Pharmacokinetics and absorption of the anticancer agents dasatinib and GDC-0941 under various gastric conditions in dogs--reversing the effect of elevated gastric pH with betaine HCl.

PubMed

Pang, Jodie; Dalziel, Gena; Dean, Brian; Ware, Joseph A; Salphati, Laurent

2013-11-04

Changes in gastric pH can impact the dissolution and absorption of compounds presenting pH-dependent solubility. We assessed, in dogs, the effects of gastric pH-modifying agents on the oral absorption of two weakly basic anticancer drugs, dasatinib and GDC-0941. We also tested whether drug-induced hypochlorhydria could be temporarily mitigated using betaine HCl. Pretreatments with pentagastrin, famotidine, betaine HCl, or combinations of famotidine and betaine HCl were administered orally to dogs prior to drug dosing. The gastric pH was measured under each condition for up to 7 h, and the exposure of the compounds tested was calculated. The average gastric pH in fasted dogs ranged from 1.45 to 3.03. Pentagastrin or betaine HCl treatments lowered the pH and reduced its variability between dogs compared to control animals. In contrast, famotidine treatment maintained gastric pH at values close to 7 for up to 5 h, while betaine HCl transiently reduced the pH to approximately 2 in the famotidine-treated dogs. Famotidine pretreatment lowered GDC-0941 exposure by 5-fold, and decreased dasatinib measurable concentrations 30-fold, compared to the pentagastrin-treated dogs. Betaine HCl restored GDC-0941 AUC in famotidine-treated dogs to levels achieved in control animals, and increased dasatinib AUC to 1.5-fold that measured in control dogs. The results confirmed the negative impact of acid-reducing agents on the absorption of weakly basic drugs. They also suggested that betaine HCl coadministration may be a viable strategy in humans treated with acid-reducing agents in order to temporarily reduce gastric pH and restore drug exposure.

Multiscale Simulations of Barrier and Aging Properties of Polymer Nanocomposites

DTIC Science & Technology

2013-10-29

Complexation Between Weakly Basic Dendrimers and Linear Polyelectrolytes: Effects of Chain Stiffness, Grafts, and pOH,” Thomas Lewis, Gunja Pandav, Ahmad Omar...November 2012. (c) Presentations 20.0010/29/2013 Venkat Ganesan, Thomas Lewis. Interactions between Grafted Cationic Dendrimers and Anionic Bilayer... dendrimers have shown great promise in drug and gene therapy applications. Despite the advantages realized through positively charged dendrimers , a

Method for loading lipid like vesicles with drugs of other chemicals

DOEpatents

Mehlhorn, R.J.

1998-06-09

A method for accumulating drugs or other chemicals within synthetic, lipid-like vesicles by means of a pH gradient imposed on the vesicles just prior to use is described. The method is suited for accumulating molecules with basic or acid moieties which are permeable to the vesicles membranes in their uncharged form and for molecules that contain charge moieties that are hydrophobic ions and can therefore cross the vesicle membranes in their charged form. The method is advantageous over prior art methods for encapsulating biologically active materials within vesicles in that is achieves very high degrees of loading with simple procedures that are economical and require little technical expertise, furthermore kits which can be stored for prolonged periods prior to use without impairment of the capacity to achieve drug accumulation are described. A related application of the method consists of using this technology to detoxify animals that have been exposed to poisons with basic, weak acid or hydrophobic charge groups within their molecular structures. 2 figs.

Method for loading lipid like vesicles with drugs of other chemicals

DOEpatents

Mehlhorn, Rolf Joachim

1998-01-01

A method for accumulating drugs or other chemicals within synthetic, lipid-like vesicles by means of a pH gradient imposed on the vesicles just prior to use is described. The method is suited for accumulating molecules with basic or acid moieties which are permeable to the vesicles membranes in their uncharged form and for molecules that contain charge moieties that are hydrophobic ions and can therefore cross the vesicle membranes in their charged form. The method is advantageous over prior art methods for encapsulating biologically active materials within vesicles in that is achieves very high degrees of loading with simple procedures that are economical and require little technical expertise, furthermore kits which can be stored for prolonged periods prior to use without impairment of the capacity to achieve drug accumulation are described. A related application of the method consists of using this technology to detoxify animals that have been exposed to poisons with basic, weak acid or hydrophobic charge groups within their molecular structures.

Effect of surfactants, gastric emptying, and dosage form on supersaturation of dipyridamole in an in vitro model simulating the stomach and duodenum.

PubMed

Mitra, A; Fadda, H M

2014-08-04

The purpose of this study was to investigate the influence of gastric emptying patterns, surfactants, and dosage form on the supersaturation of a poorly soluble weakly basic drug, dipyridamole, using an in vitro model mimicking the dynamic environment of the upper gastrointestinal tract, and, furthermore, to evaluate the usefulness of this model in establishing correlations to in vivo bioavailability for drugs with solubility/dissolution limited absorption. A simulated stomach duodenum model comprising four compartments was used to assess supersaturation and precipitation kinetics as a function of time. It integrates physiologically relevant fluid volumes, fluid transfer rates, and pH changes of the upper GI tract. Monoexponential gastric emptying patterns simulating the fasted state were compared to linear gastric emptying patterns simulating the fed state. The effect of different surfactants commonly used in oral preparations, specifically, sodium lauryl sulfate (SLS), poloxamer-188, and polysorbate-80, on dipyridamole supersaturation was investigated while maintaining surface tension of the simulated gastric fluids at physiological levels and without obtaining artificial micellar solubilization of the drug. The supersaturation behavior of different dose strengths of dipyridamole was explored. Significant levels of dipyridamole supersaturation were observed in the duodenal compartment under all the different in vivo relevant conditions explored. Dipyridamole supersaturation ratios of up to 11-fold have been observed, and supersaturation has been maintained for up to 120 min. Lower duodenal concentrations of dipyridamole were observed under linear gastric emptying patterns compared to mononexponential gastric emptying. The mean duodenal area under concentration-time curves (AUC60min) for the dipyridamole concentration profile in the duodenal compartment is significantly different for all the surfactants explored (P < 0.05). Our investigations with the different surfactants and comparison of dosage form (solution versus suspension) on the precipitation of dipyridamole revealed that crystal growth, rather than nucleation, is the rate-limiting step for the precipitation of dipyridamole. A linear dose-response relationship was found for the mean in vitro duodenal area under concentration-time curves (AUC∞) in the dose range of 25 mg to 100 mg (R(2) = 0.886). This is in agreement with the pharmacokinetic data of dipyridamole reported in the literature. The simulated stomach duodenum model can provide a reliable and discriminative screening tool for exploring the effect of different physiological variables or formulations on the supersaturation/precipitation kinetics of weakly basic drugs with solubility limited absorption. The amount of drug in solution in the duodenal compartment of the SSD correlates to bioavailability for the weakly basic drug, dipyridamole, which has solubility limited absorption and undergoes supersaturation/precipitation.

Time-course measurements of drug concentrations in hair and toenails after single administrations of pharmaceutical products.

PubMed

Kuwayama, Kenji; Miyaguchi, Hajime; Iwata, Yuko T; Kanamori, Tatsuyuki; Tsujikawa, Kenji; Yamamuro, Tadashi; Segawa, Hiroki; Inoue, Hiroyuki

2017-04-01

Hair and nails are often used to prove long-term intake of drugs in forensic drug testing. The aim of this study was to evaluate the effectiveness of drug testing using hair and nails and the feasibility of determining when drugs were ingested by measuring the time-courses of drug concentrations in hair and toenails after single administrations of various drugs. Healthy subjects ingested four pharmaceutical products containing eight active ingredients in single doses. Hair and toenails were collected at predetermined intervals, and drug concentrations in hair and nails were measured for 12 months. The administered drugs and their main metabolites were extracted using micropulverized extraction with a stainless steel bullet and were analyzed using liquid chromatography/tandem mass spectrometry. Acidic compounds such as ibuprofen and its metabolites were not detected in both specimens. Acetaminophen, a weakly acidic compound, was detected in nails more frequently than in hair. The maximum concentration of allyl isopropyl acetylurea, a neutral compound, in nails was significantly higher than in hair. Nails are an effective specimen to detect neutral and weakly acidic compounds. For fexofenadine, a zwitterionic compound, and for most basic compounds, the maximum concentrations in hair segments tended to be higher than those in nails. The hair segments showing the maximum concentrations varied between drugs, samples, and subjects. Drug concentrations in hair segments greatly depended on the selection of the hair. Careful interpretation of analytical results is required to predict the time of drug intake. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Coformer selection based on degradation pathway of drugs: a case study of adefovir dipivoxil-saccharin and adefovir dipivoxil-nicotinamide cocrystals.

PubMed

Gao, Yuan; Gao, Jing; Liu, Ziling; Kan, Hongliang; Zu, Hui; Sun, Wanjin; Zhang, Jianjun; Qian, Shuai

2012-11-15

Adefovir dipivoxil (AD) is a bis(pivaloyloxymethyl) prodrug of adefovir with chemical stability problem. It undergoes two degradation pathways including hydrolysis and dimerization during storage. Pharmaceutical cocrystallization exhibits a promising approach to enhance aqueous solubility as well as physicochemical stability. In this study we attempted to prepare and investigate the physiochemical properties of AD cocrystals, which were formed with two coformers having different acidity and alkalinity (weakly acidic saccharin (SAC) and weakly basic nicotinamide (NCT)). The presence of different coformer molecules along with AD resulted in altered physicochemical properties. AD-SAC cocrystal showed great improvement in solubility and chemical stability, while AD-NCT did not. Several potential factors giving rise to different solid-state properties were summarized. Different coformers resulted in different cocrystal formation, packing style and hydrogen bond formation. This study could provide the coformer selection strategy based on degradation pathways for some unstable drugs in pharmaceutical cocrystal design. Copyright © 2012 Elsevier B.V. All rights reserved.

Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications.

PubMed

Logan, Randall; Funk, Ryan S; Axcell, Erick; Krise, Jeffrey P

2012-08-01

Many commercially available, weakly basic drugs have been shown to be lysosomotropic, meaning they are subject to extensive sequestration in lysosomes through an ion trapping-type mechanism. The extent of lysosomal trapping of a drug is an important therapeutic consideration because it can influence both activity and pharmacokinetic disposition. The administration of certain drugs can alter lysosomes such that their accumulation capacity for co-administered and/or secondarily administered drugs is altered. In this review the authors explore what is known regarding the mechanistic basis for drug-drug interactions involving lysosomes. Specifically, the authors address the influence of drugs on lysosomal pH, volume and lipid processing. Many drugs are known to extensively accumulate in lysosomes and significantly alter their structure and function; however, the therapeutic and toxicological implications of this remain controversial. The authors propose that drug-drug interactions involving lysosomes represent an important potential source of variability in drug activity and pharmacokinetics. Most evaluations of drug-drug interactions involving lysosomes have been performed in cultured cells and isolated tissues. More comprehensive in vivo evaluations are needed to fully explore the impact of this drug-drug interaction pathway on therapeutic outcomes.

Method of detoxifying animal suffering from overdose

DOEpatents

Mehlhorn, Rolf J.

1997-01-01

A method for accumulating drugs or other chemicals within synthetic, lipid-like vesicles by means of a pH gradient imposed on the vesicles just prior to use is described. The method is suited for accumulating molecules with basic or acid moieties which are permeable to the vesicles membranes in their uncharged form and for molecules that contain charge moieties that are hydrophobic ions and can therefore cross the vesicle membranes in their charged form. The method is advantageous over prior art methods for encapsulating biologically active materials within vesicles in that it achieves very high degrees of loading with simple procedures that are economical and require little technical expertise, furthermore kits which can be stored for prolonged periods prior to use without impairment of the capacity to achieve drug accumulation are described. A related application of the method consists of using this technology to detoxify animals that have been exposed to poisons with basic, weak acid or hydrophobic charge groups within their molecular structure.

Acid-Base Interactions of Polystyrene Sulfonic Acid in Amorphous Solid Dispersions Using a Combined UV/FTIR/XPS/ssNMR Study.

PubMed

Song, Yang; Zemlyanov, Dmitry; Chen, Xin; Nie, Haichen; Su, Ziyang; Fang, Ke; Yang, Xinghao; Smith, Daniel; Byrn, Stephen; Lubach, Joseph W

2016-02-01

This study investigates the potential drug-excipient interactions of polystyrene sulfonic acid (PSSA) and two weakly basic anticancer drugs, lapatinib (LB) and gefitinib (GB), in amorphous solid dispersions. Based on the strong acidity of the sulfonic acid functional group, PSSA was hypothesized to exhibit specific intermolecular acid-base interactions with both model basic drugs. Ultraviolet (UV) spectroscopy identified red shifts, which correlated well with the color change observed in lapatinib-PSSA solutions. Fourier transform infrared (FTIR) spectra suggest the protonation of the quinazoline nitrogen atom in both model compounds, which agrees well with data from the crystalline ditosylate salt of lapatinib. X-ray photoelectron spectroscopy (XPS) detected increases in binding energy of the basic nitrogen atoms in both lapatinib and gefitinib, strongly indicating protonation of these nitrogen atoms. (15)N solid-state NMR spectroscopy provided direct spectroscopic evidence for protonation of the quinazoline nitrogen atoms in both LB and GB, as well as the secondary amine nitrogen atom in LB and the tertiary amine nitrogen atom in GB. The observed chemical shifts in the LB-PSSA (15)N spectrum also agree very well with the lapatinib ditosylate salt where proton transfer is known. Additionally, the dissolution and physical stability behaviors of both amorphous solid dispersions were examined. PSSA was found to significantly improve the dissolution of LB and GB and effectively inhibit the crystallization of LB and GB under accelerated storage conditions due to the beneficial strong intermolecular acid-base interaction between the sulfonic acid groups and basic nitrogen centers.

Absorption sites of orally administered drugs in the small intestine.

PubMed

Murakami, Teruo

2017-12-01

In pharmacotherapy, drugs are mostly taken orally to be absorbed systemically from the small intestine, and some drugs are known to have preferential absorption sites in the small intestine. It would therefore be valuable to know the absorption sites of orally administered drugs and the influencing factors. Areas covered:In this review, the author summarizes the reported absorption sites of orally administered drugs, as well as, influencing factors and experimental techniques. Information on the main absorption sites and influencing factors can help to develop ideal drug delivery systems and more effective pharmacotherapies. Expert opinion: Various factors including: the solubility, lipophilicity, luminal concentration, pKa value, transporter substrate specificity, transporter expression, luminal fluid pH, gastrointestinal transit time, and intestinal metabolism determine the site-dependent intestinal absorption. However, most of the dissolved fraction of orally administered drugs including substrates for ABC and SLC transporters, except for some weakly basic drugs with higher pKa values, are considered to be absorbed sequentially from the proximal small intestine. Securing the solubility and stability of drugs prior to reaching to the main absorption sites and appropriate delivery rates of drugs at absorption sites are important goals for achieving effective pharmacotherapy.

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

PubMed

Manga, Ramya D; Jha, Prateek K

2017-02-01

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

Binding affinity of pro-apoptotic BH3 peptides for the anti-apoptotic Mcl-1 and A1 proteins: Molecular dynamics simulations of Mcl-1 and A1 in complex with six different BH3 peptides.

PubMed

Modi, Vivek; Sankararamakrishnan, Ramasubbu

2017-05-01

The anti-apoptotic members of Bcl-2 family of proteins bind to their pro-apoptotic counterparts to induce or prevent cell death.Based on the distinct binding profiles for specific pro-apoptotic BH3 peptides, the anti-apoptotic Bcl-2 proteins can be divided into at least two subclasses. The subclass that includes Bcl-X L binds strongly to Bad BH3 peptide while it has weak binding affinity for the second subclass of Bcl-2 proteins such as Mcl-1 and A1. Anti-apoptotic Bcl-2 proteins are considered to be attractive drug targets for anti-cancer drugs. BH3-mimetic inhibitors such as ABT-737 have been shown to be specific to Bcl-X L subclass while Mcl-1 and A1 show resistance to the same drug. An efficacious inhibitor should target all the anti-apoptotic Bcl-2 proteins. Hence, development of inhibitors selective to Mcl-1 and A1 is of prime importance for targeted cancer therapeutics. The first step to achieve this goal is to understand the molecular basis of high binding affinities of specific pro-apoptotic BH3 peptides for Mcl-1 and A1. To understand the interactions between the BH3 peptides and Mcl-1/A1, we performed multi-nanosecond molecular dynamics (MD) simulations of six complex structures of Mcl-1 and A1. With the exception of Bad, all complex structures were experimentally determined. Bad complex structures were modeled. Our simulation studies identified specific pattern of polar interactions between Mcl-1/A1 and high-affinity binding BH3 peptides. The lack of such polar interactions in Bad peptide complex is attributed to specific basic residues present before and after the highly conserved Leu residue. The close approach of basic residues in Bad and Mcl-1/A1 is hypothesized to be the cause of weak binding affinity. To test this hypothesis, we generated in silico mutants of these basic residues in Bad peptide and Mcl-1/A1 proteins. MD simulations of the mutant systems established the pattern of stable polar interactions observed in high-affinity binding BH3 peptides. We have thus identified specific residue positions in Bad and Mcl-1/A1 responsible for the weak binding affinity. Results from these simulation studies will aid in the development of inhibitors specific to Mcl-1 and A1 proteins. Copyright © 2017 Elsevier Inc. All rights reserved.

Phase behavior and crystal structure of 3-(1-naphthyloxy)- and 3-(4-indolyloxy)-propane-1,2-diol, synthetic precursors of chiral drugs propranolol and pindolol

NASA Astrophysics Data System (ADS)

Bredikhin, Alexander A.; Gubaidullin, Aidar T.; Bredikhina, Zemfira A.; Fayzullin, Robert R.; Samigullina, Aida I.; Zakharychev, Dmitry V.

2013-08-01

Valuable precursors of popular chiral drugs propranolol and pindolol, 3-(1-naphthyloxy)-propane-1,2-diol 3 and 3-(4-indolyloxy)-propane-1,2-diol 4 were investigated by IR spectroscopy, DSC, and X-ray diffraction methods. Both compounds, crystallizing from enantiopure feed material, form "guaifenesin-like" crystal packing in which the classic H-bonded bilayers, framed in both sides by hydrophobic fragments of the molecules, acts as the basic crystal-forming motif. Diol 4 prone to spontaneous resolution and conserves its packing pattern crystallizing from racemate. Under the same conditions, diol 3 forms weakly stable solid racemic compound. Some reasons for such a behavior are identified and discussed.

Morbidity management and disability prevention for lymphatic filariasis in Sri Lanka: Current status and future prospects

PubMed Central

Premaratna, Ranjan; Gunaratna, Indeewarie. E.; de Silva, Nilanthi R.

2018-01-01

Background Sri Lanka was acknowledged to have eliminated lymphatic filariasis (LF) as a public health problem in 2016, largely due to its success in Mass Drug Administration (MDA) to interrupt disease transmission. Analysis of the Strengths, Weaknesses, Opportunities and Threats (SWOT) of the national Morbidity Management and Disability Prevention (MMDP) program, the other pillar of the LF control program, was carried out with the objective of evaluating it and providing recommendations to optimize the use of available resources. Methodology A situation analysis of the MMDP activities provided by the state health sector was carried out using published records, in-depth interviews with key informants of the Anti Filariasis Campaign, site-visits to filariasis clinics with informal discussions with clinic workforce and personal communications to identify strengths and weaknesses; and opportunities to overcome weaknesses and perceived threats to the program were explored. The principal strength of the MMDP program was the filariasis clinics operational in most endemic districts of Sri Lanka, providing free health care and health education to clinic attendees. The weaknesses identified were the low accessibility of clinics, incomplete coverage of the endemic region and lack of facilities for rehabilitation. The perceived threats were diversion of staff and resources for control of other vector-borne infections, under-utilization of clinics and non-compliance with recommended treatment. Enhanced high level commitment for MMDP, wider publicity and referral systems, integration of MMDP with other disease management services and collaboration with welfare organizations and research groups were identified as opportunities to overcome weaknesses and challenges. Conclusions The recommended basic package of MMDP was functional in most of the LF-endemic region. The highlighted weaknesses and challenges, unless addressed, may threaten program sustainability. The identified opportunities for improvement of the programme could ensure better attainment of the goal of the MMDP program, namely access to basic care for all affected by lymphatic filarial disease. PMID:29746479

Morbidity management and disability prevention for lymphatic filariasis in Sri Lanka: Current status and future prospects.

PubMed

Chandrasena, Nilmini; Premaratna, Ranjan; Gunaratna, Indeewarie E; de Silva, Nilanthi R

2018-05-01

Sri Lanka was acknowledged to have eliminated lymphatic filariasis (LF) as a public health problem in 2016, largely due to its success in Mass Drug Administration (MDA) to interrupt disease transmission. Analysis of the Strengths, Weaknesses, Opportunities and Threats (SWOT) of the national Morbidity Management and Disability Prevention (MMDP) program, the other pillar of the LF control program, was carried out with the objective of evaluating it and providing recommendations to optimize the use of available resources. A situation analysis of the MMDP activities provided by the state health sector was carried out using published records, in-depth interviews with key informants of the Anti Filariasis Campaign, site-visits to filariasis clinics with informal discussions with clinic workforce and personal communications to identify strengths and weaknesses; and opportunities to overcome weaknesses and perceived threats to the program were explored. The principal strength of the MMDP program was the filariasis clinics operational in most endemic districts of Sri Lanka, providing free health care and health education to clinic attendees. The weaknesses identified were the low accessibility of clinics, incomplete coverage of the endemic region and lack of facilities for rehabilitation. The perceived threats were diversion of staff and resources for control of other vector-borne infections, under-utilization of clinics and non-compliance with recommended treatment. Enhanced high level commitment for MMDP, wider publicity and referral systems, integration of MMDP with other disease management services and collaboration with welfare organizations and research groups were identified as opportunities to overcome weaknesses and challenges. The recommended basic package of MMDP was functional in most of the LF-endemic region. The highlighted weaknesses and challenges, unless addressed, may threaten program sustainability. The identified opportunities for improvement of the programme could ensure better attainment of the goal of the MMDP program, namely access to basic care for all affected by lymphatic filarial disease.

Development and validation of a general derivatization HPLC method for the trace analysis of acyl chlorides in lipophilic drug substances.

PubMed

Zheng, Xiangyuan; Luo, Lan; Zhou, Jie; Ruan, Xiaoling; Liu, Wenyuan; Zheng, Feng

2017-06-05

Acyl chlorides are important acylating agents in the synthesis of active pharmaceutical ingredients. Determining the residual acyl chlorides in drug substances is a challenge due to their high reactivity and the matrix interferences from drug substances and their related impurities. This paper describes a general derivatization HPLC method for the determination of aromatic and aliphatic acyl chlorides in lipophilic drug substances. Since most drug substances have weak absorptions in the visible range (above 380nm), the nitro-substituted anilines and nitro-substituted phenylhydrazines were selected as the derivatization reagents due to their weak basicity and red-shift of UV absorption spectra. The maximum wavelength and absorption intensity of nitro-substituted anilines decreased after derivatization with acyl chlorides, whereas the derivatization products of nitro-substituted phenylhydrazines showed the slight increases of maximum wavelength and absorbance intensity. Hence, 2-nitrophenylhydrazine was selected as the suitable derivatization reagent because the derivatives have the maximum UV wavelength absorbance at 395nm, which could largely minimize the matrix interferences. The optimization of the concentration of 2-nitrophenylhydrazine is important for the sensitivity and stability of derivatives. Other reaction conditions including reaction temperature, time and the influence of three competitive solvents (water, methanol and ethanol) on the reaction efficiency were also studied. After derivatization with 100μgmL -1 2-nitrophenylhydrazine at room temperature for 30min, the method was validated for high specificity and sensitivity with the detection limits in the range of 0.01-0.03μgmL -1 . The proposed method was applied as a generic method to determine the residual acyl chlorides in lipophilic drug substances. Copyright © 2017 Elsevier B.V. All rights reserved.

Quantitative Analysis of Therapeutic Drugs in Dried Blood Spot Samples by Paper Spray Mass Spectrometry: An Avenue to Therapeutic Drug Monitoring

NASA Astrophysics Data System (ADS)

Manicke, Nicholas Edward; Abu-Rabie, Paul; Spooner, Neil; Ouyang, Zheng; Cooks, R. Graham

2011-09-01

A method is presented for the direct quantitative analysis of therapeutic drugs from dried blood spot samples by mass spectrometry. The method, paper spray mass spectrometry, generates gas phase ions directly from the blood card paper used to store dried blood samples without the need for complex sample preparation and separation; the entire time for preparation and analysis of blood samples is around 30 s. Limits of detection were investigated for a chemically diverse set of some 15 therapeutic drugs; hydrophobic and weakly basic drugs, such as sunitinib, citalopram, and verapamil, were found to be routinely detectable at approximately 1 ng/mL. Samples were prepared by addition of the drug to whole blood. Drug concentrations were measured quantitatively over several orders of magnitude, with accuracies within 10% of the expected value and relative standard deviation (RSD) of around 10% by prespotting an internal standard solution onto the paper prior to application of the blood sample. We have demonstrated that paper spray mass spectrometry can be used to quantitatively measure drug concentrations over the entire therapeutic range for a wide variety of drugs. The high quality analytical data obtained indicate that the technique may be a viable option for therapeutic drug monitoring.

Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diaz, Dolores, E-mail: diaz.dolores@gene.com; Ford, Kevin A.; Hartley, Dylan P.

Several toxicities are clearly driven by free drug concentrations in plasma, such as toxicities related to on-target exaggerated pharmacology or off-target pharmacological activity associated with receptors, enzymes or ion channels. However, there are examples in which organ toxicities appear to correlate better with total drug concentrations in the target tissues, rather than with free drug concentrations in plasma. Here we present a case study in which a small molecule Met inhibitor, GEN-203, with significant liver and bone marrow toxicity in preclinical species was modified with the intention of increasing the safety margin. GEN-203 is a lipophilic weak base as demonstratedmore » by its physicochemical and structural properties: high LogD (distribution coefficient) (4.3) and high measured pKa (7.45) due to the basic amine (N-ethyl-3-fluoro-4-aminopiperidine). The physicochemical properties of GEN-203 were hypothesized to drive the high distribution of this compound to tissues as evidenced by a moderately-high volume of distribution (Vd > 3 l/kg) in mouse and subsequent toxicities of the compound. Specifically, the basicity of GEN-203 was decreased through addition of a second fluorine in the 3-position of the aminopiperidine to yield GEN-890 (N-ethyl-3,3-difluoro-4-aminopiperidine), which decreased the volume of distribution of the compound in mouse (Vd = 1.0 l/kg), decreased its tissue drug concentrations and led to decreased toxicity in mice. This strategy suggests that when toxicity is driven by tissue drug concentrations, optimization of the physicochemical parameters that drive tissue distribution can result in decreased drug concentrations in tissues, resulting in lower toxicity and improved safety margins. -- Highlights: ► Lower pKa for a small molecule: reduced tissue drug levels and toxicity. ► New analysis tools to assess electrostatic effects and ionization are presented. ► Chemical and PK drivers of toxicity can be leveraged to improve safety.« less

In Vitro Dissolution of Fluconazole and Dipyridamole in Gastrointestinal Simulator (GIS), Predicting in Vivo Dissolution and Drug-Drug Interaction Caused by Acid-Reducing Agents.

PubMed

Matsui, Kazuki; Tsume, Yasuhiro; Amidon, Gregory E; Amidon, Gordon L

2015-07-06

Weakly basic drugs typically exhibit pH-dependent solubility in the physiological pH range, displaying supersaturation or precipitation along the gastrointestinal tract. Additionally, their oral bioavailabilities may be affected by coadministration of acid-reducing agents that elevate gastric pH. The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, Gastrointestinal Simulator (GIS), in predicting in vivo dissolution of certain oral medications. In vitro dissolution studies of fluconazole, a BCS class I, and dipyridamole, a BCS class II weak bases (class IIb), were performed in the GIS as well as United States Pharmacopeia (USP) apparatus II and compared with the results of clinical drug-drug interaction (DDI) studies. In both USP apparatus II and GIS, fluconazole completely dissolved within 60 min regardless of pH, reflecting no DDI between fluconazole and acid-reducing agents in a clinical study. On the other hand, seven-fold and 15-fold higher concentrations of dipyridamole than saturation solubility were observed in the intestinal compartments in GIS with gastric pH 2.0. Precipitation of dipyridamole was also observed in the GIS, and the percentage of dipyridamole in solution was 45.2 ± 7.0%. In GIS with gastric pH 6.0, mimicking the coadministration of acid-reducing agents, the concentration of dipyridamole was equal to its saturation solubility, and the percentage of drug in solution was 9.3 ± 2.7%. These results are consistent with the clinical DDI study of dipyridamole with famotidine, which significantly reduced the Cmax and area under the curve. An In situ mouse infusion study combined with GIS revealed that high concentration of dipyridamole in the GIS enhanced oral drug absorption, which confirmed the supersaturation of dipyridamole. In conclusion, GIS was shown to be a useful apparatus to predict in vivo dissolution for BCS class IIb drugs.

Site specific solubility improvement using solid dispersions of HPMC-AS/HPC SSL--mixtures.

PubMed

Zecevic, Damir Elmar; Meier, Robin; Daniels, Rolf; Wagner, Karl-Gerhard

2014-07-01

Many upcoming drug candidates are pH-dependent poorly soluble weak bases in the pH range of the gastrointestinal tract. This often leads to a high in vivo variability and bioavailability issues. Aiming to overcome these limitations, the design of solid dispersions for site specific dissolution improvement or maintenance of a potent supersaturation over the entire gastro-intestinal pH-range, is proposed to assure a reliable drug therapy. Solid dispersions containing different ratios of Dipyridamole (DPD) or Griseofulvin (GRI) and the enteric polymer hydroxypropylmethylcellulose-acetate succinate (HPMC-AS) and the water soluble low-viscosity hydroxypropylcellulose (HPC-SSL) were prepared by hot melt extrusion (HME). The solid dispersions were evaluated for their solid state, dissolution characteristics applying a three pH-step dissolution method following an acidic to neutral pH transition and stability. The use of HPMC-AS in binary mixtures with DPD and GRI facilitated increased solubility and supersaturation at pH-controlled release of the preserved amorphous state of the dispersed drug, which even inverted the pH-dependent solubility profile of the weakly basic model drug (Dipyridamole). I.e. a potent site specific delivery system was created. With ternary solid dispersions of API, HPMC-AS and HPC-SSL, tailored release profiles with superior supersaturation over the applied pH-range could be obtained. At the same time, binary and ternary mixtures showed favorable stability properties at a temperature difference between glass transition temperature and the applied storage temperature of down to 16°C. Copyright © 2014 Elsevier B.V. All rights reserved.

Role of the Strength of Drug-Polymer Interactions on the Molecular Mobility and Crystallization Inhibition in Ketoconazole Solid Dispersions.

PubMed

Mistry, Pinal; Mohapatra, Sarat; Gopinath, Tata; Vogt, Frederick G; Suryanarayanan, Raj

2015-09-08

The effects of specific drug-polymer interactions (ionic or hydrogen-bonding) on the molecular mobility of model amorphous solid dispersions (ASDs) were investigated. ASDs of ketoconazole (KTZ), a weakly basic drug, with each of poly(acrylic acid) (PAA), poly(2-hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP) were prepared. Drug-polymer interactions in the ASDs were evaluated by infrared and solid-state NMR, the molecular mobility quantified by dielectric spectroscopy, and crystallization onset monitored by differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (VTXRD). KTZ likely exhibited ionic interactions with PAA, hydrogen-bonding with PHEMA, and weaker dipole-dipole interactions with PVP. On the basis of dielectric spectroscopy, the α-relaxation times of the ASDs followed the order: PAA > PHEMA > PVP. In addition, the presence of ionic interactions also translated to a dramatic and disproportionate decrease in mobility as a function of polymer concentration. On the basis of both DSC and VTXRD, an increase in strength of interaction translated to higher crystallization onset temperature and a decrease in extent of crystallization. Stronger drug-polymer interactions, by reducing the molecular mobility, can potentially delay the crystallization onset temperature as well as crystallization extent.

Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, by fathead minnows

EPA Science Inventory

Understanding the influence of pH on uptake and accumulation of ionizable pharmaceuticals by fish was recently identified as a major research need. In the present study, fathead minnows were exposed to diphenhydramine (DPH), a weakly basic pharmaceutical (pKa = 9.1). Fish were ...

A practical drug discovery project at the undergraduate level.

PubMed

Fray, M Jonathan; Macdonald, Simon J F; Baldwin, Ian R; Barton, Nick; Brown, Jack; Campbell, Ian B; Churcher, Ian; Coe, Diane M; Cooper, Anthony W J; Craven, Andrew P; Fisher, Gail; Inglis, Graham G A; Kelly, Henry A; Liddle, John; Maxwell, Aoife C; Patel, Vipulkumar K; Swanson, Stephen; Wellaway, Natalie

2013-12-01

In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively. Copyright © 2013 Elsevier Ltd. All rights reserved.

Models for financing the regulation of pharmaceutical promotion.

PubMed

Lexchin, Joel

2012-07-11

Pharmaceutical companies spend huge sums promoting their products whereas regulation of promotional activities is typically underfinanced. Any option for financing the monitoring and regulation of promotion should adhere to three basic principles: stability, predictability and lack of (perverse) ties between the level of financing and performance. This paper explores the strengths and weaknesses of six different models. All these six models considered here have positive and negative features and none may necessarily be ideal in any particular country. Different countries may choose to utilize a combination of two or more of these models in order to raise sufficient revenue. Financing of regulation of drug promotion should more than pay for itself through the prevention of unnecessary drug costs and the avoidance of adverse health effects due to inappropriate prescribing. However, it involves an initial outlay of money that is currently not being spent and many national governments, in both rich and poor countries, are unwilling to incur extra costs.

Three Years Evaluation of Drug Shortages from Educational Pharmacies in Tehran

PubMed Central

Gholami, Kheirollah; Kamalinia, Golnaz; Ahmadian Attari, Mohammad Mahdi; Salamzadeh, Jamshid

2012-01-01

The effectiveness of any drug supply systems in providing a trustworthy supply of essential drugs is a critical issue. To evaluate this effectiveness, it is necessary to watch over the status of the essential medicines in any country impartially and continuously. Some countries and also the World Health Organization (WHO) have codified a list of minimum medicines needed for a basic health care system and published them in assortments as a list of essential medicines. The aim of this study was to give an evaluation of the shortages status in Iran and identify the strengths and weaknesses of policies made in Ministry of Health during the years 2005 to 2008 in providing the essential drugs based on the WHO list of essential medicines. The reports used in this retrospective study were collected from the central purchasing unit of one of the main chain drugstores in the country (13-Aban Pharmacy) every 2 to 3 weeks. In these reports, a drug is added to the list of shortages when the requested drug is not delivered. The reports were studied and the results were analyzed based on the WHO list of essential medicines and the national drug list of Iran. The shortages always included 20 to 40 medicines from the list of essential drugs compiled by WHO. Based on this finding, the Ministry of Health and particularly Food and Drug Organization can compile a National List of Essential Medicines and try to always supply them and prevent their shortage. PMID:24250480

Diazotisation of Weakly Basic Aromatic and Heterocyclic Amines in Strongly Acid Media

NASA Astrophysics Data System (ADS)

Godovikova, Tamara I.; Rakitin, Oleg A.; Khmel'nitskii, Lenor I.

1983-05-01

The review is devoted to the diazotisation of weakly basic aromatic amines. The methods of synthesis of diazonium salts based on these amines by non-traditional methods are examined. Data on the mechanism of the diazotisation reaction in strongly acid media are surveyed. Reactions of diazonium salts leading to the synthesis of new compounds are presented. The bibliography includes 75 references.

In Vivo Predictive Dissolution: Comparing the Effect of Bicarbonate and Phosphate Buffer on the Dissolution of Weak Acids and Weak Bases.

PubMed

Krieg, Brian J; Taghavi, Seyed Mohammad; Amidon, Gordon L; Amidon, Gregory E

2015-09-01

Bicarbonate is the main buffer in the small intestine and it is well known that buffer properties such as pKa can affect the dissolution rate of ionizable drugs. However, bicarbonate buffer is complicated to work with experimentally. Finding a suitable substitute for bicarbonate buffer may provide a way to perform more physiologically relevant dissolution tests. The dissolution of weak acid and weak base drugs was conducted in bicarbonate and phosphate buffer using rotating disk dissolution methodology. Experimental results were compared with the predicted results using the film model approach of (Mooney K, Mintun M, Himmelstein K, Stella V. 1981. J Pharm Sci 70(1):22-32) based on equilibrium assumptions as well as a model accounting for the slow hydration reaction, CO2 + H2 O → H2 CO3 . Assuming carbonic acid is irreversible in the dehydration direction: CO2 + H2 O ← H2 CO3 , the transport analysis can accurately predict rotating disk dissolution of weak acid and weak base drugs in bicarbonate buffer. The predictions show that matching the dissolution of weak acid and weak base drugs in phosphate and bicarbonate buffer is possible. The phosphate buffer concentration necessary to match physiologically relevant bicarbonate buffer [e.g., 10.5 mM (HCO3 (-) ), pH = 6.5] is typically in the range of 1-25 mM and is very dependent upon drug solubility and pKa . © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

PubMed Central

Trapp, Stefan; Pechmann, Stefanie; Friedl, Astrid; Reichel, Martin; Mühle, Christiane; Terfloth, Lothar; Groemer, Teja W.; Spitzer, Gudrun M.; Liedl, Klaus R.; Gulbins, Erich; Tripal, Philipp

2011-01-01

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans. PMID:21909365

pH- and ion-sensitive polymers for drug delivery

PubMed Central

Yoshida, Takayuki; Lai, Tsz Chung; Kwon, Glen S; Sako, Kazuhiro

2013-01-01

Introduction Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body. Areas covered Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations. Expert opinion Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients. PMID:23930949

Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, in fathead minnows

EPA Science Inventory

Fathead minnows were exposed to diphenhydramine (DPH), a weakly basic pharmaceutical (pKa = 9.1), to examine pH effects on uptake and accumulation. Fish were exposed to 10 ìg/L DPH in water for up to 96 h at three nominal pH levels: 6.7, 7.7, and 8.7. In each case, an appa...

Endangered Children and Environmental Standards.

ERIC Educational Resources Information Center

Barry, Frank; Gunn, Hazel Dayton

1996-01-01

Community-based prevention-oriented approaches that provide basic supports to families are needed to address rising rates of violence, child abuse, and other socially disruptive behavior. Weak families, weak neighborhoods, and weak economies are mutually reinforcing and lead to negative behaviors by youth and others. In proposing a community…

Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria.

PubMed

Yago, Marc R; Frymoyer, Adam R; Smelick, Gillian S; Frassetto, Lynda A; Budha, Nageshwar R; Dresser, Mark J; Ware, Joseph A; Benet, Leslie Z

2013-11-04

Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric reacidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 min, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 h. Betaine HCl significantly lowered gastric pH by 4.5 (± 0.5) units from 5.2 (± 0.5) to 0.6 (± 0.2) (P < 0.001) during the 30 min interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (± 4.3) min. The reacidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (± 33) and 77 (± 30) min, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions.

Gastric Re-acidification with Betaine HCl in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria

PubMed Central

Yago, Marc Anthony R.; Frymoyer, Adam R.; Smelick, Gillian S.; Frassetto, Lynda A.; Budha, Nageshwar R.; Dresser, Mark J.; Ware, Joseph A.; Benet, Leslie Z.

2013-01-01

Previous studies have demonstrated that increased gastric pH from the use of acid-reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH-dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric re-acidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically-induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 minutes, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 hours. Betaine HCl significantly lowered gastric pH by 4.5 (±0.5) units from 5.2 (±0.5) to 0.6 (±0.2) (P <0.001) during the 30 minute interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (±4.3) minutes. The re-acidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (±33) and 77 (±30) minutes, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically-induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH-dependent solubility when administered under hypochlorhydric conditions. PMID:23980906

SWOT analysis of Banff: strengths, weaknesses, opportunities and threats of the international Banff consensus process and classification system for renal allograft pathology.

