities are suppressed by the presence of coinfecting clones, removal of susceptible clones by drug treatment could allow resistant clones to expand into the newly vacated niche space within a host. Theoretical models show that, if such competitive release occurs, it can be a potent contributor to the strength of selection, greatly accelerating the rate at which resistance spreads in a population. A variety of correlational field data suggest that competitive release could occur in human malaria populations, but direct evidence cannot be ethically obtained from human infections. Here we show competitive release after pyrimethamine curative chemotherapy of acute infections of the rodent malaria Plasmodium chabaudi in laboratory mice. The expansion of resistant parasite numbers after treatment resulted in enhanced transmission-stage densities. After the elimination or near-elimination of sensitive parasites, the number of resistant parasites increased beyond that achieved when a competitor had never been present. Thus, a substantial competitive release occurred, markedly elevating the fitness advantages of drug resistance above those arising from survival alone. This finding may explain the rapid spread of drug resistance and the subsequently brief useful lifespans of some antimalarial drugs. In a second experiment, where subcurative chemotherapy was administered, the resistant clone was only partly released from competitive suppression and experienced a restriction in the size of its expansion after treatment. This finding raises the prospect of harnessing in-host ecology to slow the spread of drug resistance. ?? 2007 by The National Academy of Sciences of the USA.

A potential model for drug screening by simulating the effect of shear stress in vivo on endothelium.

Science.gov (United States)

Xu, Yingqian; Wang, Bochu; Deng, Jia; Liu, Zerong; Zhu, Liancai

2013-01-01

The purpose of this paper was to research the potential of a dynamic cell model in drug screening by studying the influence of microvascular wall shear stress on the drug absorption of endothelial cells compared to that in the static state. The cells were grown and seeded on gelatin-coated glass slides and were pretreated with extracts of Salviae miltiorrhizae (200 μg/ml) for 1 h. Then oxidative stress damage was produced by H2O2 (300 μmol/l) for 0.5 h under the 1.5 dyn/cm2 shear stress incorporated in a parallel plate flow chamber. Morphological analysis was conducted with an inverted microscope and image analysis software, and high performance liquid chromatography-mass spectrometry was used for the detection of active compounds. We compared the drug absorption in the dynamic group with that in the static group. In the dynamic model, five compounds and two new metabolite peaks were detected. However, in the static model, four compounds were absorbed by cells, and one metabolite peak was found. This study indicated that there were some effects on the absorption and metabolism of drugs under the microvascular shear stress compared to that under stasis. We infer that shear stress in the microcirculation situation in vivo played a role in causing the differences between drug screening in vitro and in vivo.

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.

Hydrogel nanoparticles and nanocomposites for nasal drug/vaccine delivery.

Science.gov (United States)

Salatin, Sara; Barar, Jaleh; Barzegar-Jalali, Mohammad; Adibkia, Khosro; Milani, Mitra Alami; Jelvehgari, Mitra

2016-09-01

Over the past few years, nasal drug delivery has attracted more and more attentions, and been recognized as the most promising alternative route for the systemic medication of drugs limited to intravenous administration. Many experiments in animal models have shown that nanoscale carriers have the ability to enhance the nasal delivery of peptide/protein drugs and vaccines compared to the conventional drug solution formulations. However, the rapid mucociliary clearance of the drug-loaded nanoparticles can cause a reduction in bioavailability percentage after intranasal administration. Thus, research efforts have considerably been directed towards the development of hydrogel nanosystems which have mucoadhesive properties in order to maximize the residence time, and hence increase the period of contact with the nasal mucosa and enhance the drug absorption. It is most certain that the high viscosity of hydrogel-based nanosystems can efficiently offer this mucoadhesive property. This update review discusses the possible benefits of using hydrogel polymer-based nanoparticles and hydrogel nanocomposites for drug/vaccine delivery through the intranasal administration.

The health and economic effects of counterfeit drugs.

Science.gov (United States)

Blackstone, Erwin A; Fuhr, Joseph P; Pociask, Steve

2014-06-01

Counterfeit drugs comprise an increasing percentage of the US drug market and even a larger percentage in less developed countries. Counterfeit drugs involve both lifesaving and lifestyle drugs. To review the health and economic consequences of counterfeit drugs on the US public and on the healthcare system as a whole. This comprehensive review of the literature encompassed a search of MEDLINE/PubMed, Google Scholar, and ProQuest using the keywords "counterfeit drugs," "counterfeit medicines," "fake drugs," and "fake medicines." A search of the various FiercePharma daily newsletter series on the healthcare market was also conducted. In addition, the US Food and Drug Administration and the World Health Organization websites were reviewed for additional information. The issue of counterfeit drugs has been growing in importance in the United States, with the supply of these counterfeit drugs coming from all over the world. Innovation is important to economic growth and US competitiveness in the global marketplace, and intellectual property protections provide the ability for society to prosper from innovation. Especially important in terms of innovation in healthcare are the pharmaceutical and biopharmaceutical industries. In addition to taking income from consumers and drug companies, counterfeit drugs also pose health hazards to patients, including death. The case of bevacizumab (Avastin) is presented as one recent example. Internet pharmacies, which are often the source of counterfeit drugs, often falsely portray themselves as Canadian, to enhance their consumer acceptance. Adding to the problems are drug shortages, which facilitate access for counterfeits. A long and convoluted supply chain also facilitates counterfeits. In addition, the wholesale market involving numerous firms is a convenient target for counterfeit drugs. Trafficking in counterfeits can be extremely profitable; detection of counterfeits is difficult, and the penalties are modest. Counterfeit

Microbiome-mediated bile acid modification: Role in intestinal drug absorption and metabolism.

Science.gov (United States)

Enright, Elaine F; Griffin, Brendan T; Gahan, Cormac G M; Joyce, Susan A

2018-04-13

Once regarded obscure and underappreciated, the gut microbiota (the microbial communities colonizing the gastrointestinal tract) is gaining recognition as an influencer of many aspects of human health. Also increasingly apparent is the breadth of interindividual variation in these co-evolved microbial-gut associations, presenting novel quests to explore implications for disease and therapeutic response. In this respect, the unearthing of the drug-metabolizing capacity of the microbiota has provided impetus for the integration of microbiological and pharmacological research. This review considers a potential mechanism, 'microbial bile acid metabolism', by which the intricate interplay between the host and gut bacteria may influence drug pharmacokinetics. Bile salts traditionally regarded as biological surfactants, synthesized by the host and biotransformed by gut bacteria, are now also recognized as signalling molecules that affect diverse physiological processes. Accumulating data indicate that bile salts are not equivalent with respect to their physicochemical properties, micellar solubilization capacities for poorly water-soluble drugs, crystallization inhibition tendencies nor potencies for bile acid receptor activation. Herein, the origin, physicochemical properties, physiological functions, plasticity and pharmaceutical significance of the human bile acid pool are discussed. Microbial dependant differences in the composition of the human bile acid pool, simulated intestinal media and commonly used preclinical species is highlighted to better understand in vivo performance predictiveness. While the precise impact of an altered gut microbiome, and consequently bile acid pool, in the biopharmaceutical setting remains largely elusive, the objective of this article is to aid knowledge acquisition through a detailed review of the literature. Copyright © 2018 Elsevier Ltd. All rights reserved.

A primer of drug safety surveillance: an industry perspective. Part I: Information flow, new drug development, and federal regulations.

Science.gov (United States)

Allan, M C

1992-01-01

To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part I of this series provides a background for the discussion of drug safety by defining the basic terms and showing the flow of safety information through a pharmaceutical company. The customers for adverse drug event data are identified to provide a basis for providing quality service. The development of a drug product is briefly reviewed to show the evolution of safety data. Drug development and safety are defined by federal regulations. These regulations are developed by the FDA with information from pharmaceutical manufacturers. The intent of the regulations and the accompanying guidelines is described. An illustration from the news media is cited to show an alternative, positive approach to handling an adverse event report. This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text and additional readings are presented in an appendix. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction ;of the components

Interplay of biopharmaceutics, biopharmaceutics drug disposition and salivary excretion classification systems

Science.gov (United States)

Idkaidek, Nasir M.

2013-01-01

The aim of this commentary is to investigate the interplay of Biopharmaceutics Classification System (BCS), Biopharmaceutics Drug Disposition Classification System (BDDCS) and Salivary Excretion Classification System (SECS). BCS first classified drugs based on permeability and solubility for the purpose of predicting oral drug absorption. Then BDDCS linked permeability with hepatic metabolism and classified drugs based on metabolism and solubility for the purpose of predicting oral drug disposition. On the other hand, SECS classified drugs based on permeability and protein binding for the purpose of predicting the salivary excretion of drugs. The role of metabolism, rather than permeability, on salivary excretion is investigated and the results are not in agreement with BDDCS. Conclusion The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion based on permeability (not metabolism) and protein binding. PMID:24493977

Admissions of injection drug users to drug abuse treatment following HIV counseling and testing.

Science.gov (United States)

McCusker, J; Willis, G; McDonald, M; Lewis, B F; Sereti, S M; Feldman, Z T

1994-01-01

The outcomes of counseling and testing programs related to human immunodeficiency virus (HIV) infection and risk of infection among injection drug users (IDUs) are not well known or understood. A counseling and testing outcome of potential public health importance is attaining admission to drug abuse treatment by those IDUs who are either infected or who are at high risk of becoming infected. The authors investigated factors related to admission to drug abuse treatment among 519 IDUs who received HIV counseling and testing from September 1987 through December 1990 at a men's prison and at community-based testing sites in Worcester, MA. By June 1991, 123 of the 519 IDUs (24 percent) had been admitted to treatment. Variables associated with their admission included a long history of drug injection, frequent recent drug injection, cleaning injection equipment using bleach, prior drug treatment, and a positive HIV test result. Logistic regression analyses, controlling for effects of recruitment site, year, sex, and area of residence, generally confirmed the associations. IDUs in the study population who were HIV-infected sought treatment or were admitted to treatment more frequently than those who were not infected. The results indicate that access to drug abuse treatment should be facilitated for high-risk IDUs and for those who have begun to inject drugs recently.