PubMed

Mengel, M; Sis, B; Halloran, P F

2007-10-01

The Banff process defined the diagnostic histologic lesions for renal allograft rejection and created a standardized classification system where none had existed. By correcting this deficit the process had universal impact on clinical practice and clinical and basic research. All trials of new drugs since the early 1990s benefited, because the Banff classification of lesions permitted the end point of biopsy-proven rejection. The Banff process has strengths, weaknesses, opportunities and threats (SWOT). The strength is its self-organizing group structure to create consensus. Consensus does not mean correctness: defining consensus is essential if a widely held view is to be proved wrong. The weaknesses of the Banff process are the absence of an independent external standard to test the classification; and its almost exclusive reliance on histopathology, which has inherent limitations in intra- and interobserver reproducibility, particularly at the interface between borderline and rejection, is exactly where clinicians demand precision. The opportunity lies in the new technology such as transcriptomics, which can form an external standard and can be incorporated into a new classification combining the elegance of histopathology and the objectivity of transcriptomics. The threat is the degree to which the renal transplant community will participate in and support this process.

Some Viable Techniques for Assessing and Counselling Cognitive Processing Weakness

ERIC Educational Resources Information Center

Haruna, Abubakar Sadiq

2016-01-01

Cognitive Processing weakness (CPW) is a psychological problem that impedes students' ability to learn effectively in a normal school setting. Such weakness may include; auditory, visual, conceptual, sequential, speed and attention processing. This paper therefore examines the basic assessment or diagnostic approaches such as Diagnosis by…

Models for financing the regulation of pharmaceutical promotion

PubMed Central

2012-01-01

Pharmaceutical companies spend huge sums promoting their products whereas regulation of promotional activities is typically underfinanced. Any option for financing the monitoring and regulation of promotion should adhere to three basic principles: stability, predictability and lack of (perverse) ties between the level of financing and performance. This paper explores the strengths and weaknesses of six different models. All these six models considered here have positive and negative features and none may necessarily be ideal in any particular country. Different countries may choose to utilize a combination of two or more of these models in order to raise sufficient revenue. Financing of regulation of drug promotion should more than pay for itself through the prevention of unnecessary drug costs and the avoidance of adverse health effects due to inappropriate prescribing. However, it involves an initial outlay of money that is currently not being spent and many national governments, in both rich and poor countries, are unwilling to incur extra costs. PMID:22784944

Pathology consultation on urine compliance testing and drug abuse screening.

PubMed

Ward, Michael B; Hackenmueller, Sarah A; Strathmann, Frederick G

2014-11-01

Compliance testing in pain management requires a distinct approach compared with classic clinical toxicology testing. Differences in the patient populations and clinical expectations require modifications to established reporting cutoffs, assay performance expectations, and critical review of how best to apply the available testing methods. Although other approaches to testing are emerging, immunoassay screening followed by mass spectrometry confirmation remains the most common testing workflow for pain management compliance and drug abuse testing. A case-based approach was used to illustrate the complexities inherent to and uniqueness of pain management compliance testing for both clinicians and laboratories. A basic understanding of the inherent strengths and weaknesses of immunoassays and mass spectrometry provides the clinician a better understanding of how best to approach pain management compliance testing. Pain management compliance testing is a textbook example of an emerging field requiring open communication between physician and performing laboratory to fully optimize patient care. Copyright© by the American Society for Clinical Pathology.

Ion-Pairing Contribution to the Liposomal Transport of Topotecan as Revealed by Mechanistic Modeling.

PubMed

Fugit, Kyle D; Anderson, Bradley D

2017-04-01

Actively loaded liposomal formulations of anticancer agents have been widely explored due to their high drug encapsulation efficiencies and prolonged drug retention. Mathematical models to predict and optimize drug loading and release kinetics from these nanoparticle formulations would be useful in their development and may allow researchers to tune release profiles. Such models must account for the driving forces as influenced by the physicochemical properties of the drug and the microenvironment, and the liposomal barrier properties. This study employed mechanistic modeling to describe the active liposomal loading and release kinetics of the anticancer agent topotecan (TPT). The model incorporates ammonia transport resulting in generation of a pH gradient, TPT dimerization, TPT lactone ring-opening and -closing interconversion kinetics, chloride transport, and transport of TPT-chloride ion-pairs to describe the active loading and release kinetics of TPT in the presence of varying chloride concentrations. Model-based predictions of the kinetics of active loading at varying loading concentrations of TPT and release under dynamic dialysis conditions were in reasonable agreement with experiments. These findings identify key attributes to consider in optimizing and predicting loading and release of liposomal TPT that may also be applicable to liposomal formulations of other weakly basic pharmaceuticals. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Gauge Bosons--The Ties That Bind.

ERIC Educational Resources Information Center

Hill, Christopher T.

1982-01-01

Discusses four basic forces/interactions in nature (strong force, weak force, electromagnetic force and gravity), associated with elementary particles. Focuses on "gauge bosons" (for example, photons), thought to account for strong, weak, and electromagnetic forces. (Author/JN)

Weakly Coretractable Modules

NASA Astrophysics Data System (ADS)

Hadi, Inaam M. A.; Al-aeashi, Shukur N.

2018-05-01

If R is a ring with identity and M is a unitary right R-module. Here we introduce the class of weakly coretractable module. Some basic properties are investigated and some relationships between these modules and other related one are introduced.

Psychotropics and weak opioid analgesics in plasma samples of older hip fracture patients - detection frequencies and consistency with drug records.

PubMed

Waade, Ragnhild Birkeland; Molden, Espen; Martinsen, Mette Irene; Hermann, Monica; Ranhoff, Anette Hylen

2017-07-01

To determine use of psychotropic drugs and weak opioids in hip fracture patients by analysing plasma samples at admission, and compare detected drug frequencies with prescription registry data and drug records. Plasma from 250 hip fracture patients aged ≥65 years sampled at hospital admission were analysed by ultra-performance liquid chromatography-tandem mass spectrometry methods for detection of psychotropic drugs and weak opioid analgesics (alcohol also determined). Odds ratios for drugs detected in plasma of hip fracture patients vs. prescription frequencies of the same drugs in an age-, time- and region-matched reference population were calculated. Moreover, recorded and measured drugs were compared. Psychotropic drugs and/or weak opioid analgesics were detected in 158 (63%) of the patients (median age 84 years; 76% females), while alcohol was found in 19 patients (7.6%). The occurrence of diazepam (odds ratio 1.6; 95% confidence interval 1.1-2.4), nitrazepam (2.3; 1.3-4.1), selective serotonin reuptake inhibitors (1.9; 1.3-2.9) and mirtazapine (2.3; 1.2-4.3) was significantly higher in plasma samples of hip fracture patients than in prescription data from the reference population. Poor consistency between recorded and measured drugs was disclosed for z-hypnotics and benzodiazepines; e.g. diazepam was detected in 29 (11.6%), but only recorded in six (2.4%) of the patients. Plasma analysis shows that use of antidepressants and benzodiazepines in hip fracture patients is significantly more frequent than respective prescription frequencies in the general elderly population. Moreover, consistency between recorded and actual use of psychotropic fall-risk drugs is poor at hospital admission of hip fracture patients. © 2017 The British Pharmacological Society.

Differences in medication knowledge and risk of errors between graduating nursing students and working registered nurses: comparative study.

PubMed

Simonsen, Bjoerg O; Daehlin, Gro K; Johansson, Inger; Farup, Per G

2014-11-21

Nurses experience insufficient medication knowledge; particularly in drug dose calculations, but also in drug management and pharmacology. The weak knowledge could be a result of deficiencies in the basic nursing education, or lack of continuing maintenance training during working years. The aim of this study was to compare the medication knowledge, certainty and risk of error between graduating bachelor students in nursing and experienced registered nurses. Bachelor students in closing term and registered nurses with at least one year job experience underwent a multiple choice test in pharmacology, drug management and drug dose calculations: 3x14 questions with 3-4 alternative answers (score 0-42). Certainty of each answer was recorded with score 0-3, 0-1 indicating need for assistance. Risk of error was scored 1-3, where 3 expressed high risk: being certain that a wrong answer was correct. The results are presented as mean and (SD). Participants were 243 graduating students (including 29 men), aged 28.2 (7.6) years, and 203 registered nurses (including 16 men), aged 42.0 (9.3) years and with a working experience of 12.4 years (9.2). The knowledge among the nurses was found to be superior to that of the students: 68.9%(8.0) and 61.5%(7.8) correct answers, respectively, (p < 0.001). The difference was largest in drug management and dose calculations. The improvement occurred during the first working year. The nurses expressed higher degree of certainty and the risk of error was lower, both overall and for each topic (p < 0.01). Low risk of error was associated with high knowledge and high sense of coping (p < 0.001). The medication knowledge among experienced nurses was superior to bachelor students in nursing, but nevertheless insufficient. As much as 25% of the answers to the drug management questions would lead to high risk of error. More emphasis should be put into the basic nursing education and in the introduction to medication procedures in clinical practice to improve the nurses' medication knowledge and reduce the risk of error.

Teaching Basic Algebra Courses at the College Level

ERIC Educational Resources Information Center

Mallenby, Michel L.; Mallenby, Douglas W.

2004-01-01

Three dysfunctional behaviors of basic algebra students are described: Silence as Camouflage, Wing and a Prayer, and Ignorance is OK. These behavior patterns are explained, and beneficial teaching methods that address the weaknesses are presented.

Determination of the n-octanol/water partition coefficients of weakly ionizable basic compounds by reversed-phase high-performance liquid chromatography with neutral model compounds.

PubMed

Liang, Chao; Han, Shu-ying; Qiao, Jun-qin; Lian, Hong-zhen; Ge, Xin

2014-11-01

A strategy to utilize neutral model compounds for lipophilicity measurement of ionizable basic compounds by reversed-phase high-performance liquid chromatography is proposed in this paper. The applicability of the novel protocol was justified by theoretical derivation. Meanwhile, the linear relationships between logarithm of apparent n-octanol/water partition coefficients (logKow '') and logarithm of retention factors corresponding to the 100% aqueous fraction of mobile phase (logkw ) were established for a basic training set, a neutral training set and a mixed training set of these two. As proved in theory, the good linearity and external validation results indicated that the logKow ''-logkw relationships obtained from a neutral model training set were always reliable regardless of mobile phase pH. Afterwards, the above relationships were adopted to determine the logKow of harmaline, a weakly dissociable alkaloid. As far as we know, this is the first report on experimental logKow data for harmaline (logKow = 2.28 ± 0.08). Introducing neutral compounds into a basic model training set or using neutral model compounds alone is recommended to measure the lipophilicity of weakly ionizable basic compounds especially those with high hydrophobicity for the advantages of more suitable model compound choices and convenient mobile phase pH control. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Severe infection in critical emergency care].

PubMed

Matsuda, Naoyuki; Takatani, Yudai; Higashi, Tomoko; Inaba, Masato; Ejima, Tadashi

2016-02-01

In the emergency and critical care medicine, infection is easy to merge to various basic conditions and diseases. In the social structure aging in critical care, the immune weakness was revealed as the result of severe infection and septic shock in the reduced function of neutrophils and lymphocytes. In the life-saving emergency care, cardiovascular diseases, diabetes, chronic renal failure and lever dysfunction are often observed, and the underlying diseases have the foundation of biological invasion after a first inflammatory attack of surgery, trauma, burn, and systemic injury. It will be placed into a susceptible situation such as artificial respiratory management. In this review, we discussed severe infection in emergency and critical care. It is necessary to pay attention to the drug resistance bacterias in own critical care setting by trends.

Effect of formulation pH on transdermal penetration of antiemetics formulated in poloxamer lecithin organogel.

PubMed

Woodall, Rachel; Arnold, John J; McKay, Doug; Asbill, C Scott

2013-01-01

The purpose of this study was to assess the impact of altering formulation pH on the transdermal penetration of several commonly used antiemetic, weakly basic drugs incorporated into poloxamer lecithin organogel vehicle. Poloxamer lecithin organogel formulations containing promethazine hydrochloride (25 mg/mL), metoclopramide hydrochloride (10 mg/mL), and ondansetron hydrochloride (8 mg/mL) were examined for both drug release and transdermal penetration across porcine skin in modified Franz diffusion cells for a period of 24 hours. For the transdermal studies, each antiemetic drug was formulated at a pH above and below their acid dissociation constant (pKa) in an attempt to assure that the drug would be primarily in their respective ionized or non-ionized states. In addition, drug content in skin was assessed at the end of the 24-hour experiment. Drug content analysis was determined via high-performance liquid chromatography. As a percent of total drug release from the poloxamer lecithin organogel vehicle, promethazine hydrochloride demonstrated the most transdermal drug penetration after 24 hours (30.2% +/- 20.2%), followed by ondansetron hydrochloride (2.7% +/- 1.1%) and metoclopramide hydrochloride (1.8% +/- 1.6%). Subsequently, the pH of the Pluronic F-127 gel was adjusted in order to ensure that each antiemetic drug would be primarily in its unionized state. The transdermal permeation of each antiemetic drug primarily in its unionized state increased over that observed with the drug primarily in its ionized state after 24 hours (promethazine: 1.6-fold increase; metoclopramide: 1.3-fold increase; ondansetron: 1.8-fold increase). A similar trend was noted in the amount of each drug found in the skin after 24 hours (promethazine: 1.2-fold increase; metoclopramide: 2.4-fold increase; ondansetron: 3.0-fold increase). These results suggest that proper optimization of drug ionization state may be a useful strategy for compounding pharmacists to increase the efficacy of drugs intended for inclusion in transdermal formulations.

Adult Education Association of the U.S.A.; Adult Basic Education Study 1965-66.

ERIC Educational Resources Information Center

Firoza, Ahmed, Ed.

The adult basic education (ABE) programs currently conducted by non-governmental organizations in the United States, are reviewed in this document. Attention is focused on the significance of voluntary efforts in adult basic education programs; and strengths and weaknesses, gaps between needs and resources, and limiting factors are identified.…

Adaptive Response and Tolerance to Weak Acids in Saccharomyces cerevisiae: A Genome-Wide View

PubMed Central

Mira, Nuno P.; Teixeira, Miguel Cacho

2010-01-01

Abstract Weak acids are widely used as food preservatives (e.g., acetic, propionic, benzoic, and sorbic acids), herbicides (e.g., 2,4-dichlorophenoxyacetic acid), and as antimalarial (e.g., artesunic and artemisinic acids), anticancer (e.g., artesunic acid), and immunosuppressive (e.g., mycophenolic acid) drugs, among other possible applications. The understanding of the mechanisms underlying the adaptive response and resistance to these weak acids is a prerequisite to develop more effective strategies to control spoilage yeasts, and the emergence of resistant weeds, drug resistant parasites or cancer cells. Furthermore, the identification of toxicity mechanisms and resistance determinants to weak acid-based pharmaceuticals increases current knowledge on their cytotoxic effects and may lead to the identification of new drug targets. This review integrates current knowledge on the mechanisms of toxicity and tolerance to weak acid stress obtained in the model eukaryote Saccharomyces cerevisiae using genome-wide approaches and more detailed gene-by-gene analysis. The major features of the yeast response to weak acids in general, and the more specific responses and resistance mechanisms towards a specific weak acid or a group of weak acids, depending on the chemical nature of the side chain R group (R-COOH), are highlighted. The involvement of several transcriptional regulatory networks in the genomic response to different weak acids is discussed, focusing on the regulatory pathways controlled by the transcription factors Msn2p/Msn4p, War1p, Haa1p, Rim101p, and Pdr1p/Pdr3p, which are known to orchestrate weak acid stress response in yeast. The extrapolation of the knowledge gathered in yeast to other eukaryotes is also attempted. PMID:20955006

Lysosomes as mediators of drug resistance in cancer.

PubMed

Zhitomirsky, Benny; Assaraf, Yehuda G

2016-01-01

Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug resistance as well as novel modalities to overcome this chemoresistance. Copyright © 2015 Elsevier Ltd. All rights reserved.

Modulation of the partition coefficient between octanol and buffer at pH 7.4 and pKa to achieve the optimum balance of blood clearance and volume of distribution for a series of tetrahydropyran histamine type 3 receptor antagonists.

PubMed

Hay, Tanya; Jones, Rhys; Beaumont, Kevin; Kemp, Mark

2009-09-01

The relationship between rat pharmacokinetics and physicochemical parameters [the partition coefficient between octanol and buffer at pH 7.4 (log D((7.4))) and pK(a)] was studied for a series of tetrahydropyran compounds. Sixteen compounds ranging in log D((7.4)) 0.1 to 1.8 were administered intravenously to rats, and the pharmacokinetic parameters were determined from blood concentration time curves. Across the series, a weak correlation was observed between log D((7.4)) and blood clearance, suggesting that log D((7.4)) values less than 0.5 were required to prevent clearance at hepatic blood flow. In terms of the volume of distribution (V(d)), the compounds fell into three distinct subseries characterized by the number of basic centers and differences in ionization of each basic center at physiological pH. These were referred to as the monobasic, weak second base, and strong second base subseries. All the compounds exhibited V(d) greater than body water, as would be expected from their lipophilic and basic nature. For a given clog P, the strong second base subseries showed higher V(d) than the weak second base subseries, which in turn exhibited higher values than the monobasic subseries. In addition, for the weak second base subseries, V(d) could be tuned by modulating the pK(a) of the second basic center. This relationship was rationalized in respect to the interactions of the ionizable centers with phospholipid heads in the cell membrane and/or lysosomal trapping. Compounds in the weak second base subseries showed optimal V(d), and when combined with a log D((7.4)) of 0.1, driving to moderate blood clearance, one compound showed the optimal pharmacokinetic profile.

42 CFR 423.308 - Definitions and terminology.

Code of Federal Regulations, 2010 CFR

2010-10-01

... exclude any costs attributable to benefits beyond basic prescription drug coverage, but also to exclude... benefits beyond basic prescription drug coverage, but also to exclude any prescription drug coverage costs... assistance outside the Part D benefit, provided that documentation of such nominal cost-sharing has been...

The extracellular microenvironment explains variations in passive drug transport across different airway epithelial cell types.

PubMed

Min, Kyoung Ah; Talattof, Arjang; Tsume, Yasuhiro; Stringer, Kathleen A; Yu, Jing-Yu; Lim, Dong Hyun; Rosania, Gus R

2013-08-01

We sought to identify key variables in cellular architecture and physiology that might explain observed differences in the passive transport properties of small molecule drugs across different airway epithelial cell types. Propranolol (PR) was selected as a weakly basic, model compound to compare the transport properties of primary (NHBE) vs. tumor-derived (Calu-3) cells. Differentiated on Transwell™ inserts, the architecture of pure vs. mixed cell co-cultures was studied with confocal microscopy followed by quantitative morphometric analysis. Cellular pharmacokinetic modeling was used to identify parameters that differentially affect PR uptake and transport across these two cell types. Pure Calu-3 and NHBE cells possessed different structural and functional properties. Nevertheless, mixed Calu-3 and NHBE cell co-cultures differentiated as stable cell monolayers. After measuring the total mass of PR, the fractional areas covered by Calu-3 and NHBE cells allowed deconvoluting the transport properties of each cell type. Based on the apparent thickness of the unstirred, cell surface aqueous layer, local differences in the extracellular microenvironment explained the measured variations in passive PR uptake and permeation between Calu-3 and NHBE cells. Mixed cell co-cultures can be used to compare the local effects of the extracellular microenvironment on drug uptake and transport across two epithelial cell types.

The Extracellular Microenvironment Explains Variations in Passive Drug Transport across Different Airway Epithelial Cell Types

PubMed Central

Min, Kyoung Ah; Talattof, Arjang; Tsume, Yasuhiro; Stringer, Kathleen A.; Yu, Jing-yu; Lim, Dong Hyun; Rosania, Gus R.

2013-01-01

Purpose We sought to identify key variables in cellular architecture and physiology that might explain observed differences in the passive transport properties of small molecule drugs across different airway epithelial cell types. Methods Propranolol (PR) was selected as a weakly basic, model compound to compare the transport properties of primary (NHBE) vs. tumor-derived (Calu-3) cells. Differentiated on Transwell™ inserts, the architecture of pure vs. mixed cell co-cultures was studied with confocal microscopy followed by quantitative morphometric analysis. Cellular pharmacokinetic modeling was used to identify parameters that differentially affect PR uptake and transport across these two cell types. Results Pure Calu-3 and NHBE cells possessed different structural and functional properties. Nevertheless, mixed Calu-3 and NHBE cell co-cultures differentiated as stable cell monolayers. After measuring the total mass of PR, the fractional areas covered by Calu-3 and NHBE cells allowed deconvoluting the transport properties of each cell type. Based on the apparent thickness of the unstirred, cell surface aqueous layer, local differences in extracellular microenvironment explained the measured variations in passive PR uptake and permeation between Calu-3 and NHBE cells. Conclusion Mixed cell co-cultures can be used to compare the local effects of the extracellular microenvironment on drug uptake and transport across two epithelial cell types. PMID:23708857

Previniendo el Uso de Drogas entre Ninos y Adolescentes: Una Guia Basada en Investigaciones (Preventing Drug Use among Children and Adolescents: A Research-Based Guide).

ERIC Educational Resources Information Center

Sloboda, Zili; David, Susan L.

This question and answer guide provides an overview of the research on the origins and pathways of drug abuse, the basic principles derived from effective drug abuse prevention research, and the application of research results to the prevention of drug use among young people. The basic principles derived from drug abuse prevention research are…

Surface Warfare Officers Initial Training For Future Success

DTIC Science & Technology

2018-03-01

updating and creating learning modules and Surface Warfare Officer School (SWOS) staffing as well as weaknesses in the methodologies used for...and Surface Warfare Officer School (SWOS) staffing as well as weaknesses in the methodologies used for training. We conclude that the Basic Division... METHODOLOGY ....................................................................................9 1. Staff Interviews

The Utility of the Pattern of the Strengths and Weaknesses Approach

ERIC Educational Resources Information Center

Fiorello, Catherine A.; Flanagan, Dawn P.; Hale, James B.

2014-01-01

Unlike ability-achievement discrepancy and response-to-intervention approaches, the processing strengths and weaknesses (PSW) approach is the only empirically based approach that attempts to identify the pattern of deficit in the basic psychological processes that interferes with academic achievement for children with specific learning…

Pharmacokinetic Drug Interactions with Panax ginseng.

PubMed

Ramanathan, Meenakshi R; Penzak, Scott R

2017-08-01

Panax ginseng is widely used as an adaptogen throughout the world. The major active constituents of P. ginseng are ginsenosides. Most naturally occurring ginsenosides are deglycosylated by colonic bacteria to intestinal metabolites. Ginsenosides along with these metabolites are widely accepted as being responsible for the pharmacologic activity and drug interaction potential of ginseng. Numerous preclinical studies have assessed the influence of various ginseng components on cytochrome P450 (CYP), glucuronidation, and drug transport activity. Results from these investigations have been largely inconclusive due to the use of different ginseng products and variations in methodology between studies. Drug interaction studies in humans have been conflicting and have largely yielded negative results or results that suggest only a weak interaction. One study using a midazolam probe found weak CYP3A induction and another using a fexofenadine probe found weak P-gp inhibition. Despite several case reports indicating a drug interaction between warfarin and P. ginseng, pharmacokinetic studies involving these agents in combination have failed to find significant pharmacokinetic or pharmacodynamic interactions. To this end, drug interactions involving P. ginseng appear to be rare; however, close clinical monitoring is still suggested for patients taking warfarin or CYP3A or P-gp substrates with narrow therapeutic indices.

Electromembrane extraction using two separate cells: A new design for simultaneous extraction of acidic and basic compounds.

PubMed

Nojavan, Saeed; Asadi, Sakine

2016-02-01

Simultaneous extraction of acidic and basic analytes from a sample is seen to be a challenging task. In this work, a novel and efficient electromembrane extraction (EME) method based on two separate cells was applied to simultaneously extract and preconcentrate two acidic drugs (naproxen and ibuprofen) along with a basic drug (ketamine). Once both cells were filled with the sample solution, basic drug was extracted from one cell with the other cell used to extract acidic drugs. The employed supported liquid membranes for the extraction of acidic and basic drugs were 2-ethyl hexanol and 1-octanol, respectively. Under an applied potential of 250 V in the course of the extraction process, acidic, and basic drugs were extracted from a 3.0 mL aqueous sample solution into 25 μL acceptor solutions. The pH values of the donor and acceptor solutions in the cathodic cell were 5.0 and 1.5, respectively, the corresponding values in the anodic cell were, however, 8.0 and 12.5, respectively. The rates of recovery obtained within 20 min of extraction time at a stirring rate of 750 rpm ranged from 45 to 54%. With correlation coefficients ranging from 0.990 to 0.996, the proposed EME technique provided good linearity over a concentration range of 20-1000 ng/mL. The LOD for all drugs was found to be 6.7 ng/mL, while reproducibility ranged from 7 to 12% (n = 5). Finally, applying the proposed method to determine and quantify the drugs in urine and wastewater samples, satisfactory results were achieved. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cationic double-chained surfactant as pseudostationary phase in micellar electrokinetic capillary chromatography for drug separations.

PubMed

Li, Yanqing; Liu, Qian; Yao, Shouzhuo

2008-05-15

The cationic double-chained surfactant didodecyldimethylammonium bromide (DDAB) was used as pseudostationary phase (PSP) in micellar electrokinetic capillary chromatography (MEKC). Its performance on the three kinds of drugs, i.e., basic, acidic, and neutral drugs, was systematically investigated. Nicotine, cotinine, caffeine, lidocaine, and procaine were selected as the model basic drugs. Good baseline separation and high efficiency were obtained under the optimal separation condition that consisted of 50mM phosphate (pH 4.0) and 0.08 mM DDAB. Three basic phenylenediamine isomers can also be well separated with DDAB in buffer. In addition, DDAB can form cationic bilayer on the capillary wall, thus the wall adsorption of basic analytes was greatly suppressed. Compared with commonly used CTAB, the separation of basic drugs was significantly improved with a much lower amount of DDAB present in the buffer. The DDAB-involved MEKC also showed superiority to CTAB upon the separation of acidic drugs, amoxicillin and ampicillin. In the case of neutral compounds, a good separation of resorcinol, 1-naphthol and 2-naphthol was achieved with 0.1mM DDAB and 30% (v/v) acetonitrile (ACN) present in buffer. Hence, it was concluded that the double-chained cationic surfactant DDAB can be a good substitute for traditional single-chained surfactant CTAB in MEKC.

Effect of basic and acidic additives on the separation of some basic drug enantiomers on polysaccharide-based chiral columns with acetonitrile as mobile phase.

PubMed

Gogaladze, Khatuna; Chankvetadze, Lali; Tsintsadze, Maia; Farkas, Tivadar; Chankvetadze, Bezhan

2015-03-01

The separation of enantiomers of 16 basic drugs was studied using polysaccharide-based chiral selectors and acetonitrile as mobile phase with emphasis on the role of basic and acidic additives on the separation and elution order of enantiomers. Out of the studied chiral selectors, amylose phenylcarbamate-based ones more often showed a chiral recognition ability compared to cellulose phenylcarbamate derivatives. An interesting effect was observed with formic acid as additive on enantiomer resolution and enantiomer elution order for some basic drugs. Thus, for instance, the enantioseparation of several β-blockers (atenolol, sotalol, toliprolol) improved not only by the addition of a more conventional basic additive to the mobile phase, but also by the addition of an acidic additive. Moreover, an opposite elution order of enantiomers was observed depending on the nature of the additive (basic or acidic) in the mobile phase. © 2015 Wiley Periodicals, Inc.

An Integrated Visualization and Basic Molecular Modeling Laboratory for First-Year Undergraduate Medicinal Chemistry

ERIC Educational Resources Information Center

Hayes, Joseph M.

2014-01-01

A 3D model visualization and basic molecular modeling laboratory suitable for first-year undergraduates studying introductory medicinal chemistry is presented. The 2 h practical is embedded within a series of lectures on drug design, target-drug interactions, enzymes, receptors, nucleic acids, and basic pharmacokinetics. Serving as a teaching aid…

UPTAKE AND ELIMINATION OF IONIZABLE ORGANIC CHEMICALS AT FISH GILLS: PART I. MODEL FORMULATION, PARAMETERIZATION, AND BEHAVIOR

EPA Science Inventory

Effects of pH and alkalinity on uptake and elimination of ionizable organic chemicals at the gills of large rainbow trout were studied. Increased pH reduced uptake rates of weakly-acidic chlorinated phenols and increased that of weakly-basic 3,4-dichlorobenzylamine, indicating gr...

Basics of Sterile Compounding: Biopharmaceutics of Injectable Dosage Forms.

PubMed

Akers, Michael J

2017-01-01

Biopharmaceutics studies the relationship between the drug product and what happens after the product is administered. Since the majority of injectables are administered by the intravenous route, thus avoiding the need for drug absorption, not many articles are published compared to other routes of drug administration. However, other routes of administration for drug injection are becoming more frequent because of greater commercial availability of sustained- and controlled-release drug delivery systems. This article reviews basic principles of drug absorption, distribution, metabolism, and elimination of injectable drugs and certain physicochemical and physiological factors affecting injectable drug biopharmaceutics. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Weak affinity chromatography for evaluation of stereoisomers in early drug discovery.

PubMed

Duong-Thi, Minh-Dao; Bergström, Maria; Fex, Tomas; Svensson, Susanne; Ohlson, Sten; Isaksson, Roland

2013-07-01

In early drug discovery (e.g., in fragment screening), recognition of stereoisomeric structures is valuable and guides medicinal chemists to focus only on useful configurations. In this work, we concurrently screened mixtures of stereoisomers and estimated their affinities to a protein target (thrombin) using weak affinity chromatography-mass spectrometry (WAC-MS). Affinity determinations by WAC showed that minor changes in stereoisomeric configuration could have a major impact on affinity. The ability of WAC-MS to provide instant information about stereoselectivity and binding affinities directly from analyte mixtures is a great advantage in fragment library screening and drug lead development.

Pilot Study of Essential Drug Quality in Two Major Cities in India

PubMed Central

Bate, Roger; Tren, Richard; Mooney, Lorraine; Hess, Kimberly; Mitra, Barun; Debroy, Bibek; Attaran, Amir

2009-01-01

Background India is an increasingly influential player in the global pharmaceutical market. Key parts of the drug regulatory system are controlled by the states, each of which applies its own standards for enforcement, not always consistent with others. A pilot study was conducted in two major cities in India, Delhi and Chennai, to explore the question/hypothesis/extent of substandard and counterfeit drugs available in the market and to discuss how the Indian state and federal governments could improve drug regulation and more importantly regulatory enforcement to combat these drugs. Methodology/Principal Findings Random samples of antimalarial, antibiotic, and antimycobacterial drugs were collected from pharmacies in urban and peri-urban areas of Delhi and Chennai, India. Semi-quantitative thin-layer chromatography and disintegration testing were used to measure the concentration of active ingredients against internationally acceptable standards. 12% of all samples tested from Delhi failed either one or both tests, and were substandard. 5% of all samples tested from Chennai failed either one or both tests, and were substandard. Spatial heterogeneity between pharmacies was observed, with some having more or less substandard drugs (30% and 0% respectively), as was product heterogeneity, with some drugs being more or less frequently substandard (12% and 7% respectively). Conclusions/Significance In a study using basic field-deployable techniques of lesser sensitivity rather than the most advanced laboratory-based techniques, the prevalence of substandard drugs in Delhi and Chennai is confirmed to be roughly in accordance with the Indian government's current estimates. However, important spatial and product heterogeneity exists, which suggests that India's substandard drug problem is not ubiquitous, but driven by a subset of manufacturers and pharmacies which thrive in an inadequately regulated environment. It is likely that the drug regulatory system in India needs to be improved for domestic consumption, and because India is an increasingly important exporter of drugs for both developed and developing countries. Some poor countries with high burdens of disease have weak drug regulatory systems and import many HIV/AIDS, tuberculosis and malaria drugs from India. PMID:19547757

Patterns of Drug Use: The Role of Dichotomous Conceptualizations.

ERIC Educational Resources Information Center

Charvat, Jeffrey L.

The popular conception of illegal drug use as inevitably pushing users toward compulsive drug abuse, and the ideological stance that drug use is a moral weakness, are offered by many as justification for punitive drug control. Challenging this view are the research on "set and setting" as determinants of the consequences of drug use, and…

Evaluation of innovative stationary phase ligand chemistries and analytical conditions for the analysis of basic drugs by supercritical fluid chromatography.

PubMed

Desfontaine, Vincent; Veuthey, Jean-Luc; Guillarme, Davy

2016-03-18

Similar to reversed phase liquid chromatography, basic compounds can be highly challenging to analyze by supercritical fluid chromatography (SFC), as they tend to exhibit poor peak shape, especially those with high pKa values. In this study, three new stationary phase ligand chemistries available in sub -2 μm particle sizes, namely 2-picolylamine (2-PIC), 1-aminoanthracene (1-AA) and diethylamine (DEA), were tested in SFC conditions for the analysis of basic drugs. Due to the basic properties of these ligands, it is expected that the repulsive forces may improve peak shape of basic substances, similarly to the widely used 2-ethypyridine (2-EP) phase. However, among the 38 tested basic drugs, less of 10% displayed Gaussian peaks (asymmetry between 0.8 and 1.4) using pure CO2/methanol on these phases. The addition of 10mM ammonium formate as mobile phase additive, drastically improved peak shapes and increased this proportion to 67% on 2-PIC. Introducing the additive in the injection solvent rather than in the organic modifier, gave acceptable results for 2-PIC only, with 31% of Gaussian peaks with an average asymmetry of 1.89 for the 38 selected basic drugs. These columns were also compared to hybrid silica (BEH), DIOL and 2-EP stationary phases, commonly employed in SFC. These phases commonly exhibit alternative retention and selectivity. In the end, the two most interesting ligands used as complementary columns were 2-PIC and BEH, as they provided suitable peak shapes for the basic drugs and almost orthogonal selectivities. Copyright © 2016 Elsevier B.V. All rights reserved.

Propagation Characteristics Of Weakly Guiding Optical Fibers

NASA Technical Reports Server (NTRS)

Manshadi, Farzin

1992-01-01

Report discusses electromagnetic propagation characteristics of weakly guiding optical-fiber structures having complicated shapes with cross-sectional dimensions of order of wavelength. Coupling, power-dividing, and transition dielectric-waveguide structures analyzed. Basic data computed by scalar-wave, fast-Fourier-transform (SW-FFT) technique, based on numerical solution of scalar version of wave equation by forward-marching fast-Fourier-transform method.

Mind the Gap! A Journey towards Computational Toxicology.

PubMed

Mangiatordi, Giuseppe Felice; Alberga, Domenico; Altomare, Cosimo Damiano; Carotti, Angelo; Catto, Marco; Cellamare, Saverio; Gadaleta, Domenico; Lattanzi, Gianluca; Leonetti, Francesco; Pisani, Leonardo; Stefanachi, Angela; Trisciuzzi, Daniela; Nicolotti, Orazio

2016-09-01

Computational methods have advanced toxicology towards the development of target-specific models based on a clear cause-effect rationale. However, the predictive potential of these models presents strengths and weaknesses. On the good side, in silico models are valuable cheap alternatives to in vitro and in vivo experiments. On the other, the unconscious use of in silico methods can mislead end-users with elusive results. The focus of this review is on the basic scientific and regulatory recommendations in the derivation and application of computational models. Attention is paid to examine the interplay between computational toxicology and drug discovery and development. Avoiding the easy temptation of an overoptimistic future, we report our view on what can, or cannot, realistically be done. Indeed, studies of safety/toxicity represent a key element of chemical prioritization programs carried out by chemical industries, and primarily by pharmaceutical companies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Arginine-glycine-aspartic acid-polyethylene glycol-polyamidoamine dendrimer conjugate improves liver-cell aggregation and function in 3-D spheroid culture.

PubMed

Chen, Zhanfei; Lian, Fen; Wang, Xiaoqian; Chen, Yanling; Tang, Nanhong

The polyamidoamine (PAMAM) dendrimer, a type of macromolecule material, has been used in spheroidal cell culture and drug delivery in recent years. However, PAMAM is not involved in the study of hepatic cell-spheroid culture or its biological activity, particularly in detoxification function. Here, we constructed a PAMAM-dendrimer conjugate decorated by an integrin ligand: arginine-glycine-aspartic acid (RGD) peptide. Our studies demonstrate that RGD-polyethylene glycol (PEG)-PAMAM conjugates can promote singly floating hepatic cells to aggregate together in a sphere-like growth with a weak reactive oxygen species. Moreover, RGD-PEG-PAMAM conjugates can activate the AKT-MAPK pathway in hepatic cells to promote cell proliferation and improve basic function and ammonia metabolism. Together, our data support the hepatocyte sphere treated by RGD-PEG-PAMAM conjugates as a potential source of hepatic cells for a biological artificial liver system.

Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Protein-Protein Interaction as a Target for Next-Generation Anti-influenza Therapeutics.

PubMed

Massari, Serena; Goracci, Laura; Desantis, Jenny; Tabarrini, Oriana

2016-09-08

The limited therapeutic options against the influenza virus (flu) and increasing challenges in drug resistance make the search for next-generation agents imperative. In this context, heterotrimeric viral PA/PB1/PB2 RNA-dependent RNA polymerase is an attractive target for a challenging but strategic protein-protein interaction (PPI) inhibition approach. Since 2012, the inhibition of the polymerase PA-PB1 subunit interface has become an active field of research following the publication of PA-PB1 crystal structures. In this Perspective, we briefly discuss the validity of flu polymerase as a drug target and its inhibition through a PPI inhibition strategy, including a comprehensive analysis of available PA-PB1 structures. An overview of all of the reported PA-PB1 complex formation inhibitors is provided, and approaches used for identification of the inhibitors, the hit-to-lead studies, and the emerged structure-activity relationship are described. In addition to highlighting the strengths and weaknesses of all of the PA-PB1 heterodimerization inhibitors, we analyze their hypothesized binding modes and alignment with a pharmacophore model that we have developed.

The effect of pH, buffer capacity and ionic strength on quetiapine fumarate release from matrix tablets prepared using two different polymeric blends.

PubMed

Hamed, Rania; AlJanabi, Reem; Sunoqrot, Suhair; Abbas, Aiman

2017-08-01

The objective of this study was to investigate the effect of the different physiological parameters of the gastrointestinal (GI) fluid (pH, buffer capacity, and ionic strength) on the in vitro release of the weakly basic BCS class II drug quetiapine fumarate (QF) from two once-a-day matrix tablet formulations (F1 and F2) developed as potential generic equivalents to Seroquel ® XR. F1 tablets were prepared using blends of high and low viscosity grades of hydroxypropyl methylcellulose (HPMC K4M and K100LV, respectively), while F2 tablets were prepared from HPMC K4M and PEGylated glyceryl behenate (Compritol ® HD5 ATO). The two formulations attained release profiles of QF over 24 h similar to that of Seroquel ® XR using the dissolution medium published by the Food and Drug Administration (FDA). A series of solubility and in vitro dissolution studies was then carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH, buffer capacity and ionic strength range of the GIT. Solubility studies revealed that QF exhibits a typical weak base pH-dependent solubility profile and that the solubility of QF increases with increasing the buffer capacity and ionic strength of the media. The release profiles of QF from F1, F2 and Seroquel ® XR tablets were found to be influenced by the pH, buffer capacity and ionic strength of the dissolution media to varying degrees. Results highlight the importance of studying the physiological variables along the GIT in designing controlled release formulations for more predictive in vitro-in vivo correlations.

Basic Movement Activities. Perceptual Motor Development. Book 1.

ERIC Educational Resources Information Center

Capon, Jack J.