Pharmacotherapies for decreasing maladaptive choice in drug addiction: Targeting the behavior and the drug.

Science.gov (United States)

Perkins, Frank N; Freeman, Kevin B

2018-01-01

Drug addiction can be conceptualized as a disorder of maladaptive decision making in which drugs are chosen at the expense of pro-social, nondrug alternatives. The study of decision making in drug addiction has focused largely on the role of impulsivity as a facilitator of addiction, in particular the tendency for drug abusers to choose small, immediate gains over larger but delayed outcomes (i.e., delay discounting). A parallel line of work, also focused on decision making in drug addiction, has focused on identifying the determinants underlying the choice to take drugs over nondrug alternatives (i.e., drug vs. nondrug choice). Both tracks of research have been valuable tools in the development of pharmacotherapies for treating maladaptive decision making in drug addiction, and a number of common drugs have been studied in both designs. However, we have observed that there is little uniformity in the administration regimens of potential treatments between the designs, which hinders congruence in the development of single treatment strategies to reduce both impulsive behavior and drug choice. The current review provides an overview of the drugs that have been tested in both delay-discounting and drug-choice designs, and focuses on drugs that reduced the maladaptive choice in both designs. Suggestions to enhance congruence between the findings in future studies are provided. Finally, we propose the use of a hybridized, experimental approach that may enable researchers to test the effectiveness of therapeutics at decreasing impulsive and drug choice in a single design. Published by Elsevier Inc.

Rule Based Expert System for Monitoring Real Time Drug Supply in Hospital Using Radio Frequency Identification Technology

Science.gov (United States)

Driandanu, Galih; Surarso, Bayu; Suryono

2018-02-01

A radio frequency identification (RFID) has obtained increasing attention with the emergence of various applications. This study aims to examine the implementation of rule based expert system supported by RFID technology into a monitoring information system of drug supply in a hospital. This research facilitates in monitoring the real time drug supply by using data sample from the hospital pharmacy. This system able to identify and count the number of drug and provide warning and report in real time. the conclusion is the rule based expert system and RFID technology can facilitate the performance in monitoring the drug supply quickly and precisely.

A study of the energy absorption and exposure buildup factors of some anti-inflammatory drugs

International Nuclear Information System (INIS)

Ekinci, Neslihan; Kavaz, Esra; Özdemir, Yüksel

2014-01-01

Human radiation exposure is increasing due to radiation development in science and technology. The development of radioprotective agents is important for protecting patients from the side effects of radiotherapy and for protecting the public from unwanted irradiation. Radioprotective agents are used to reduce the damage caused by radiation in healthy tissues. There are several classes of radioprotective compounds that are under investigation. Analgesics and anti-inflammatory compounds are being considered for treating or preventing the effects of damage due to radiation exposure, or for increasing the chance of survival after exposure to a high dose of radiation. In this study, we investigated the radioprotective effects of some analgesic and anti-inflammatory compounds by evaluating buildup factors. The gamma ray energy absorption (EABF) and exposure buildup factors (EBF) were calculated to select compounds in a 0.015–15 MeV energy region up to a penetration depth of 40 mfp (mean free path). Variations of EABF and EBF with incident photon energy and penetration depth elements were also investigated. Significant variations in both EABF and EBF values were observed for several compounds at the moderate energy region. At energies below 0.15 MeV, EABF and EBF values increased with decreasing equivalent atomic number (Z eq ) of the samples. In addition, EABF and EBF were the largest for ibuprofen, aspirin, paracetamol, naproxen and ketoprofen at 0.05 and 0.06 MeV, respectively, and the EABF value was 0.1 MeV for aceclofenac. From these results, we concluded that the buildup of photons is less for aceclofenac compared to other materials. - Highlights: • Buildup factors of anti-inflammatory drugs have been calculated by a G-P fitting method. • Z eff of diclofenac was observed higher than other compounds. • It was found that buildup of photons is less for aceclofenac and diclofenac. • It would be appealing to use aceclofenac and diclofenac as radioprotective

X-ray Absorption Spectroscopy

Energy Technology Data Exchange (ETDEWEB)

Yano, Junko; Yachandra, Vittal K.

2009-07-09

This review gives a brief description of the theory and application of X-ray absorption spectroscopy, both X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS), especially, pertaining to photosynthesis. The advantages and limitations of the methods are discussed. Recent advances in extended EXAFS and polarized EXAFS using oriented membranes and single crystals are explained. Developments in theory in understanding the XANES spectra are described. The application of X-ray absorption spectroscopy to the study of the Mn4Ca cluster in Photosystem II is presented.