This textbook on basic movement activities for children in the primary grades is divided into two sections. The first section presents methods of evaluating the physical strengths and weaknesses of individual children. The seven tests outlined and illustrated provide the teacher with the means for assessing each child's abilities and potential for…

The Risks and Opportunities Associated with Weak Arithmatic Skills of Accounting Students

ERIC Educational Resources Information Center

Kerr, Stephen; Krull, George

2017-01-01

This paper explored the authors' concerns about students enrolled in their introductory accounting course. Anecdotal evidence suggested that students struggle with basic arithmetic concepts that underlie basic business transactions even though their math placement and ACT scores are high. A survey of 125 students in a first accounting course was…

The Use of Basic Writing Materials in ESL Writing Classes.

ERIC Educational Resources Information Center

England, Lizabeth

Similarities between the weaknesses found among English as a first language students and English as a second language (ESL) students suggest the need to use basic writing materials with English as a second language students. Prewriting materials should be chosen in an effort to teach students some criteria for analyzing, evaluating, and…

BASIC, Logo, and Pilot: A Comparison of Three Computer Languages.

ERIC Educational Resources Information Center

Maddux, Cleborne D.; Cummings, Rhoda E.

1985-01-01

Following a brief history of Logo, BASIC, and Pilot programing languages, common educational programing tasks (input from keyboard, evaluation of keyboard input, and computation) are presented in each language to illustrate how each can be used to perform the same tasks and to demonstrate each language's strengths and weaknesses. (MBR)

The physiological determinants of drug-induced lysosomal stress resistance

PubMed Central

Woldemichael, Tehetina; Rosania, Gus R.

2017-01-01

Many weakly basic, lipophilic drugs accumulate in lysosomes and exert complex, pleiotropic effects on organelle structure and function. Thus, modeling how perturbations of lysosomal physiology affect the maintenance of lysosomal ion homeostasis is necessary to elucidate the key factors which determine the toxicological effects of lysosomotropic agents, in a cell-type dependent manner. Accordingly, a physiologically-based mathematical modeling and simulation approach was used to explore the dynamic, multi-parameter phenomenon of lysosomal stress. With this approach, parameters that are either directly involved in lysosomal ion transportation or lysosomal morphology were transiently altered to investigate their downstream effects on lysosomal physiology reflected by the changes they induce in lysosomal pH, chloride, and membrane potential. In addition, combinations of parameters were simultaneously altered to assess which parameter was most critical for recovery of normal lysosomal physiology. Lastly, to explore the relationship between organelle morphology and induced stress, we investigated the effects of parameters controlling organelle geometry on the restoration of normal lysosomal physiology following a transient perturbation. Collectively, our results indicate a key, interdependent role of V-ATPase number and membrane proton permeability in lysosomal stress tolerance. This suggests that the cell-type dependent regulation of V-ATPase subunit expression and turnover, together with the proton permeability properties of the lysosomal membrane, is critical to understand the differential sensitivity or resistance of different cell types to the toxic effects of lysosomotropic drugs. PMID:29117253

Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture.

PubMed

Joshi, Hemant N; Tejwani, Ravindra W; Davidovich, Martha; Sahasrabudhe, Vaishali P; Jemal, Mohammed; Bathala, Mohinder S; Varia, Sailesh A; Serajuddin, Abu T M

2004-01-09

Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.1mg/ml at pH 1.5, < 1 microg/ml aqueous solubility between pH 3.5 and 5.5 at 24+/-1 degrees C, and no detectable solubility (< 0.02 microg/ml) at pH greater than 5.5. Two solid dispersion formulations of the drug, one in Gelucire 44/14 and another one in a mixture of polyethylene glycol 3350 (PEG 3350) with polysorbate 80, were prepared by dissolving the drug in the molten carrier (65 degrees C) and filling the melt in hard gelatin capsules. From the two solid dispersion formulations, the PEG 3350-polysorbate 80 was selected for further development. The oral bioavailability of this formulation in dogs was compared with that of a capsule containing micronized drug blended with lactose and microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate 80 and water. For intravenous administration, a solution in a mixture of propylene glycol, polysorbate 80 and water was used. Absolute oral bioavailability values from the capsule containing micronized drug, the capsule containing solid dispersion and the oral liquid were 1.7+/-1.0%, 35.8+/-5.2% and 59.6+/-21.4%, respectively. Thus, the solid dispersion provided a 21-fold increase in bioavailability of the drug as compared to the capsule containing micronized drug. A capsule formulation containing 25 mg of drug with a total fill weight of 600 mg was subsequently selected for further development. The selected solid dispersion formulation was physically and chemically stable under accelerated storage conditions for at least 6 months. It is hypothesized that polysorbate 80 ensures complete release of drug in a metastable finely dispersed state having a large surface area, which facilitates further solubilization by bile acids in the GI tract and the absorption into the enterocytes. Thus, the bioavailability of this poorly water-soluble drug was greatly enhanced by formulation as a solid dispersion in a surface-active carrier.

A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poulin, Patrick, E-mail: patrick-poulin@videotron.ca; Ekins, Sean; Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, MD 21201

A general toxicity of basic drugs is related to phospholipidosis in tissues. Therefore, it is essential to predict the tissue distribution of basic drugs to facilitate an initial estimate of that toxicity. The objective of the present study was to further assess the original prediction method that consisted of using the binding to red blood cells measured in vitro for the unbound drug (RBCu) as a surrogate for tissue distribution, by correlating it to unbound tissue:plasma partition coefficients (Kpu) of several tissues, and finally to predict volume of distribution at steady-state (V{sub ss}) in humans under in vivo conditions. Thismore » correlation method demonstrated inaccurate predictions of V{sub ss} for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V{sub ss} of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models.« less

Efficient in situ separation and production of L-lactic acid by Bacillus coagulans using weak basic anion-exchange resin.

PubMed

Zhang, Yitong; Qian, Zijun; Liu, Peng; Liu, Lei; Zheng, Zhaojuan; Ouyang, Jia

2018-02-01

To get rid of the dependence on lactic acid neutralizer, a simple and economical approach for efficient in situ separation and production of L-lactic acid was established by Bacillus coagulans using weak basic anion-exchange resin. During ten tested resins, the 335 weak basic anion-exchange resins demonstrated the highest adsorption capacity and selectivity for lactic acid recovery. The adsorption study of the 335 resins for lactic acid confirmed that it is an efficient adsorbent under fermentation condition. Langmuir models gave a good fit to the equilibrium data at 50 °C and the maximum adsorption capacity for lactic acid by 335 resins was about 402 mg/g. Adsorption kinetic experiments showed that pseudo-second-order kinetics model gave a good fit to the adsorption rate. When it was used for in situ fermentation, the yield of L-lactic acid by B. coagulans CC17 was close to traditional fermentation and still maintained at about 82% even after reuse by ten times. These results indicated that in situ separation and production of L-lactic acid using the 335 resins were efficient and feasible. This process could greatly reduce the dosage of neutralizing agent and potentially be used in industry.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tessore, Nicolas; Metcalf, R. Benton; Winther, Hans A.

A number of alternatives to general relativity exhibit gravitational screening in the non-linear regime of structure formation. We describe a set of algorithms that can produce weak lensing maps of large scale structure in such theories and can be used to generate mock surveys for cosmological analysis. By analysing a few basic statistics we indicate how these alternatives can be distinguished from general relativity with future weak lensing surveys.

What does the American Board of Surgery In-Training/Surgical Basic Science Examination tell us about graduate surgical education?

PubMed

DaRosa, D A; Shuck, J M; Biester, T W; Folse, R

1993-01-01

This research sought to identify the strengths and weakness in residents' basic science knowledge and, second, to determine whether they progressively improve in their abilities to recall basic science information and clinical management facts, to analyze cause-effect relationships, and to solve clinical problems. Basic science knowledge was assessed by means of the results of the January 1990 American Board of Surgery's In-Training/Surgical Basic Science Exam (IT/SBSE). Postgraduate year (PGY) 1 residents' scores were compared with those of PGY5 residents. Content related to a question was considered "known" if 67% or more of the residents in each of the two groups answered it correctly. Findings showed 44% of the content tested by the basic science questions were unknown by new and graduating residents. The second research question required the 250 IT/SBSE questions to be classified into one of three levels of thinking abilities: recall, analysis, and inferential thinking. Profile analysis (split-plot analysis of variance) for each pair of resident levels indicated significant (P < 0.001) differences in performance on questions requiring factual recall, analysis, and inference between all levels except for PGY3s and PGY4s. The results of this research enable program directors to evaluate strengths and weaknesses in residency training curricula and the cognitive development of residents.

In vitro and physiologically‐based pharmacokinetic based assessment of drug–drug interaction potential of canagliflozin

PubMed Central

Dallas, Shannon; Sensenhauser, Carlo; Lim, Heng Keang; Scheers, Ellen; Verboven, Peter; Cuyckens, Filip; Leclercq, Laurent; Evans, David C.; Kelley, Michael F.; Johnson, Mark D.; Snoeys, Jan

2016-01-01

Aims Canagliflozin is a recently approved drug for use in the treatment of type 2 diabetes. The potential for canagliflozin to cause clinical drug–drug interactions (DDIs) was assessed. Methods DDI potential of canagliflozin was investigated using in vitro test systems containing drug metabolizing enzymes or transporters. Basic predictive approaches were applied to determine potential interactions in vivo. A physiologically‐based pharmacokinetic (PBPK) model was developed and clinical DDI simulations were performed to determine the likelihood of cytochrome P450 (CYP) inhibition by canagliflozin. Results Canagliflozin was primarily metabolized by uridine 5′‐diphospho‐glucuronosyltransferase 1A9 and 2B4 enzymes. Canagliflozin was a substrate of efflux transporters (P‐glycoprotein, breast cancer resistance protein and multidrug resistance‐associated protein‐2) but was not a substrate of uptake transporters (organic anion transporter polypeptide isoforms OATP1B1, OATP1B3, organic anion transporters OAT1 and OAT3, and organic cationic transporters OCT1, and OCT2). In inhibition assays, canagliflozin was shown to be a weak in vitro inhibitor (IC50) of CYP3A4 (27 μmol l –1, standard error [SE] 4.9), CYP2C9 (80 μmol l –1, SE 8.1), CYP2B6 (16 μmol l–1, SE 2.1), CYP2C8 (75 μmol l –1, SE 6.4), P‐glycoprotein (19.3 μmol l –1, SE 7.2), and multidrug resistance‐associated protein‐2 (21.5 μmol l –1, SE 3.1). Basic models recommended in DDI guidelines (US Food & Drug Administration and European Medicines Agency) predicted moderate to low likelihood of interaction for these CYPs and efflux transporters. PBPK DDI simulations of canagliflozin with CYP probe substrates (simvastatin, S‐warfarin, bupropion, repaglinide) did not show relevant interaction in humans since mean areas under the concentration‐time curve and maximum plasma concentration ratios for probe substrates with and without canagliflozin and its 95% CIs were within 0.80–1.25. Conclusions In vitro DDI followed by a predictive or PBPK approach was applied to determine DDI potential of canagliflozin. Overall, canagliflozin is neither a perpetrator nor a victim of clinically important interactions. PMID:27862160

Design of tablets for the delayed and complete release of poorly water-soluble weak base drugs using SBE7M-β-CD as a solubilizing agent.

PubMed

Rao, Venkatramana M; Zannou, Erika A; Stella, Valentino J

2011-04-01

The challenge of designing a delayed-release oral dosage form is significantly increased when the drug substance is poorly water soluble. This manuscript describes the design and characterization of a novel controlled-release film-coated tablet for the pH-triggered delayed and complete release of poorly water-soluble weak base drugs. Delivery of weak bases is specifically highlighted with the use of dipyridamole and prazosin as model compounds. Tailored delayed release is achieved with a combination of an insoluble but semipermeable polymer and an enteric polymer, such as cellulose acetate and hydroxypropyl cellulose phthalate, respectively, as coatings. The extent of the time lag prior to complete release depends on the film-coating composition and thickness. Complete release is achieved by the addition of a cyclodextrin, namely SBE7M-β-CD with or without a pH modifier added to the tablet core to ensure complete solubilization and release of the drug substance. The film-coating properties allow the complex formation/solubilization to occur in situ. Additionally, the drug release rate can be modulated on the basis of the cyclodextrin to drug molar ratio. This approach offers a platform technology for delayed release of potent but poorly soluble drugs and the release can be modulated by adjusting the film-coating composition and thickness and/or the cyclodextrin and pH modifier, if necessary. Copyright © 2010 Wiley-Liss, Inc.

Septic Arthritis

MedlinePlus

... Weak immune system. People with a weak immune system are at greater risk of septic arthritis. This includes people with diabetes, kidney and liver problems, and those taking drugs that suppress their immune systems. Joint trauma. Animal bites, puncture woods or cuts ...

Biodegradation and bio-sorption of antibiotics and non-steroidal anti-inflammatory drugs using immobilized cell process.

PubMed

Yu, Tsung-Hsien; Lin, Angela Yu-Chen; Panchangam, Sri Chandana; Hong, Pui-Kwan Andy; Yang, Ping-Yi; Lin, Cheng-Fang

2011-08-01

In the present study, the removal mechanisms of four antibiotics (sulfamethoxazole, sulfadimethoxine, sulfamethazine, and trimethoprim) and four non-steroidal anti-inflammatory drugs (acetaminophen, ibuprofen, ketoprofen, and naproxen) in immobilized cell process were investigated using batch reactors. This work principally explores the individual or collective roles of biodegradation and bio-sorption as removal routes of the target pharmaceuticals and the results were validated by various experimental and analytical tools. Biodegradation and bio-sorption were found as dominant mechanisms for the drug removal, while volatilization and hydrolysis were negligible for all target pharmaceuticals. The target pharmaceuticals responded to the two observed removal mechanisms in different ways, typically: (1) strong biodegradability and bio-sorption by acetaminophen, (2) strong biodegradability and weak bio-sorption by sulfamethoxazole, sulfadimethoxine, ibuprofen and naproxen, (3) low biodegradability and weak bio-sorption by sulfamethazine and ketoprofen, and (4) low biodegradability and medium bio-sorption by trimethoprim. In the sorption/desorption experiment, acetaminophen, sulfamethoxazole and sulfadimethoxine were characterized by strong sorption and weak desorption. A phenomenon of moderate sorption and well desorption was observed for sulfamethazine, trimethoprim and naproxen. Both ibuprofen and ketoprofen were weakly sorbed and strongly desorbed. Copyright © 2011 Elsevier Ltd. All rights reserved.

Are Online Quizzes an Effective Tool for Mastering Basic Algebra?

ERIC Educational Resources Information Center

Read, Wayne; Higgins, Patrick

2012-01-01

On-line quizzes are used to help first year University Mathematics students identify weaknesses in their basic skills and improve them. Quizzes developed as a formative tool have been utilised at JCU [James Cook University] for eight years. However, before this research no-one has questioned the effectiveness of quizzes for this task. We present a…

[Right-to-health litigation in three Latin American countries: a systematic literature review].

PubMed

Reveiz, Ludovic; Chapman, Evelina; Torres, Rubén; Fitzgerald, James F; Mendoza, Adriana; Bolis, Mónica; Salgado, Osvaldo

2013-03-01

Identify and evaluate studies that analyzed characteristics of right-to-health litigation in Brazil, Colombia, and Costa Rica. Studies were evaluated that analyzed characteristics of right-to-health litigation identified through a search of PubMed, LILACS, Cochrane Library, and Scirus (April 2012). Two reviewers evaluated the studies. Variables collected were, among others, grounds for litigation, proportion of lawsuits for benefits covered by the health system, and lawsuits on high-cost technologies. Thirty studies were identified (Brazil 19, Colombia 10, and Costa Rica 1). Judgments were frequently in favor of plaintiffs: Colombia (75%-87%), Costa Rica (89.7%), and Brazil (70%-100%). In Colombia, lawsuits were filed for benefits included in the Compulsory Health Plan (range: 41%-69.9%). In Brazil there was considerable variation in the amount of lawsuits between the Exceptional Circumstance Drug Dispensing Program (13%-31%) and basic medicines in the Unified Health System (approximately 50%). Lawsuits on drugs varied as a percentage of all lawsuits (Colombia 11.9%-35.6%, Costa Rica 30.2%, and Brazil 49.6%). A study in Brazil found a statistically significant difference when comparing lawsuits on exceptional drugs versus all other drugs, by social class; and in another study, according to lawsuits from municipalities with better socioeconomic indicators. A concentration of lawsuits on drug prescribing by a limited group of physicians was reported. Prescribing was not always supported by scientific evidence. Another study found that in half of the cases, the cost of legal proceedings was higher than the cost of the services being claimed. There are similarities in the grounds, nature, and impact of litigation in the context of the countries studied. The studies included show weaknesses of health systems to ensure access to different services as well as in the introduction of new health technologies.

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

PubMed

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

2017-08-25

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

Family, Religiosity, and the Risk of Adolescent Drug Use.

ERIC Educational Resources Information Center

Bahr, Stephen J.; Maughan, Suzanne L.; Marcos, Anastasios C.; Li, Bingdao

1998-01-01

Uses data from a random sample of 13,250 adolescents. Results show that mother/adolescent bonding and family drug problems have modest, indirect effects on the likelihood of adolescent drug use; father/adolescent bonding, parental monitoring, and family aggression have relatively weak effects on adolescent drug use; and religious students do not…

Evaluation of the in vitro/in vivo potential of five berries (bilberry, blueberry, cranberry, elderberry, and raspberry ketones) commonly used as herbal supplements to inhibit uridine diphospho-glucuronosyltransferase.

PubMed

Choi, Eu Jin; Park, Jung Bae; Yoon, Kee Dong; Bae, Soo Kyung

2014-10-01

In this study, we evaluated inhibitory potentials of popularly-consumed berries (bilberry, blueberry, cranberry, elderberry, and raspberry ketones) as herbal supplements on UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 in vitro. We also investigated the potential herb-drug interaction via UGT1A1 inhibition by blueberry in vivo. We demonstrated that these berries had only weak inhibitory effects on the five UGTs. Bilberry and elderberry had no apparent inhibitions. Blueberry weakly inhibited UGT1A1 with an IC50 value of 62.4±4.40 μg/mL and a Ki value of 53.1 μg/mL. Blueberry also weakly inhibited UGT2B7 with an IC50 value of 147±11.1 μg/mL. In addition, cranberry weakly inhibited UGT1A9 activity (IC50=458±49.7 μg/mL) and raspberry ketones weakly inhibited UGT2B7 activity (IC50=248±28.2 μg/mL). Among tested berries, blueberry showed the lowest IC50 value in the inhibition of UGT1A1 in vitro. However, the co-administration of blueberry had no effect on the pharmacokinetics of irinotecan and its active metabolite, SN-38, which was mainly eliminated via UGT1A1, in vivo. Our data suggests that these five berries are unlikely to cause clinically significant herb-drug interactions mediated via inhibition of UGT enzymes involved in drug metabolism. These findings should enable an understanding of herb-drug interactions for the safe use of popularly-consumed berries. Copyright © 2014 Elsevier Ltd. All rights reserved.

Methods, strengths, weaknesses, and limitations of bioequivalence tests with special regard to immunosuppressive drugs.

PubMed

van Gelder, Teun; Gabardi, Steven

2013-08-01

Within the field of solid organ transplantation, the patents for a number of immunosuppressive drugs have expired in the last few years. Tacrolimus, cyclosporine, and mycophenolate mofetil are now available as generic drugs. In some countries, the market penetration of these generic formulations is as high as 70%, whereas in some other countries, this figure is below 10%. Several professional societies have published position papers on the risks and benefits of generic substitution of immunosuppressive drugs. It often appears that transplant professionals are not fully aware of the requirements for registration of generic drugs. This article describes the registration requirements with a focus on bioequivalence testing, the strengths and weaknesses in this process, and the differences between Europe and the US. © 2013 The Authors Transplant International © 2013 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd.

From basic to clinical neuropharmacology: targetophilia or pharmacodynamics?

PubMed

Green, A Richard; Aronson, Jeffrey K

2012-06-01

Historically, much drug discovery and development in psychopharmacology tended to be empirical. However, over the last 20 years it has primarily been target oriented, with synthesis and selection of compounds designed to act at a specific neurochemical site. Such compounds are then examined in functional animal models of disease. There is little evidence that this approach (which we call 'targetophilia') has enhanced the discovery process and some indications that it may have retarded it. A major problem is the weakness of many animal models in mimicking the disease and the lack of appropriate biochemical markers of drug action in animals and patients. In this review we argue that preclinical studies should be conducted as if they were clinical studies in design, analysis, and reporting, and that clinical pharmacologists should be involved at the earliest stages, to help ensure that animal models reflect as closely as possible the clinical disease. In addition, their familiarity with pharmacokinetic-pharmacodynamic integration (PK-PD) would help ensure that appropriate dosing and drug measurement techniques are applied to the discovery process, thereby producing results with relevance to therapeutics. Better integration of experimental and clinical pharmacologists early in the discovery process would allow observations in animals and patients to be quickly exchanged between the two disciplines. This non-linear approach to discovery used to be the way research proceeded, and it resulted in productivity that has never been bettered. It also follows that occasionally 'look-see' studies, a proven technique for drug discovery, deserve to be reintroduced. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Hollow multilayer microcapsules for pH-/thermally responsive drug delivery using aliphatic poly(urethane-amine) as smart component.

PubMed

Shi, Jun; Du, Chao; Shi, Jin; Wang, Yaming; Cao, Shaokui

2013-04-01

Hollow multilayer microcapsules made of aliphatic poly(urethane-amine) (PUA) and sodium poly(styrene sulfonate) (PSS), templated on PSS-doped CaCO3 particles, are prepared for pH-/thermally responsive drug delivery. The electrostatic interaction and hydrogen bonding under weak-acid conditions between aliphatic PUA and PSS contribute to the formation of multilayer microcapsules. Scanning electron microscopy (SEM) results demonstrate an obvious variation of the hollow multilayer microcapsules in response to changes in temperature and pH value. Drug-release behaviors using DOX as a model drug demonstrate that the drug release increases on decreasing the pH value because of the interaction weakness between aliphatic PUA and PSS in acidic conditions. Moreover, the drug release is higher at 55 °C than that at 37 °C for the sake of the shrinkage of aliphatic PUA above its lower critical solution temperature (LCST). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

"Weak" opioid analgesics. Codeine, dihydrocodeine and tramadol: no less risky than morphine.

PubMed

2016-02-01

So-called weak opioid analgesics are often used to treat severe pain, or when paracetamol or a nonsteroidal anti-inflammatory drug (NSAID) proves inadequate. But are weak opioids any more effective than paracetamol or NSAIDs on nociceptive pain, and are they better tolerated than morphine? To answer these questions, we conducted a review of literature using the standard Prescrire methodology. The potency of codeine and tramadol is strongly influenced by the cytochrome P450 isoenzyme CYP2D6 genotype, which varies widely from one person to another. This explains reports of overdosing or underdosing after administration of standard doses of the two drugs. The potency of morphine and that of buprenorphine, an opioid receptor agonist-antagonist, appears to be independent of CYP2D6 activity. All "weak" opioids can have the same dose-dependent adverse effects as morphine. There is no evidence that, at equivalent analgesic efficacy, weak opioids carry a lower risk of addiction than low-dose morphine. Respiratory depression can occur in ultrarapid metabolisers after brief exposure to standard doses of codeine or tramadol. Similar cases have been reported with dihydrocodeine in patients with renal failure. In addition, tramadol can cause a serotonin syndrome, hypoglycaemia, hyponatraemia and seizures. Several trials have compared different weak opioids in patients with post-operative pain. A single dose of a weak opioid, possibly combined with paracetamol, has greater analgesic efficacy than paracetamol alone but is not more effective than an NSAID alone. There is a dearth of evidence on weak opioids in patients with chronic pain. Available trials fail to show that a weak opioid has markedly superior analgesic efficacy to paracetamol or an NSAID. Sublingual buprenorphine at analgesic doses appears less likely to cause respiratory depression, but it seems to have weak analgesic efficacy. In practice, when opioid therapy is needed, there is no evidence that codeine, dihydrocodeine or tramadol is less risky than morphine at its lowest effective dose. Compared to morphine, the efficacy of these drugs varies more from one patient to another, and their multiple pharmacokinetic interactions can be difficult to manage. There is also a sometimes unpredictable risk of serious over-dose. Tramadol has additional adverse effects unrelated to its opioid effects. Weak opioids require at least as much vigilance as morphine, despite the major differences in their reputation and regulation.

Weak bases and formation of a less soluble lauryl sulfate salt/complex in sodium lauryl sulfate (SLS) containing media.

PubMed

Bhattachar, Shobha N; Risley, Donald S; Werawatganone, Pornpen; Aburub, Aktham

2011-06-30

This work reports on the solubility of two weakly basic model compounds in media containing sodium lauryl sulfate (SLS). Results clearly show that the presence of SLS in the media (e.g. simulated gastric fluid or dissolution media) can result in an underestimation of solubility of some weak bases. We systematically study this phenomenon and provide evidence (chromatography and pXRD) for the first time that the decrease in solubility is likely due to formation of a less soluble salt/complex between the protonated form of the weak base and lauryl sulfate anion. Copyright © 2011 Elsevier B.V. All rights reserved.

42 CFR 422.262 - Beneficiary premiums.

Code of Federal Regulations, 2011 CFR

2011-10-01

... and Plan Approval § 422.262 Beneficiary premiums. (a) Determination of MA monthly basic beneficiary premium. (1) For an MA plan with an unadjusted statutory non-drug bid amount that is less than the relevant unadjusted non-drug benchmark amount, the basic beneficiary premium is zero. (2) For an MA plan...

42 CFR 422.262 - Beneficiary premiums.

Code of Federal Regulations, 2012 CFR

2012-10-01

... Information and Plan Approval § 422.262 Beneficiary premiums. (a) Determination of MA monthly basic beneficiary premium. (1) For an MA plan with an unadjusted statutory non-drug bid amount that is less than the relevant unadjusted non-drug benchmark amount, the basic beneficiary premium is zero. (2) For an MA plan...

42 CFR 422.262 - Beneficiary premiums.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Information and Plan Approval § 422.262 Beneficiary premiums. (a) Determination of MA monthly basic beneficiary premium. (1) For an MA plan with an unadjusted statutory non-drug bid amount that is less than the relevant unadjusted non-drug benchmark amount, the basic beneficiary premium is zero. (2) For an MA plan...

42 CFR 422.262 - Beneficiary premiums.

Code of Federal Regulations, 2010 CFR

2010-10-01

... and Plan Approval § 422.262 Beneficiary premiums. (a) Determination of MA monthly basic beneficiary premium. (1) For an MA plan with an unadjusted statutory non-drug bid amount that is less than the relevant unadjusted non-drug benchmark amount, the basic beneficiary premium is zero. (2) For an MA plan...

42 CFR 422.262 - Beneficiary premiums.

Code of Federal Regulations, 2014 CFR

2014-10-01

... Information and Plan Approval § 422.262 Beneficiary premiums. (a) Determination of MA monthly basic beneficiary premium. (1) For an MA plan with an unadjusted statutory non-drug bid amount that is less than the relevant unadjusted non-drug benchmark amount, the basic beneficiary premium is zero. (2) For an MA plan...

Basic College-Level Pharmacology: Therapeutic Drug Range Lesson Plan.

ERIC Educational Resources Information Center

Laipply, Richelle S.

2000-01-01

Investigations of scientific concepts using inquiry can be included in the traditional college lecture. This lesson uses the Learning Cycle to demonstrate therapeutic drug range, a basic concept in pharmaceutical science. Students use graphing to discover patterns as a part of data analysis and interpretation of provided investigation data.…

Basic Radio Circuits and Vacuum Tube AM Troubleshooting; Radio and Television Service, Intermediate: 9785.03.

ERIC Educational Resources Information Center

Dade County Public Schools, Miami, FL.

The 135-hour quinmester course covers study of basic radio circuits as applied to vacuum tube radios in six blocks of instruction: orientation; AM receivers with tubes; no signal, audio failure; distortion; weak, noisy signals; and a post-test. Each block is subdivided into several units, and block objectives are outlined. Completion of AC…

Drug policy, harm and human rights: a rationalist approach.

PubMed

Stevens, Alex

2011-05-01

It has recently been argued that drug-related harms cannot be compared, so making it impossible to choose rationally between various drug policy options. Attempts to apply international human rights law to this area are valid, but have found it difficult to overcome the problems in applying codified human rights to issues of drug policy. This article applies the rationalist ethical argument of Gewirth (1978) to this issue. It outlines his argument to the 'principle of generic consistency' and the hierarchy of basic, nonsubtractive and additive rights that it entails. It then applies these ideas to drug policy issues, such as whether there is a right to use drugs, whether the rights of drug 'addicts' can be limited, and how different harms can be compared in choosing between policies. There is an additive right to use drugs, but only insofar as this right does not conflict with the basic and nonsubtractive rights of others. People whose freedom to choose whether to use drugs is compromised by compulsion have a right to receive treatment. They retain enforceable duties not to inflict harms on others. Policies which reduce harms to basic and nonsubtractive rights should be pursued, even if they lead to harms to additive rights. There exists a sound, rational, extra-legal basis for the discussion of drug policy and related harms which enables commensurable discussion of drug policy options. Copyright © 2011 Elsevier B.V. All rights reserved.

A Basic Balance.

ERIC Educational Resources Information Center

Science and Children, 1995

1995-01-01

Presents an activity for students to construct their own two-cup balances. Suggests some alternatives for rejuvenating weak bar magnets. Describes how to remove burnt carbon deposits from glass vessels. (NB)

Two-step voltage dual electromembrane extraction: A new approach to simultaneous extraction of acidic and basic drugs.

PubMed

Asadi, Sakine; Nojavan, Saeed

2016-06-07

In the present work, acidic and basic drugs were simultaneously extracted by a novel method of high efficiency herein referred to as two-step voltage dual electromembrane extraction (TSV-DEME). Optimizing effective parameters such as composition of organic liquid membrane, pH values of donor and acceptor solutions, voltage and duration of each step, the method had its figures of merit investigated in pure water, human plasma, wastewater, and breast milk samples. Simultaneous extraction of acidic and basic drugs was done by applying potentials of 150 V and 400 V for 6 min and 19 min as the first and second steps, respectively. The model compounds were extracted from 4 mL of sample solution (pH = 6) into 20 μL of each acceptor solution (32 mM NaOH for acidic drugs and 32 mM HCL for basic drugs). 1-Octanol was immobilized within the pores of a porous hollow fiber of polypropylene, as the supported liquid membrane (SLM) for acidic drugs, and 2-ethyle hexanol, as the SLM for basic drugs. The proposed TSV-DEME technique provided good linearity with the resulting correlation coefficients ranging from 0.993 to 0.998 over a concentration range of 1-1000 ng mL(-1). The limit of detections of the drugs were found to range within 0.3-1.5 ng mL(-1), while the corresponding repeatability ranged from 7.7 to 15.5% (n = 4). The proposed method was further compared to simple dual electromembrane extraction (DEME), indicating significantly higher recoveries for TSV-DEME procedure (38.1-68%), as compared to those of simple DEME procedure (17.7-46%). Finally, the optimized TSV-DEME was applied to extract and quantify model compounds in breast milk, wastewater, and plasma samples. Copyright © 2016 Elsevier B.V. All rights reserved.

An Empirical Examination of the Anomie Theory of Drug Use.

ERIC Educational Resources Information Center

Dull, R. Thomas

1983-01-01

Investigated the relationship between anomie theory, as measured by Srole's Anomie Scale, and self-admitted drug use in an adult population (N=1,449). Bivariate cross-comparison correlations indicated anomie was significantly correlated with several drug variables, but these associations were extremely weak and of little explanatory value.…

Electrokinetic migration across artificial liquid membranes Tuning the membrane chemistry to different types of drug substances.

PubMed

Gjelstad, Astrid; Rasmussen, Knut Einar; Pedersen-Bjergaard, Stig

2006-08-18

Twenty different basic drugs were electrokinetically extracted across a thin artificial organic liquid membrane with a 300 V d.c. electrical potential difference as the driving force. From a 300 microl aqueous sample (acidified corresponding to 10mM HCl), the drugs were extracted for 5 min through a 200 microm artificial liquid membrane of a water immiscible organic solvent immobilized in the pores of a polypropylene hollow fiber, and into a 30 microl aqueous acceptor solution of 10mM HCl inside the lumen of the hollow fiber. Hydrophobic basic drugs (logP>1.7) were effectively isolated utilizing 2-nitrophenyl octyl ether (NPOE) as the artificial liquid membrane, with recoveries up to 83%. For more hydrophilic basic drugs (logP<1.0), a mixture of NPOE and 25% (w/w) di-(2-ethylhexyl) phosphate (DEHP) was required to ensure efficient extraction, resulting in recoveries up to 75%. DEHP was expected to act as an ion-pair reagent ion-pairing the protonated hydrophilic drugs at the interface between the sample and the membrane, resulting in permeation of the interface.

Polymeric micelles as a new drug carrier system and their required considerations for clinical trials.

PubMed

Yokoyama, Masayuki

2010-02-01

A polymeric micelle is a macromolecular assembly composed of an inner core and an outer shell, and most typically is formed from block copolymers. In the last two decades, polymeric micelles have been actively studied as a new type of drug carrier system, in particular for drug targeting of anticancer drugs to solid tumors. In this review, polymeric micelle drug carrier systems are discussed with a focus on toxicities of the polymeric micelle carrier systems and on pharmacological activities of the block copolymers. In the first section, the importance of the above-mentioned evaluation of these properties is explained, as this importance does not seem to be well recognized compared with the importance of targeting and enhanced pharmacological activity of drugs, particularly in the basic studies. Then, designs, types and classifications of the polymeric micelle system are briefly summarized and explained, followed by a detailed discussion regarding several examples of polymeric micelle carrier systems. Readers will gain a strategy of drug delivery with polymeric carriers as well as recent progress of the polymeric micelle carrier systems in their basic studies and clinical trials. The purpose of this review is to achieve tight connections between the basic studies and clinical trials.

Recommendations for postmarketing surveillance studies in haemophilia and other bleeding disorders.

PubMed

Lassila, R; Rothschild, C; De Moerloose, P; Richards, M; Perez, R; Gajek, H

2005-07-01

Prospective surveillance studies to monitor drug safety in the postapproval period are rarely employed systematically, although they are of greatest value for caregivers, drug users and regulatory authorities. Safety issues have affected not only conventional pharmaceuticals, but also especially coagulation factors in haemophilia treatment. The reputation of postmarketing surveillance (PMS) studies has been questionable, mainly due to their misuse to solicit prescriptions. Other weaknesses include inappropriate design, lack of standardized observation, limited follow-up periods, absence of rigour in identifying potential adverse drug effects, and infrequent publication. Although well-designed clinical trials represent the gold standard for generating sound clinical evidence, a number of aspects would make PMS studies valuable, if properly conducted. One of their main advantages is broader inclusion, and absence of an 'experimental' design. Lack of proper guidelines, and standardization may constitute a reason for the generally low quality of PMS studies. This paper proposes guidelines for haemophilia-specific PMS studies, in order to improve the acceptance of a basically valuable tool. In the absence of consistent regulatory guidance it will be especially important that the design and supervision of PMS studies involves physicians from the beginning. This will not only make such studies more scientifically relevant, but also help to implement them into daily clinical practice. Specifically in haemophilia, PMS studies may provide valuable data on clinical outcomes, or Quality of Life, which is of great importance when considering adequate standards of care in haemophilia patients.

The danger of imperfect regulation: OxyContin use in the United States and Canada.

PubMed

Lexchin, Joel; Kohler, Jillian Clare

2011-01-01

Drug companies aggressively market their products to increase sales and economic rewards. Different countries have different regulatory regimes for controlling promotion. In the United States control rests directly with the Food and Drug Administration whereas Canada relies on a mixture of voluntary self-regulation and an autonomous agency. Each method has significant weaknesses. We examine these weaknesses by analyzing the promotion of OxyContin (the time release version of the opioid oxycodone) by Purdue in Canada and the United States. We then look at the association between promotion and the misuse and abuse of OxyContin in both countries. Finally, we advance specific recommendations for regulating promotion for drugs that may have a high abuse potential.

Weak characteristic information extraction from early fault of wind turbine generator gearbox

NASA Astrophysics Data System (ADS)

Xu, Xiaoli; Liu, Xiuli

2017-09-01

Given the weak early degradation characteristic information during early fault evolution in gearbox of wind turbine generator, traditional singular value decomposition (SVD)-based denoising may result in loss of useful information. A weak characteristic information extraction based on μ-SVD and local mean decomposition (LMD) is developed to address this problem. The basic principle of the method is as follows: Determine the denoising order based on cumulative contribution rate, perform signal reconstruction, extract and subject the noisy part of signal to LMD and μ-SVD denoising, and obtain denoised signal through superposition. Experimental results show that this method can significantly weaken signal noise, effectively extract the weak characteristic information of early fault, and facilitate the early fault warning and dynamic predictive maintenance.

Designing an extended release waxy matrix tablet containing nicardipine–hydroxy propyl β cyclodextrin complex

PubMed Central

Al-Zein, Hind; Sakeer, Khalil; Alanazi, Fars K.

2011-01-01

Aim The current study aimed to prepare a sustained release tablet for a drug which has poor solubility in alkaline medium using complexation with cyclodextrin. Nicardipine hydrochloride (NC) a weak basic drug was chosen as a model drug for this study. Method Firstly the most suitable binary system NC-HPβCD was selected in order to improve drug solubility in the intestinal media and then embedding the complexed drug into a plastic matrix, by fusion method, consists of glycerol monostearate (GMS) as an inert waxy substance and polyethylene glycol 4000 (PEG4000) as a channeling agent, after that the final solid dispersion [(NC:HPβCD):GMS:PEG4000] which was prepared at different ratios was mixed with other excipients, avicel PH101, lactose, and talc, to get a tablet owning dissolution profile complying with the FDA and USP requirements for the extended release solid dosage forms. Results Infrared spectroscopy (IR), differential scanning colorimetry (DSC), polarized microscopy and X-ray diffractometry proved that the coevaporation technique was effective in preparing amorphous cyclodextrin complexes with NC and trapping of NC within the HPβCD cavity by dissolving both in ethanol and evaporate the solvent using a rotavapor at 65 °C. Dissolution profile of NC enhanced significantly in pH 6.8 from NC:HPβCD inclusion complex prepared by the rotavapor (t-test Student p < 0.05). The release of NC from tablet containing [(NC:HPβCD):GMS:PEG4000] [(1):0.75:0.5] (w/w/w) solid dispersion (F8) was complying with the FDA dissolution requirements for extended release dosage forms, and studying the kinetics of the release showed that the diffusional contribution is the major factor controlling the drug release from that formula. Conclusion The prepared waxy matrix tablet containing NC complexes with CD shows promising results as extended release tablets. PMID:23960765

Prediction of pH dependent absorption using in vitro, in silico, and in vivo rat models: Early liability assessment during lead optimization.

PubMed

Saxena, Ajay; Shah, Devang; Padmanabhan, Shweta; Gautam, Shashyendra Singh; Chowan, Gajendra Singh; Mandlekar, Sandhya; Desikan, Sridhar

2015-08-30

Weakly basic compounds which have pH dependent solubility are liable to exhibit pH dependent absorption. In some cases, a subtle change in gastric pH can significantly modulate the plasma concentration of the drug and can lead to sub-therapeutic exposure of the drug. Evaluating the risk of pH dependent absorption and potential drug-drug interaction with pH modulators are important aspects of drug discovery and development. In order to assess the risk around the extent of decrease in the systemic exposure of drugs co-administered with pH modulators in the clinic, a pH effect study is carried out, typically in higher species, mostly dog. The major limitation of a higher species pH effect study is the resource and material requirement to assess this risk. Hence, these studies are mostly restricted to promising or advanced leads. In our current work, we have used in vitro aqueous solubility, in silico simulations using GastroPlus™ and an in vivo rat pH effect model to provide a qualitative assessment of the pH dependent absorption liability. Here, we evaluate ketoconazole and atazanavir with different pH dependent solubility profiles and based on in vitro, in silico and in vivo results, a different extent of gastric pH effect on absorption is predicted. The prediction is in alignment with higher species and human pH effect study results. This in vitro, in silico and in vivo (IVISIV) correlation is then extended to assess pH absorption mitigation strategy. The IVISIV predicts pH dependent absorption for BMS-582949 whereas its solubility enhancing prodrug, BMS-751324 is predicted to mitigate this liability. Overall, the material requirement for this assessment is substantially low which makes this approach more practical to screen multiple compounds during lead optimization. Copyright © 2015 Elsevier B.V. All rights reserved.