Atomic absorption spectrometry using tungsten and molybdenum tubes as metal atomizer

International Nuclear Information System (INIS)

Kaneco, Satoshi; Katsumata, Hideyuki; Ohta, Kiyohisa; Suzuki, Tohru

2007-01-01

We have developed a metal tube atomizer for the electrothermal atomization atomic absorption spectrometry (ETA-AAS). Tungsten, molybdenum, platinum tube atomizers were used as the metal atomizer for ETA-AAS. The atomization characteristics of various metals using these metal tube atomizers were investigated. The effects of heating rate of atomizer, atomization temperature, pyrolysis temperature, argon purge gas flow rate and hydrogen addition on the atomic absorption signal were investigated for the evaluation of atomization characteristics. Moreover, ETA-AAS with metal tube atomizer has been combined with the slurry-sampling techniques. Ultrasonic slurry-sampling ETA-AAS with metal tube atomizer were effective for the determination of trace metal elements in biological materials, calcium drug samples, herbal medicine samples, vegetable samples and fish samples. Furthermore, a preconcentration method of trace metals involving adsorption on a metal wire has been applied to ETA-AAS with metal tube atomizer. (author)

Study of percutaneous absorption of diclofenac diethylamine in the presence of cetrimide through hairless rabbit skin

International Nuclear Information System (INIS)

Hussain, S. N.; Rabbain, M.; Amir, M. F.

2006-01-01

In the present study, the effect of Cetrimide as an enhancer on transdermal absorption of 1% diclofenac diethylamine (Non-steroidal Anti-inflammatory Drug) through hairless rabbit skin was evaluated in vitro study at various concentrations to improve the skin permeability. From the data, Cetrimide shows the small lag time which gives a picture about its enhancing effect. The permeability co-efficient and flux rate calculated for diclofenac diethylamine in the presence of Cetrimide shows that the penetration of drug through hairless rabbit skin has been significantly increased. (author)

Dietary and biliary cholesterol absorption in rats. Effect of dietary cholesterol level and cholesterol saturation of bile

International Nuclear Information System (INIS)

Wilson, M.D.

1985-01-01

The principal objective of this research was to determine if cholesterol introduced into the duodenum of rats in a micellar form as occurs with bile, is absorbed more efficiently than cholesterol presented in a nonmicellar form, as occurs with dietary cholesterol. Cholesterol absorption was measured during the constant intraduodenal infusion of liquid diets ([ 14 C] cholesterol) and artificial biles ([ 3 H] cholesterol) in thoracic lymph duct cannulated rats. Percentage absorption was calculated by dividing the rate of appearance of radiolabeled cholesterol in lymph by its rate of infusion when lymph cholesterol specific activity was constant. Results provide strong evidence that under certain conditions biliary cholesterol is more efficiently absorbed than is dietary cholesterol, and that this differential must be considered when evaluating the influence of diet or drug therapy on cholesterol absorption

Using a digital multimeter to capture spectral information generated by a spectrophotometer broadcast / atomic absorption

International Nuclear Information System (INIS)

Villalobos Chaves, Alberto E.

2006-01-01

Spectral analysis capability of the information generated by a spectrophotometer broadcast / shimadzu AA 640-13 atomic absorption has increased, through the capture of data, using a digital multimeter as the interface between the spectrophotometer and a computer. To facilitate the identification of analytes was created Chromulan format files for the 99 chemical elements reported in the literature, and covering the region between 200 nm and 900 nm, the subject of this study. (author) [es

Impact of Drug Metabolism/Pharmacokinetics and Their Relevance upon Taxus-based Drug Development.

Science.gov (United States)

Hao, Da-Cheng; Ge, Guang-Bo; Wang, Ping; Yang, Ling

2018-05-22

Drug metabolism and pharmacokinetic (DMPK) studies of Taxus natural products, their semi-synthetic derivatives and analogs are indispensable in the optimization of lead compounds and clinical therapy. These studies can lead to development of new drug entities with improved absorption, distribution, metabolism, excretion and toxicity (ADME/T) profiles. To date, there have been no comprehensive reviews of the DMPK features of Taxus derived medicinal compounds.Natural and semi-synthetic taxanes may cause and could be affected by drug-drug interaction (DDI). Hence ADME/T studies of various taxane-containing formulations are important; to date these studies indicate that the role of cytochrome p450s and drug transporters is more prominent than phase II drug metabolizing enzymes. Mechanisms of taxane DMPK mediated by nuclear receptors, microRNAs, and single nucleotide polymorphisms are being revealed. Herein we review the latest knowledge on these topics, as well as the gaps in knowledge of the DMPK issues of Taxus compounds. DDIs significantly impact the PK/pharmacodynamics performance of taxanes and co-administered chemicals, which may inspire researchers to develop novel formula. While the ADME/T profiles of some taxanes are well defined, DMPK studies should be extended to more Taxus compounds, species, and Taxus -involved formulations, which would be streamlined by versatile omics platforms and computational analyses. Further biopharmaceutical investigations will be beneficial tothe translation of bench findings to the clinical applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effect of increased surface hydrophobicity via drug conjugation on the clearance of inhaled PEGylated polylysine dendrimers.

Science.gov (United States)

Haque, Shadabul; McLeod, Victoria M; Jones, Seth; Fung, Sandy; Whittaker, Michael; McIntosh, Michelle; Pouton, Colin; Owen, David J; Porter, Christopher J H; Kaminskas, Lisa M

2017-10-01

PEGylated polylysine dendrimers are attractive and well tolerated inhalable drug delivery platforms that have the potential to control the release, absorption kinetics and lung retention time of conjugated drugs. The clinical application of these systems though, would likely require partial substitution of surface PEG groups with drug molecules that are anticipated to alter their lung clearance kinetics and clearance pathways. In the current study, we therefore evaluated the impact of increased surface hydrophobicity via substitution of 50% surface PEG groups with a model hydrophobic drug (α-carboxyl OtButylated methotrexate) on the lung clearance of a Generation 5 PEGylated polylysine dendrimer in rats. PEG substitution with OtBu-methotrexate accelerated lung clearance of the dendrimer by increasing polylysine scaffold catabolism, improving systemic absorption of the intact dendrimer and low molecular weight products of scaffold catabolism, and enhancing mucociliary clearance. These results suggest that the conjugation of hydrophobic drug on the surface of a PEGylated dendrimer is likely to accelerate lung clearance when compared to a fully PEGylated dendrimer. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

On the Nature of Extraversion: Variation in Conditioned Contextual Activation of Dopamine-Facilitated Affective, Cognitive, and Motor Processes

Directory of Open Access Journals (Sweden)

Richard allen Depue

2013-06-01

Full Text Available Research supports an association between extraversion and dopamine (DA functioning. DA facilitates incentive motivation and the conditioning and incentive encoding of contexts that predict reward. Therefore, we assessed whether extraversion is related to the efficacy of acquiring conditioned contextual facilitation of three processes that are dependent on DA: motor velocity, positive affect, and visuospatial working memory. We exposed high and low extraverts to three days of association of drug reward (methylphenidate, MP with a particular laboratory context (Paired group, a test day of conditioning, and three days of extinction in the same laboratory. A Placebo group and an Unpaired group (that had MP in a different laboratory context served as controls. Conditioned contextual facilitation was assessed by (i presenting video clips that varied in their pairing with drug and laboratory context and in inherent incentive value, and (ii measuring increases from day 1 to Test day on the three processes above. Results showed acquisition of conditioned contextual facilitation across all measures to video clips that had been paired with drug and laboratory context in the Paired high extraverts, but no conditioning in the Paired low extraverts (nor in either of the control groups. Increases in the Paired high extraverts were correlated across the three measures. Also, conditioned facilitation was evident on the first day of extinction in Paired high extraverts, despite the absence of the unconditioned effects of MP. By the last day of extinction, responding returned to day 1 levels. The findings suggest that extraversion is associated with variation in the acquisition of contexts that predict reward. Over time, this variation may lead to differences in the breadth of networks of conditioned contexts. Thus, individual differences in extraversion may be maintained by activation of differentially encoded central representations of incentive contexts that

Drug detection by terahertz time-domain spectroscopy

International Nuclear Information System (INIS)

Duan Ruixin; Zhu Yiming; Zhao Hongwei

2013-01-01

Due to unique spectral region, functional imaging ability, excellent penetration and safety characteristics of terahertz radiation, the terahertz technology rapidly becomes a vital method to detect and analyze drugs. In this paper, firstly, we identify the functional groups of anti-diabetic drugs by density functional theory (DFT), HIPHOP models and experimental results from terahertz time-domain spectroscopy measurements. Secondly, we identify four kinds of herbs of radix curcumae by using the support vector machine (SVM) analysis. Besides, we analyze the absorption of anhydrous and hydrous glucose, and determine the state of water in the crystalized D-glucose·H 2 O through the results of differential scanning calorimetry measurement. Finally, we summarize the advantages and disadvantages of terahertz time-domain spectroscopy method in drug detection and analyzing. (authors)

Platinum assay by neutron activation analysis and atomic absorption spectroscopy in cisplatin treated pregnant mice

International Nuclear Information System (INIS)

Esposito, M.; Collecchi, P.; Oddone, M.; Meloni, S.

1986-01-01

Cisplatin (CDDP) is an antineoplastic drug used in the treatment of a wide variety of tumors. This paper describes an investigation carried out on pregnant mice after intragastric or intraperitoneally treatment with CDDP from day 11 to 13 of gestation. Platinum content in different tissues, namely liver, kidney, placenta and brain, was determined at 18 day of pregnancy. Two analytical techniques were used, i.e. neutron activation analysis and atomic absorption spectroscopy. Results of both techniques are presented and discussed in terms of precision, accuracy and sensitivity. Neutron activation analysis appears to provide results better correlated with the drug treatment. (author)

Platinum assay by neutron activation analysis and atomic absorption spectroscopy in cisplatin treated pregnant mice

International Nuclear Information System (INIS)

Esposito, M.; Collecchi, P.; Oddone, M.; Meloni, S.