Extra-weak chemiluminescence produced by autoxidation of kampo extract preparations stored in heat-stressed conditions.

PubMed

Sato, H; Hirayama, H; Yamamoto, T; Ishizawa, F; Mizugaki, M

1998-06-01

The purpose of this study was to evaluate the usefulness of extra-weak chemiluminescence (CL) measurement as a rapid method to estimate the stability of Kampo extract preparations. It was found that the Kampo drugs that emit little CL were stable, while those with higher CL were comparatively unstable with regard to the various stability markers, including change of coloration (browning), contents of specific ingredients, high molecular compounds, amino acids and sugars under various conditions of heat storage. Excellent correlation existed between the CL of Kampo drugs and the coloration (delta E* (ab)) and the other above-mentioned evaluation markers. From this investigation, it was deduced that the CL of Kampo drugs originates in the early stage of the Maillard reaction and reflects the stability of the preparations, and that CL is useful for estimating the stability of Kampo drugs.

Fragment screening for drug leads by weak affinity chromatography (WAC-MS).

PubMed

Ohlson, Sten; Duong-Thi, Minh-Dao

2018-02-23

Fragment-based drug discovery is an important tool for design of small molecule hit-to-lead compounds against various biological targets. Several approved drugs have been derived from an initial fragment screen and many such candidates are in various stages of clinical trials. Finding fragment hits, that are suitable for optimisation by medicinal chemists, is still a challenge as the binding between the small fragment and its target is weak in the range of mM to µM of K d and irrelevant non-specific interactions are abundant in this area of transient interactions. Fortunately, there are methods that can study weak interactions quite efficiently of which NMR, surface plasmon resonance (SPR) and X-ray crystallography are the most prominent. Now, a new technology based on zonal affinity chromatography, weak affinity chromatography (WAC), has been introduced which has remedied many of the problems with other technologies. By combining WAC with mass spectrometry (WAC-MS), it is a powerful tool to identify binders quantitatively in terms of affinity and kinetics either from fragment libraries or from complex mixtures of biological extracts. As WAC-MS can be multiplexed by analysing mixtures of fragments (20-100 fragments) in one sample, this approach yields high throughput, where a whole library of e.g. >2000 fragments can be analysed quantitatively within a day. WAC-MS is easy to perform, where the robustness and quality of HPLC is fully utilized. This review will highlight the rationale behind the application of WAC-MS for fragment screening in drug discovery. Copyright © 2018 Elsevier Inc. All rights reserved.

Brief Screening and Intervention for Alcohol and Drug Use in a College Student Health Clinic: Feasibility, Implementation, and Outcomes

ERIC Educational Resources Information Center

Amaro, Hortensia; Reed, Elizabeth; Rowe, Erin; Picci, Jennifer; Mantella, Philomena; Prado, Guillermo

2010-01-01

Objective: Evaluation of the Brief Alcohol Screen and Intervention in College Students (BASICS) in a university primary care setting. Participants/Methods: Undergraduates (N = 449) participated in BASICS and electronic surveys assessing frequency/quantity of alcohol and drug use, psychosocial and mental health outcomes, and demographic…

78 FR 69133 - Drug Enforcement Administration

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-18

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., California 94085, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule...

Scientific and personal recollections of Roberto Petronzio

NASA Astrophysics Data System (ADS)

Parisi, Giorgio

2018-03-01

This paper aims to recall some of the main contributions of Roberto Petronzio to physics, with a particular regard to the period we have been working together. His seminal contributions cover an extremely wide range of topics: the foundation of the perturbative approach to QCD, various aspects of weak interaction theory, from basic questions (e.g. the mass of the Higgs) to lattice weak interaction, lattice QCD from the beginning to most recent computations.

Basic obstetric pharmacology

PubMed Central

Zhao, Yang; Hebert, Mary F.; Venkataramanan, Raman

2017-01-01

Pregnancy is associated with a variety of physiological changes that can alter the pharmacokinetics and pharmacodynamics of several drugs. However, limited data exists on the pharmacokinetics and pharmacodynamics of the majority of the medications used in pregnancy. In this article, we first describe basic concepts (drug absorption, bioavailability, distribution, metabolism, elimination, and transport) in pharmacokinetics. Then, we discuss several physiological changes that occur during pregnancy that theoretically affect absorption, distribution, metabolism, and elimination. Further, we provide a brief review of the literature on the clinical pharmacokinetic studies performed in pregnant women in recent years. In general, pregnancy increases the clearance of several drugs and correspondingly decreases drug exposure during pregnancy. Based on current drug exposure measurements during pregnancy, alterations in the dose or dosing regimen of certain drugs are essential during pregnancy. More pharmacological studies in pregnant women are needed to optimize drug therapy in pregnancy. PMID:25281357

[Decentralization, AIDS, and harm reduction: the implementation of public policies in Rio de Janeiro, Brazil].

PubMed

Fonseca, Elize Massard da; Nunn, Amy; Souza-Junior, Paulo Borges; Bastos, Francisco Inácio; Ribeiro, José Mendes

2007-09-01

This paper assesses how decentralization of resources and initiatives by the Brazilian National SDT/AIDS Program has impacted the transfer of funds for programs to prevent HIV/AIDS among injecting drug users in Rio de Janeiro, Brazil (1999-2006). The effects of the decentralization policy on Rio de Janeiro's Syringe Exchange Programs (SEPs) are assessed in detail. Decentralization effectively took place in Rio de Janeiro in 2006, with the virtual elimination of any direct transfer from the Federal government. The elimination of direct transfers forced SEPs to seek alternative funding sources. The structure of local SEPs appears to be weak and has been further undermined by current funding constraints. Of 22 SEPs operating in 2002, only two are still operational in 2006, basically funded by the State Health Secretariat and one municipal government. The current discontinuity of SEP operations may favor the resurgence of AIDS in the IDU population. A more uniform, regulated decentralization process is thus needed.

Manipulation of in vitro collagen matrix architecture for scaffolds of improved physiological relevance

NASA Astrophysics Data System (ADS)

Hapach, Lauren A.; VanderBurgh, Jacob A.; Miller, Joseph P.; Reinhart-King, Cynthia A.

2015-12-01

Type I collagen is a versatile biomaterial that is widely used in medical applications due to its weak antigenicity, robust biocompatibility, and its ability to be modified for a wide array of applications. As such, collagen has become a major component of many tissue engineering scaffolds, drug delivery platforms, and substrates for in vitro cell culture. In these applications, collagen constructs are fabricated to recapitulate a diverse set of conditions. Collagen fibrils can be aligned during or post-fabrication, cross-linked via numerous techniques, polymerized to create various fibril sizes and densities, and copolymerized into a wide array of composite scaffolds. Here, we review approaches that have been used to tune collagen to better recapitulate physiological environments for use in tissue engineering applications and studies of basic cell behavior. We discuss techniques to control fibril alignment, methods for cross-linking collagen constructs to modulate stiffness, and composite collagen constructs to better mimic physiological extracellular matrix.

Floating lipid beads for the improvement of bioavailability of poorly soluble basic drugs: in-vitro optimization and in-vivo performance in humans.

PubMed

Abouelatta, Samar M; Aboelwafa, Ahmed A; Khalil, Rawia M; ElGazayerly, Omaima N

2015-01-01

The challenge in developing oral drug delivery systems of poorly soluble basic drugs is primarily due to their pH dependent solubility. Cinnarizine (CNZ), a model for a poorly soluble basic drug, has pH dependent solubility; where it dissolves readily at low pH in the stomach and exhibits a very low solubility at pH values greater than 4. It is also characterized by a short half life of 3-6h, which requires frequent daily administration resulting in poor patient compliance. In an attempt to solve these problems, extended release floating lipid beads were formulated. A 2(4) full factorial design was utilized for optimization of the effects of various independent variables; lipid:drug ratio, % Pluronic F-127, % Sterotex, and Gelucire 43/01:Gelucire 50/13 ratio, on the loading efficiency and release of CNZ from the lipid beads. In-vivo pharmacokinetic study of the optimized CNZ-lipid beads compared to Stugeron® (reference standard) was performed in healthy human volunteers. A promising approach for enhancing the bioavailability of the poorly soluble basic drug, CNZ, utilizing novel and simple floating lipid beads was successfully developed. Zero order release profile of CNZ was achieved for 12h. Mean AUC0-24 and AUC0-∞ of the optimized CNZ-loaded lipid beads were 4.23 and 6.04 times that of Stugeron® tablets respectively. Copyright © 2014 Elsevier B.V. All rights reserved.

Weak Bond-Based Injectable and Stimuli Responsive Hydrogels for Biomedical Applications

PubMed Central

Ding, Xiaochu; Wang, Yadong

2017-01-01

Here we define hydrogels crosslinked by weak bonds as physical hydrogels. They possess unique features including reversible bonding, shear thinning and stimuli-responsiveness. Unlike covalently crosslinked hydrogels, physical hydrogels do not require triggers to initiate chemical reactions for in situ gelation. The drug can be fully loaded in a pre-formed hydrogel for delivery with minimal cargo leakage during injection. These benefits make physical hydrogels useful as delivery vehicles for applications in biomedical engineering. This review focuses on recent advances of physical hydrogels crosslinked by weak bonds: hydrogen bonds, ionic interactions, host-guest chemistry, hydrophobic interactions, coordination bonds and π-π stacking interactions. Understanding the principles and the state of the art of gels with these dynamic bonds may give rise to breakthroughs in many biomedical research areas including drug delivery and tissue engineering. PMID:29062484

Lack of mutagens in deep-fat-fried foods obtained at the retail level.

PubMed

Taylor, S L; Berg, C M; Shoptaugh, N H; Scott, V N

1982-04-01

The basic methylene chloride extract from 20 of 30 samples of foods fried in deep fat failed to elicit any mutagenic response that could be detected in the Salmonella typhimurium/mammalian microsome assay. The basic extracts of the remaining ten samples (all three chicken samples studied, two of the four potato-chip samples, one of four corn-chip samples, the sample of onion rings, two of six doughnuts, and one of three samples of french-fried potato) showed evidence of weak mutagenic activity. In these samples, amounts of the basic extract equivalent to 28.5-57 g of the original food sample were required to produce revertants at levels of 2.6-4.8 times the background level. Only two of the acidic methylene chloride extracts from the 30 samples exhibited mutagenic activity greater than 2.5 times the background reversion level, and in both cases (one corn-chip and one shrimp sample) the mutagenic response was quite weak. The basic extract of hamburgers fried in deep fat in a home-style fryer possessed higher levels of mutagenic activity (13 times the background reversion level). However, the mutagenic activity of deep-fried hamburgers is some four times lower than that of pan-fried hamburgers.

Investigation of pH Influence on Skin Permeation Behavior of Weak Acids Using Nonsteroidal Anti-Inflammatory Drugs.

PubMed

Chantasart, Doungdaw; Chootanasoontorn, Siriwan; Suksiriworapong, Jiraphong; Li, S Kevin

2015-10-01

As a continuing effort to understand the skin permeation behavior of weak acids and bases, the objectives of the present study were to evaluate skin permeation of nonsteroidal anti-inflammatory drugs (NSAIDs) under the influence of pH, investigate the mechanism of pH effect, and examine a previous hypothesis that the effective skin pH for drug permeation is different from donor solution pH. In vitro permeability experiments were performed in side-by-side diffusion cells with diclofenac, ibuprofen, flurbiprofen, ketoprofen, and naproxen and human skin. The donor solution pH significantly affected skin permeation of NSAIDs, whereas no effect of the receiver pH was observed. Similar to previous observations, the apparent permeability coefficient versus donor solution pH relationships deviated from the predictions (fractions of unionized NSAIDs) according to the acid/base theory. The influences of the viable epidermis barrier, polar pathway transport, ion permeation across skin, and effective skin pH were investigated. The effective pH values for skin permeation determined using the NSAIDs (weak acids) in this study were different from those obtained previously with a weak base at the same donor solution pH conditions, suggesting that the observed permeability-pH relationships could not be explained solely by possible pH differences between skin and donor solution. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Particle Physics Primer: Explaining the Standard Model of Matter.

ERIC Educational Resources Information Center

Vondracek, Mark

2002-01-01

Describes the Standard Model, a basic model of the universe that describes electromagnetic force, weak nuclear force radioactivity, and the strong nuclear force responsible for holding particles within the nucleus together. (YDS)

Controlled Fabrication of Functional Capsules Based on the Synergistic Interaction between Polyphenols and MOFs under Weak Basic Condition.

PubMed

Wang, Hui; Zhu, Wei; Ping, Yuan; Wang, Chen; Gao, Ning; Yin, Xianpeng; Gu, Chen; Ding, Dan; Brinker, C Jeffrey; Li, Guangtao

2017-04-26

Metal-organic coordination materials with controllable nanostructures are of widespread interest due to the coupled benefits of inorganic/organic building blocks and desired architectures. In this work, based on the finding of a synergistic interaction between metal-organic frameworks (MOFs) and natural polyphenols under weak basic condition, a facile strategy has been developed for directly fabricating diverse phenolic-inspired functional materials or metal-phenolic frameworks (MPFs) with controlled hollow nanostructures (polyhedral core-shell, rattle-like, hollow cage, etc.) and controllable size, morphology, and roughness, as well as composition. By further incorporating the diverse functionalities of polyphenols such as low toxicity and therapeutic properties, catalytic activity, and ability to serve as carbon precursors, into the novel assemblies, diverse artificially designed nanoarchitectures with target functionalities have been generated for an array of applications.

Adsorption behavior of benzenesulfonic acid by novel weakly basic anion exchange resins.

PubMed

Sun, Yue; Zuo, Peng; Luo, Junfen; Singh, Rajendra Prasad

2017-04-01

Two novel weakly basic anion exchange resins (SZ-1 and SZ-2) were prepared via the reaction of macroporous chloromethylated polystyrene-divinylbenzene (Cl-PS-DVB) beads with dicyclohexylamine and piperidine, respectively. The physicochemical structures of the resulting resins were characterized using Fourier Transform Infrared Spectroscopy and pore size distribution analysis. The adsorption behavior of SZ-1 and SZ-2 for benzenesulfonic acid (BA) was evaluated, and the common commercial weakly basic anion exchanger D301 was also employed for comparison purpose. Adsorption isotherms and influence of solution pH, temperature and coexisting competitive inorganic salts (Na 2 SO 4 and NaCl) on adsorption behavior were investigated and the optimum desorption agent was obtained. Adsorption isotherms of BA were found to be well represented by the Langmuir model. Thermodynamic parameters involving ΔH, ΔG and ΔS were also calculated and the results indicate that adsorption is an exothermic and spontaneous process. Enhanced selectivity of BA sorption over sulfate on the two novel resins was observed by comparison with the commercial anion exchanger D301. The fact that the tested resins loaded with BA can be efficiently regenerated by NaCl solution indicates the reversible sorption process. From a mechanistic viewpoint, this observation clearly suggests that electrostatic interaction is the predominant adsorption mechanism. Furthermore, results of column tests show that SZ-1 possesses a better adsorption property than D301, which reinforces the feasibility of SZ-1 for potential industrial application. Copyright © 2016. Published by Elsevier B.V.

Intensive Care Unit–Acquired Weakness: Implications for Physical Therapist Management

PubMed Central

Moss, Marc; Quan, Dianna; Schenkman, Margaret

2012-01-01

Patients admitted to the intensive care unit (ICU) can develop a condition referred to as “ICU-acquired weakness.” This condition is characterized by profound weakness that is greater than might be expected to result from prolonged bed rest. Intensive care unit–acquired weakness often is accompanied by dysfunction of multiple organ systems. Individuals with ICU-acquired weakness typically have significant activity limitations, often requiring physical assistance for even the most basic activities associated with bed mobility. Many of these individuals have activity limitations months to years after hospitalization. The purpose of this article is to review evidence that guides physical rehabilitation of people with ICU-acquired weakness. Included are diagnostic criteria, medical management, and prognostic indicators, as well as criteria for beginning physical rehabilitation, with an emphasis on patient safety. Data are presented indicating that rehabilitation can be implemented with very few adverse effects. Evidence is provided for appropriate measurement approaches and for physical intervention strategies. Finally, some of the key issues are summarized that should be investigated to determine the best intervention guidelines for individuals with ICU-acquired weakness. PMID:22282769

Acidic and basic drugs in medicinal chemistry: a perspective.

PubMed

Charifson, Paul S; Walters, W Patrick

2014-12-11

The acid/base properties of a molecule are among the most fundamental for drug action. However, they are often overlooked in a prospective design manner unless it has been established that a certain ionization state (e.g., quaternary base or presence of a carboxylic acid) appears to be required for activity. In medicinal chemistry optimization programs it is relatively common to attenuate basicity to circumvent undesired effects such as lack of biological selectivity or safety risks such as hERG or phospholipidosis. However, teams may not prospectively explore a range of carefully chosen compound pKa values as part of an overall chemistry strategy or design hypothesis. This review summarizes the potential advantages and disadvantages of both acidic and basic drugs and provides some new analyses based on recently available public data.

In Vitro-In Vivo Extrapolation of Metabolism- and Transporter-Mediated Drug-Drug Interactions-Overview of Basic Prediction Methods.

PubMed

Yoshida, Kenta; Zhao, Ping; Zhang, Lei; Abernethy, Darrell R; Rekić, Dinko; Reynolds, Kellie S; Galetin, Aleksandra; Huang, Shiew-Mei

2017-09-01

Evaluation of drug-drug interaction (DDI) risk is vital to establish benefit-risk profiles of investigational new drugs during drug development. In vitro experiments are routinely conducted as an important first step to assess metabolism- and transporter-mediated DDI potential of investigational new drugs. Results from these experiments are interpreted, often with the aid of in vitro-in vivo extrapolation methods, to determine whether and how DDI should be evaluated clinically to provide the basis for proper DDI management strategies, including dosing recommendations, alternative therapies, or contraindications under various DDI scenarios and in different patient population. This article provides an overview of currently available in vitro experimental systems and basic in vitro-in vivo extrapolation methodologies for metabolism- and transporter-mediated DDIs. Published by Elsevier Inc.

RP-HPLC ANALYSIS OF ACIDIC AND BASIC DRUGS IN SYSTEMS WITH DIETHYLAMINE AS ELUENTS ADDITIVE.

PubMed

Petruczynik, Anna; Wroblewski, Karol; Strozek, Szymon; Waksmundzka-Hajnos, Monika

2016-11-01

The chromatographic behavior of some basic and acidic drugs was studied on Cl 8, Phenyl-Hexyl and Polar RP columns with methanol or acetonitrile as organic modifiers of aqueous mobile phases containing addition of diethylamine. Diethylamine plays a double function of silanol blocker reagent in analysis of basic drugs and ion-pair reagent in analysis of acidic drugs. Most symmetrical peaks and highest system efficiency were obtained on Phenyl-Hexyl and Polar RP columns in tested mobile phase systems compared to results obtained on C18 column. A new rapid, simple, specific and accurate reverse phase liquid chromatographic method was developed for the simultaneous determination of atorvastatin - antihyperlipidemic drug and amlodipine - calcium channel blocker in one pharmaceutical formulation. Atorvastatin is an acidic compounds while amlodipine is a basic substance. The chromatographic separation was carried out on Phenyl-Hexyl column by gradient elution mode with acetonitrile as organic modifier, acetate buffer at pH 3.5 and Q.025 M/L diethylamine. The proposed method was validated for specificity, precision, accuracy, linearity, and robustness. The linearity range of atorvastatin and amlodipine for 5 - 100 μg/mL was obtained with limits of-detection (LOD) 3.2750 gg/mL and 3.2102 μg/mL, respectively. The proposed method made use of DAD as a tool for peak identity and purity confirmation.

Medication-related clinical decision support in computerized provider order entry systems: a review.

PubMed

Kuperman, Gilad J; Bobb, Anne; Payne, Thomas H; Avery, Anthony J; Gandhi, Tejal K; Burns, Gerard; Classen, David C; Bates, David W

2007-01-01

While medications can improve patients' health, the process of prescribing them is complex and error prone, and medication errors cause many preventable injuries. Computer provider order entry (CPOE) with clinical decision support (CDS), can improve patient safety and lower medication-related costs. To realize the medication-related benefits of CDS within CPOE, one must overcome significant challenges. Healthcare organizations implementing CPOE must understand what classes of CDS their CPOE systems can support, assure that clinical knowledge underlying their CDS systems is reasonable, and appropriately represent electronic patient data. These issues often influence to what extent an institution will succeed with its CPOE implementation and achieve its desired goals. Medication-related decision support is probably best introduced into healthcare organizations in two stages, basic and advanced. Basic decision support includes drug-allergy checking, basic dosing guidance, formulary decision support, duplicate therapy checking, and drug-drug interaction checking. Advanced decision support includes dosing support for renal insufficiency and geriatric patients, guidance for medication-related laboratory testing, drug-pregnancy checking, and drug-disease contraindication checking. In this paper, the authors outline some of the challenges associated with both basic and advanced decision support and discuss how those challenges might be addressed. The authors conclude with summary recommendations for delivering effective medication-related clinical decision support addressed to healthcare organizations, application and knowledge base vendors, policy makers, and researchers.

21 CFR 201.129 - Drugs; exemption for radioactive drugs for research use.

Code of Federal Regulations, 2011 CFR

2011-04-01

... to human research subjects during the course of a research project intended to obtain basic research... labeled drug or regarding human physiology, pathophysiology, or biochemistry (but not intended for...

Role of analgesics, sedatives, neuromuscular blockers, and delirium.

PubMed

Hall, Jesse B; Schweickert, William; Kress, John P

2009-10-01

A major focus on critical care medicine concerns the institution of life-support therapies, such as mechanical ventilation, during periods of organ failure to permit a window of opportunity to diagnose and treat underlying disorders so that patients may be returned to their prior functional status upon recovery. With the growing success of these intensive care unit-based therapies and longer-term follow-up of patients, severe weakness involving the peripheral nervous system and muscles has been identified in many recovering patients, often confounding the time course or magnitude of recovery. Mechanical ventilation is often accompanied by pharmacologic treatments including analgesics, sedatives, and neuromuscular blockers. These drugs and the encephalopathies accompanying some forms of critical illness result in a high prevalence of delirium in mechanically ventilated patients. These drug effects likely contribute to an impaired ability to assess the magnitude of intensive care unit-acquired weakness, to additional time spent immobilized and mechanically ventilated, and to additional weakness from the patient's relative immobility and bedridden state. This review surveys recent literature documenting these relationships and identifying approaches to minimize pharmacologic contributions to intensive care unit-acquired weakness.

Practical Nursing Education. A Guide for Teaching Basic Concepts and Skills in the Use of Drugs. Pamphlet Number 4.

ERIC Educational Resources Information Center

Smith, Elizabeth M.

Intended to assist teachers in either basic or continuing education programs to convey knowledge, techniques, and attitudes pertaining to drugs, the pamphlet outlines instruction which is estimated to require 70 to 100 hours of which 50 to 80 should be scheduled for classroom work and 20 hours for clinical work. Three units containing concepts…

Weakly Nonlinear Rayleigh–Taylor Instability in Cylindrically Convergent Geometry

NASA Astrophysics Data System (ADS)

Guo, Hong-Yu; Wang, Li-Feng; Ye, Wen-Hua; Wu, Jun-Feng; Zhang, Wei-Yan

2018-05-01

Not Available Supported by the National Natural Science Foundation of China under Grant Nos 11275031, 11475034, 11575033 and 11274026, and the National Basic Research Program of China under Grant No 2013CB834100.

Really a Matter of Data: A Reply to Solomon.

ERIC Educational Resources Information Center

Sroufe, L. Alan

1980-01-01

Replies to Solomon's paper that basic criticisms made earlier of Shaffran and Decaries' study still apply. Views the study as essentially a confirmation of the null hypothesis based on weak measures. (Author/RH)

Organic synthesis toward small-molecule probes and drugs

PubMed Central

Schreiber, Stuart L.

2011-01-01

“Organic synthesis” is a compound-creating activity often focused on biologically active small molecules. This special issue of PNAS explores innovations and trends in the field that are enabling the synthesis of new types of small-molecule probes and drugs. This perspective article frames the research described in the special issue but also explores how these modern capabilities can both foster a new and more extensive view of basic research in the academy and promote the linkage of life-science research to the discovery of novel types of small-molecule therapeutics [Schreiber SL (2009) Chem Bio Chem 10:26–29]. This new view of basic research aims to bridge the chasm between basic scientific discoveries in life sciences and new drugs that treat the root cause of human disease—recently referred to as the “valley of death” for drug discovery. This perspective article describes new roles that modern organic chemistry will need to play in overcoming this challenge. PMID:21464328

On the effect of basic and acidic additives on the separation of the enantiomers of some basic drugs with polysaccharide-based chiral selectors and polar organic mobile phases.

PubMed

Mosiashvili, L; Chankvetadze, L; Farkas, T; Chankvetadze, B

2013-11-22

This article reports the systematic study of the effect of basic and acidic additives on HPLC separation of enantiomers of some basic chiral drugs on polysaccharide-based chiral columns under polar organic mobile-phase conditions. In contrary to generally accepted opinion that the basic additives improve the separation of enantiomers of basic compounds, the multiple scenarios were observed including the increase, decrease, disappearance and appearance of separation, as well as the reversal of the enantiomer elution order of studied basic compounds induced by the acidic additives. These effects were observed on most of the studied 6 chiral columns in 2-propanol and acetonitrile as mobile phases and diethylamine as a basic additive. As acidic additives formic acid was used systematically and acetic acid and trifluoroacetic acid were applied for comparative purposes. This study illustrates that the minor acidic additives to the mobile phase can be used as for the adjustment of separation selectivity and the enantiomer elution order of basic compounds, as well as for study of chiral recognition mechanisms with polysaccharide-based chiral stationary phases. Copyright © 2013 Elsevier B.V. All rights reserved.

AT1 receptor blocker losartan protects against mechanical ventilation-induced diaphragmatic dysfunction

PubMed Central

Kwon, Oh Sung; Smuder, Ashley J.; Wiggs, Michael P.; Hall, Stephanie E.; Sollanek, Kurt J.; Morton, Aaron B.; Talbert, Erin E.; Toklu, Hale Z.; Tumer, Nihal

2015-01-01

Mechanical ventilation is a life-saving intervention for patients in respiratory failure. Unfortunately, prolonged ventilator support results in diaphragmatic atrophy and contractile dysfunction leading to diaphragm weakness, which is predicted to contribute to problems in weaning patients from the ventilator. While it is established that ventilator-induced oxidative stress is required for the development of ventilator-induced diaphragm weakness, the signaling pathway(s) that trigger oxidant production remain unknown. However, recent evidence reveals that increased plasma levels of angiotensin II (ANG II) result in oxidative stress and atrophy in limb skeletal muscles. Using a well-established animal model of mechanical ventilation, we tested the hypothesis that increased circulating levels of ANG II are required for both ventilator-induced diaphragmatic oxidative stress and diaphragm weakness. Cause and effect was determined by administering an angiotensin-converting enzyme inhibitor (enalapril) to prevent ventilator-induced increases in plasma ANG II levels, and the ANG II type 1 receptor antagonist (losartan) was provided to prevent the activation of ANG II type 1 receptors. Enalapril prevented the increase in plasma ANG II levels but did not protect against ventilator-induced diaphragmatic oxidative stress or diaphragm weakness. In contrast, losartan attenuated both ventilator-induced oxidative stress and diaphragm weakness. These findings indicate that circulating ANG II is not essential for the development of ventilator-induced diaphragm weakness but that activation of ANG II type 1 receptors appears to be a requirement for ventilator-induced diaphragm weakness. Importantly, these experiments provide the first evidence that the Food and Drug Administration-approved drug losartan may have clinical benefits to protect against ventilator-induced diaphragm weakness in humans. PMID:26359481

On a nonlinear model for tumour growth with drug application

NASA Astrophysics Data System (ADS)

Donatelli, Donatella; Trivisa, Konstantina

2015-05-01

We investigate the dynamics of a nonlinear system modelling tumour growth with drug application. The tumour is viewed as a mixture consisting of proliferating, quiescent and dead cells as well as a nutrient in the presence of a drug. The system is given by a multi-phase flow model: the densities of the different cells are governed by a set of transport equations, the density of the nutrient and the density of the drug are governed by rather general diffusion equations, while the velocity of the tumour is given by Brinkman's equation. The domain occupied by the tumour in this setting is a growing continuum Ω with boundary ∂Ω both of which evolve in time. Global-in-time weak solutions are obtained using an approach based on penalization of the boundary behaviour, diffusion and viscosity in the weak formulation. Both the solutions and the domain are rather general, no symmetry assumption is required and the result holds for large initial data. This article is part of a research programme whose aim is the investigation of the effect of drug application in tumour growth.

Pluronic-Functionalized Silica-Lipid Hybrid Microparticles: Improving the Oral Delivery of Poorly Water-Soluble Weak Bases.

PubMed

Rao, Shasha; Richter, Katharina; Nguyen, Tri-Hung; Boyd, Ben J; Porter, Christopher J H; Tan, Angel; Prestidge, Clive A

2015-12-07

A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases.

[Adverse muscle effects of a podofyllotoxin-containing cytotoxic drug product with simvastatin].

PubMed

Kaipiainen-Seppänen, Oili; Savolainen, Elina; Elfving, Pia; Kononoff, Aulikki

2009-01-01

With the ageing population, drug interactions pose an increasing challenge to health professionals. We describe four patients, for whom concurrent administration of a podofyllotoxin-containing cytotoxic drug product and simvastatin caused severe adverse effects on muscles, including muscle pain, soreness or fatigue or weakness, and in some patients also disintegration of muscle tissue, i.e. rhabdomyolysis. The metabolism of both drugs proceeds via the common CYP3A4 enzyme pathway.

Bridging the translational gap: collaborative drug development and dispelling the stigma of commercialization.

PubMed

Yu, Helen W H

2016-02-01

The current drug discovery and development process is stalling the translation of basic science into lifesaving products. Known as the 'Valley of Death', the traditional technology transfer model fails to bridge the gap between early-stage discoveries and preclinical research to advance innovations beyond the discovery phase. In addition, the stigma associated with 'commercialization' detracts from the importance of efficient translation of basic research. Here, I introduce a drug discovery model whereby the respective expertise of academia and industry are brought together to take promising discoveries through to proof of concept as a way to derisk the drug discovery and development process. Known as the 'integrated drug discovery model', I examine here the extent to which existing legal frameworks support this model. Copyright © 2015 Elsevier Ltd. All rights reserved.

The antinociceptive effect of zolpidem and zopiclone in mice.

PubMed

Pick, Chaim G; Chernes, Yakov; Rigai, Tova; Rice, Kenner C; Schreiber, Shaul

2005-07-01

Zolpidem and zopiclone are two of a newer hypno-sedative class of drugs, the "Z compounds". Their use for the treatment of short-term insomnia has been expanding constantly during the last two decades. The "Z compounds" are considered to cause less significant rebound insomnia or tolerance than the conventional hypnotic benzodiazepines. Their possible antinociceptive effect and interaction with the opioid system has not been studied yet. Our results demonstrate a significant difference between the antinociceptive properties of zopiclone and zolpidem when injected s.c. in the hotplate analgesic assay in mice. Zopiclone induced a weak, dose-dependent antinociceptive effect, antagonized only by the alpha2-adrenergic receptor antagonist yohimbine. Zolpidem induced a weak, biphasic dose-dependent antinociceptive effect, antagonized primarily by the non-selective opioid antagonist naloxone and by yohimbine. The weak antinociceptive effect of both drugs, evident only at very high doses (far beyond those used clinically to induce sleep), implies no clinical use for zopiclone or zolpidem in the management of pain. However, the possible interaction of zolpidem with the opioid system should be further investigated (in behavioral models, which do not overlap with the acute-pain antinociception model we used), both for possible side effects in special populations (i.e. elderly) and for possible drug-drug interactions, in order to minimize possible hazards and maximize clinical beneficial effects of its use for sleep.

21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.

Code of Federal Regulations, 2010 CFR

2010-04-01

... an exhaustive review of labeling claims made for drugs marketed under new-drug and antibiotic drug... classification in lieu of the Academy's classification. (d) For new drugs and antibiotics, supplements to provide... purchaser or prescriber is not misled by being left unaware through the sponsor's silence that a basic...

Update on managing Bell's palsy.

PubMed

2008-07-01

Each year in the UK, around 1 in 5,000 people develops Bell's palsy--idiopathic unilateral lower motor neurone facial weakness of rapid onset. Of those who are not treated, about 16% end up with permanent moderate to severe weakness, which can result in facial dysfunction and disfigurement, and psychological difficulties. There has been longstanding controversy about what, if any, treatment should be given, with potential alternatives including corticosteroids, antiviral drugs, acupuncture and physiotherapy. We last reviewed this condition in 2006, indicating that "published trials on the efficacy of drug treatments have been poor and no firm conclusions can be drawn about the benefit of any single drug", and "it is unclear what place, if any, acupuncture and physiotherapy have in the management of patients with Bell's palsy". Here we update our conclusions in the light of recently published evidence.

Cranial Neuropathies and Neuromuscular Weakness: A Case of Mistaken Identity

PubMed Central

Adams, Daniel Z.; King, Andrew; Kaide, Colin

2017-01-01

We describe a case of wound botulism initially thought to represent Miller-Fisher variant Guillain-Barré syndrome (MFS). Botulism classically presents with the so-called “four D’s” (diplopia, dysarthria, dysphagia, dry mouth) with symmetric, descending weakness. MFS presents with a triad of limb-ataxia, areflexia, and ophthalmoplegia, with variable cranial nerve and extremity involvement. The distinction can be difficult but is important as early initiation of botulinum antitoxin is associated with improved patient outcomes in cases of botulism. Furthermore, it is important to recognize intravenous drug use as a risk factor in the development of botulism, especially given an increase in injection drug use. PMID:29849352

Cranial Neuropathies and Neuromuscular Weakness: A Case of Mistaken Identity.

PubMed

Adams, Daniel Z; King, Andrew; Kaide, Colin

2017-08-01

We describe a case of wound botulism initially thought to represent Miller-Fisher variant Guillain-Barré syndrome (MFS). Botulism classically presents with the so-called "four D's" (diplopia, dysarthria, dysphagia, dry mouth) with symmetric, descending weakness. MFS presents with a triad of limb-ataxia, areflexia, and ophthalmoplegia, with variable cranial nerve and extremity involvement. The distinction can be difficult but is important as early initiation of botulinum antitoxin is associated with improved patient outcomes in cases of botulism. Furthermore, it is important to recognize intravenous drug use as a risk factor in the development of botulism, especially given an increase in injection drug use.

Illegal drugs, anti-drug policy failure, and the need for institutional reforms in Colombia.

PubMed

Thoumi, Francisco E

2012-01-01

This paper is inspired by two anomalies encountered in the study of the illegal drugs industry. First, despite the very high profits of coca/cocaine and poppy/opium/heroin production, most countries that can produce do not. Why, for example, does Colombia face much greater competition in the international coffee, banana, and other legal product markets than in cocaine? And second, though illegal drugs are clearly associated with violence, why is it that illegal drug trafficking organizations have been so much more violent in Colombia and Mexico than in the rest of the world? The answers to these questions cannot be found in factors external to Colombia (and Mexico). They require identifying the societal weaknesses of each country. To do so, the history of the illegal drugs industry is surveyed, a simple model of human behavior that stresses the conflict between formal (legal) and informal (socially accepted) norms as a source of the weaknesses that make societies vulnerable is formulated. The reasons why there is a wide gap between formal and informal norms in Colombia are explored and the effectiveness of anti-drug policies is considered to explain why they fail to achieve their posited goals. The essay ends with reflections and conclusion on the need for institutional change.

Weak interactions at high energies. [Lectures, review

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ellis, J.

1978-08-01

Review lectures are presented on the phenomenological implications of the modern spontaneously broken gauge theories of the weak and electromagnetic interactions, and some observations are made about which high energy experiments probe what aspects of gauge theories. Basic quantum chromodynamics phenomenology is covered including momentum dependent effective quark distributions, the transverse momentum cutoff, search for gluons as sources of hadron jets, the status and prospects for the spectroscopy of fundamental fermions and how fermions may be used to probe aspects of the weak and electromagnetic gauge theory, studies of intermediate vector bosons, and miscellaneous possibilities suggested by gauge theories frommore » the Higgs bosons to speculations about proton decay. 187 references. (JFP)« less

Ingenious pH-sensitive dextran/mesoporous silica nanoparticles based drug delivery systems for controlled intracellular drug release.

PubMed

Zhang, Min; Liu, Jia; Kuang, Ying; Li, Qilin; Zheng, Di-Wei; Song, Qiongfang; Chen, Hui; Chen, Xueqin; Xu, Yanglin; Li, Cao; Jiang, Bingbing

2017-05-01

In this work, dextran, a polysaccharide with excellent biocompatibility, is applied as the "gatekeeper" to fabricate the pH-sensitive dextran/mesoporous silica nanoparticles (MSNs) based drug delivery systems for controlled intracellular drug release. Dextran encapsulating on the surface of MSNs is oxidized by NaIO 4 to obtain three kinds of dextran dialdehydes (PADs), which are then coupled with MSNs via pH-sensitive hydrazone bond to fabricate three kinds of drug carriers. At pH 7.4, PADs block the pores to prevent premature release of anti-cancer drug doxorubicin hydrochloride (DOX). However, in the weakly acidic intracellular environment (pH∼5.5) the hydrazone can be ruptured; and the drug can be released from the carriers. The drug loading capacity, entrapment efficiency and release rates of the drug carriers can be adjusted by the amount of NaIO 4 applied in the oxidation reaction. And from which DOX@MSN-NH-N=C-PAD 10 is chosen as the most satisfactory one for the further in vitro cytotoxicity studies and cellular uptake studies. The results demonstrate that DOX@MSN-NH-N=C-PAD 10 with an excellent pH-sensitivity can enter HeLa cells to release DOX intracellular due to the weakly acidic pH intracellular and kill the cells. In our opinion, the ingenious pH-sensitive drug delivery systems have application potentials for cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Introduction to molecular topology: basic concepts and application to drug design.

PubMed

Gálvez, Jorge; Gálvez-Llompart, María; García-Domenech, Ramón

2012-09-01

In this review it is dealt the use of molecular topology (MT) in the selection and design of new drugs. After an introduction of the actual methods used for drug design, the basic concepts of MT are defined, including examples of calculation of topological indices, which are numerical descriptors of molecular structures. The goal is making this calculation familiar to the potential students and allowing a straightforward comprehension of the topic. Finally, the achievements obtained in this field are detailed, so that the reader can figure out the great interest of this approach.

7 CFR 1710.127 - Drug free workplace.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 11 2012-01-01 2012-01-01 false Drug free workplace. 1710.127 Section 1710.127 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF... and Basic Policies § 1710.127 Drug free workplace. Borrowers are required to comply with the Drug Free...

7 CFR 1710.127 - Drug free workplace.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 11 2014-01-01 2014-01-01 false Drug free workplace. 1710.127 Section 1710.127 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF... and Basic Policies § 1710.127 Drug free workplace. Borrowers are required to comply with the Drug Free...

7 CFR 1710.127 - Drug free workplace.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 11 2013-01-01 2013-01-01 false Drug free workplace. 1710.127 Section 1710.127 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF... and Basic Policies § 1710.127 Drug free workplace. Borrowers are required to comply with the Drug Free...

7 CFR 1710.127 - Drug free workplace.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 11 2011-01-01 2011-01-01 false Drug free workplace. 1710.127 Section 1710.127 Agriculture Regulations of the Department of Agriculture (Continued) RURAL UTILITIES SERVICE, DEPARTMENT OF... and Basic Policies § 1710.127 Drug free workplace. Borrowers are required to comply with the Drug Free...

78 FR 64960 - National Institute on Drug Abuse; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-30

... unwarranted invasion of personal privacy. Name of Committee: National Institute on Drug Abuse Special Emphasis..., Ph.D., Scientific Review Officer, Office of Extramural Affairs, National Institute on Drug Abuse, NIH... . Name of Committee: National Institute on Drug Abuse Special Emphasis Panel; CEBRA: Cutting-Edge Basic...

Influence of enteric-coated lactose on the release profile of 4-aminopyridine from HPMC matrix tablets.

PubMed

Martínez-González, Ilona; Villafuerte-Robles, Leopoldo

2004-01-01

A weakly basic experimental drug, 4-aminopyridine, was taken as a model to study the influence of enteric-coated lactose (EL) on the release profile from hydroxypropyl methylcellulose matrices. Powder mixtures were wet-granulated with water. The dried granulation was compressed with a hydraulic press at 85 MPa. Dissolution studies were made using HCl 0.1 N and then phosphate buffer pH 7.4. Dissolution curves were described by M(t)/M(inf) = k*t(N). A trend toward increasing exponent (n) and decreasing release constant (k) values is observed with increasing EL concentrations up to 9%; this is attributed to an increasing obstruction of the diffusion path by isolated EL particles that are insoluble in HCl and are surrounded by a water-filled space. After a critical EL concentration, the water-filled spaces surrounding EL particles percolate, producing the opposite effect, increasing the release constant and decreasing the exponent (n) values as the EL proportion increases from 10% to 50%. EL particles (2% to 9%) decrease the drug and water transport in matrices dissolving in HCl. Thereafter, at pH 7.4, the pores formed by dissolution of EL particles produce the opposite. Both processes contribute to flattening the release profile. Release profiles with decreasing release constant values show a logarithmic trend toward increasing values of the exponent (n), changing from diffusion toward relaxation-erosion-controlled processes.

Selective potentiation of 2-APB-induced activation of TRPV1–3 channels by acid

PubMed Central

Gao, Luna; Yang, Pu; Qin, Peizhong; Lu, Yungang; Li, Xinxin; Tian, Quan; Li, Yang; Xie, Chang; Tian, Jin-bin; Zhang, Chengwei; Tian, Changlin; Zhu, Michael X.; Yao, Jing

2016-01-01

Temperature-sensitive TRP channels are important for responses to pain and inflammation, to both of which tissue acidosis is a major contributing factor. However, except for TRPV1, acid-sensing by other ThermoTRP channels remains mysterious. We show here that unique among TRPV1–3 channels, TRPV3 is directly activated by protons from cytoplasmic side. This effect is very weak and involves key cytoplasmic residues L508, D512, S518, or A520. However, mutations of these residues did not affect a strong proton induced potentiation of TRPV3 currents elicited by the TRPV1–3 common agonist, 2-aminoethoxydiphenyl borate (2-APB), no matter if the ligand was applied from extracellular or cytoplasmic side. The acid potentiation was common among TRPV1–3 and only seen with 2-APB-related ligands. Using 1H-nuclear magnetic resonance to examine the solution structures of 2-APB and its analogs, we observed striking structural differences of the boron-containing compounds at neutral/basic as compared to acidic pH, suggesting that a pH-dependent configuration switch of 2-APB-based drugs may underlie their functionality. Supporting this notion, protons also enhanced the inhibitory action of 2-APB on TRPM8. Collectively, our findings reveal novel insights into 2-APB action on TRP channels, which should facilitate the design of new drugs for these channels. PMID:26876731

[Parenting Information: Drugs. Informacion Para los Padres: Sobre las Drojas.

ERIC Educational Resources Information Center

Moreno, Steve

These two booklets provide basic information about drugs and drug abuse and are part of a series of 22 booklets, designed specifically to help parents understand their children and help them to learn. "Let's Talk about Drug Abuse," (booklet #18), reviews foreign substances or drugs young people are often exposed to (i.e., tobacco,…

Basic evaluation of typical nanoporous silica nanoparticles in being drug carrier: Structure, wettability and hemolysis.

PubMed

Li, Jing; Guo, Yingyu

2017-04-01

Herein, the present work devoted to study the basic capacity of nanoporous silica nanoparticles in being drug carrier that covered structure, wettability and hemolysis so as to provide crucial evaluation. Typical nanoporous silica nanoparticles that consist of nanoporous silica nanoparticles (NSN), amino modified nanoporous silica nanoparticles (amino-NSN), carboxyl modified nanoporous silica nanoparticles (carboxyl-NSN) and hierachical nanoporous silica nanoparticles (hierachical-NSN) were studied. The results showed that their wettability and hemolysis were closely related to structure and surface modification. Basically, wettability became stronger as the amount of OH on the surface of NSN was higher. Both large nanopores and surface modification can reduce the wettability of NSN. Furthermore, NSN series were safe to be used when they circulated into the blood in low concentration, while if high concentration can not be avoided during administration, high porosity or amino modification of NSN were safer to be considered. It is believed that the basic evaluation of NSN can make contribution in providing scientific instruction for designing drug loaded NSN systems. Copyright © 2016 Elsevier B.V. All rights reserved.

Maternal drug use: evaluation of risks to breast-fed infants.

PubMed

Kirksey, A; Groziak, S M

1984-01-01

This paper, based on a review of the literature, evaluates the risks to infants of maternal drug use during lactation. The potential harm of a particular drug to the breastfed infant is related both to the complex mechanism of milk synthesis and secretion and the mode of passage of the drug from plasma into milk. The 1st part of the paper discusses mammary cell and milk synthesis, milk secretion and composition, the mode of passage of drugs into milk, and factors influencing drug concentrations in milk. Drug concentrations in milk are dependent on 6 major factors: drug dosage, proportion bound in plasma, molecular weight, lipid solubility, degree of ionization, and pH difference between plasma and milk. Drugs that are weak acids are ionized to a greater extent and are more protein-bound than weak alkaline drugs. The 2nd part of the paper evaluates the risks to breastfed infants of selected pharmacons. Some categories of drugs that contain pharmacons that should be limited or avoided by nursing mothers are alkylating agents, analgesics and anti-inflammatory agents, anticoagulants, anticonvulsants, anti-infective agents, central nervous system stimulants, hormones, laxatives, minerals, provitamins, psychotherapeutic agents, thyroid affecting agents, and vitamins. The following precautions are suggested to minimize the risks of potentially harmful pharmacons: 1) all unnecessary medications should be avoided by nrusing mothers; 2) if medication is necessary during lactation, drug dosage should be controlled and the infant should be monitored for adverse symptoms; 3) drugs should be administered shortly after breastfeeding and the interval prolonged before the next feeding; and 4) if the infant must be fed soon after a potentially harmful drug has been taken by the mother, bottle feeding is recommended.

Velocity Measurement by Scattering from Index of Refraction Fluctuations Induced in Turbulent Flows

NASA Technical Reports Server (NTRS)

Lading, Lars; Saffman, Mark; Edwards, Robert

1996-01-01

Induced phase screen scattering is defined as scatter light from a weak index of refraction fluctuations induced by turbulence. The basic assumptions and requirements for induced phase screen scattering, including scale requirements, are presented.

Prescription Drug Abuse - Multiple Languages

MedlinePlus

... Spanish) PDF The basics - Opioids, part 1 - English MP3 The basics - Opioids, part 1 - español (Spanish) MP3 The basics - Opioids, part 1 - English MP4 The ... español (Spanish) PDF Pain - Opioids, part 2 - English MP3 Pain - Opioids, part 2 - español (Spanish) MP3 Pain - ...

[Separation of purines, pyrimidines, pterins and flavonoids on magnolol-bonded silica gel stationary phase by high performance liquid chromatography].

PubMed

Chen, Hong; Li, Laishen; Zhang, Yang; Zhou, Rendan

2012-10-01

A new magnolol-bonded silica gel stationary phase (MSP) was used to separate the basic drugs including four purines, eight pyrimidines, four pterins and five flavonoids as polar representative samples by high performance liquid chromatography (HPLC). To clarify the separation mechanism, a commercial ODS column was also tested under the same chromatographic conditions. The high selectivities and fast baseline separations of the above drugs were achieved by using simple mobile phases on MSP. Although there is no end-caped treatment, the peak shapes of basic drugs containing nitrogen such as purines, pyrimidines and pterins were rather symmetrical on MSP, which indicated the the magnolol as ligand with multi-sites could shield the side effect of residual silanol groups on the surface of silica gel. Although somewhat different in the separation resolution, it was found that the elution orders of some drugs were generally similar on both MSP and ODS. The hydrophobic interaction should play a significant role in the separations of the above basic drugs, which was attributed to their reversed-phase property in the nature. However, MSP could provide the additional sites for many polar solutes, which was a rational explanation for the high selectivity of MSP. For example, in the separation of purines, pyrimidines and pterins on MSP, hydrogen-bonding and dipole-dipole interactions played leading roles besides hydrophobic interaction. Some solute molecules (such as mercaptopurine, vitexicarpin) and MSP can form the strong pi-pi stacking in the separation process. All enhanced the retention and improved the separation selectivity of MSP, which facilitated the separation of the basic drugs.

In Vivo Measurement of Drug Efficacy in Breast Cancer

DTIC Science & Technology

2016-10-01

analysis. At the clinical level, this study will result in pertinent data regarding several agents currently in clinical trials. At the basic science ...clinical level, this study will result in pertinent data regarding several agents currently in clinical trials. At the basic science level, we will...mg/kg BLZ-945 or encapsulated drug were tested in BALB/C mice expressing tumors in mammary fat pads, showing limited additional efficacy as seen

Extreme Basicity of Biguanide Drugs in Aqueous Solutions: Ion Transfer Voltammetry and DFT Calculations.

PubMed

Langmaier, Jan; Pižl, Martin; Samec, Zdeněk; Záliš, Stanislav

2016-09-22

Ion transfer voltammetry is used to estimate the acid dissociation constants Ka1 and Ka2 of the mono- and diprotonated forms of the biguanide drugs metformin (MF), phenformin (PF), and 1-phenylbiguanide (PB) in an aqueous solution. Measurements gave the pKa1 values for MFH(+), PFH(+), and PBH(+) characterizing the basicity of MF, PF, and PB, which are significantly higher than those reported in the literature. As a result, the monoprotonated forms of these biguanides should prevail in a considerably broader range of pH 1-15 (MFH(+), PFH(+)) and 2-13 (PBH(+)). DFT calculations with solvent correction were performed for possible tautomeric forms of neutral, monoprotonated, and diprotonated species. Extreme basicity of all drugs is confirmed by DFT calculations of pKa1 for the most stable tautomers of the neutral and protonated forms with explicit water molecules in the first solvation sphere included.

76 FR 81979 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-29

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... Cordova, California 95670, made application to the Drug Enforcement Administration (DEA) as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Thebaine (9333) II Poppy...

76 FR 30970 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-27

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana (7360) I...

77 FR 2324 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-17

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana (7360) I...

Simulating the thermodynamics of charging in weak polyelectrolytes: the Debye-Hückel limit

NASA Astrophysics Data System (ADS)

Rathee, Vikramjit S.; Sikora, Benjamin J.; Sidky, Hythem; Whitmer, Jonathan K.

2018-01-01

The coil-globule transition in weak (annealed) polyelectrolytes involves a subtle balance of pH, charge strength, and solvation forces. In this work, we utilize a coarse-grained hybrid grand-canonical Monte Carlo and molecular dynamics approach to explore the swelling behavior of weak linear and star polyelectrolytes under different ionic screening conditions and pH. Importantly, we are able to quantify topology-dependent effects in charging which arise at the core of star polymers. Our results are suggestive of suppression of charging in star weak polyelectrolytes in comparison to linear weak polyelectrolytes. Furthermore, we characterize the coil-globule transition in linear and star weak polyelectrolyte through expanded ensemble density-of-states simulations which suggest a change from a first order to second order phase transition moving from linear to star polyelectrolytes. Lastly, we characterize the inhomogeneous charging across the weak star polyelectrolyte through observed shifts in {{Δ }}{{{pK}}}{{o}}, and compare with experimental work. We discuss these results in relation to surfaces functionalized by weak polyelectrolyte brushes and weak polyelectrolyte-based drug delivery applications.

HIV Treatment: The Basics

MedlinePlus

... AIDS Drugs Clinical Trials Apps skip to content HIV Treatment Home Understanding HIV/AIDS Fact Sheets HIV ... 4 p.m. ET) Send us an email HIV Treatment: The Basics Last Reviewed: March 22, 2018 ...

Information needs for making clinical recommendations about potential drug-drug interactions: a synthesis of literature review and interviews.

PubMed

Romagnoli, Katrina M; Nelson, Scott D; Hines, Lisa; Empey, Philip; Boyce, Richard D; Hochheiser, Harry

2017-02-22

Drug information compendia and drug-drug interaction information databases are critical resources for clinicians and pharmacists working to avoid adverse events due to exposure to potential drug-drug interactions (PDDIs). Our goal is to develop information models, annotated data, and search tools that will facilitate the interpretation of PDDI information. To better understand the information needs and work practices of specialists who search and synthesize PDDI evidence for drug information resources, we conducted an inquiry that combined a thematic analysis of published literature with unstructured interviews. Starting from an initial set of relevant articles, we developed search terms and conducted a literature search. Two reviewers conducted a thematic analysis of included articles. Unstructured interviews with drug information experts were conducted and similarly coded. Information needs, work processes, and indicators of potential strengths and weaknesses of information systems were identified. Review of 92 papers and 10 interviews identified 56 categories of information needs related to the interpretation of PDDI information including drug and interaction information; study design; evidence including clinical details, quality and content of reports, and consequences; and potential recommendations. We also identified strengths/weaknesses of PDDI information systems. We identified the kinds of information that might be most effective for summarizing PDDIs. The drug information experts we interviewed had differing goals, suggesting a need for detailed information models and flexible presentations. Several information needs not discussed in previous work were identified, including temporal overlaps in drug administration, biological plausibility of interactions, and assessment of the quality and content of reports. Richly structured depictions of PDDI information may help drug information experts more effectively interpret data and develop recommendations. Effective information models and system designs will be needed to maximize the utility of this information.

Adsorption of drugs onto a pH responsive poly(N,N-dimethyl aminoethyl methacrylate) grafted anion-exchange membrane in vitro.

PubMed

Karppi, Jouni; Akerman, Satu; Akerman, Kari; Sundell, Annika; Nyyssönen, Kristiina; Penttilä, Ilkka

2007-06-29

The influence of charge and lipophilicity of acidic and basic model drugs on their adsorption onto poly(N,N-dimethyl aminoethyl methacrylic acid) grafted poly(vinylidene fluoride) (DMAEMA-PVDF) membranes was evaluated. The effect of serum proteins (albumin, IgG) and hormones (cortisol, free thyroxine (T(4)F) and thyrotropin (TSH)) on drug adsorption was also studied. Acidic model drugs (antiepileptics and benzodiazepies) adsorbed to a greater extent onto the membrane from Hepes buffer at ionic strength of 25mM and pH 7.0 than basic drugs (antidepressants) did. Adsorption of acidic model drugs was based on electrostatic interactions between positively charged tertiary amino groups of DMAEMA side-chain and acidic negatively charged drug. Albumin diminished the adsorption of drugs from serum onto the membrane. Lipophilicity was related to the adsorption of acidic model drugs from serum onto the membrane. The degree of grafting had the greatest effect on adsorption of lipophilic drugs, but no influence was observed on adsorption of hydrophilic drugs. The present results showed that acidic drugs and albumin adsorbed onto the membrane, which suggests that the PVDF-DMAEMA membrane may be suitable for separating acidic drugs from protein-free substances for subsequent monitoring and evaluation.

Student Drug and Alcohol Abuse. How Schools Can Help Combat Series.

ERIC Educational Resources Information Center

Towers, Richard L.

This book was written to help school personnel combat drug and alcohol abuse among students. It gives readers a basic understanding of drugs and their effects on the mind and body. The stages of chemical dependency and the vocabulary of the drug scene are reviewed and reasons that children and adolescents take drugs are discussed. Signs of student…

Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications.

PubMed

Kawabata, Yohei; Wada, Koichi; Nakatani, Manabu; Yamada, Shizuo; Onoue, Satomi

2011-11-25

The poor oral bioavailability arising from poor aqueous solubility should make drug research and development more difficult. Various approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs. To complete development works within a limited amount of time, the establishment of a suitable formulation strategy should be a key consideration for the pharmaceutical development of poorly water-soluble drugs. In this article, viable formulation options are reviewed on the basis of the biopharmaceutics classification system of drug substances. The article describes the basic approaches for poorly water-soluble drugs, such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification. Literature-based examples of the formulation options for poorly water-soluble compounds and their practical application to marketed products are also provided. Classification of drug candidates based on their biopharmaceutical properties can provide an indication of the difficulty of drug development works. A better understanding of the physicochemical and biopharmaceutical properties of drug substances and the limitations of each delivery option should lead to efficient formulation development for poorly water-soluble drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

Soluble Synthetic Analogs of Malaria Pigment: Structure of Mesohematin Anhydride [FeIII(MP-IX)]2 and Solution Interaction with Chloroquine

DOE Office of Scientific and Technical Information (OSTI.GOV)

D Bohle; E Dodd; A Kosar

Changing the vinyl groups of hematin anhydride to either ethyl or hydrogen groups results in increased solubility (Por=porphyrin). Determination of the weak binding constants of the antimalarial drug chloroquine to dimers of these hematin anhydride analogues suggests that solution-phase heme/drug interactions alone are unlikely to be the origin of the action of the drug.

Pharmaceutical applications of cyclodextrins: basic science and product development.

PubMed

Loftsson, Thorsteinn; Brewster, Marcus E

2010-11-01

Drug pipelines are becoming increasingly difficult to formulate. This is punctuated by both retrospective and prospective analyses that show that while 40% of currently marketed drugs are poorly soluble based on the definition of the biopharmaceutical classification system (BCS), about 90% of drugs in development can be characterized as poorly soluble. Although a number of techniques have been suggested for increasing oral bioavailability and for enabling parenteral formulations, cyclodextrins have emerged as a productive approach. This short review is intended to provide both some basic science information as well as data on the ability to develop drugs in cyclodextrin-containing formulations. There are currently a number of marketed products that make use of these functional solubilizing excipients and new product introduction continues to demonstrate their high added value. The ability to predict whether cyclodextrins will be of benefit in creating a dosage form for a particular drug candidate requires a good working knowledge of the properties of cyclodextrins, their mechanism of solubilization and factors that contribute to, or detract from, the biopharmaceutical characteristics of the formed complexes. We provide basic science information as well as data on the development of drugs in cyclodextrin-containing formulations. Cyclodextrins have emerged as an important tool in the formulator's armamentarium to improve apparent solubility and dissolution rate for poorly water-soluble drug candidates. The continued interest and productivity of these materials bode well for future application and their currency as excipients in research, development and drug product marketing. © 2010 The Authors. Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain.

75 FR 75498 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-03

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... 23805-9372, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the basic classes of controlled substances: Drug Schedule Amphetamine (1100...

76 FR 7234 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-09

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of... 08066-1742, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Phenylacetone...

76 FR 7233 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-09

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of..., made application by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Methamphetamine (1105) II...

78 FR 52802 - Manufacturer of Controlled Substances; Notice of Registration: Navinta, LLC

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-26

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., made application to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Pentobarbital (2270) II...

76 FR 77258 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-12

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Tetrahydrocannabinols (7370) I 3,4...

76 FR 7234 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-09

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Codeine-N-oxide (9053) I...

78 FR 69134 - Manufacturer of Controlled Substances; Notice of Registration; Apertus Pharmaceuticals

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-18

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., Missouri 63011, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule...

The potential influence of CO2, as an agent for euthanasia, on the pharmacokinetics of basic compounds in rodents.

PubMed

Angus, Derek W; Baker, James A; Mason, Rona; Martin, Iain J

2008-02-01

Rodent tissue distribution and pharmacokinetic studies were performed on basic compounds Org A and Org B in support of central nervous system drug discovery programs. A consistent observation from these studies was that drug concentrations in plasma obtained by cardiac puncture after CO(2) euthanasia were markedly higher compared with those from other sampling methods (serial sampling, isoflurane anesthesia, or cervical dislocation). Further investigations demonstrated that CO(2) euthanasia led to a reduction in blood pH in both rats and mice, which was not observed with the other sampling methods. The use of CO(2) euthanasia resulted in a decrease in the brain/plasma ratio of Org B, largely as a result of increased plasma concentrations. The pharmacokinetics of a basic drug, raloxifene, in rat were also influenced by sampling technique. CO(2) euthanasia before sampling, resulted in a 2- to 3-fold increase in the area under the drug concentration-time curve, a decrease in plasma clearance, and a decrease in the steady-state volume of distribution compared with isoflurane anesthesia. It is proposed that a decrease in the pH of blood relative to that of other tissues, as a consequence of CO(2) exposure, results in a redistribution of basic compounds out of the tissues, leading to higher concentrations in plasma.

Quantitative structure-permeability relationships at various pH values for acidic and basic drugs and drug-like compounds.

PubMed

Oja, M; Maran, U

2015-01-01

Absorption in gastrointestinal tract compartments varies and is largely influenced by pH. Therefore, considering pH in studies and analyses of membrane permeability provides an opportunity to gain a better understanding of the behaviour of compounds and to obtain good permeability estimates for prediction purposes. This study concentrates on relationships between the chemical structure and membrane permeability of acidic and basic drugs and drug-like compounds. The membrane permeability of 36 acidic and 61 basic compounds was measured using the parallel artificial membrane permeability assay (PAMPA) at pH 3, 5, 7.4 and 9. Descriptive and/or predictive single-parameter quantitative structure-permeability relationships were derived for all pH values. For acidic compounds, membrane permeability is mainly influenced by hydrogen bond donor properties, as revealed by models with r(2) > 0.8 for pH 3 and pH 5. For basic compounds, the best (r(2) > 0.7) structure-permeability relationships are obtained with the octanol-water distribution coefficient for pH 7.4 and pH 9, indicating the importance of partition properties. In addition to the validation set, the prediction quality of the developed models was tested with folic acid and astemizole, showing good matches between experimental and calculated membrane permeabilities at key pHs. Selected QSAR models are available at the QsarDB repository ( http://dx.doi.org/10.15152/QDB.166 ).

Is dependence on one drug associated with dependence on other drugs? The cases of alcohol, caffeine and nicotine.

PubMed

Hughes, J R; Oliveto, A H; MacLaughlin, M

2000-01-01

Several studies have correlated the use of one drug with that of another drug; however, whether dependence on one drug is associated with dependence on another drug, independent of any use/use association, is unclear. We asked 196 randomly-selected subjects the DSM-IV criteria for dependence as applied to alcohol, caffeine, and nicotine. Among ever users, the severity of alcohol vs nicotine dependence and alcohol vs caffeine dependence was related, but this relationship was weak (r = .22 & .31). Nicotine and caffeine dependence were not correlated. These results fail to confirm theories of commonality that hypothesize dependence on one drug predisposes to dependence on another drug.

Antiviral drug research proposal activity.

PubMed

Injaian, Lisa; Smith, Ann C; Shipley, Jennifer German; Marbach-Ad, Gili; Fredericksen, Brenda

2011-01-01

The development of antiviral drugs provides an excellent example of how basic and clinical research must be used together in order to achieve the final goal of treating disease. A Research Oriented Learning Activity was designed to help students to better understand how basic and clinical research can be combined toward a common goal. Through this project students gained a better understanding of the process of scientific research and increased their information literacy in the field of virology. The students worked as teams to research the many aspects involved in the antiviral drug design process, with each student becoming an "expert" in one aspect of the project. The Antiviral Drug Research Proposal (ADRP) culminated with students presenting their proposals to their peers and local virologists in a poster session. Assessment data showed increased student awareness and knowledge of the research process and the steps involved in the development of antiviral drugs as a result of this activity.

Antiviral Drug Research Proposal Activity †

PubMed Central

Injaian, Lisa; Smith, Ann C.; Shipley, Jennifer German; Marbach-Ad, Gili; Fredericksen, Brenda

2011-01-01

The development of antiviral drugs provides an excellent example of how basic and clinical research must be used together in order to achieve the final goal of treating disease. A Research Oriented Learning Activity was designed to help students to better understand how basic and clinical research can be combined toward a common goal. Through this project students gained a better understanding of the process of scientific research and increased their information literacy in the field of virology. The students worked as teams to research the many aspects involved in the antiviral drug design process, with each student becoming an “expert” in one aspect of the project. The Antiviral Drug Research Proposal (ADRP) culminated with students presenting their proposals to their peers and local virologists in a poster session. Assessment data showed increased student awareness and knowledge of the research process and the steps involved in the development of antiviral drugs as a result of this activity. PMID:23653735

Drug Treatment Centers in Afghanistan: Creating a Participatory Approach to Tackling the Drug Trade

DTIC Science & Technology

2012-12-01

Anti-Government Forces AIDS: Acquired Immunodeficiency Syndrome ANP: Afghan National Police ART: Anti-Retroviral Treatment BPHS: Basic Package of...treatment centers do performance reviews, corruption within the drug treatment clinics, and how management monitor staff burnout . While clinical governance

76 FR 30969 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-27

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of... renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Phenylacetone (8501) II Coca Leaves (9040) II...

75 FR 10313 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-05

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the basic classes of controlled substances listed in schedules I and II: Drug Schedule Gamma...

76 FR 77253 - Importer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-12

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of... application by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Noroxymorphone (9668) II Sufentanil (9740...

78 FR 23958 - Manufacturer of Controlled Substances; Notice of Registration; S & B Pharma Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-23

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances...-3232, made application to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Gamma Hydroxybutyric Acid...

77 FR 60145 - Manufacturer of Controlled Substances; Notice of Registration; Apertus Pharmaceuticals, LLC

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-02

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., Missouri 63011, made application to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Alfentanil (9737) II...

77 FR 30028 - Manufacturer of Controlled Substances; Notice of Registration; Johnson Matthey, Inc...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-21

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Gamma Hydroxybutyric Acid (2010) I Amphetamine (1100) II...

77 FR 30028 - Manufacturer of Controlled Substances; Notice of Registration; Cedarburg Pharmaceuticals, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-21

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... Circle, Grafton, Wisconsin 53024, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug...

77 FR 64144 - Manufacturer of Controlled Substances; Notice of Registration; Lin Zhi International, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-18

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., California 94085, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the basic classes of controlled substances: Drug Schedule...

78 FR 5500 - Manufacturer of Controlled Substances; Notice of Registration; Noramco, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-25

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... 19801-4417, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Codeine-N...

78 FR 23959 - Manufacturer of Controlled Substances; Notice of Registration; PCAS-Nanosyn, LLC

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-23

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., California 95403, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule...

75 FR 10314 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-05

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... 94085, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the basic classes of controlled substances listed in schedules I and II: Drug...

78 FR 23597 - Manufacturer of Controlled Substances, Notice of Registration, National Center for Natural...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-19

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., Mississippi 38677, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule...

77 FR 31390 - Manufacturer of Controlled Substances; Notice of Registration; Pcas-Nanosyn, LLC

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-25

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., California 95403, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule...

Small Molecule Docking from Theoretical Structural Models

NASA Astrophysics Data System (ADS)

Novoa, Eva Maria; de Pouplana, Lluis Ribas; Orozco, Modesto

Structural approaches to rational drug design rely on the basic assumption that pharmacological activity requires, as necessary but not sufficient condition, the binding of a drug to one or several cellular targets, proteins in most cases. The traditional paradigm assumes that drugs that interact only with a single cellular target are specific and accordingly have little secondary effects, while promiscuous molecules are more likely to generate undesirable side effects. However, current examples indicate that often efficient drugs are able to interact with several biological targets [1] and in fact some dirty drugs, such as chlorpromazine, dextromethorphan, and ibogaine exhibit desired pharmacological properties [2]. These considerations highlight the tremendous difficulty of designing small molecules that both have satisfactory ADME properties and the ability of interacting with a limited set of target proteins with a high affinity, avoiding at the same time undesirable interactions with other proteins. In this complex and challenging scenario, computer simulations emerge as the basic tool to guide medicinal chemists during the drug discovery process.

Associations Between Long-Term Gang Membership and Informal Social Control Processes, Drug Use, and Delinquent Behavior Among Mexican American Youth

PubMed Central

Cepeda, Alice; Saint Onge, Jarron M.; Nowotny, Kathryn M.; Valdez, Avelardo

2018-01-01

Research has found that among juveniles weak ties to informal social control entities such as parents, school, and conventional peers increase the probability of the initiation and continuation of deviant behaviors such as drug use and crime. Given the weak ties of formal social control mechanisms in highly disadvantaged communities, informal social control mechanisms are often an important deterrent that reduce or moderate engagement in deviant behaviors among serious and persistent offenders. This analysis examines the association between long-term gang membership and adolescent informal social control processes, drug use, and delinquency. This research is based on data from a study of 160 Mexican American male gang members between the ages of 16 and 20. Findings suggest that among gang members in this context, commonly studied informal control mechanisms such as the family and schools do not function to deter long-term gang membership that is associated with serious criminal and violent behavior and drug use. The implications for future research on desistance or continuation of antisocial behavior across the life course are discussed. PMID:25979430

Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline.

PubMed

Sateia, Michael J; Buysse, Daniel J; Krystal, Andrew D; Neubauer, David N; Heald, Jonathan L

2017-02-15

The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults, when such treatment is clinically indicated. Unlike previous meta-analyses, which focused on broad classes of drugs, this guideline focuses on individual drugs commonly used to treat insomnia. It includes drugs that are FDA-approved for the treatment of insomnia, as well as several drugs commonly used to treat insomnia without an FDA indication for this condition. This guideline should be used in conjunction with other AASM guidelines on the evaluation and treatment of chronic insomnia in adults. The American Academy of Sleep Medicine commissioned a task force of four experts in sleep medicine. A systematic review was conducted to identify randomized controlled trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence. The task force developed recommendations and assigned strengths based on the quality of evidence, the balance of benefits and harms, and patient values and preferences. Literature reviews are provided for those pharmacologic agents for which sufficient evidence was available to establish recommendations. The AASM Board of Directors approved the final recommendations. The following recommendations are intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment of chronic insomnia in adults, when such treatment is indicated. Under GRADE, a STRONG recommendation is one that clinicians should, under most circumstances, follow. A WEAK recommendation reflects a lower degree of certainty in the outcome and appropriateness of the patient-care strategy for all patients, but should not be construed as an indication of ineffectiveness. GRADE recommendation strengths do not refer to the magnitude of treatment effects in a particular patient, but rather, to the strength of evidence in published data. Downgrading the quality of evidence for these treatments is predictable in GRADE, due to the funding source for most pharmacological clinical trials and the attendant risk of publication bias; the relatively small number of eligible trials for each individual agent; and the observed heterogeneity in the data. The ultimate judgment regarding propriety of any specific care must be made by the clinician in light of the individual circumstances presented by the patient, available diagnostic tools, accessible treatment options, and resources. We suggest that clinicians use suvorexant as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use eszopiclone as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use zaleplon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use zolpidem as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use triazolam as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use temazepam as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use ramelteon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians use doxepin as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use trazodone as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use tiagabine as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use diphenhydramine as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use melatonin as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use tryptophan as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). We suggest that clinicians not use valerian as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK). © 2017 American Academy of Sleep Medicine

Psychology of Terrorism

DTIC Science & Technology

2007-12-14

society.” Sigmund Freud (1927, p.7) -The basic idea that will be developed in this essay is that a symbolic equation is unconsciously made between acts...and criminology literature, this model has weak logical, theoretical, and empirical foundations. -The enemy that we see, according to Freud , is

Improving Biopharmaceutical Properties of Vinpocetine Through Cocrystallization.

PubMed

Golob, Samuel; Perry, Miranda; Lusi, Matteo; Chierotti, Michele R; Grabnar, Iztok; Lassiani, Lucia; Voinovich, Dario; Zaworotko, Michael J

2016-12-01

Vinpocetine is a poorly water soluble weakly basic drug (pK a  = 7.1) used for the treatment of several cerebrovascular and cognitive disorders. Because existing formulations exhibit poor bioavailability and scarce absorption, a dosage form with improved pharmacokinetic properties is highly desirable. Cocrystallization represents a promising approach to generate diverse novel crystal forms and to improve the aqueous solubility and in turn the oral bioavailability. In this article, a novel ionic cocrystal of vinpocetine is described, using boric acid as a coformer, and fully characterized (by means of differential scanning calorimetry, solid-state nuclear magnetic resonance, powder and single-crystal X-ray diffraction, and powder dissolution test). Pharmacokinetic performance was also tested in a human pilot study. This pharmaceutical ionic cocrystal exhibits superior solubilization kinetics and modulates important pharmacokinetic values such as maximum concentration in plasma (C max ), time to maximum concentration (t max ), and area under the plasma concentration-time curve (AUC) of the poorly soluble vinpocetine and it therefore offers an innovative approach to improve its bioavailability. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride.

PubMed

Sáez, C; González-Baena, A C; Japón, M A; Giráldez, J; Segura, D I; Rodríguez-Vallejo, J M; González-Esteban, J; Miranda, G; Torrubia, F

1999-07-01

The development of benign prostatic hyperplasia (BPH) is an androgen-dependent process which may be mediated by a number of locally produced growth factors. One of these, the basic fibroblast growth factor (bFGF or FGF2), has a mitogenic effect on prostatic stroma. High expression levels of bFGF have been reported in BPH. FGFR1 and FGFR2 receptors, that exhibit affinity for bFGF, have been identified in normal and hyperplastic prostate. Finasteride, a 5alpha-reductase inhibitor, is an effective drug in the treatment of BPH, inducing regressive changes in the prostate of treated patients, even though its mechanisms of action are not yet completely elucidated. This study was designed to assess the effects of finasteride on the expression levels of bFGF, FGFR1, and FGFR2 in patients with BPH. The expression levels of bFGF, FGFR1, and FGFR2 in 9 patients with prostatic hyperplasia treated with finasteride were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA expression and were compared with those of 9 control patients with untreated BPH. Immunohistochemistry showed strong bFGF immunoreactivity in the prostatic stroma of untreated patients, this being somewhat weaker in the epithelium. In treated patients, epithelial immunoreactivity was practically negative, and a considerable reduction in stromal immunoreactivity was seen. These findings were also confirmed by RT-PCR. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR2 exhibited strong stromal immunoreactivity, becoming weaker in the basal epithelium. No differences were seen in the expression of both receptors between the groups of treated and untreated patients. A marked reduction in bFGF levels is seen in BPH treated with finasteride in comparison to untreated BPH. In our opinion, finasteride may act as a negative regulator of bFGF expression, counteracting the role of bFGF in the development of BPH.

Bridging the Gap Between Science and Clinical Efficacy: Physiology, Imaging, and Modeling of Aerosols in the Lung.

PubMed

Darquenne, Chantal; Fleming, John S; Katz, Ira; Martin, Andrew R; Schroeter, Jeffry; Usmani, Omar S; Venegas, Jose; Schmid, Otmar

2016-04-01

Development of a new drug for the treatment of lung disease is a complex and time consuming process involving numerous disciplines of basic and applied sciences. During the 2015 Congress of the International Society for Aerosols in Medicine, a group of experts including aerosol scientists, physiologists, modelers, imagers, and clinicians participated in a workshop aiming at bridging the gap between basic research and clinical efficacy of inhaled drugs. This publication summarizes the current consensus on the topic. It begins with a short description of basic concepts of aerosol transport and a discussion on targeting strategies of inhaled aerosols to the lungs. It is followed by a description of both computational and biological lung models, and the use of imaging techniques to determine aerosol deposition distribution (ADD) in the lung. Finally, the importance of ADD to clinical efficacy is discussed. Several gaps were identified between basic science and clinical efficacy. One gap between scientific research aimed at predicting, controlling, and measuring ADD and the clinical use of inhaled aerosols is the considerable challenge of obtaining, in a single study, accurate information describing the optimal lung regions to be targeted, the effectiveness of targeting determined from ADD, and some measure of the drug's effectiveness. Other identified gaps were the language and methodology barriers that exist among disciplines, along with the significant regulatory hurdles that need to be overcome for novel drugs and/or therapies to reach the marketplace and benefit the patient. Despite these gaps, much progress has been made in recent years to improve clinical efficacy of inhaled drugs. Also, the recent efforts by many funding agencies and industry to support multidisciplinary networks including basic science researchers, R&D scientists, and clinicians will go a long way to further reduce the gap between science and clinical efficacy.

Bridging the Gap Between Science and Clinical Efficacy: Physiology, Imaging, and Modeling of Aerosols in the Lung

PubMed Central

Fleming, John S.; Katz, Ira; Martin, Andrew R.; Schroeter, Jeffry; Usmani, Omar S.; Venegas, Jose

2016-01-01

Abstract Development of a new drug for the treatment of lung disease is a complex and time consuming process involving numerous disciplines of basic and applied sciences. During the 2015 Congress of the International Society for Aerosols in Medicine, a group of experts including aerosol scientists, physiologists, modelers, imagers, and clinicians participated in a workshop aiming at bridging the gap between basic research and clinical efficacy of inhaled drugs. This publication summarizes the current consensus on the topic. It begins with a short description of basic concepts of aerosol transport and a discussion on targeting strategies of inhaled aerosols to the lungs. It is followed by a description of both computational and biological lung models, and the use of imaging techniques to determine aerosol deposition distribution (ADD) in the lung. Finally, the importance of ADD to clinical efficacy is discussed. Several gaps were identified between basic science and clinical efficacy. One gap between scientific research aimed at predicting, controlling, and measuring ADD and the clinical use of inhaled aerosols is the considerable challenge of obtaining, in a single study, accurate information describing the optimal lung regions to be targeted, the effectiveness of targeting determined from ADD, and some measure of the drug's effectiveness. Other identified gaps were the language and methodology barriers that exist among disciplines, along with the significant regulatory hurdles that need to be overcome for novel drugs and/or therapies to reach the marketplace and benefit the patient. Despite these gaps, much progress has been made in recent years to improve clinical efficacy of inhaled drugs. Also, the recent efforts by many funding agencies and industry to support multidisciplinary networks including basic science researchers, R&D scientists, and clinicians will go a long way to further reduce the gap between science and clinical efficacy. PMID:26829187

Toward an In Vivo Dissolution Methodology: A Comparison of Phosphate and Bicarbonate Buffers

PubMed Central

Sheng, Jennifer J.; McNamara, Daniel P.; Amidon, Gordon L.

2011-01-01

Purpose To evaluate the difference between the pharmaceutical phosphate buffers and the gastrointestinal bicarbonates in dissolution of ketoprofen and indomethacin, to illustrate the dependence of buffer differential on biopharmaceutical properties of BCS II weak acids, and to recommend phosphate buffers equivalent to bicarbonates. Methods The intrinsic dissolution rates of, ketoprofen and indomethacin, were experimentally measured using rotating disk method at 37°C in USP SIF/FaSSIF and various concentrations of bicarbonates. Theoretical models including an improved reaction plane model and a film model were applied to estimate the surrogate phosphate buffers equivalent to the bicarbonates. Results Experimental results show that the intrinsic dissolution rates of ketoprofen and indomethacin, in USP and FaSSIF phosphate buffers are 1.5–3.0 times of that in the 15 mM bicarbonates. Theoretical analysis demonstrates that the buffer differential is largely dependent on the drug pKa and secondly on solubility, and weakly dependent on the drug diffusivity. Further, in accordance with the drug pKa, solubility and diffusivity, simple phosphate surrogate was proposed to match an average bicarbonate value (15 mM) of the upper gastrointestinal region. Specifically, phosphate buffers of 13–15 mM and 3–4 mM were recommended for ketoprofen and indomethacin, respectively. For both ketoprofen and indomethacin, the intrinsic dissolution using the phosphate surrogate buffers closely approximated the 15 mM bicarbonate buffer. Conclusions This work demonstrates the substantial difference between pharmaceutical phosphates and physiological bicarbonates in determining the drug intrinsic dissolution rates of BCS II weak acids, such as ketoprofen and indomethacin. Surrogate phosphates were recommended in order to closely reflect the in vivo dissolution of ketoprofen and indomethacin in gastrointestinal bicarbonates, which has significant implications for defining buffer systems for BCS II weak acids in developing in vitro bioequivalence dissolution methodology. PMID:19183104

Drug Abuse Information, Teacher Resource Material.