1987-01-01

Cisplatin (CDDP) is an antineoplastic drug used in the treatment of a wide variety of tumors. This paper describes an investigation carried out on pregnant mice after intragastric or intraperitoneal treatment with CDDP from the 11st to 13rd day of gestation. Platinum content in different liver, kidney, placenta and brain tissues, was determined at 18. day of pregnancy. Neutron activation analysis and atomic absorption spectroscopy were used. Results of both techniques are presented and discussed in terms of precision, accuracy and sensitivity. Neutron activation analysis appears to provide better results correlated with the drug treatment. (author) 10 refs.; 4 tables

Synthesis and evaluation of mesoporous carbon/lipid bilayer nanocomposites for improved oral delivery of the poorly water-soluble drug, nimodipine.

Science.gov (United States)

Zhang, Yanzhuo; Zhao, Qinfu; Zhu, Wufu; Zhang, Lihua; Han, Jin; Lin, Qisi; Ai, Fengwei

2015-07-01

A novel mesoporous carbon/lipid bilayer nanocomposite (MCLN) with a core-shell structure was synthesized and characterized as an oral drug delivery system for poorly water-soluble drugs. The objective of this study was to investigate the potential of MCLN-based formulation to modulate the in vitro release and in vivo absorption of a model drug, nimodipine (NIM). NIM-loaded MCLN was prepared by a procedure involving a combination of thin-film hydration and lyophilization. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), specific surface area analysis, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were employed to characterize the NIM-loaded MCLN formulation. The effect of MCLN on cell viability was assessed using the MTT assay. In addition, the oral bioavailability of NIM-loaded MCLN in beagle dogs was compared with that of the immediate-release formulation, Nimotop®. Our results demonstrate that the NIM-loaded MCLN formulation exhibited a typical sustained release pattern. The NIM-loaded MCLN formulation achieved a greater degree of absorption and longer lasting plasma drug levels compared with the commercial formulation. The relative bioavailability of NIM for NIM-loaded MCLN was 214%. MCLN exhibited negligible toxicity. The data reported herein suggest that the MCLN matrix is a promising carrier for controlling the drug release rate and improving the oral absorption of poorly water-soluble drugs.

Drug abuse: consequences in terms of family pathology and disintegration.

Science.gov (United States)

Visser, L

1991-01-01

This article examines some of the consequences of drug addiction in terms of family pathology and family disintegration. It briefly elucidates the role of the family in developing and maintaining drug addiction in family members. The concept of 'secondary' sufferers of the illness of drug addiction is examined. An actual case history will be presented in order to facilitate analysis of some of the forms of pathology and disintegration so often seen in the family of the drug addict. Within the family context, the question of who, if anyone, is the victim of drug addiction, is raised.

Practice Facilitators' and Leaders' Perspectives on a Facilitated Quality Improvement Program.

Science.gov (United States)

McHugh, Megan; Brown, Tiffany; Liss, David T; Walunas, Theresa L; Persell, Stephen D

2018-04-01

Practice facilitation is a promising approach to helping practices implement quality improvements. Our purpose was to describe practice facilitators' and practice leaders' perspectives on implementation of a practice facilitator-supported quality improvement program and describe where their perspectives aligned and diverged. We conducted interviews with practice leaders and practice facilitators who participated in a program that included 35 improvement strategies aimed at the ABCS of heart health (aspirin use in high-risk individuals, blood pressure control, cholesterol management, and smoking cessation). Rapid qualitative analysis was used to collect, organize, and analyze the data. We interviewed 17 of the 33 eligible practice leaders, and the 10 practice facilitators assigned to those practices. Practice leaders and practice facilitators both reported value in the program's ability to bring needed, high-quality resources to practices. Practice leaders appreciated being able to set the schedule for facilitation and select among the 35 interventions. According to practice facilitators, however, relying on practice leaders to set the pace of the intervention resulted in a lower level of program intensity than intended. Practice leaders preferred targeted assistance, particularly electronic health record documentation guidance and linkages to state smoking cessation programs. Practice facilitators reported that the easiest interventions were those that did not alter care practices. The dual perspectives of practice leaders and practice facilitators provide a more holistic picture of enablers and barriers to program implementation. There may be greater opportunities to assist small practices through simple, targeted practice facilitator-supported efforts rather than larger, comprehensive quality improvement projects. © 2018 Annals of Family Medicine, Inc.

Undefined role of mucus as a barrier in ocular drug delivery.