ERIC Educational Resources Information Center

Bowen, Haskell, Comp.

This informational publication is to be used as an aid for teachers, bringing them basic facts regarding drugs and drug abuse. Its purpose is to (1) give additional teacher background information and (2) enrich any course of study that has been developed on drug abuse. To use the material most effectively, it is suggested the teacher have an…

A Role for Weak Electrostatic Interactions in Peripheral Membrane Protein Binding

PubMed Central

Khan, Hanif M.; He, Tao; Fuglebakk, Edvin; Grauffel, Cédric; Yang, Boqian; Roberts, Mary F.; Gershenson, Anne; Reuter, Nathalie

2016-01-01

Bacillus thuringiensis phosphatidylinositol-specific phospholipase C (BtPI-PLC) is a secreted virulence factor that binds specifically to phosphatidylcholine (PC) bilayers containing negatively charged phospholipids. BtPI-PLC carries a negative net charge and its interfacial binding site has no obvious cluster of basic residues. Continuum electrostatic calculations show that, as expected, nonspecific electrostatic interactions between BtPI-PLC and membranes vary as a function of the fraction of anionic lipids present in the bilayers. Yet they are strikingly weak, with a calculated ΔGel below 1 kcal/mol, largely due to a single lysine (K44). When K44 is mutated to alanine, the equilibrium dissociation constant for small unilamellar vesicles increases more than 50 times (∼2.4 kcal/mol), suggesting that interactions between K44 and lipids are not merely electrostatic. Comparisons of molecular-dynamics simulations performed using different lipid compositions reveal that the bilayer composition does not affect either hydrogen bonds or hydrophobic contacts between the protein interfacial binding site and bilayers. However, the occupancies of cation-π interactions between PC choline headgroups and protein tyrosines vary as a function of PC content. The overall contribution of basic residues to binding affinity is also context dependent and cannot be approximated by a rule-of-thumb value because these residues can contribute to both nonspecific electrostatic and short-range protein-lipid interactions. Additionally, statistics on the distribution of basic amino acids in a data set of membrane-binding domains reveal that weak electrostatics, as observed for BtPI-PLC, might be a less unusual mechanism for peripheral membrane binding than is generally thought. PMID:27028646

[Improve the accessibility of essential drugs for the populations of one medical region in Burkina Faso].

PubMed

Ridde, Valéry; Nitièma, Abdoulaye P; Dadjoari, Moussa

2005-01-01

Despite the formulation of the Bamako initiative in 1992 in Burkina Faso, not until 2001 and the launching of a project by a nongovernmental organization was the policy really implemented in a region of the country. One of the goals of this policy is to improve access to health care by using generic essential drugs. The objective of this article is to summarize the results of the evaluation of the project's ability to improve the population's access to drugs. The project lasted three years (2001-2003) and the interventions took place in 41 basic health centres of three districts. According to WHO, improving access to drugs requires consideration of four essential factors: rational use, affordable prices, financial viability, and effectiveness of the distribution. The average number of drugs prescribed per prescription sheet (n = 1061) was 2.4; 93% of the drugs were prescribed by their generic name (international non-proprietary names); 44% of infant diarrheas were treated with oral rehydration salt. National drug prices were respected but not the directives aiming at exempting from payment or subsidizing certain population sub-groups (children, indigents). The average annual cash flow of the basic health centres was 1.2 million F CFA and it increased by 854% compared to the beginning of the project. The cost-recovery scheme for administrative expenses was 106%. The average annual availability of the 10 essential drugs was 89%. Utilization rates increased (0.13 in 1999 to 0.21 in 2003) but not significantly differently than in other basic health centres of the area not supported by the project (p = 0.084). The project succeeded in improving access to these drugs for the overall population but not for the worst-off. The drugs are now geographically available for all and financially accessible for those who can afford to pay. The intervention strategy supported the sustainability of the project's activities but much remains to be done to provide the poorest with access to drugs.

76 FR 62449 - Manufacturer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-07

... basic classes of controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to cultivate marihuana for the National Institute on Drug Abuse for research...

21 CFR 177.1850 - Textryls.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Textryls. 177.1850 Section 177.1850 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) INDIRECT FOOD ADDITIVES: POLYMERS Substances for Use as Basic Components of Single and...

77 FR 12621 - Importer of Controlled Substances; Notice of Registration; Mylan Pharmaceuticals Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-01

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of..., Morgantown, West Virginia 26505, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule...

77 FR 60145 - Manufacturer of Controlled Substances ISP, Inc.; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-02

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances ISP... application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule 2,5-Dimethoxyamphetamine (7396) I...

77 FR 47116 - Manufacturer of Controlled Substances; Notice of Registration; Cambrex Charles City, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-07

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... City, Iowa 50616, made application by letter to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule...

77 FR 40087 - Manufacturer of Controlled Substances; Notice of Registration; Cerilliant Corporation

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-06

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances... Rock, Texas 78665-2402, made application by letter to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule 4...

77 FR 31389 - Importer of Controlled Substances; Notice of Registration; Penick Corporation

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-25

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of..., made application by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Coca Leaves (9040) II Raw...

75 FR 10312 - Importer of Controlled Substances Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-05

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances Notice of... by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the basic classes of controlled substances listed in schedule II: Drug Schedule Opium, raw (9600) II Poppy Straw...

77 FR 50163 - Manufacturer of Controlled Substances, Notice of Registration, Cody Laboratories, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-20

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., Wyoming 82414, made application by letter to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule 4-Anilino...

77 FR 13633 - Manufacturer of Controlled Substances; Notice of Registration; National Center for Natural...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-07

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., University, Mississippi 38677, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule...

77 FR 70187 - Importer of Controlled Substances; Notice of Registration; Lipomed, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-23

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of... letter to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Bufotenine (7433) I Diethyltryptamine (7434) I 1...

77 FR 70187 - Importer of Controlled Substances; Notice of Registration; Mylan Technologies, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-23

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of..., made application by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Methylphenidate (1724) II...

77 FR 30028 - Manufacturer of Controlled Substances; Notice of Registration; Cambrex Charles City, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-21

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., Charles City, Iowa 50616, made application by letter to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule...

Recent advances in inkjet dispensing technologies: applications in drug discovery.

PubMed

Zhu, Xiangcheng; Zheng, Qiang; Yang, Hu; Cai, Jin; Huang, Lei; Duan, Yanwen; Xu, Zhinan; Cen, Peilin

2012-09-01

Inkjet dispensing technology is a promising fabrication methodology widely applied in drug discovery. The automated programmable characteristics and high-throughput efficiency makes this approach potentially very useful in miniaturizing the design patterns for assays and drug screening. Various custom-made inkjet dispensing systems as well as specialized bio-ink and substrates have been developed and applied to fulfill the increasing demands of basic drug discovery studies. The incorporation of other modern technologies has further exploited the potential of inkjet dispensing technology in drug discovery and development. This paper reviews and discusses the recent developments and practical applications of inkjet dispensing technology in several areas of drug discovery and development including fundamental assays of cells and proteins, microarrays, biosensors, tissue engineering, basic biological and pharmaceutical studies. Progression in a number of areas of research including biomaterials, inkjet mechanical systems and modern analytical techniques as well as the exploration and accumulation of profound biological knowledge has enabled different inkjet dispensing technologies to be developed and adapted for high-throughput pattern fabrication and miniaturization. This in turn presents a great opportunity to propel inkjet dispensing technology into drug discovery.

Micro-electromembrane extraction across free liquid membranes. Extractions of basic drugs from undiluted biological samples.

PubMed

Kubáň, Pavel; Boček, Petr

2014-04-11

This contribution describes properties and utilization of free liquid membranes (FLMs) in micro-electromembrane extraction (μ-EME) of analytes from samples with complex matrices. An FLM was formed as a plug of a selected organic solvent, 1-ethyl-2-nitrobenezene (ENB) or 2-nitrophenyloctyl ether, in a narrow bore polymeric tubing and was sandwiched between a plug of aqueous donor and aqueous acceptor solution. The FLM acted as a phase interface that enabled selective transfer of analytes from donor into acceptor solution. Acceptor solution after μ-EME was analysed by capillary electrophoresis (CE). Fundamental characteristics of FLMs were depicted and discussed by presenting experimental data on their performance for various basic operational parameters, such as composition and volume of donor/acceptor solution, applied extraction voltage, thickness of FLM and extraction time. Positively charged basic drugs (nortriptyline, haloperidol and loperamide) and their solutions in water, urine and blood serum served as model samples. It was shown that FLMs may offer fast, efficient and selective pretreatment of crude biological samples providing that basic operational parameters of μ-EME are set properly. At optimised conditions, basic drugs in 1.5μL of a biological sample were transferred across 1.5μL of FLM (ENB) into 1.5μL of acceptor solution in about 5min at an extraction voltage of 100V. Repeatability values of μ-EMEs and CE-UV analyses of the three basic drugs were better than 7.7% for peak areas, recoveries ranged between 19 and 52% and linear relationship was obtained for analytical signal vs. concentration in 1-50mgL(-1) range (r(2) better than 0.996). Limits of detection, defined as 3×S/N, were below 1mgL(-1) for all examined matrices. Copyright © 2014 Elsevier B.V. All rights reserved.

Basic management of medical emergencies: recognizing a patient's distress.

PubMed

Reed, Kenneth L

2010-05-01

Medical emergencies can happen in the dental office, possibly threatening a patient's life and hindering the delivery of dental care. Early recognition of medical emergencies begins at the first sign of symptoms. The basic algorithm for management of all medical emergencies is this: position (P), airway (A), breathing (B), circulation (C) and definitive treatment, differential diagnosis, drugs, defibrillation (D). The dentist places an unconscious patient in a supine position and comfortably positions a conscious patient. The dentist then assesses airway, breathing and circulation and, when necessary, supports the patient's vital functions. Drug therapy always is secondary to basic life support (that is, PABCD). Prompt recognition and efficient management of medical emergencies by a well-prepared dental team can increase the likelihood of a satisfactory outcome. The basic algorithm for managing medical emergencies is designed to ensure that the patient's brain receives a constant supply of blood containing oxygen.

76 FR 5829 - Manufacturer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-02

... bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana.... In reference to drug code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol as a...

76 FR 51401 - Manufacturer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-18

... bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana... development and for distribution to its customers. In reference to drug code 7360 (Marihuana), the company...

WEAKLY SYNCHRYRONIZED SUBPOPULATION DYNAMICS IN WISCONSIN FROGS AND TOADS

EPA Science Inventory

Spatial synchrony in population dynamics is a topic of increasing interest in basic and applied ecology. We used data from 18 years of frog and toad calling surveys conducted throughout Wisconsin to determine the level of intraspecific synchrony among survey sites, and the relat...

Emergence of cytotoxic resistance in cancer cell populations: Single-cell mechanisms and population-level consequences

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lorenzi, Tommaso; Chisholm, Rebecca H.; Lorz, Alexander

We formulate an individual-based model and a population model of phenotypic evolution, under cytotoxic drugs, in a cancer cell population structured by the expression levels of survival-potential and proliferation-potential. We apply these models to a recently studied experimental system. Our results suggest that mechanisms based on fundamental laws of biology can reversibly push an actively-proliferating, and drug-sensitive, cell population to transition into a weakly-proliferative and drug-tolerant state, which will eventually facilitate the emergence of more potent, proliferating and drug-tolerant cells.

DrugMetZ DB: an anthology of human drug metabolizing Chytochrome P450 enzymes.

PubMed

Antony, Tresa Remya Thomas; Nagarajan, Shanthi

2006-11-14

Understandings the basics of Cytochrome P450 (P450 or CYP) will help to discern drug metabolism. CYP, a super-family of heme-thiolate proteins, are found in almost all living organisms and is involved in the biotransformation of a diverse range of xenobiotics, therapeutic drugs and toxins. Here, we describe DrugMetZ DB, a database for CYP metabolizing drugs. The DB is implemented in MySQL, PHP and HTML. www.bicpu.edu.in/DrugMetZDB/

Implementation of basic chemistry experiment based on metacognition to increase problem-solving and build concept understanding

NASA Astrophysics Data System (ADS)

Zuhaida, A.

2018-04-01

Implementation of the experiment have the three aspects of the goal: 1) develop basic skills of experimenting; 2) develop problem-solving skills with a scientific approach; 3) improve understanding of the subject matter. On the implementation of the experiment, students have some weaknesses include: observing, identifying problems, managing information, analyzing, and evaluating. This weakness is included in the metacognition indicator.The objective of the research is to implementation of Basic Chemistry Experiment based on metacognition to increase problem-solving skills and build concept understanding for students of Science Education Department. The method of this research is a quasi- experimental method with pretest-posttest control group design. Problem-solving skills are measured through performance assessments using rubrics from problem solving reports, and results presentation. The conceptual mastery is measured through a description test. The result of the research: (1) improve the problem solving skills of the students with very high category; (2) increase the students’ concept understanding better than the conventional experiment with the result of N-gain in medium category, and (3) increase student's response positively for learning implementation. The contribution of this research is to extend the implementation of practical learning for some subjects, and to improve the students' competence in science.

Interaction between DNA and Drugs Having Protonable Basic Groups: Characterization through Affinity Constants, Drug Release Kinetics, and Conformational Changes

PubMed Central

Alarcón, Liliana P.; Baena, Yolima; Manzo, Rubén H.

2017-01-01

This paper reports the in vitro characterization of the interaction between the phosphate groups of DNA and the protonated species of drugs with basic groups through the determination of the affinity constants, the reversibility of the interaction, and the effect on the secondary structure of the macromolecule. Affinity constants of the counterionic condensation DNA–drug were in the order of 106. The negative electrokinetic potential of DNA decreased with the increase of the proportion of loading drugs. The drugs were slowly released from the DNA–drug complexes and had release kinetics consistent with the high degree of counterionic condensation. The circular dichroism profile of DNA was not modified by complexation with atenolol, lidocaine, or timolol, but was significantly altered by the more lipophilic drugs benzydamine and propranolol, revealing modifications in the secondary structure of the DNA. The in vitro characterization of such interactions provides a physicochemical basis that would contribute to identify the effects of this kind of drugs in cellular cultures, as well as side effects observed under their clinical use. Moreover, this methodology could also be projected to the fields of intracellular DNA transfection and the use of DNA as a carrier of active drugs. PMID:28054999

21 CFR 177.1060 - n-Alkylglutarimide/acrylic copolymers.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false n-Alkylglutarimide/acrylic copolymers. 177.1060 Section 177.1060 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) INDIRECT FOOD ADDITIVES: POLYMERS Substances for Use as Basic Components of Single and Repeated...

78 FR 23959 - Manufacturer of Controlled Substances; Notice of Registration; Alltech Associates, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-23

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., Deerfield, Illinois 60015, made application to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule 2C-T-2 (2...

78 FR 64015 - Importer of Controlled Substances, Notice of Registration, Siegfried (USA), LLC

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-25

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances, Notice of..., New Jersey 08070, made application by letter to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Opium, raw...

77 FR 50162 - Importer of Controlled Substances; Notice of Registration; Almac Clinical Services, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-20

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Importer of Controlled Substances; Notice of..., Pennsylvania 18964, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as an importer of the following basic classes of controlled substances: Drug Schedule Oxycodone (9143...

21 CFR 177.1340 - Ethylene-methyl acrylate copolymer resins.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Ethylene-methyl acrylate copolymer resins. 177.1340 Section 177.1340 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) INDIRECT FOOD ADDITIVES: POLYMERS Substances for Use as Basic Components of Single and...

21 CFR 177.1600 - Polyethylene resins, carboxyl modified.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Polyethylene resins, carboxyl modified. 177.1600 Section 177.1600 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) INDIRECT FOOD ADDITIVES: POLYMERS Substances for Use as Basic Components of Single and Repeated...

21 CFR 177.1640 - Polystyrene and rubber-modified polystyrene.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Polystyrene and rubber-modified polystyrene. 177.1640 Section 177.1640 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) INDIRECT FOOD ADDITIVES: POLYMERS Substances for Use as Basic Components of Single and...

A Practical Approach to Rural Drug Abuse Programming.

ERIC Educational Resources Information Center

Rozelle, George R.; And Others

1980-01-01

Reviews characteristics of rural drug abuse and general considerations for rural service delivery. Describes the Prevention Project, a rural drug abuse program in Florida, and explains its development, philosophy, and teaching techniques, including a basic educational module for use with rural youth. Includes recommendations for similar programs.…

Amphetamine. Report Series 28, No. 1.

ERIC Educational Resources Information Center

National Inst. on Drug Abuse (DHEW/PHS), Rockville, MD. National Clearinghouse for Drug Abuse Information.

This report, prepared by the National Clearinghouse for Drug Abuse Information, presents substantial information on the use and abuse of the drug "family" known as amphetamines. A brief history of the drug is given, along with its basic pharmacology. The current medical uses for amphetamines include: (1) short-term treatment of obesity,…

Back to basics: the role of health insurance in getting a physical exam.

PubMed

McBride, Duane C; Drumm, Rene D; Terry-McElrath, Yvonne; Chitwood, Dale D

2005-01-01

The social work profession has a long history of advocacy to improve the human condition, especially for groups of people at high risk of discrimination and marginalization. Social workers have been instrumental in identifying, assessing, treating, and preventing illicit drug use as part of this commitment to advocacy. One component of social work's endeavors on behalf of drug users and other populations- at-risk has been advocating for increased access to health care. This article examines the role that having health insurance plays in obtaining the most basic of all health care-getting a physical examination. Featuring a sample of 1,271 chronic and injecting street drug users and comparison group non-users, the analysis demonstrates that having health insurance enhances access and utilization of health care among this at-risk population. Subjects who had health insurance for even one month of the past twelve were twice as likely to participate in basic health care by having a physical exam.

77 FR 2324 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-17

... manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana (7360) I... distribution to its customers. In reference to drug code 7360 (Marihuana), the company plans to bulk...

76 FR 51401 - Manufacturer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-18

... a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana... ingredients (APIs) for distribution to its customers. In reference to drug code 7360 (Marihuana), the company...

76 FR 17968 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-31

... manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana (7360) I... distribution to its customers. In reference to drug code 7360 (Marihuana), the company plans to bulk...

Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: itraconazole.

PubMed

Taupitz, Thomas; Dressman, Jennifer B; Buchanan, Charles M; Klein, Sandra

2013-04-01

The aim of the present series of experiments was to improve the solubility and dissolution/precipitation behaviour of a poorly soluble, weakly basic drug, using itraconazole as a case example. Binary inclusion complexes of itraconazole with two commonly used cyclodextrin derivatives and a recently introduced cyclodextrin derivative were prepared. Their solubility and dissolution behaviour was compared with that of the pure drug and the marketed formulation Sporanox®. Ternary complexes were prepared by addition of Soluplus®, a new highly water soluble polymer, during the formation of the itraconazole/cyclodextrin complex. A solid dispersion made of itraconazole and Soluplus® was also studied as a control. Solid state analysis was performed for all formulations and for pure itraconazole using powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicated that with all formulation approaches, the aqueous solubility of itraconazole formed with hydroxypropyl-β-cyclodextrin (HP-β-CD) or hydroxybutenyl-β-cyclodextrin (HBen-β-CD) and Soluplus® proved to be the most favourable formulation approaches. Whereas the marketed formulation and the pure drug showed very poor dissolution, both of these ternary inclusion complexes resulted in fast and extensive release of itraconazole in all test media. Using the results of the dissolution experiments, a newly developed physiologically based pharmacokinetic (PBPK) in silico model was applied to compare the in vivo behaviour of Sporanox® with the predicted performance of the most promising ternary complexes from the in vitro studies. The PBPK modelling predicted that the bioavailability of itraconazole is likely to be increased after oral administration of ternary complex formulations, especially when itraconazole is formulated as a ternary complex comprising HP-β-CD or HBen-β-CD and Soluplus®. Copyright © 2012 Elsevier B.V. All rights reserved.

Drugs and the Nation's High School Students: Five Year National Trends. 1979 Highlights.

ERIC Educational Resources Information Center

Johnston, Lloyd D.; And Others

The current prevalence of drug use among American high school seniors, and trends in drug use since 1975, were investigated as part of the program entitled "Monitoring the Future: A Continuing Study of the Lifestyles and Values of Youth," funded by the National Institute on Drug Abuse. The basic research design involved data collection from high…

Weak decays of heavy hadrons into dynamically generated resonances

DOE PAGES

Oset, Eulogio; Liang, Wei -Hong; Bayar, Melahat; ...

2016-01-28

In this study, we present a review of recent works on weak decay of heavy mesons and baryons with two mesons, or a meson and a baryon, interacting strongly in the final state. The aim is to learn about the interaction of hadrons and how some particular resonances are produced in the reactions. It is shown that these reactions have peculiar features and act as filters for some quantum numbers which allow to identify easily some resonances and learn about their nature. The combination of basic elements of the weak interaction with the framework of the chiral unitary approach allowmore » for an interpretation of results of many reactions and add a novel information to different aspects of the hadron interaction and the properties of dynamically generated resonances.« less

Bridging online and offline social networks: Multiplex analysis

NASA Astrophysics Data System (ADS)

Filiposka, Sonja; Gajduk, Andrej; Dimitrova, Tamara; Kocarev, Ljupco

2017-04-01

We show that three basic actor characteristics, namely normalized reciprocity, three cycles, and triplets, can be expressed using an unified framework that is based on computing the similarity index between two sets associated with the actor: the set of her/his friends and the set of those considering her/him as a friend. These metrics are extended to multiplex networks and then computed for two friendship networks generated by collecting data from two groups of undergraduate students. We found that in offline communication strong and weak ties are (almost) equally presented, while in online communication weak ties are dominant. Moreover, weak ties are much less reciprocal than strong ties. However, across different layers of the multiplex network reciprocities are preserved, while triads (measured with normalized three cycles and triplets) are not significant.

Effects of imposed acid-base derangement on the cardiovascular effects and pharmacokinetics of bupivacaine and thiopental.

PubMed

Mather, Laurence E; Ladd, Leigh A; Copeland, Susan E; Chang, Dennis H-T

2004-06-01

By changing physicochemical properties such as effective lipophilicity, changes in blood pH could alter the distribution, elimination, and effects of weakly ionizing drugs. The authors examined the outcome of imposed acid-base derangement on cardiovascular effects and myocardial and whole body pharmacokinetics of bupivacaine, a weak base, and thiopental, a weak acid. Intravenous infusions of rac-bupivacaine HCl (37.5 mg) or rac-thiopental sodium (250 mg, subanesthetic dose) were administered over 3 min to previously instrumented conscious ewes with normal blood pH, acidemia imposed by lactic acid infusion, or alkalemia imposed by bicarbonate infusion. Hemodynamic and electrocardiographic effects were recorded; arterial and coronary sinus drug blood concentrations were analyzed by chiral high-performance liquid chromatography. Bupivacaine decreased myocardial contractility, coronary perfusion, heart rate, and cardiac output; however, cardiac output and stroke volume were not as affected by bupivacaine with acidemia. Thiopental decreased myocardial contractility and stroke volume and increased heart rate; acidemia enhanced the tachycardia and produced a greater decrease in stroke volume than with alkalemia. Taken as a whole, the cardiovascular changes were not systematically modified by acid-base derangement. Overall, the tissue distribution of bupivacaine was favored by alkalemia, but thiopental pharmacokinetics were essentially unaffected by acid-base derangement. Acid-base derangement did not influence the kinetics of either drug enantioselectively. At the doses used, the hemodynamic and electrocardiographic effects of bupivacaine and thiopental were not systematically modified by acid-base derangement, nor were there changes in regional or whole body pharmacokinetics of either drug that were clearly related to acid-base status.

Understanding the interplay of weak forces in [3,3]-sigmatropic rearrangement for stereospecific synthesis of diamines.

PubMed

So, Soon Mog; Mui, Leo; Kim, Hyunwoo; Chin, Jik

2012-08-21

Chiral diamines are important building blocks for constructing stereoselective catalysts, including transition metal based catalysts and organocatalysts that facilitate oxidation, reduction, hydrolysis, and C-C bond forming reactions. These molecules are also critical components in the synthesis of drugs, including antiviral agents such as Tamiflu and Relenza and anticancer agents such as oxaliplatin and nutlin-3. The diaza-Cope rearrangement reaction provides one of the most versatile methods for rapidly generating a wide variety of chiral diamines stereospecifically and under mild conditions. Weak forces such as hydrogen bonding, electronic, steric, oxyanionic, and conjugation effects can drive this equilibrium process to completion. In this Account, we examine the effect of these individual weak forces on the value of the equilibrium constant for the diaza-Cope rearrangement reaction using both computational and experimental methods. The availability of a wide variety of aldehydes and diamines allows for the facile synthesis of the diimines needed to study the weak forces. Furthermore, because the reaction generally takes place cleanly at ambient temperature, we can easily measure equilibrium constants for rearrangement of the diimines. We use the Hammett equation to further examine the electronic and oxyanionic effects. In addition, computations and experiments provide us with new insights into the origin and extent of stereospecificity for this rearrangement reaction. The diaza-Cope rearrangement, with its unusual interplay between weak forces and the equilibrium constant of the reaction, provides a rare opportunity to study the effects of the fundamental weak forces on a chemical reaction. Among these many weak forces that affect the diaza-Cope rearrangement, the anion effect is the strongest (10.9 kcal/mol) followed by the resonance-assisted hydrogen-bond effect (7.1 kcal/mol), the steric effect (5.7 kcal/mol), the conjugation effect (5.5 kcal/mol), and the electronic effect (3.2 kcal/mol). Based on both computation and experimental data, the effects of these weak forces are additive. Understanding the interplay of the weak forces in the [3,3]-sigmatropic reaction is interesting in its own right and also provides valuable insights for the synthesis of chiral diamine based drugs and catalysts in excellent yield and enantiopurity.

Sense of coherence and diabetes: a prospective occupational cohort study.

PubMed

Kouvonen, Anne M; Väänänen, Ari; Woods, Stephen A; Heponiemi, Tarja; Koskinen, Aki; Toppinen-Tanner, Salla

2008-02-06

Sense of coherence (SOC) is an individual characteristic related to a positive life orientation leading to effective coping. A weak SOC has been associated with indicators of general morbidity and mortality. However, the relationship between SOC and diabetes has not been studied in prospective design. The present study prospectively examined the relationship between a weak SOC and the incidence of diabetes. The relationship between a weak SOC and the incidence of diabetes was investigated among 5827 Finnish male employees aged 18-65 at baseline (1986). SOC was measured by questionnaire survey at baseline. Data on prescription diabetes drugs from 1987 to 2004 were obtained from the Drug Imbursement Register held by the Social Insurance Institution. During the follow-up, 313 cases of diabetes were recorded. A weak SOC was associated with a 46% higher risk of diabetes in participants who had been = <50 years of age on entry into the study. This association was independent of age, education, marital status, psychological distress, self-rated health, smoking status, binge drinking and physical activity. No similar association was observed in older employees. The results suggest that besides focusing on well-known risk factors for diabetes, strengthening SOC in employees of = <50 years of age can also play a role in attempts to tackle increasing rates of diabetes.

Prescriptive Profile Procedure for Children With Learning Disabilities.

ERIC Educational Resources Information Center

Levine, Eleanor; Fineman, Carol

The Prescriptive Profile Procedure (PPP) attempts to provide teachers of learning disabled elementary school children with a procedure of individualized diagnosis and educational prescription which encompasses strengths and weaknesses in prerequisite skills, basic school subjects, and behavioral factors. A competency statement and six to 12…

What Developmental Educators Should Know About Learning Styles and Cognitive Styles.

ERIC Educational Resources Information Center

Lemire, David

2002-01-01

Considers three serious problems associated with learning styles: confusion in definitions, weaknesses in reliability and validity, and the identification of relevant characteristics in instructional settings, or aptitude-treatment interactions. Discusses four basic groups of learning styles that developmental educators should be aware of.…

Ternary mixed-mode silica sorbent of solid-phase extraction for determination of basic, neutral and acidic drugs in human serum.

PubMed

Jin, Shupei; Qiao, Yinghua; Xing, Jun

2018-06-01

In this study, a ternary mixed-mode silica sorbent (TMSS) with octamethylene, carboxyl, and amino groups was prepared via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction and a subsequent reduction of azide to primary amine. While used in solid-phase extraction (SPE), the retention behavior of TMSS towards a total of nine kinds of basic, neutral, and acidic drugs was investigated in detail. The results revealed that hydrophobic, ion-exchange interaction, and electrostatic repulsion between TMSS and the analytes were closely related to the retention behavior of TMSS. Besides, the log K ow value of the analyte was also a factor influencing the retention behavior of analytes on TMSS. The nine analytes could be retained by TMSS simultaneously and then, were eluted into two fractions according to the acid-base property of the analytes for further determinations. The acidic and neutral analytes were in one fraction, and the basic ones in the other fraction. When used to treat the human serum spiked with the nine drugs, TMSS offered higher recoveries than BakerBond CBA and comparable recoveries to Oasis WCX. It should be noted TMSS had better purifying capability for human serum than Oasis WCX. Under the optimized SPE conditions, a method of SPE hyphenated to high-performance liquid chromatography-ultraviolet detection (HPLC-UV) for determination of the basic, neutral, and acidic drugs spiked in human serum was established. For the nine drugs, the linear ranges were all between 5.0 and 1000 μg L -1 with correlation coefficients (R 2 ) above 0.9990, and the limits of detection (LODs) were in the range of 0.8-2.3 μg L -1 . The intra-day and inter-day relative standard deviations (RSDs) were less than 5.3 and 8.8%, respectively. Graphical abstract Treating drugs in human serum by SPE with ternary mixed-mode silica sorbent.

Development, Verification, and Prediction of Osimertinib Drug-Drug Interactions Using PBPK Modeling Approach to Inform Drug Label.

PubMed

Pilla Reddy, Venkatesh; Walker, Michael; Sharma, Pradeep; Ballard, Peter; Vishwanathan, Karthick

2018-02-22

Osimertinib is a potent, highly selective, irreversible inhibitor of epidermal growth factor receptor (EGFR) and T790M resistance mutation. In vitro metabolism data suggested osimertinib is a substrate of cytochrome P450 (CYP)3A4/5, a weak inducer of CYP3A, and an inhibitor of breast cancer resistance protein (BCRP). A combination of in vitro data, clinical pharmacokinetic data, and drug-drug interaction (DDI) data of osimertinib in oncology patients were used to develop the physiologically based pharmacokinetic (PBPK) model and verify the DDI data of osimertinib. The model predicted the observed monotherapy concentration profile of osimertinib within 1.1-fold, and showed good predictability (within 1.7-fold) to the observed peak plasma concentration (C max ) and area under the curve (AUC) DDI ratio changes, when co-administered with rifampicin, itraconazole, and simvastatin, but not with rosuvastatin. Based on observed clinical data and PBPK simulations, the recommended dose of osimertinib when dosed with strong CYP3A inducers is 160 mg once daily. PBPK modeling suggested no dose adjustment with moderate and weak CYP3A inducers. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for CPT: Pharmacometrics & Systems Pharmacology.

Gelatin Nano-coating for Inhibiting Surface Crystallization of Amorphous Drugs.

PubMed

Teerakapibal, Rattavut; Gui, Yue; Yu, Lian

2018-01-05

Inhibit the fast surface crystallization of amorphous drugs with gelatin nano-coatings. The free surface of amorphous films of indomethacin or nifedipine was coated by a gelatin solution (type A or B) and dried. The coating's effect on surface crystallization was evaluated. Coating thickness was estimated from mass change after coating. For indomethacin (weak acid, pK a  = 4.5), a gelatin coating of either type deposited at pH 5 and 10 inhibited its fast surface crystal growth. The coating thickness was 20 ± 10 nm. A gelatin coating deposited at pH 3, however, provided no protective effect. These results suggest that an effective gelatin coating does not require that the drug and the polymer have opposite charges. The ineffective pH 3 coating might reflect the poor wetting of indomethacin's neutral, hydrophobic surface by the coating solution. For nifedipine (weak base, pK a  = 2.6), a gelatin coating of either type deposited at pH 5 inhibited its fast surface crystal growth. Gelatin nano-coatings can be conveniently applied to amorphous drugs from solution to inhibit fast surface crystallization. Unlike strong polyelectrolyte coatings, a protective gelatin coating does not require strict pairing of opposite charges. This could make gelatin coating a versatile, pharmaceutically acceptable coating for stabilizing amorphous drugs.

77 FR 75670 - Manufacturer of Controlled Substances, Notice of Registration, AMRI Rensselaer, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-21

... bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana... development and for distribution to its customers. In reference to drug code 7360 (Marihuana), the company...

77 FR 52368 - Manufacturer of Controlled Substances; Notice of Registration; Austin Pharma, LLC.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-29

... a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana... ingredients (APIs) for distribution to its customers. In reference to drug code 7360 (Marihuana), the company...

Guided solitary waves.

PubMed

Miles, J

1980-04-01

Transversely periodic solitary-wave solutions of the Boussinesq equations (which govern wave propagation in a weakly dispersive, weakly nonlinear physical system) are determined. The solutions for negative dispersion (e.g., gravity waves) are singular and therefore physically unacceptable. The solutions for positive dispersion (e.g., capillary waves or magnetosonic waves in a plasma) are physically acceptable except in a limited parametric interval, in which they are complex. The two end points of this interval are associated with (two different) resonant interactions among three basic solitary waves, two of which are two-dimensional complex conjugates and the third of which is one-dimensional and real.

Analysis of impact of “strong DC and weak AC” on receiving-end power system

NASA Astrophysics Data System (ADS)

Wang, Qiang; Li, Tianran; Yang, Pengcheng

2018-02-01

The rapid development of UHVDC transmission project has brought abundant power supply to the receiving-end power system area, but also many security and stability problems. This paper summarizes four elements that affect the strength of AC system, and then simulates the most basic two-terminal single-pole UHV transmission system by MATLAB/Simulink. It analyses the impact of receiving-end AC power system strength on real-time power, frequency and voltage. Finally, in view of operation risk of “strong DC and weak AC”, this paper puts forward three countermeasures.

Effect of n-octanol in the mobile phase on lipophilicity determination by reversed-phase high-performance liquid chromatography on a modified silica column.

PubMed

Benhaim, Deborah; Grushka, Eli

2008-10-31

In this study, we show that the addition of n-octanol to the mobile phase improves the chromatographic determination of lipophilicity parameters of xenobiotics (neutral solutes, acidic, neutral and basic drugs) on a Phenomenex Gemini C18 column. The Gemini C18 column is a new generation hybrid silica-based column with an extended pH range capability. The wide pH range (2-12) afforded the examination of basic drugs and acidic drugs in their neutral form. Extrapolated retention factor values, [Formula: see text] , obtained on the above column with the n-octanol-modified mobile phase were very well correlated (1:1 correlation) with literature values of logP (logarithm of the partition coefficient in n-octanol/water) of neutral compounds and neutral drugs (69). In addition, we found good linear correlations between measured [Formula: see text] values and calculated values of the logarithm of the distribution coefficient at pH 7.0 (logD(7.0)) for ionized acidic and basic drugs (r(2)=0.95). The Gemini C18 phase was characterized using the linear solvation energy relationship (LSER) model of Abraham. The LSER system constants for the column were compared to the LSER constants of n-octanol/water extraction system using the Tanaka radar plots. The comparison shows that the two methods are nearly equivalent.

PET IMAGING STUDIES IN DRUG ABUSE RESEARCH.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, J.S.; Volkow, N.D.; Ding, Y.S.

There is overwhelming evidence that addiction is a disease of the brain (Leshner, 1997). Yet public perception that addiction is a reflection of moral weakness or a lack of willpower persists. The insidious consequence of this perception is that we lose sight of the fact that there are enormous medical consequences of addiction including the fact that a large fraction of the total deaths from cancer and heart disease are caused by smoking addiction. Ironically the medical school that educates physicians in addiction medicine and the cancer hospital that has a smoking cessation clinic are vanishingly rare and efforts atmore » harm reduction are frequently met with a public indignation. Meanwhile the number of people addicted to substances is enormous and increasing particularly the addictions to cigarettes and alcohol. It is particularly tragic that addiction usually begins in adolescence and becomes a chronic relapsing problem and there are basically no completely effective treatments. Clearly we need to understand how drugs of abuse affect the brain and we need to be creative in using this information to develop effective treatments. Imaging technologies have played a major role in the conceptualization of addiction as a disease of the brain (Fowler et al., 1998a; Fowler et al., 1999a). New knowledge has been driven by advances in radiotracer design and chemistry and positron emission tomography (PET) instrumentation and the integration of these scientific tools with the tools of biochemistry, pharmacology and medicine. This topic cuts across the medical specialties of neurology, psychiatry, cancer and heart disease because of the high medical, social and economic toll that drugs of abuse, including and especially the legal drugs, cigarettes and alcohol, take on society. In this chapter we will begin by highlighting the important role that chemistry has played in making it possible to quantitatively image the movement of drugs as well as their effects on the human brain. This will be followed by highlights of PET studies of the acute effects of the psychostimulant drugs cocaine and methylphenidate (ritalin) and studies of the chronic effects of cocaine and of tobacco smoke on the human brain. This chapter concludes with the description of a study which uses brain imaging coupled with a specific pharmacological challenge to address the age-old question of why some people who experiment with drugs become addicted while others do not.« less

Montmorillonite-lipid hybrid carriers for ionizable and neutral poorly water-soluble drugs: Formulation, characterization and in vitro lipolysis studies.