Science.gov (United States)

Ruponen, Marika; Urtti, Arto

2015-10-01

Mucus layer covers the ocular surface, and soluble mucins are also present in the tear fluid. After topical ocular drug administration, the drugs and formulations may interact with mucus layer that may act as a barrier in ocular drug delivery. In this mini-review, we illustrate the mucin composition of the ocular surface and discuss the influence of mucus layer on ocular drug absorption. Based on the current knowledge the role of mucus barrier in drug delivery is still undefined. Furthermore, interactions with mucus may prolong the retention of drug formulations on the ocular surface. Mucus may decrease or increase ocular bioavailability depending on the magnitude of its role as barrier or retention site, respectively. Mechanistic studies are needed to clarify the role of mucin in ocular drug delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate

Energy Technology Data Exchange (ETDEWEB)

Jia, Yongming [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Liu, Zhihao; Wang, Changyuan; Meng, Qiang; Huo, Xiaokui; Liu, Qi; Sun, Huijun [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian 116044 (China); Sun, Pengyuan; Yang, Xiaobo; Ma, Xiaodong [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Liu, Kexin, E-mail: kexinliu@dlmedu.edu.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044 (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian 116044 (China)

2016-09-01

The purpose of present study was to investigate the effect of resveratrol (Res) on altering methotrexate (MTX) pharmacokinetics and clarify the related molecular mechanism. Res significantly increased rat intestinal absorption of MTX in vivo and in vitro. Simultaneously, Res inhibited MTX efflux transport in MDR1-MDCK and MRP2-MDCK cell monolayers, suggesting that the target of drug interaction was MDR1 and MRP2 in the intestine during the absorption process. Furthermore, there was a significant decrease in renal clearance of MTX after simultaneous intravenous administration. Similarly, MTX uptake was markedly inhibited by Res in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1 and OAT3 were involved in the drug interaction in the kidney. Additionally, concomitant administration of Res decreased cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and ameliorated nephrotoxicity caused by MTX in rats. Conversely, intestinal damage caused by MTX was not exacerbated after Res treatment. In conclusion, Res enhanced MTX absorption in intestine and decreased MTX renal elimination by inhibiting P-gp, MRP2, OAT1 and OAT3 in vivo and in vitro. Res improved MTX-induced renal damage without increasing intestinal toxicity. - Highlights: • DDI between MTX and Res will occur when they are co-administered. • The first targets of the DDI are P-gp and MRP2 located in intestine. • The second targets of the DDI are OAT1 and OAT3 in kidney. • Res improved MTX-induced renal damage without increasing intestinal toxicity.

Drug interactions evaluation: An integrated part of risk assessment of therapeutics

International Nuclear Information System (INIS)

Zhang, Lei; Reynolds, Kellie S.; Zhao, Ping; Huang, Shiew-Mei

2010-01-01

Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance ( (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf)) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industry and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a 'Drug Development and Drug Interactions' website to provide up-to-date information regarding evaluation of drug interactions ( (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm)). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.

Bile Acid Signaling in Metabolic Disease and Drug Therapy

Science.gov (United States)

Li, Tiangang

2014-01-01

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid–activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein–coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. PMID:25073467

Home Manufacture of Drugs: An Online Investigation and a Toxicological Reality Check of Online Discussions on Drug Chemistry.

Science.gov (United States)

Hearne, Evelyn; Alves, Emanuele Amorim; Van Hout, Marie Claire; Grund, Jean-Paul C

2017-01-01

Emerging trends in market dynamics and the use of new psychoactive substances are both a public health concern and a complex regulatory issue. One novel area of investigation is the availability of homemade opioids, amphetamines and dissociatives, and the potential fueling of interest in clandestine home manufacture of drugs via the Internet. We illustrate here how online communal folk pharmacology of homemade drugs on drug website forums may actually inform home manufacture practices or contribute to the reduction of harms associated with this practice. Discrepancies between online information around purification and making homemade drugs safer, and the synthesis of the same substances in a proper laboratory environment, exist. Moderation and shutdown of synthesis queries and discussions online are grounded in drug websites adhering to harm-reduction principles by facilitating discussions around purification of homemade drugs only. Drug discussion forums should consider reevaluating their policies on chemistry discussions in aiming to reach people who cannot or will not refrain from cooking their own drugs with credible information that may contribute to reductions in the harms associated with this practice.

Nanotechnology-based polymeric bio(muco)adhesive platforms for controlling drug delivery - properties, methodologies and applications

International Nuclear Information System (INIS)

Carvalho, Flavia Chiva; Chorilli, Marlus; Gremiao, Maria Palmira Daflon

2014-01-01

Studies using bio(muco)adhesive drug delivery systems have recently gained great interest, which can promote drug targeting and more specific contact of the drug delivery system with the various absorptive membranes of the body. This technological platform associated with nanotechnology offers potential for controlling drug delivery; therefore, they are excellent strategies to increase the bioavailability of drugs. The objective of this work was to study nanotechnology-based polymeric bio(muco)adhesive platforms for controlling drug delivery, highlighting their properties, how the bio(muco)adhesion can be measured and their potential applications for different routes of administration. (author)

In Vivo Dissolution and Systemic Absorption of Immediate Release Ibuprofen in Human Gastrointestinal Tract under Fed and Fasted Conditions.

Science.gov (United States)

Koenigsknecht, Mark J; Baker, Jason R; Wen, Bo; Frances, Ann; Zhang, Huixia; Yu, Alex; Zhao, Ting; Tsume, Yasuhiro; Pai, Manjunath P; Bleske, Barry E; Zhang, Xinyuan; Lionberger, Robert; Lee, Allen; Amidon, Gordon L; Hasler, William L; Sun, Duxin

2017-12-04

In vivo drug dissolution in the gastrointestinal (GI) tract is largely unmeasured. The purpose of this clinical study was to evaluate the in vivo drug dissolution and systemic absorption of the BCS class IIa drug ibuprofen under fed and fasted conditions by direct sampling of stomach and small intestinal luminal content. Expanding current knowledge of drug dissolution in vivo will help to establish physiologically relevant in vitro models predictive of drug dissolution. A multilumen GI catheter was orally inserted into the GI tract of healthy human subjects. Subjects received a single oral dose of ibuprofen (800 mg tablet) with 250 mL of water under fasting and fed conditions. The GI catheter facilitated collection of GI fluid from the stomach, duodenum, and jejunum. Ibuprofen concentration in GI fluid supernatant and plasma was determined by LC-MS/MS. A total of 23 subjects completed the study, with 11 subjects returning for an additional study visit (a total of 34 completed study visits). The subjects were primarily white (61%) and male (65%) with an average age of 30 years. The subjects had a median [min, max] weight of 79 [52, 123] kg and body mass index of 25.7 [19.4, 37.7] kg/m 2 . Ibuprofen plasma levels were higher under fasted conditions and remained detectable for 28 h under both conditions. The AUC 0-24 and C max were lower in fed subjects vs fasted subjects, and T max was delayed in fed subjects vs fasted subjects. Ibuprofen was detected immediately after ingestion in the stomach under fasting and fed conditions until 7 h after dosing. Higher levels of ibuprofen were detected in the small intestine soon after dosing in fasted subjects compared to fed. In contrast to plasma drug concentration, overall gastric concentrations remained higher under fed conditions due to increased gastric pH vs fasting condition. The gastric pH increased to near neutrality after feedingbefore decreasing to acidic levels after 7 h. Induction of the fed state reduced systemic

Facilitating RNA structure prediction with microarrays.

Science.gov (United States)

Kierzek, Elzbieta; Kierzek, Ryszard; Turner, Douglas H; Catrina, Irina E

2006-01-17

Determining RNA secondary structure is important for understanding structure-function relationships and identifying potential drug targets. This paper reports the use of microarrays with heptamer 2'-O-methyl oligoribonucleotides to probe the secondary structure of an RNA and thereby improve the prediction of that secondary structure. When experimental constraints from hybridization results are added to a free-energy minimization algorithm, the prediction of the secondary structure of Escherichia coli 5S rRNA improves from 27 to 92% of the known canonical base pairs. Optimization of buffer conditions for hybridization and application of 2'-O-methyl-2-thiouridine to enhance binding and improve discrimination between AU and GU pairs are also described. The results suggest that probing RNA with oligonucleotide microarrays can facilitate determination of secondary structure.

Precise control of the drug kinetics by means of non-invasive magnetic drug delivery system

International Nuclear Information System (INIS)

Chuzawa, M.; Mishima, F.; Akiyama, Y.; Nishijima, S.

2013-01-01

Highlights: ► We examined the kinetics of ferromagnetic drugs by simulation. ► We tried to accumulate the magnetic drug in the target part by rotating a magnet. ► Ferromagnetic drugs were accumulated in the target part along the rotating axis. ► Ferromagnetic drugs could be swept downstream in the off-axis part. -- Abstract: In order to solve the problems of the side effects and medical lowering, has been advanced a study on the drug delivery system (DDS) to accumulate the drugs locally in the body with minimum dosage. The DDS is a system that controls the drug kinetics in the body precisely and accumulates the drug locally at the target part, keeping the drugs at high density. Among the DDS, the magnetic drug delivery system (MDDS) is the one that we studied. This is a technique to accumulate drugs by using the magnetic force as the physical driving force. Our previous researches showed the possibility of the technique of MDDS to accumulate the drugs with higher accumulation rate and locality than the traditional methods. It is necessary to apply a strong external magnetic field and a high magnetic gradient to accumulate the ferromagnetic drugs at a deep diseased part non-invasively. However, by applying a static magnetic field from one direction, the drug accumulates only at the surface of the body locates near the magnet. In this study, we tried to change the magnetic field applied by a superconducting bulk magnet with time, in order to make a constant and strong magnetic field applied in the center of the body and to accumulate the ferromagnetic drugs at the deep target part in the body. First of all, the effect of the surface treatment of the ferromagnetic drugs to prevent its absorption in the normal tissue was examined. Then, to increase the accumulation rate of the ferromagnetic drugs at the target part, the distribution of magnetic field was changed, and the optimum spatial and temporal conditions of magnetic field were examined