PubMed

Dening, Tahnee J; Rao, Shasha; Thomas, Nicky; Prestidge, Clive A

2017-06-30

Lipid-based formulations (LBFs) are a popular strategy for enhancing the gastrointestinal solubilization and absorption of poorly water-soluble drugs. In light of this, montmorillonite-lipid hybrid (MLH) particles, composed of medium-chain triglycerides, lecithin and montmorillonite clay platelets, have been developed as a novel solid-state LBF. Owing to the unique charge properties of montmorillonite, whereby the clay platelet surfaces carry a permanent negative charge and the platelet edges carry a pH-dependent charge, three model poorly water-soluble drugs with different charge properties; blonanserin (weak base, pKa 7.7), ibuprofen (weak acid, pKa 4.5) and fenofibrate (neutral), were formulated as MLH particles and their performance during biorelevant in vitro lipolysis at pH 7.5 was investigated. For blonanserin, drug solubilization during in vitro lipolysis was significantly reduced 3.4-fold and 3.2-fold for MLH particles in comparison to a control lipid solution and silica-lipid hybrid (SLH) particles, respectively. It was hypothesized that strong electrostatic interactions between the anionic montmorillonite platelet surfaces and cationic blonanserin molecules were responsible for the inferior performance of MLH particles. In contrast, no significant influence on drug solubilization was observed for ibuprofen- and fenofibrate-loaded MLH particles. The results of the current study indicate that whilst MLH particles are a promising novel formulation strategy for poorly water-soluble drugs, drug ionization tendency and the potential for drug-clay interactions must be taken into consideration to ensure an appropriate performance. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of Phospholipidosis on the Cellular Pharmacokinetics of ChloroquineS⃞

PubMed Central

Zheng, Nan; Zhang, Xinyuan

2011-01-01

In vivo, the weakly basic, lipophilic drug chloroquine (CQ) accumulates in the kidney to concentrations more than a thousand-fold greater than those in plasma. To study the cellular pharmacokinetics of chloroquine in cells derived from the distal tubule, Madin-Darby canine kidney cells were incubated with CQ under various conditions. CQ progressively accumulated without exhibiting steady-state behavior. Experiments failed to yield evidence that known active transport mechanisms mediated CQ uptake at the plasma membrane. CQ induced a phospholipidosis-like phenotype, characterized by the appearance of numerous multivesicular and multilamellar bodies (MLBs/MVBs) within the lumen of expanded cytoplasmic vesicles. Other induced phenotypic changes including changes in the volume and pH of acidic organelles were measured, and the integrated effects of all these changes were computationally modeled to establish their impact on intracellular CQ mass accumulation. Based on the passive transport behavior of CQ, the measured phenotypic changes fully accounted for the continuous, nonsteady-state CQ accumulation kinetics. Consistent with the simulation results, Raman confocal microscopy of live cells confirmed that CQ became highly concentrated within induced, expanded cytoplasmic vesicles that contained multiple MLBs/MVBs. Progressive CQ accumulation was increased by sucrose, a compound that stimulated the phospholipidosis-like phenotype, and was decreased by bafilomycin A1, a compound that inhibited this phenotype. Thus, phospholipidosis-associated changes in organelle structure and intracellular membrane content can exert a major influence on the local bioaccumulation and biodistribution of drugs. PMID:21156819

Adsorption mechanism of acids and bases in reversed-phase liquid chromatography in weak buffered mobile phases designed for liquid chromatography/mass spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gritti, Fabrice; Guiochon, Georges A

2009-01-01

The overloaded band profiles of five acido-basic compounds were measured, using weakly buffered mobile phases. Low buffer concentrations were selected to provide a better understanding of the band profiles recorded in LC/MS analyses, which are often carried out at low buffer concentrations. In this work, 10 {micro}L samples of a 50 mM probe solution were injected into C{sub 18}-bonded columns using a series of five buffered mobile phases at {sub W}{sup S}pH between 2 and 12. The retention times and the shapes of the bands were analyzed based on thermodynamic arguments. A new adsorption model that takes into account themore » simultaneous adsorption of the acidic and the basic species onto the endcapped adsorbent, predicts accurately the complex experimental profiles recorded. The adsorption mechanism of acido-basic compounds onto RPLC phases seems to be consistent with the following microscopic model. No matter whether the acid or the base is the neutral or the basic species, the neutral species adsorbs onto a large number of weak adsorption sites (their saturation capacity is several tens g/L and their equilibrium constant of the order of 0.1 L/g). In contrast, the ionic species adsorbs strongly onto fewer active sites (their saturation capacity is about 1 g/L and their equilibrium constant of the order of a few L/g). From a microscopic point of view and in agreement with the adsorption isotherm of the compound measured by frontal analysis (FA) and with the results of Monte-Carlo calculations performed by Schure et al., the first type of adsorption sites are most likely located in between C{sub 18}-bonded chains and the second type of adsorption sites are located deeper in contact with the silica surface. The injected concentration (50 mM) was too low to probe the weakest adsorption sites (saturation capacity of a few hundreds g/L with an equilibrium constant of one hundredth of L/g) that are located at the very interface between the C{sub 18}-bonded layer and the bulk phase.« less

Adsorption mechanism of acids and bases in reversed-phase liquid chromatography in weak buffered mobile phases designed for liquid chromatography/mass spectrometry.

PubMed

Gritti, Fabrice; Guiochon, Georges

2009-03-06

The overloaded band profiles of five acido-basic compounds were measured, using weakly buffered mobile phases. Low buffer concentrations were selected to provide a better understanding of the band profiles recorded in LC/MS analyses, which are often carried out at low buffer concentrations. In this work, 10 microL samples of a 50 mM probe solution were injected into C(18)-bonded columns using a series of five buffered mobile phases at (SW)pH between 2 and 12. The retention times and the shapes of the bands were analyzed based on thermodynamic arguments. A new adsorption model that takes into account the simultaneous adsorption of the acidic and the basic species onto the endcapped adsorbent, predicts accurately the complex experimental profiles recorded. The adsorption mechanism of acido-basic compounds onto RPLC phases seems to be consistent with the following microscopic model. No matter whether the acid or the base is the neutral or the basic species, the neutral species adsorbs onto a large number of weak adsorption sites (their saturation capacity is several tens g/L and their equilibrium constant of the order of 0.1 L/g). In contrast, the ionic species adsorbs strongly onto fewer active sites (their saturation capacity is about 1g/L and their equilibrium constant of the order of a few L/g). From a microscopic point of view and in agreement with the adsorption isotherm of the compound measured by frontal analysis (FA) and with the results of Monte-Carlo calculations performed by Schure et al., the first type of adsorption sites are most likely located in between C(18)-bonded chains and the second type of adsorption sites are located deeper in contact with the silica surface. The injected concentration (50 mM) was too low to probe the weakest adsorption sites (saturation capacity of a few hundreds g/L with an equilibrium constant of one hundredth of L/g) that are located at the very interface between the C(18)-bonded layer and the bulk phase.

Magnetic studies on Shergotty and other SNC meteorites

NASA Technical Reports Server (NTRS)

Cisowski, S. M.

1986-01-01

The results of a study of basic magnetic properties of meteorites within the SNC group, including the four known shergottites and two nakhlites, are presented. An estimate is made of the strength of the magnetic field which produced the remanent magnetization of the Shergotty meteorite, for the purpose of constraining the choices for the parent body of these SNC meteorites. Remanence measurements in several subsamples of Shergotty and Zagami meteorites reveal a large variation in intensity that does not seem to be related to the abundance of remanence carriers. The other meteorites carry only weak remanence, suggesting weak magnetizing fields as the source of their magnetic signal. A paleointensity experiment on a weakly magnetized subsample of Shergotty revealed a low temperature component of magnetization acquired in a field of 2000 gammas, and a high temperature component reflecting a paleofield strength of between 250 and 1000 gammas. The weak field environment that these meteorites seem to reflect is consistent with either a Martian or asteroidal origin, but inconsistent with a terrestrial origin.

LSD and the Student: Approaches to Educational Strategies.

ERIC Educational Resources Information Center

Cohen, Allan Y.

There are three basic functions of the college relevant to the drug abuse problem: the therapeutic, the preventative, and the developmental. The first principle of psychedelic drug education may be termed the sympathetic attitude. It involves a thorough understanding of drugs on the part of the college administration, plus the ability to treat…

An Outline on Psychotropic Drug Use in the Developmentally Disabled Patient. Monograph #102.

ERIC Educational Resources Information Center

Vander Zanden, Jeanne A.

This introduction to basic principles of psychotropic drug use in developmentally disabled patients is intended to provide personnel working in the field with information on appropriate clinical use as well as potential risks. Presented in outline form, information is provided on five classes of psychotropic drugs: antipsychotics; antidepressants;…

International Drug Use; Research Issues 23.

ERIC Educational Resources Information Center

Austin, Gregory A., Ed.; And Others

This collection of resources contains 95 summaries of research conducted on drug use in countries other than the United States, and is designed to be an introductory set of readings which provide a basic familiarity with drug use patterns in foreign countries. The first section contains 23 studies on the United Kingdom while the second section…

Evaluation of DILearn: An Interactive Computer-Assisted Learning Program for Drug Information.

ERIC Educational Resources Information Center

Tunget, Cynthia L.; And Others

1993-01-01

Use of an interactive computer-assisted learning program to teach basic skills in obtaining drug information was investigated with 26 doctoral pharmacy students and a control group of 25 students receiving lecture instruction. Findings indicated no significant differences in short-term retention of drug information between groups and that students…

21 CFR 177.1400 - Hydroxyethyl cellulose film, water-insoluble.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Hydroxyethyl cellulose film, water-insoluble. 177.1400 Section 177.1400 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) INDIRECT FOOD ADDITIVES: POLYMERS Substances for Use as Basic Components of Single and...

Treating Drug Addiction in the Minority Communities: The Decade Ahead.

ERIC Educational Resources Information Center

Drew, Joseph S.

While scholars are not in accord on the basic causes of contemporary drug abuse among minority Americans, most do agree that the social milieu of the drug abuser is fundamental. It has been urged that racism, poverty, police brutality and harrassment, the economics of addiction, the hopelessness of ghetto life, peer pressure, educational…

Paroxetine

MedlinePlus

... sleepiness or feeling ''drugged'' nausea vomiting diarrhea constipation gas stomach pain heartburn changes in ability to taste ... symptoms yellowing of the skin and eyes aggressive behavior muscle pain, stiffness, or weakness sudden muscle twitching ...

The Effect of Nizatidine, a MATE2K Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Volunteers

PubMed Central

Morrissey, Kari M.; Stocker, Sophie L.; Chen, Eugene C.; Castro, Richard A.; Brett, Claire M.; Giacomini, Kathleen M.

2015-01-01

Background and Objectives In the proximal tubule, basic drugs are transported from the renal cells to the tubule lumen through the concerted action of the H+/organic cation antiporters, multidrug and toxin extrusion 1 (MATE1) and 2K (MATE2K). Dual inhibitors of the MATE transporters have been shown to have a clinically relevant effect on the pharmacokinetics of concomitantly administered basic drugs. However, the clinical impact of selective renal organic cation transport inhibition on the pharmacokinetics and pharmacodynamics of basic drugs, such as metformin, is unknown. This study sought to identify a selective MATE2K inhibitor in vitro and to determine its clinical impact on the pharmacokinetics and pharmacodynamics of metformin in healthy subjects. Methods A strategic cell-based screen of 71 U.S. Food and Drug Administration (FDA)-approved medications was conducted to identify selective inhibitors of renal organic cation transporters that are capable of inhibiting at clinically relevant concentrations. From this screen, nizatidine was identified and predicted to be a clinically potent and selective inhibitor of MATE2K-mediated transport. The effect of nizatidine on the pharmacokinetics and pharmacodynamics of metformin was evaluated in 12 healthy volunteers in an open-label, randomized, two-phase crossover drug-drug interaction (DDI) study. Results In healthy volunteers, the MATE2K-selective inhibitor, nizatidine, significantly increased the apparent volume of distribution, half-life and hypoglycemic activity of metformin. However, despite achieving unbound maximum concentrations greater than the in vitro inhibition potency (IC50) of MATE2K-mediated transport, nizatidine did not affect the renal clearance or net secretory clearance of metformin. Conclusion This study demonstrates that a selective inhibition of MATE2K by nizatidine, affected the apparent volume of distribution, tissue levels and peripheral effects of metformin. However, nizatidine did not alter systemic concentrations or the renal clearance of metformin, suggesting that specific MATE2K inhibition may not be sufficient to cause renal DDIs with basic drugs. PMID:26507723

Recent advances in basic and clinical nanomedicine.

PubMed

Morrow, K John; Bawa, Raj; Wei, Chiming

2007-09-01

Nanomedicine is a global business enterprise. Industry and governments clearly are beginning to envision nanomedicine's enormous potential. A clear definition of nanotechnology is an issue that requires urgent attention. This problem exists because nanotechnology represents a cluster of technologies, each of which may have different characteristics and applications. Although numerous novel nanomedicine-related applications are under development or nearing commercialization, the process of converting basic research in nanomedicine into commercially viable products will be long and difficult. Although realization of the full potential of nanomedicine may be years or decades away, recent advances in nanotechnology-related drug delivery, diagnosis, and drug development are beginning to change the landscape of medicine. Site-specific targeted drug delivery and personalized medicine are just a few concepts that are on the horizon.

A Population Genetic Model for the Initial Spread of Partially Resistant Malaria Parasites under Anti-Malarial Combination Therapy and Weak Intrahost Competition

PubMed Central

Kim, Yuseob; Escalante, Ananias A.; Schneider, Kristan A.

2014-01-01

To develop public-health policies that extend the lifespan of affordable anti-malarial drugs as effective treatment options, it is necessary to understand the evolutionary processes leading to the origin and spread of mutations conferring drug resistance in malarial parasites. We built a population-genetic model for the emergence of resistance under combination drug therapy. Reproductive cycles of parasites are specified by their absolute fitness determined by clinical parameters, thus coupling the evolutionary-genetic with population-dynamic processes. Initial mutations confer only partial drug-resistance. Therefore, mutant parasites rarely survive combination therapy and within-host competition is very weak among parasites. The model focuses on the early phase of such unsuccessful recurrent mutations. This ends in the rare event of mutants enriching in an infected individual from which the successful spread of resistance over the entire population is initiated. By computer simulations, the waiting time until the establishment of resistant parasites is analysed. Resistance spreads quickly following the first appearance of a host infected predominantly by mutant parasites. This occurs either through a rare transmission of a resistant parasite to an uninfected host or through a rare failure of drugs in removing “transient” mutant alleles. The emergence of resistance is delayed with lower mutation rate, earlier treatment, higher metabolic cost of resistance, longer duration of high drug dose, and higher drug efficacy causing a stronger reduction in the sensitive and resistant parasites’ fitnesses. Overall, contrary to other studies’ proposition, the current model based on absolute fitness suggests that aggressive drug treatment delays the emergence of drug resistance. PMID:25007207

Approaches to Teaching.

ERIC Educational Resources Information Center

Fenstermacher, Gary D.; Soltis, Jonas F.

This book is designed to help teachers critically assess major ideas about what teaching is and should be. Using both classical and contemporary perspectives, three basic approaches to teaching are offered, and the strengths and weaknesses of each are explored. The "executive approach" views the teacher as an executor, using the best learning…

Multi-Database Searching in the Behavioral Sciences--Part I: Basic Techniques and Core Databases.

ERIC Educational Resources Information Center

Angier, Jennifer J.; Epstein, Barbara A.

1980-01-01

Outlines practical searching techniques in seven core behavioral science databases accessing psychological literature: Psychological Abstracts, Social Science Citation Index, Biosis, Medline, Excerpta Medica, Sociological Abstracts, ERIC. Use of individual files is discussed and their relative strengths/weaknesses are compared. Appended is a list…

Quality Assurance Systems, TQM, and the New Collegialism.

ERIC Educational Resources Information Center

Harvey, Lee

This report discusses the application of the International Organization for Standards's ISO9000 quality assurance standard and Total Quality Management (TQM) to higher education in light of the "new collegialism." It defines the basic elements of ISO9000 and TQM, reviews the strengths and weaknesses of both approaches, and notes efforts…

Using Design Principles to Teach Technical Communication.

ERIC Educational Resources Information Center

Markel, Mike

1995-01-01

Compares the writing of two students--a competent writer and a weak one--in a technical communication course before and after discussion of design principles. Finds that a basic understanding of design principles helped them improve document macrostructure but had little effect on document microstructure. Suggests that integrating document design…

Video Based Developmental Mathematics Learning System For Community College Students.

ERIC Educational Resources Information Center

Gormley, Tyrone D.

The University of Maine at Augusta uses an individualized video-taped mathematics instructional system to eliminate students' math weaknesses before they attempt college math. The course, "1 Mth Developmental Mathematics," is part of the Educational Assistance Program and teaches basic skills and concepts of arithmetic and algebra. The…

Achievement Testing--A Look at Trends.

ERIC Educational Resources Information Center

Bligh, Harold F.

The strengths and weakness of standardized tests, and trends in achievement testing in the last 15 years are examined. The discussion of achievement tests includes survey, instructional, diagnostic, and basic skills tests, as well as tests used for formative and summative evaluation. Minimum competency tests are not examined in detail. Advantages…

Alcohol, drugs, and driving

DOT National Transportation Integrated Search

1974-03-01

An invitational symposium was held October 13-15, 1972, at a remote Vermont inn and was attended by 35 research and/or administrative specialists in alcohol, drugs and/or highway safety. The basic purpose was publication of the proceedings to incorpo...

Management of Atopic Dermatitis in Japan.

PubMed

Saeki, Hidehisa

2017-01-01

The guidelines for the treatment of atopic dermatitis (AD) issued by the Japanese Dermatological Association (JDA), which are basically designed for dermatologists, were first prepared in 2000 and revised in 2016. The guidelines for AD of the Japanese Society of Allergology (JSA), which are basically designed for allergologists, including internists, otorhinolaryngologists, ophthalmologists, and dermatologists, were first prepared in 2009 and revised in 2014. In this article, I review the definition, pathophysiology, etiology, epidemiology, diagnosis, severity classification, examination for diagnosis and severity assessment, and treatments for AD in Japan according to these two guidelines for AD (JDA and JSA). Based on the definition and diagnostic criteria for AD of the JDA, patients meeting three basic criteria, 1) pruritus, 2) typical morphology and distribution of the eczema, and 3) chronic or chronically relapsing course, are regarded as having AD. Treatment measures for AD basically consist of drug therapy, skin care, and elimination of exacerbating factors. Drugs that potently reduce AD-related inflammation in the skin are topical corticosteroids and tacrolimus. It is most important to promptly and accurately reduce inflammation related to AD by using these topical anti-inflammatory drugs. Proactive therapy refers to a treatment method in which, after inducing remission, a topical corticosteroid or tacrolimus ointment is intermittently applied to the skin in addition to skin care with moisturizers in order to maintain remission.

The principle of safety evaluation in medicinal drug - how can toxicology contribute to drug discovery and development as a multidisciplinary science?

PubMed

Horii, Ikuo

2016-01-01

Pharmaceutical (drug) safety assessment covers a diverse science-field in the drug discovery and development including the post-approval and post-marketing phases in order to evaluate safety and risk management. The principle in toxicological science is to be placed on both of pure and applied sciences that are derived from past/present scientific knowledge and coming new science and technology. In general, adverse drug reactions are presented as "biological responses to foreign substances." This is the basic concept of thinking about the manifestation of adverse drug reactions. Whether or not toxic expressions are extensions of the pharmacological effect, adverse drug reactions as seen from molecular targets are captured in the category of "on-target" or "off-target", and are normally expressed as a biological defense reaction. Accordingly, reactions induced by pharmaceuticals can be broadly said to be defensive reactions. Recent molecular biological conception is in line with the new, remarkable scientific and technological developments in the medical and pharmaceutical areas, and the viewpoints in the field of toxicology have shown that they are approaching toward the same direction as well. This paper refers to the basic concept of pharmaceutical toxicology, the differences for safety assessment in each stage of drug discovery and development, regulatory submission, and the concept of scientific considerations for risk assessment and management from the viewpoint of "how can multidisciplinary toxicology contribute to innovative drug discovery and development?" And also realistic translational research from preclinical to clinical application is required to have a significant risk management in post market by utilizing whole scientific data derived from basic and applied scientific research works. In addition, the significance for employing the systems toxicology based on AOP (Adverse Outcome Pathway) analysis is introduced, and coming challenges on precision medicine are to be addressed for the new aspect of efficacy and safety evaluation.

Quantitation of small intestinal permeability during normal human drug absorption

PubMed Central

2013-01-01

Background Understanding the quantitative relationship between a drug’s physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations. Methods Given the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function (“Averaged Model” (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface. Results Theoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 μm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting that it is nearly completely absorbed in the first part of the intestine where the pH is about 5.4. Conclusions The AM deconvolution method provides an accurate estimate of the human intestinal permeability. The results for these 90 drugs should provide a useful benchmark for evaluating QSAR models. PMID:23800230

The Effects of Obesity on Drug Metabolism in Children.

PubMed

Oeser, Steffen G; Rougee, Luc R A; Collier, Abby C

2015-01-01

Obesity in children is a significant clinical concern. There are many anecdotes and case studies regarding specific reactions of obese children to medications including therapeutic failure, adverse drug reactions and/or requirements for higher weight-adjusted dosing. There isis, however, a lack of basic and clinical data dissecting the mechanisms of these effects on pharmaceutical efficacy and safety. At present it is unknown how much of the difference in drug disposition in obese children can be attributed to obesity, to maturation or to an interaction between the two. Since a major determinant of drug disposition is hepatic metabolism, here we review how obesity alters hepatic drug disposition in children. Basic as well as clinical data summarizing the current knowledge of biochemical, physiological and clinical effects of pediatric obesity on drug disposition are considered. We conclude that there is a dire need for increased research into the direct effects of obesity on absorption, distribution, metabolism and excretion, as well as changes to pharmacokinetic parameters such as bioavailability and clearance. Increased effort in this area may elucidate the effects of obesity on clinical drug disposition with sufficient detail to provide better dosing guidelines where needed for children.

21 CFR 320.25 - Guidelines for the conduct of an in vivo bioavailability study.

Code of Federal Regulations, 2014 CFR

2014-04-01

... physician determines that there is a potential benefit to the patient. (b) Basic design. The basic design of... to or to meet any comparative labeling claims made in relation to the drug product that is the...

21 CFR 320.25 - Guidelines for the conduct of an in vivo bioavailability study.

Code of Federal Regulations, 2012 CFR

2012-04-01

... physician determines that there is a potential benefit to the patient. (b) Basic design. The basic design of... to or to meet any comparative labeling claims made in relation to the drug product that is the...

21 CFR 320.25 - Guidelines for the conduct of an in vivo bioavailability study.

Code of Federal Regulations, 2011 CFR

2011-04-01

... physician determines that there is a potential benefit to the patient. (b) Basic design. The basic design of... to or to meet any comparative labeling claims made in relation to the drug product that is the...

21 CFR 320.25 - Guidelines for the conduct of an in vivo bioavailability study.

Code of Federal Regulations, 2013 CFR

2013-04-01

... physician determines that there is a potential benefit to the patient. (b) Basic design. The basic design of... to or to meet any comparative labeling claims made in relation to the drug product that is the...

Basic Body Awareness Therapy for patients with stroke: Experiences among participating patients and physiotherapists.

PubMed

Lindvall, Mialinn Arvidsson; Anderzén Carlsson, Agneta; Forsberg, Anette

2016-01-01

After a stroke many patients have muscle weakness, spasticity and compromised sensation leading to decreased postural stability. Basic Body Awareness Therapy includes slow movements that challenge postural control. The aim was to describe experiences of 8 weeks of Basic Body Awareness Therapy from the perspective of both patients with stroke and physiotherapists. This study had a qualitative design. Twenty-one patients and four physiotherapists were interviewed. The interviews were analysed using manifest and latent content analysis. One overall theme emerged "Simple yet challenging" which was based on six categories: "Facing one's limitations", "Individualized movements", "A feeling of harmony", "Improved balance", "Integrated knowledge" and "Frustration and doubt". The patients described improvement in balance and stability, as well as increased wellbeing. The patients and physiotherapists related that Basic Body Awareness Therapy challenges balance but also provides an opportunity to reflect on the body. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Design principles of a microtubule polymerase

PubMed Central

Geyer, Elisabeth A; Miller, Matthew P; Brautigam, Chad A; Biggins, Sue

2018-01-01

Stu2/XMAP215 microtubule polymerases use multiple tubulin-binding TOG domains and a lattice-binding basic region to processively promote faster elongation. How the domain composition and organization of these proteins dictate polymerase activity, end localization, and processivity is unknown. We show that polymerase activity does not require different kinds of TOGs, nor are there strict requirements for how the TOGs are linked. We identify an unexpected antagonism between the tubulin-binding TOGs and the lattice-binding basic region: lattice binding by the basic region is weak when at least two TOGs engage tubulins, strong when TOGs are empty. End-localization of Stu2 requires unpolymerized tubulin, at least two TOGs, and polymerase competence. We propose a ‘ratcheting’ model for processivity: transfer of tubulin from TOGs to the lattice activates the basic region, retaining the polymerase at the end for subsequent rounds of tubulin binding and incorporation. These results clarify design principles of the polymerase. PMID:29897335

Subcutaneous drug infusions: a review of problems and solutions.

PubMed

Mitten, T

2001-02-01

Subcutaneous drug infusion using a portable syringe driver has had a significant impact on patient comfort in palliative care. It permits the continuous delivery of a range of drug therapies, so bypassing problems of dysphagia, weakness and the inability of many patients in the terminal phase to take oral medication. The devices are not problem-free, however. Mechanical problems, reactions at the infusion site and difficulties with the mixing of drugs in the syringe are all widely recognized. This article reviews some general issues with the operation of portable syringe drivers, and discusses a range of potential problems and their solutions.

Preparation and characterization of silica xerogels as carriers for drugs.

PubMed

Czarnobaj, K

2008-11-01

The aim of the present study was to utilize the sol-gel method to synthesize different forms of xerogel matrices for drugs and to investigate how the synthesis conditions and solubility of drugs influence the change of the profile of drug release and the structure of the matrices. Silica xerogels doped with drugs were prepared by the sol-gel method from a hydrolyzed tetraethoxysilane (TEOS) solution containing two model compounds: diclofenac diethylamine, (DD)--a water-soluble drug or ibuprofen, (IB)--a water insoluble drug. Two procedures were used for the synthesis of sol-gel derived materials: one-step procedure (the sol-gel reaction was carried out under acidic or basic conditions) and the two-step procedure (first, hydrolysis of TEOS was carried out under acidic conditions, and then condensation of silanol groups was carried out under basic conditions) in order to obtain samples with altered microstructures. In vitro release studies of drugs revealed a similar release profile in two steps: an initial diffusion-controlled release followed by a slower release rate. In all the cases studied, the released amount of DD was higher and the released time was shorter compared with IB for the same type of matrices. The released amount of drugs from two-step prepared xerogels was always lower than that from one-step base-catalyzed xerogels. One-step acid-catalyzed xerogels proved unsuitable as the carriers for the examined drugs.

Impact of severity of drug use on discrete emotions recognition in polysubstance abusers.

PubMed

Fernández-Serrano, María José; Lozano, Oscar; Pérez-García, Miguel; Verdejo-García, Antonio

2010-06-01

Neuropsychological studies support the association between severity of drug intake and alterations in specific cognitive domains and neural systems, but there is disproportionately less research on the neuropsychology of emotional alterations associated with addiction. One of the key aspects of adaptive emotional functioning potentially relevant to addiction progression and treatment is the ability to recognize basic emotions in the faces of others. Therefore, the aims of this study were: (i) to examine facial emotion recognition in abstinent polysubstance abusers, and (ii) to explore the association between patterns of quantity and duration of use of several drugs co-abused (including alcohol, cannabis, cocaine, heroin and MDMA) and the ability to identify discrete facial emotional expressions portraying basic emotions. We compared accuracy of emotion recognition of facial expressions portraying six basic emotions (measured with the Ekman Faces Test) between polysubstance abusers (PSA, n=65) and non-drug using comparison individuals (NDCI, n=30), and used regression models to explore the association between quantity and duration of use of the different drugs co-abused and indices of recognition of each of the six emotions, while controlling for relevant socio-demographic and affect-related confounders. Results showed: (i) that PSA had significantly poorer recognition than NDCI for facial expressions of anger, disgust, fear and sadness; (ii) that measures of quantity and duration of drugs used significantly predicted poorer discrete emotions recognition: quantity of cocaine use predicted poorer anger recognition, and duration of cocaine use predicted both poorer anger and fear recognition. Severity of cocaine use also significantly predicted overall recognition accuracy. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research

PubMed Central

Oertel, Bruno Georg; Lötsch, Jörn

2013-01-01

The medical impact of pain is such that much effort is being applied to develop novel analgesic drugs directed towards new targets and to investigate the analgesic efficacy of known drugs. Ongoing research requires cost-saving tools to translate basic science knowledge into clinically effective analgesic compounds. In this review we have re-examined the prediction of clinical analgesia by human experimental pain models as a basis for model selection in phase I studies. The overall prediction of analgesic efficacy or failure of a drug correlated well between experimental and clinical settings. However, correct model selection requires more detailed information about which model predicts a particular clinical pain condition. We hypothesized that if an analgesic drug was effective in an experimental pain model and also a specific clinical pain condition, then that model might be predictive for that particular condition and should be selected for development as an analgesic for that condition. The validity of the prediction increases with an increase in the numbers of analgesic drug classes for which this agreement was shown. From available evidence, only five clinical pain conditions were correctly predicted by seven different pain models for at least three different drugs. Most of these models combine a sensitization method. The analysis also identified several models with low impact with respect to their clinical translation. Thus, the presently identified agreements and non-agreements between analgesic effects on experimental and on clinical pain may serve as a solid basis to identify complex sets of human pain models that bridge basic science with clinical pain research. PMID:23082949

76 FR 4918 - Drug-Induced Liver Injury: Are We Ready to Look?; Public Conference; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-27

... Research Manufacturers of America to discuss and debate issues regarding drug-induced liver injury (DILI... of both basic science and clinical experts, and selecting for specific debate and discussion issues...

Noncompliance and drug toxicity in black, poor, and aged patients.

PubMed

Miller, R L; Algee, J

1978-10-01

Drug toxicity is a common medical problem. Continued increases in drug toxicity are related to the extensive, indiscriminate use of drugs. This is a national health problem which is caused partly by gaps in pharmacology as a basic and clinical science and partly by the rapid proliferation of drugs (the drug explosion) in the past 30 years. Socioeconomically disadvantaged (black, poor, and aged) patients are particularly vulnerable to compliance problems and drug toxicity. In this presentation we discuss the basis for this increased vulnerability and suggest strategies that practicing physicians can use to minimize both compliance problems and drug toxicity.

Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline

PubMed Central

Sateia, Michael J.; Buysse, Daniel J.; Krystal, Andrew D.; Neubauer, David N.; Heald, Jonathan L.

2017-01-01

Introduction: The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults, when such treatment is clinically indicated. Unlike previous meta-analyses, which focused on broad classes of drugs, this guideline focuses on individual drugs commonly used to treat insomnia. It includes drugs that are FDA-approved for the treatment of insomnia, as well as several drugs commonly used to treat insomnia without an FDA indication for this condition. This guideline should be used in conjunction with other AASM guidelines on the evaluation and treatment of chronic insomnia in adults. Methods: The American Academy of Sleep Medicine commissioned a task force of four experts in sleep medicine. A systematic review was conducted to identify randomized controlled trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence. The task force developed recommendations and assigned strengths based on the quality of evidence, the balance of benefits and harms, and patient values and preferences. Literature reviews are provided for those pharmacologic agents for which sufficient evidence was available to establish recommendations. The AASM Board of Directors approved the final recommendations. Recommendations: The following recommendations are intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment of chronic insomnia in adults, when such treatment is indicated. Under GRADE, a STRONG recommendation is one that clinicians should, under most circumstances, follow. A WEAK recommendation reflects a lower degree of certainty in the outcome and appropriateness of the patient-care strategy for all patients, but should not be construed as an indication of ineffectiveness. GRADE recommendation strengths do not refer to the magnitude of treatment effects in a particular patient, but rather, to the strength of evidence in published data. Downgrading the quality of evidence for these treatments is predictable in GRADE, due to the funding source for most pharmacological clinical trials and the attendant risk of publication bias; the relatively small number of eligible trials for each individual agent; and the observed heterogeneity in the data. The ultimate judgment regarding propriety of any specific care must be made by the clinician in light of the individual circumstances presented by the patient, available diagnostic tools, accessible treatment options, and resources. We suggest that clinicians use suvorexant as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use eszopiclone as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use zaleplon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use zolpidem as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use triazolam as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use temazepam as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use ramelteon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians use doxepin as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use trazodone as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use tiagabine as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use diphenhydramine as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use melatonin as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use tryptophan as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) We suggest that clinicians not use valerian as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK) Citation: Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307–349. PMID:27998379

Computer-Aided Drug Discovery: Molecular Docking of Diminazene Ligands to DNA Minor Groove

ERIC Educational Resources Information Center

Kholod, Yana; Hoag, Erin; Muratore, Katlynn; Kosenkov, Dmytro

2018-01-01

The reported project-based laboratory unit introduces upper-division undergraduate students to the basics of computer-aided drug discovery as a part of a computational chemistry laboratory course. The students learn to perform model binding of organic molecules (ligands) to the DNA minor groove with computer-aided drug discovery (CADD) tools. The…

The Challenge in Higher Education: Confronting and Reducing Substance Abuse on Campus.

ERIC Educational Resources Information Center

US Department of Justice, 2004

2004-01-01

The Office of National Drug Control Policy put together this guide to give administrators at institutions of higher education a basic understanding of illegal drug use among the college population and to urge their support in ridding campuses of this threat. People start using drugs for many reasons including peer pressure, thrills, or in search…

21 CFR 177.1520 - Olefin polymers.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Olefin polymers. 177.1520 Section 177.1520 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) INDIRECT FOOD ADDITIVES: POLYMERS Substances for Use as Basic Components of Single and Repeated Use Food Contact Surfaces § 177.1520 Olefin polymers. The olefi...

Effects of Manufacturing Methods on Dissolution and Absorption of Ketoconazole in the Presence of Organic Acid as a pH Modifier.

PubMed

Adachi, Masashi; Hinatsu, Yuta; Kusamori, Kosuke; Katsumi, Hidemasa; Sakane, Toshiyasu; Nakatani, Manabu; Wada, Koichi; Yamamoto, Akira

2017-05-01

Poorly water-soluble compounds have a potential risk of low and variable bioavailability caused by incomplete dissolution. Incorporation of organic acids as pH modifiers is effective method for solubility enhancement of basic compounds and requires no special technique and equipment. The purpose of this study was to evaluate the effect of manufacturing method on the extent of drug solubility enhancement. We successfully prepared the granules and tablets containing ketoconazole (KZ), which is weakly basic, as a model compound and citric acid as a pH modifier using conventional wet and dry granulations. KZ solubility under non-sink condition was enhanced with supersaturation using both wet and dry granulations. High-shear granulation was the most effective method in terms of KZ dissolution enhancement, because both an intimate contact and strong bonding between KZ and incorporated acid were achieved. KZ dissolved amount from the granules prepared by high-shear granulation was about eight times higher than that from the granules without the acid. The granulation involved to suppress a diffusion of acid dissolved, leading to the effectively maintained supersaturation state. The bioavailability of KZ after oral administration to rats was improved by applying high-shear granulation with citric acid independent of gastrointestinal pH. The granules prepared by high-shear granulation showed the bioavailability about 1.7-fold higher than that of the physical mixture in rats with and without neutralization of stomach. As a result, both the dissolution and absorption rates of KZ after oral administration were enhanced using conventional manufacturing technology.

n→π* Non-Covalent Interaction is Weak but Strong in Action

NASA Astrophysics Data System (ADS)

Singh, Santosh Kumar; Das, Aloke

2017-06-01

n→π* interaction is a newly discovered non-covalent interaction which involves delocalization of lone pair (n) electrons of an electronegative atom into π* orbital of a carbonyl group or an aromatic ring. It is widely observed in materials, biomolecules (protein, DNA, RNA), amino acids, neurotransmitter and drugs. However, due to its weak strength and counterintuitive nature its existence is debatable. Such weak interactions are often masked by solvent effects in condense phase or physiological conditions thereby, making it difficult to prove the presence of such weak interactions. Therefore, we have used isolated gas phase spectroscopy in combination with quantum chemical calculations to study n→π* interaction in several molecules where, our molecular systems are free from solvent effects or any external forces. Herein I will be discussing two of the molecular systems (phenyl formate and salicin) where, we have observed the significance of n→π* interaction in determining the conformational specificity of the molecules. We have proved the existence of n→π* interaction for the first time through IR spectroscopy by probing the carbonyl stretching frequency of phenyl formate. Our study is further pursued on a drug named salicin where, we have observed that its conformational preferences is ruled by n→π* interaction even though a strong hydrogen bonding interaction is present in the molecule. Our results show that n→π* interaction, in spite of its weak strength, should not be overlooked as it existence can play an important role in governing the structures of molecules like other strong non-covalent interactions do.

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

PubMed

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§

PubMed Central

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

Increasing both the public health potential of basic research and the scientist satisfaction. An international survey of bio-scientists.

PubMed

Sorrentino, Carmen; Boggio, Andrea; Confalonieri, Stefano; Hemenway, David; Scita, Giorgio; Ballabeni, Andrea

2016-01-01

Basic scientific research generates knowledge that has intrinsic value which is independent of future applications. Basic research may also lead to practical benefits, such as a new drug or diagnostic method. Building on our previous study of basic biomedical and biological researchers at Harvard, we present findings from a new survey of similar scientists from three countries. The goal of this study was to design policies to enhance both the public health potential and the work satisfaction and test scientists' attitudes towards these factors. The present survey asked about the scientists' motivations, goals and perspectives along with their attitudes concerning  policies designed to increase both the practical (i.e. public health) benefits of basic research as well as their own personal satisfaction. Close to 900 basic investigators responded to the survey; results corroborate the main findings from the previous survey of Harvard scientists. In addition, we find that most bioscientists disfavor present policies that require a discussion of the public health potential of their proposals in grants but generally favor softer policies aimed at increasing the quality of work and the potential practical benefits of basic research. In particular, bioscientists are generally supportive of those policies entailing the organization of more meetings between scientists and the general public, the organization of more academic discussion about the role of scientists in the society, and the implementation of a "basic bibliography" for each new approved drug.

Increasing both the public health potential of basic research and the scientist satisfaction. An international survey of bio-scientists

PubMed Central

Sorrentino, Carmen; Boggio, Andrea; Confalonieri, Stefano; Hemenway, David; Scita, Giorgio; Ballabeni, Andrea

2016-01-01

Basic scientific research generates knowledge that has intrinsic value which is independent of future applications. Basic research may also lead to practical benefits, such as a new drug or diagnostic method. Building on our previous study of basic biomedical and biological researchers at Harvard, we present findings from a new survey of similar scientists from three countries. The goal of this study was to design policies to enhance both the public health potential and the work satisfaction and test scientists’ attitudes towards these factors. The present survey asked about the scientists’ motivations, goals and perspectives along with their attitudes concerning  policies designed to increase both the practical (i.e. public health) benefits of basic research as well as their own personal satisfaction. Close to 900 basic investigators responded to the survey; results corroborate the main findings from the previous survey of Harvard scientists. In addition, we find that most bioscientists disfavor present policies that require a discussion of the public health potential of their proposals in grants but generally favor softer policies aimed at increasing the quality of work and the potential practical benefits of basic research. In particular, bioscientists are generally supportive of those policies entailing the organization of more meetings between scientists and the general public, the organization of more academic discussion about the role of scientists in the society, and the implementation of a “basic bibliography” for each new approved drug. PMID:27347372

Computer-aided drug discovery.

PubMed

Bajorath, Jürgen

2015-01-01

Computational approaches are an integral part of interdisciplinary drug discovery research. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true impact on drug discovery at different levels. If applied in a scientifically meaningful way, computational methods improve the ability to identify and evaluate potential drug molecules, but there remain weaknesses in the methods that preclude naïve applications. Herein, current trends in computer-aided drug discovery are reviewed, and selected computational areas are discussed. Approaches are highlighted that aid in the identification and optimization of new drug candidates. Emphasis is put on the presentation and discussion of computational concepts and methods, rather than case studies or application examples. As such, this contribution aims to provide an overview of the current methodological spectrum of computational drug discovery for a broad audience.

[Towards an unified theory of the universe basic forces ("the everything theory")].

PubMed

Aguilar Peris, José

2004-01-01

Numerous efforts have been made in order to unify all the basic forces in nature. In 1967 the fusion of electromagnetic and weak forces was obtained and in 1973 a theoretical bridge between the electroweak and the strong forces have been constructed. This theory is waiting for experimental proofs in the CERN large hadron collider. The last stage would be "the everything theory", which includes the gravitational force. Only the so called superstring theory is a good candidate to overcome the incompatibility of the quantum mechanics and the general relativity, but this theory is not already achieved.

Monitoring binding affinity between drug and α1-acid glycoprotein in real time by Venturi easy ambient sonic-spray ionization mass spectrometry.

PubMed

Liu, Ning; Lu, Xin; Yang, YuHan; Yao, Chen Xi; Ning, BaoMing; He, Dacheng; He, Lan; Ouyang, Jin

2015-10-01

A new approach for monitoring the binding affinity between drugs and alpha 1-acid glycoprotein in real time was developed based on a combination of drug-protein reaction followed by Venturi easy ambient sonic-spray ionization mass spectrometry determination of the free drug concentrations. A known basic drug, propranolol was used to validate the new built method. Binding constant values calculated by venturi easy ambient sonic-spray ionization mass spectrometry was in good accordance with a traditional ultrafiltration combined with high performance liquid chromatography method. Then six types of basic drugs were used as the samples to conduct the real time analysis. Upon injection of alpha 1-acid glycoprotein to the drug mixture, the ion chromatograms were extracted to show the changes in the free drug concentrations in real time. By observing the drop-out of six types of drugs during the whole binding reaction, the binding affinities of different drugs were distinguished. A volume shift validating experiment and an injection delay correcting experiment were also performed to eliminate extraneous factors and verify the reliability of our experiment. Therefore, the features of Venturi easy ambient sonic-spray ionization mass spectrometry (V-EASI-MS) and the experimental results indicate that our technique is likely to become a powerful tool for monitoring drug-AGP binding affinity in real time. Copyright © 2015 Elsevier B.V. All rights reserved.

Contribution of NIH funding to new drug approvals 2010–2016

PubMed Central

Beierlein, Jennifer M.; Khanuja, Navleen Surjit; McNamee, Laura M.; Ledley, Fred D.

2018-01-01

This work examines the contribution of NIH funding to published research associated with 210 new molecular entities (NMEs) approved by the Food and Drug Administration from 2010–2016. We identified >2 million publications in PubMed related to the 210 NMEs (n = 131,092) or their 151 known biological targets (n = 1,966,281). Of these, >600,000 (29%) were associated with NIH-funded projects in RePORTER. This funding included >200,000 fiscal years of NIH project support (1985–2016) and project costs >$100 billion (2000–2016), representing ∼20% of the NIH budget over this period. NIH funding contributed to every one of the NMEs approved from 2010–2016 and was focused primarily on the drug targets rather than on the NMEs themselves. There were 84 first-in-class products approved in this interval, associated with >$64 billion of NIH-funded projects. The percentage of fiscal years of project funding identified through target searches, but not drug searches, was greater for NMEs discovered through targeted screening than through phenotypic methods (95% versus 82%). For targeted NMEs, funding related to targets preceded funding related to the NMEs, consistent with the expectation that basic research provides validated targets for targeted screening. This analysis, which captures basic research on biological targets as well as applied research on NMEs, suggests that the NIH contribution to research associated with new drug approvals is greater than previously appreciated and highlights the risk of reducing federal funding for basic biomedical research. PMID:29440428

Landscape of Innovation for Cardiovascular Pharmaceuticals: From Basic Science to New Molecular Entities.

PubMed

Beierlein, Jennifer M; McNamee, Laura M; Walsh, Michael J; Kaitin, Kenneth I; DiMasi, Joseph A; Ledley, Fred D

2017-07-01

This study examines the complete timelines of translational science for new cardiovascular therapeutics from the initiation of basic research leading to identification of new drug targets through clinical development and US Food and Drug Administration (FDA) approval of new molecular entities (NMEs) based on this research. This work extends previous studies by examining the association between the growth of research on drug targets and approval of NMEs associated with these targets. Drawing on research on innovation in other technology sectors, where technological maturity is an important determinant in the success or failure of new product development, an analytical model was used to characterize the growth of research related to the known targets for all 168 approved cardiovascular therapeutics. Categorizing and mapping the technological maturity of cardiovascular therapeutics reveal that (1) there has been a distinct transition from phenotypic to targeted methods for drug discovery, (2) the durations of clinical and regulatory processes were significantly influenced by changes in FDA practice, and (3) the longest phase of the translational process was the time required for technology to advance from initiation of research to a statistically defined established point of technology maturation (mean, 30.8 years). This work reveals a normative association between metrics of research maturation and approval of new cardiovascular therapeutics and suggests strategies for advancing translational science by accelerating basic and applied research and improving the synchrony between the maturation of this research and drug development initiatives. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Frequency and level of evidence used in recommendations by the National Comprehensive Cancer Network guidelines beyond approvals of the US Food and Drug Administration: retrospective observational study.

PubMed

Wagner, Jeffrey; Marquart, John; Ruby, Julia; Lammers, Austin; Mailankody, Sham; Kaestner, Victoria; Prasad, Vinay

2018-03-07

To determine the differences between recommendations by the National Comprehensive Cancer Network (NCNN) guidelines and Food and Drug Administration approvals of anticancer drugs, and the evidence cited by the NCCN to justify recommendations where differences exist. Retrospective observational study. National Comprehensive Cancer Network and FDA. 47 new molecular entities approved by the FDA between 2011 and 2015. Comparison of all FDA approved indications (new and supplemental) with all NCCN recommendations as of 25 March 2016. When the NCCN made recommendations beyond the FDA's approvals, the recommendation was classified and the cited evidence noted. 47 drugs initially approved by the FDA between 2011 and 2015 for adult hematologic or solid cancers were examined. These 47 drugs were authorized for 69 FDA approved indications, whereas the NCCN recommended these drugs for 113 indications, of which 69 (62%) overlapped with the 69 FDA approved indications and 44 (39%) were additional recommendations. The average number of recommendations beyond the FDA approved indications was 0.92. 23% (n=10) of the additional recommendations were based on evidence from randomized controlled trials, and 16% (n=7) were based on evidence from phase III studies. During 21 months of follow-up, the FDA granted approval to 14% (n=6) of the additional recommendations. The NCCN frequently recommends beyond the FDA approved indications even for newer, branded drugs. The strength of the evidence cited by the NCCN supporting such recommendations is weak. Our findings raise concern that the NCCN justifies the coverage of costly, toxic cancer drugs based on weak evidence. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Illicit Drugs: Contaminants in the Environment and Utility in Forensic Epidemiology

EPA Science Inventory

The published literature surrounding the origin, occurrence, fate, and effects of illicit drug ingredients (IDIs) in the environment is examined. Similarities exist with medical pharmaceuticals, particularly with regard to the basic processes by which these ingredients enter the ...

75 FR 63491 - National Institute on Drug Abuse; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-15

... Drug Abuse Special Emphasis Panel, NIDA Research Education and Science Education Program Review (R25... Panel, NIDA Basic Science Conference Grant (R13) Review. Date: October 27, 2010. Time: 9 a.m. to 5 p.m...

Technical Modification Within the Healthcare Industry: Improving Both the Efficacy of the National Drug Code Carrier and the Accessibility of Electronic Health Records to Reduce Adverse Drug Events

DTIC Science & Technology

2013-06-01

with an EHR .................................................. 97 C. SWOT ANALYSIS OF USING QR CODES WITH THE NDC AND WITH EHRS...96 Figure 41. SWOT analysis ................................................................................... 99 xiii LIST OF...Coordinator for Health Information Technology OTC Over-the-Counter PHI Personal Health Information QR Quick Response SWOT Strengths, Weaknesses

Current situation and future usage of anticancer drug databases.

PubMed

Wang, Hongzhi; Yin, Yuanyuan; Wang, Peiqi; Xiong, Chenyu; Huang, Lingyu; Li, Sijia; Li, Xinyi; Fu, Leilei

2016-07-01

Cancer is a deadly disease with increasing incidence and mortality rates and affects the life quality of millions of people per year. The past 15 years have witnessed the rapid development of targeted therapy for cancer treatment, with numerous anticancer drugs, drug targets and related gene mutations been identified. The demand for better anticancer drugs and the advances in database technologies have propelled the development of databases related to anticancer drugs. These databases provide systematic collections of integrative information either directly on anticancer drugs or on a specific type of anticancer drugs with their own emphases on different aspects, such as drug-target interactions, the relationship between mutations in drug targets and drug resistance/sensitivity, drug-drug interactions, natural products with anticancer activity, anticancer peptides, synthetic lethality pairs and histone deacetylase inhibitors. We focus on a holistic view of the current situation and future usage of databases related to anticancer drugs and further discuss their strengths and weaknesses, in the hope of facilitating the discovery of new anticancer drugs with better clinical outcomes.

Assessing the Impact of Drug Use and Drug Selling on Violent Offending in a Panel of Delinquent Youth

PubMed Central

Phillips, Matthew D.

2016-01-01

Despite a vast number of empirical studies arguing for or against a causal relationship between illegal drug use and selling and violent behavior, the debate continues. In part this is due to methodological weaknesses of previous research. Using data from the Rochester Youth Development Study, the current study seeks to improve on prior research designs to allow for a more precise examination of the mechanisms that lead from an individual’s drug use (chiefly, marijuana use in the current sample) and drug selling to violent action. Results will allow for greater confidence in making causal inference regarding a long-standing concern in the discipline. PMID:26889079

Disentangling incentives effects of insurance coverage from adverse selection in the case of drug expenditure: a finite mixture approach.

PubMed

Munkin, Murat K; Trivedi, Pravin K

2010-09-01

This paper takes a finite mixture approach to model heterogeneity in incentive and selection effects of drug coverage on total drug expenditure among the Medicare elderly US population. Evidence is found that the positive drug expenditures of the elderly population can be decomposed into two groups different in the identified selection effects and interpreted as relatively healthy with lower average expenditures and relatively unhealthy with higher average expenditures, accounting for approximately 25 and 75% of the population, respectively. Adverse selection into drug insurance appears to be strong for the higher expenditure component and weak for the lower expenditure group. Copyright (c) 2010 John Wiley & Sons, Ltd.

Sleep complaints: Whenever possible, avoid the use of sleeping pills.

PubMed

2008-10-01

(1) Most sleep complaints involve difficulties in getting to sleep or staying asleep, or not feeling refreshed on awakening. Misconceptions and worrying over the lack of sleep and its consequences can contribute to reinforcing these disorders; (2) How can patients who complain of poor-quality sleep be helped, without resorting to treatments that can have adverse effects? To answer this question, we conducted a systematic review of the literature based on the standard Prescrire procedure; (3) One effective approach is to explain the basic physiology of sleep, to discuss misconceptions, and to adopt a strategy of "stimulus control". This method has a similar efficacy to prescribing a benzodiazepine. and the effect is longer lasting; (4) Moderate, regular physical exercise, especially in the morning, seems to help some patients, but the evidence is weak; (5) Some clinical trials of phytotherapy have shown a positive risk-benefit balance of weak aqueous or hydroalcoholic valerian extracts. Efficacy is limited, however; (6) A meta-analysis of placebo-controlled trials showed that benzodiazepines and related drugs increase the duration of sleep and help patients to fall asleep sooner. However, none of these trials provides comparative data spanning periods of more than two weeks. Efficacy is uncertain in the longer term, as patients quickly develop a tolerance to the hypnotic effects of benzodiazepines; (7) The adverse effects of benzodiazepines include frequent memory disorders, daytime drowsiness, falls, fractures and road accidents, and a withdrawal syndrome after treatment cessation. Related drugs such as zolpidem and zopiclone provoke similar adverse effects; (8) Sedative antihistamines have not been as well-evaluated as benzodiazepines in this setting. Small comparative trials of doxylamine and diphenhydramine showed no major difference in efficacy versus benzodiazepines and related drugs. The main adverse effects of sedative antihistamines are daytime drowsiness and altered vigilance, and atropinic effects; (9) Case-control studies showed a statistical link between benzodiazepine use in early pregnancy and birth defects such as cleft lip. In contrast, data on the use of doxylamine during pregnancy are reassuring; (10) Other sedative psychotropics have not been adequately tested in this setting or have been shown to have a negative risk-benefit balance; (11) In practice, patients who complain of poor-quality sleep should be given appropriate information on the mechanisms of normal sleep and related misconceptions, on the best methods for getting to sleep, and on the dangers of sedative psychotropics (dependence, withdrawal syndrome). When prescribing or dispensing a benzodiazepine to a woman of child-bearing age, the risk of birth defects, although not clearly demonstrated, must be mentioned.

75 FR 32943 - Food and Drug Administration Modernization Act of 1997: Modifications to the List of Recognized...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-10

... basic safety and essential performance--Collateral standard: Electromagnetic compatibility--Requirements... standard: Electromagnetic compatibility--Requirements and tests 5-34 5-53 IEC 60601-1-2 Third edition 2007... for basic safety and essential performance--Collateral standard: Electromagnetic compatibility...

Drugs and aggression.

PubMed

Rasia-Filho, Alberto A; Giovenardi, Márcia; de Almeida, Rosa M M

2008-01-01

Aggression is conceived as a social behavior that, in conjunct with motor and visceral displays, is related with acts for obtaining a specific goal or is directed against threatening stimuli with the intention of causing harm, either for attack or defense. Here it is reviewed basic concepts and aspects for the classification of aggression, the behavioral displays regarded as aggressive in animal models, the basic neural circuits that are involved to them and the pharmacological approaches involving some neurotransmitters (5-HT, dopamine and GABA) and drugs that can be used to identify the neural basis of aggression and to modulate its expression. Drug patents are referred in the text. Data are based on experiments developed mainly with rodents; however, some research hypotheses that may well give some insights for the clinical sciences in men were also included.

Meaningful Reading Gains by Adult Literacy Learners

ERIC Educational Resources Information Center

Scarborough, Hollis S.; Sabatini, John P.; Shore, Jane; Cutting, Laurie E.; Pugh, Kenneth; Katz, Leonard

2013-01-01

To obtain a fuller picture of the efficacy of reading instruction programs for adult literacy learners, gains by individual students were examined in a sample (n = 148) in which weak to moderate gains at the group level had been obtained in response to tutoring interventions that focused on strengthening basic decoding and fluency skills of low…

"A-LM German": How to Make it Work.

ERIC Educational Resources Information Center

Hartmetz, Dieter

1978-01-01

The A-LM German materials are analyzed in terms of their weakness and positive features, and suggestions for their use and adaptation are presented. It is argued that: the basic dialogue is almost unusable; the structure drills are repetitive and often not challenging; the taped arrangement of the listening exercises is awkward; the dialogue…

39 CFR 501.8 - Postage Evidencing System test and approval.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Service Web site at http://www.usps.com/postagesolutions/programdoc.html or requests for copies may be.... (b) As provided in § 501.11, the provider has a duty to report security weaknesses to the Postal... basic features or safeguards may be made except as authorized or ordered by the Postal Service in...

Improving English Listening Proficiency: The Application of ARCS Learning-Motivational Model

ERIC Educational Resources Information Center

Zhang, Jianfeng

2015-01-01

Language learning motivation is one of vital factors which strongly correlates to the success in second language acquisition. Listening proficiency, as one of the basic language abilities, is paid much attention in English instruction, but presently the college English listening teaching is a weak link in English language teaching in China, which…

Teacher Perspectives of Challenges within the Norwegian Educational System

ERIC Educational Resources Information Center

Anderson, Sarah K.; Terras, Katherine L.

2015-01-01

This research examines teacher perspectives' of educational challenges in Norway. Norway is one of the most well-resourced, prosperous, social welfare states in the world, yet the OECD (2011) recognized students' weak basic skills and insufficient teacher ability in content and pedagogy, along with engagement and imbalanced resources as points for…

The Effectiveness of Ineffectiveness: A New Approach to Assessing Patterns of Organizational Effectiveness.

ERIC Educational Resources Information Center

Cameron, Kim S.

A way to assess and improve organizational effectiveness is discussed, with a focus on factors that inhibit successful organizational performance. The basic assumption is that it is easier, more accurate, and more beneficial for individuals and organizations to identify criteria of ineffectiveness (faults and weaknesses) than to identify criteria…

Are School Districts Immune to a Weak Economy? Don't Believe It!

ERIC Educational Resources Information Center

Horner, Jeffrey

2009-01-01

Why should school districts worry about today's down economy? After all, the vast majority of their income comes from state legislatures and local property taxes, with some additional funding from the federal government. This funding is unaffected by downturns in sales, the stock market, and other basic economic indicators. School business…

Alcoholism among Hispanics--A Growing Concern.

ERIC Educational Resources Information Center

Garcia, Rolando

1979-01-01

A major concern to anyone involved in the alcoholism field is the basic understanding of alcoholism as a disease that Hispanics have not yet completely accepted. Hispanics have usually labeled the use of alcoholic beverages as being embedded into Hispanic culture and have viewed alcoholism as an individual weakness to be endured in silence. (NQ)

Structure-activity relationships studies on weakly basic N-arylsulfonylindoles with an antagonistic profile in the 5-HT6 receptor

NASA Astrophysics Data System (ADS)

Mella, Jaime; Villegas, Francisco; Morales-Verdejo, César; Lagos, Carlos F.; Recabarren-Gajardo, Gonzalo

2017-07-01

We recently reported a series of 39 weakly basic N-arylsulfonylindoles as novel 5-HT6 antagonists. Eight of the compounds exhibited moderate to high binding affinities, with 2-(4-(2-Methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol 16 showing the highest binding affinity (pKi = 7.87). Given these encouraging results and as a continuation of our research, we performed an extensive step-by-step search for the best 3D-QSAR model that allows us to rationally propose novel molecules with improved 5-HT6 affinity based on our previously reported series. A comparative molecular similarity indices analysis (CoMSIA) model built on a docking-based alignment was developed, wherein steric, electrostatic, hydrophobic and hydrogen bond properties are correlated with biological activity. The model was validated internally and externally (q2 = 0.721; r2pred = 0.938), and identified the sulfonyl and hydroxyl groups and the piperazine ring among the main regions of the molecules that can be modified to create new 5-HT6 antagonists.

Dynamics of epidemic spreading model with drug-resistant variation on scale-free networks

NASA Astrophysics Data System (ADS)

Wan, Chen; Li, Tao; Zhang, Wu; Dong, Jing

2018-03-01

Considering the influence of the virus' drug-resistant variation, a novel SIVRS (susceptible-infected-variant-recovered-susceptible) epidemic spreading model with variation characteristic on scale-free networks is proposed in this paper. By using the mean-field theory, the spreading dynamics of the model is analyzed in detail. Then, the basic reproductive number R0 and equilibriums are derived. Studies show that the existence of disease-free equilibrium is determined by the basic reproductive number R0. The relationships between the basic reproductive number R0, the variation characteristic and the topology of the underlying networks are studied in detail. Furthermore, our studies prove the global stability of the disease-free equilibrium, the permanence of epidemic and the global attractivity of endemic equilibrium. Numerical simulations are performed to confirm the analytical results.

Teachers' Drug Reference: A Guide to Medical Conditions and Drugs Commonly Used in School-Aged Children.

ERIC Educational Resources Information Center

Agins, Alan P.

This book provides a guide to approximately 175 drugs used with children. An introduction precedes the three major sections of the guide. Section 1 provides an overview of pharmacology and therapeutics in chapters on the basics of pharmacology, the language of pharmacology and therapeutics, compliance, side effects, and medications in school.…

The Research and Evaluation of Drug-Use Habits of People in North Cyprus

ERIC Educational Resources Information Center

Gürman, Mustafa; Demirdamar, Rümeysa; Basgut, Bilgen

2017-01-01

The purpose of this study is to determine the drug-use habits in North Cyprus and to prepare a demographic study of drug wastage. A total of 450 questionnaires containing 36 questions were handed out in 5 major cities of North Cyprus. Participants' pharmaceutical consumption habits and basic knowledge on rational use were compared with respect to…

Parent & Educators' Drug Reference: A Guide to Common Medical Conditions & Drugs Used in School-Aged Children.

ERIC Educational Resources Information Center

Agins, Alan P.

This book provides a guide to more than 180 drugs used for children. An introduction precedes the four major sections of the guide. Section 1 provides an overview of pharmacology and therapeutics in chapters on the basics of pharmacology, the language of pharmacology and therapeutics, compliance, side effects, medications in school, and drug…

Long-Term Evaluation of a Life Skills Approach for Alcohol and Drug Abuse Prevention.

ERIC Educational Resources Information Center

Brochu, Serge; Souliere, Michelle

1988-01-01

Three-day life skills re-education program, embedded in 10-week new employee basic training had no long-term effects on alcohol and drug knowledge and attitudes. Findings suggest that primary prevention program targeting adults may be too late to affect alcohol and drug habits, life skills approach may work best in secondary prevention efforts,…

T's and Blues. Specialized Information Service.

ERIC Educational Resources Information Center

Do It Now Foundation, Phoenix, AZ.

This compilation of journal articles provides basic information on abuse of Talwin, a mild prescription painkiller (T's), and Pyribenzamine, a nonprescription antihistimine (Blues). These two drugs, taken in combination, produce an effect similar to that produced by heroin. Stories from "Drug Survival News,""Emergency…

Teaching Toxicology as a Basic Medical Science

ERIC Educational Resources Information Center

Gralla, Edward J.

1976-01-01

A 4-year effort at Yale University School of Medicine to teach toxicology as an elective basic science from the standpoint of organ-specific toxic effects is described. The objective of the successful multidisciplinary program is to prepare physicians to understand, recognize, and manage adverse effects from drugs and other environmental…

21 CFR 1303.25 - Increase in individual manufacturing quotas.

Code of Federal Regulations, 2010 CFR

2010-04-01

... holds an individual manufacturing quota for a basic class of controlled substance listed in Schedule I... exceeds the aggregate of all the individual manufacturing quotas for the basic class of controlled... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Increase in individual manufacturing quotas. 1303...

Painting proteins with covalent labels: what's in the picture?

PubMed

Fitzgerald, Michael C; West, Graham M

2009-06-01

Knowledge about the structural and biophysical properties of proteins when they are free in solution and/or in complexes with other molecules is essential for understanding the biological processes that proteins regulate. Such knowledge is also important to drug discovery efforts, particularly those focused on the development of therapeutic agents with protein targets. In the last decade a variety of different covalent labeling techniques have been used in combination with mass spectrometry to probe the solution-phase structures and biophysical properties of proteins and protein-ligand complexes. Highlighted here are five different mass spectrometry-based covalent labeling strategies including: continuous hydrogen/deuterium (H/D) exchange labeling, hydroxyl radical-mediated footprinting, SUPREX (stability of unpurified proteins from rates of H/D exchange), PLIMSTEX (protein-ligand interaction by mass spectrometry, titration, and H/D exchange), and SPROX (stability of proteins from rates of oxidation). The basic experimental protocols used in each of the above-cited methods are summarized along with the kind of biophysical information they generate. Also discussed are the relative strengths and weaknesses of the different methods for probing the wide range of conformational states that proteins and protein-ligand complexes can adopt when they are in solution.

Combining "Bottom-up" and "Top-down" Approaches to Assess the Impact of Food and Gastric pH on Pictilisib (GDC-0941) Pharmacokinetics.

PubMed

Lu, Tong; Fraczkiewicz, Grazyna; Salphati, Laurent; Budha, Nageshwar; Dalziel, Gena; Smelick, Gillian S; Morrissey, Kari M; Davis, John D; Jin, Jin Y; Ware, Joseph A

2017-11-01

Pictilisib, a weakly basic compound, is an orally administered, potent, and selective pan-inhibitor of phosphatidylinositol 3-kinases for oncology indications. To investigate the significance of high-fat food and gastric pH on pictilisib pharmacokinetics (PK) and enable label recommendations, a dedicated clinical study was conducted in healthy volunteers, whereby both top-down (population PK, PopPK) and bottom-up (physiologically based PK, PBPK) approaches were applied to enhance confidence of recommendation and facilitate the clinical development through scenario simulations. The PopPK model identified food (for absorption rate constant (K a )) and proton pump inhibitors (PPI, for relative bioavailability (F rel ) and K a ) as significant covariates. Food and PPI also impacted the variability of F rel . The PBPK model accounted for the supersaturation tendency of pictilisib, and gastric emptying physiology successfully predicted the food and PPI effect on pictilisib absorption. Our research highlights the importance of applying both quantitative approaches to address critical drug development questions. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

The potential of a dielectrophoresis activated cell sorter (DACS) as a next generation cell sorter

NASA Astrophysics Data System (ADS)

Lee, Dongkyu; Hwang, Bohyun; Kim, Byungkyu

2016-12-01

Originally introduced by H. A. Pohl in 1951, dielectrophoretic (DEP) force has been used as a striking tool for biological particle manipulation (or separation) for the last few decades. In particular, dielectrophoresis activated cell sorters (DACSes) have been developed for applications in various biomedical fields. These applications include cell replacement therapy, drug screening and medical diagnostics. Since a DACS does not require a specific bio-marker, it is able to function as a biological particle sorting tool with numerous configurations for various cells [e.g. red blood cells (RBCs), white blood cells (WBCs), circulating tumor cells, leukemia cells, breast cancer cells, bacterial cells, yeast cells and sperm cells]. This article explores current DACS capabilities worldwide, and it also looks at recent developments intended to overcome particular limitations. First, the basic theories are reviewed. Then, representative DACSes based on DEP trapping, traveling wave DEP systems, DEP field-flow fractionation and DEP barriers are introduced, and the strong and weak points of each DACS are discussed. Finally, for the purposes of commercialization, prerequisites regarding throughput, efficiency and recovery rates are discussed in detail through comparisons with commercial cell sorters (e.g. fluorescent activated and magnetic activated cell sorters).

Asymmetry at the molecular level in biology

NASA Astrophysics Data System (ADS)

Johnson, Louise N.

2005-10-01

Naturally occurring biological molecules are made of homochiral building blocks. Proteins are composed of L-amino acids (and not D-amino acids); nucleic acids such as DNA have D-ribose sugars (and not L-ribose sugars). It is not clear why nature selected a particular chirality. Selection could have occurred by chance or as a consequence of basic physical chemistry. Possible proposals, including the contribution of the parity violating the weak nuclear force, are discussed together with the mechanisms by which this very small contribution might be amplified. Homochirality of the amino acids has consequences for protein structure. Helices are right handed and beta sheets have a left-hand twist. When incorporated into the tertiary structure of a protein these chiralities limit the topologies of connections between helices and sheets. Polypeptides comprised of D-amino acids can be synthesized chemically and have been shown to adopt stable structures that are the mirror image of the naturally occurring L-amino acid polypeptides. Chirality is important in drug design. Three examples are discussed: penicillin; the CD4 antagonistic peptides; and thalidomide. The absolute hand of a biological structure can only be established by X-ray crystallographic methods using the technique of anomalous scattering.

Hydrogen storage and evolution catalysed by metal hydride complexes.

PubMed

Fukuzumi, Shunichi; Suenobu, Tomoyoshi

2013-01-07

The storage and evolution of hydrogen are catalysed by appropriate metal hydride complexes. Hydrogenation of carbon dioxide by hydrogen is catalysed by a [C,N] cyclometalated organoiridium complex, [Ir(III)(Cp*)(4-(1H-pyrazol-1-yl-κN(2))benzoic acid-κC(3))(OH(2))](2)SO(4) [Ir-OH(2)](2)SO(4), under atmospheric pressure of H(2) and CO(2) in weakly basic water (pH 7.5) at room temperature. The reverse reaction, i.e., hydrogen evolution from formate, is also catalysed by [Ir-OH(2)](+) in acidic water (pH 2.8) at room temperature. Thus, interconversion between hydrogen and formic acid in water at ambient temperature and pressure has been achieved by using [Ir-OH(2)](+) as an efficient catalyst in both directions depending on pH. The Ir complex [Ir-OH(2)](+) also catalyses regioselective hydrogenation of the oxidised form of β-nicotinamide adenine dinucleotide (NAD(+)) to produce the 1,4-reduced form (NADH) under atmospheric pressure of H(2) at room temperature in weakly basic water. In weakly acidic water, the complex [Ir-OH(2)](+) also catalyses the reverse reaction, i.e., hydrogen evolution from NADH to produce NAD(+) at room temperature. Thus, interconversion between NADH (and H(+)) and NAD(+) (and H(2)) has also been achieved by using [Ir-OH(2)](+) as an efficient catalyst and by changing pH. The iridium hydride complex formed by the reduction of [Ir-OH(2)](+) by H(2) and NADH is responsible for the hydrogen evolution. Photoirradiation (λ > 330 nm) of an aqueous solution of the Ir-hydride complex produced by the reduction of [Ir-OH(2)](+) with alcohols resulted in the quantitative conversion to a unique [C,C] cyclometalated Ir-hydride complex, which can catalyse hydrogen evolution from alcohols in a basic aqueous solution (pH 11.9). The catalytic mechanisms of the hydrogen storage and evolution are discussed by focusing on the reactivity of Ir-hydride complexes.

Possible drug-drug interaction in dogs and cats resulted from alteration in drug metabolism: A mini review.

PubMed

Sasaki, Kazuaki; Shimoda, Minoru

2015-05-01

Pharmacokinetic drug-drug interactions (in particular at metabolism) may result in fatal adverse effects in some cases. This basic information, therefore, is needed for drug therapy even in veterinary medicine, as multidrug therapy is not rare in canines and felines. The aim of this review was focused on possible drug-drug interactions in dogs and cats. The interaction includes enzyme induction by phenobarbital, enzyme inhibition by ketoconazole and fluoroquinolones, and down-regulation of enzymes by dexamethasone. A final conclusion based upon the available literatures and author's experience is given at the end of the review.

Noncompliance and Drug Toxicity in Black, Poor, and Aged Patients

PubMed Central

Miller, Russell L.; Algee, John

1978-01-01

Drug toxicity is a common medical problem. Continued increases in drug toxicity are related to the extensive, indiscriminate use of drugs. This is a national health problem which is caused partly by gaps in pharmacology as a basic and clinical science and partly by the rapid proliferation of drugs (the drug explosion) in the past 30 years. Socioeconomically disadvantaged (black, poor, and aged) patients are particularly vulnerable to compliance problems and drug toxicity. In this presentation we discuss the basis for this increased vulnerability and suggest strategies that practicing physicians can use to minimize both compliance problems and drug toxicity. PMID:712862

Scopolamine effects on visual discrimination: modifications related to stimulus control

DOE Office of Scientific and Technical Information (OSTI.GOV)

Evans, H.L.

1975-01-01

Stumptail monkeys (Macaca arctoides) performed a discrete trial, three-choice visual discrimination. The discrimination behavior was controlled by the shape of the visual stimuli. Strength of the stimuli in controlling behavior was systematically related to a physical property of the stimuli, luminance. Low luminance provided weak control, resulting in a low accuracy of discrimination, a low response probability and maximal sensitivity to scopolamine (7.5-60 ..mu..g/kg). In contrast, high luminance provided strong control of behavior and attenuated the effects of scopolamine. Methylscopolamine had no effect in doses of 30 to 90 ..mu..g/kg. Scopolamine effects resembled the effects of reducing stimulus control inmore » undrugged monkeys. Since behavior under weak control seems to be especially sensitive to drugs, manipulations of stimulus control may be particularly useful whenever determination of the minimally-effective dose is important, as in behavioral toxicology. Present results are interpreted as specific visual effects of the drug, since nonsensory factors such as base-line response rate, reinforcement schedule, training history, motor performance and motivation were controlled. Implications for state-dependent effects of drugs are discussed.« less

Emulating weak localization using a solid-state quantum circuit.

PubMed

Chen, Yu; Roushan, P; Sank, D; Neill, C; Lucero, Erik; Mariantoni, Matteo; Barends, R; Chiaro, B; Kelly, J; Megrant, A; Mutus, J Y; O'Malley, P J J; Vainsencher, A; Wenner, J; White, T C; Yin, Yi; Cleland, A N; Martinis, John M

2014-10-14

Quantum interference is one of the most fundamental physical effects found in nature. Recent advances in quantum computing now employ interference as a fundamental resource for computation and control. Quantum interference also lies at the heart of sophisticated condensed matter phenomena such as Anderson localization, phenomena that are difficult to reproduce in numerical simulations. Here, employing a multiple-element superconducting quantum circuit, with which we manipulate a single microwave photon, we demonstrate that we can emulate the basic effects of weak localization. By engineering the control sequence, we are able to reproduce the well-known negative magnetoresistance of weak localization as well as its temperature dependence. Furthermore, we can use our circuit to continuously tune the level of disorder, a parameter that is not readily accessible in mesoscopic systems. Demonstrating a high level of control, our experiment shows the potential for employing superconducting quantum circuits as emulators for complex quantum phenomena.

Acute neuromuscular weakness in a boy with a facial abscess contaminated with Clostridium botulinum.

PubMed

Olson, Scott C; Bergen, Carly M; Andre-von Arnim, Amelie Saint; D'Angeli, Marisa A; Goldoft, Marcia J; Russell, Denny; Atkins, Robert C

2012-12-01

Wound botulism arising from skin and soft tissue infection is rare in children, most cases being reported in adult intravenous drug users. Cranial nerve palsies are the primary presenting sign, followed by descending neuromuscular weakness. Diagnosis relies on isolation of either toxigenic Clostridium botulinum species or toxin from wound or blood samples. We present an unusual case of wound botulism in a pediatric patient with the intent to inform the reader and improve the time to diagnosis in such cases.

Statistical investigation of simulated intestinal fluid composition on the equilibrium solubility of biopharmaceutics classification system class II drugs.

PubMed

Khadra, Ibrahim; Zhou, Zhou; Dunn, Claire; Wilson, Clive G; Halbert, Gavin

2015-01-25

A drug's solubility and dissolution behaviour within the gastrointestinal tract is a key property for successful administration by the oral route and one of the key factors in the biopharmaceutics classification system. This property can be determined by investigating drug solubility in human intestinal fluid (HIF) but this is difficult to obtain and highly variable, which has led to the development of multiple simulated intestinal fluid (SIF) recipes. Using a statistical design of experiment (DoE) technique this paper has investigated the effects and interactions on equilibrium drug solubility of seven typical SIF components (sodium taurocholate, lecithin, sodium phosphate, sodium chloride, pH, pancreatin and sodium oleate) within concentration ranges relevant to human intestinal fluid values. A range of poorly soluble drugs with acidic (naproxen, indomethacin, phenytoin, and piroxicam), basic (aprepitant, carvedilol, zafirlukast, tadalafil) or neutral (fenofibrate, griseofulvin, felodipine and probucol) properties have been investigated. The equilibrium solubility results determined are comparable with literature studies of the drugs in either HIF or SIF indicating that the DoE is operating in the correct space. With the exception of pancreatin, all of the factors individually had a statistically significant influence on equilibrium solubility with variations in magnitude of effect between the acidic and basic or neutral compounds and drug specific interactions were evident. Interestingly for the neutral compounds pH was the factor with the second largest solubility effect. Around one third of all the possible factor combinations showed a significant influence on equilibrium solubility with variations in interaction significance and magnitude of effect between the acidic and basic or neutral compounds. The least number of significant media component interactions were noted for the acidic compounds with three and the greatest for the neutral compounds at seven, with again drug specific effects evident. This indicates that a drug's equilibrium solubility in SIF is influenced depending upon drug type by between eight to fourteen individual or combinations of media components with some of these drug specific. This illustrates the complex nature of these fluids and provides for individual drugs a visualisation of the possible solubility envelope within the gastrointestinal tract, which may be of importance for modelling in vivo behaviour. In addition the results indicate that the design of experiment approach can be employed to provide greater detail of drug solubility behaviour, possible drug specific interactions and influence of variations in gastrointestinal media components due to disease. The approach is also feasible and amenable to adaptation for high throughput screening of drug candidates. Copyright © 2014 Elsevier B.V. All rights reserved.

Self-assembly of model graft copolymers of agarose and weak polyelectrolyte-based amphiphilic diblock copolymers: controlled drug release and degradation.

PubMed

Muppalla, Ravikumar; Jewrajka, Suresh K; Prasad, Kamalesh

2013-06-01

Polysaccharide-based copolymers are promising biomaterials due to their biocompatibility and biodegradability. For potential biomedical applications the copolymer as a whole and all the degraded species must be biocompatible and easily removable from the system. In this regards, new model pH-responsive seaweed agarose (Agr) grafted with weak polyelectrolyte-based well-defined amphiphilic block copolymers ca. poly[(methyl methacrylate)-b-(2-dimethylamino)ethyl methacrylate)] (PMMA-b-PDMA) were designed and synthesized to study the self-assembly, degradation, and in vitro hydrophobic/hydrophilic drug release behavior. The graft copolymer solutions display extremely low critical micelle concentration (CMC) and form pH responsive stable micelles. The degradation study of the graft copolymer reveals that the entire degraded components are well soluble/dispersible in water due to formation of mixed micelles. The micelles are also strongly adsorbed on the mica surface owing to electrostatic interaction. One application of the graft copolymer micelles is that it can entrap both hydrophilic and poorly water soluble hydrophobic drugs effectively and exhibit slow release kinetics. The release kinetics of both the hydrophilic and poorly water soluble hydrophobic drugs change with pH as well as with the composition of the graft copolymer. Copyright © 2012 Wiley Periodicals, Inc.

Regulatory Requirements for Devices for the Handicapped.

ERIC Educational Resources Information Center

Stigi, John, Ed.; Rivera, Richard J., Ed.

This booklet explains in question/answer form the basic regulatory requirements established by the Food and Drug Administration (FDA) of the federal government concerning the manufacture, marketing and distribution of medical devices (including implantable devices and devices previously regulated as drugs) for persons with disabilities. Topics…

21 CFR 177.2000 - Vinylidene chloride/methyl acrylate/methyl methacrylate polymers.

Code of Federal Regulations, 2014 CFR

2014-04-01

... methacrylate polymers. 177.2000 Section 177.2000 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) INDIRECT FOOD ADDITIVES: POLYMERS Substances for Use as Basic.../methyl methacrylate polymers. The vinylidene chloride/methyl acrylate/methyl methacrylate polymers (CAS...

Nonsteroidal anti-inflammatory drugs, traditional opioids, and tramadol: contrasting therapies for the treatment of chronic pain.

PubMed

Aronson, M D

1997-01-01

The treatment of chronic pain is an important function of physicians. In the United States, available drug treatments for chronic pain currently include simple analgesics such as acetaminophen, salicylates and other nonsteroidal anti-inflammatory drugs, traditional opioid drugs, and adjuvant agents (eg, antidepressants, anticonvulsants). Typically, the choice of a drug is made by balancing the indications for treatment, the clinical efficacy of the drug, and its toxicity. An understanding of the mechanism of action of these drugs helps to establish their role in therapy. Tramadol is an effective analgesic that works through a combined mechanism of weak mu receptor binding and the inhibition of serotonin and norepinephrine reuptake. Tramadol has a favorable adverse-effect profile and therefore is likely to have an important role in the management of chronic pain syndromes.

[Does the public sector have an independent research role in the development of drugs?].

PubMed

Poulsen, Henrik Enghusen; Grønlykke, Thor Buch

2003-04-14

Exclusively private companies do drug development. The State contributes with education of academics and basic research constituting the basis of half of the drugs developed by the private companies. The Danish private drug research amounts to six billion DKK per year, corresponding to the estimated price of the development of one new drug. The development shows a negative tendency. There are doubts about the scientific credibility, the number of new drugs is declining, drug development costs are rising, and the competitiveness in Europe is declining compared with the one of The United States. Continued improvement of Danish drug development can be achieved by stimulation of the public research related to drug development.

A multiscale model on hospital infections coupling macro and micro dynamics

NASA Astrophysics Data System (ADS)

Wang, Xia; Tang, Sanyi

2017-09-01

A multiscale model of hospital infections coupling the micro model of the growth of bacteria and the macro model describing the transmission of the bacteria among patients and health care workers (HCWs) was established to investigate the effects of antibiotic treatment on the transmission of the bacteria among patients and HCWs. The model was formulated by viewing the transmission rate from infected patients to HCWs and the shedding rate of bacteria from infected patients to the environment as saturated functions of the within-host bacterial load. The equilibria and the basic reproduction number of the coupled system were studied, and the global dynamics of the disease free equilibrium and the endemic equilibrium were analyzed in detail by constructing two Lyapunov functions. Furthermore, effects of drug treatment in the within-host model on the basic reproduction number and the dynamics of the coupled model were studied by coupling a pharmacokinetics model with the within-host model. Sensitive analysis indicated that the growth rate of the bacteria, the maximum drug effect and the dosing interval are the three most sensitive parameters contributing to the basic reproduction number. Thus, adopting ;wonder; drugs to decrease the growth rate of the bacteria or to increase the drug's effect is the most effective measure but changing the dosage regime is also effective. A quantitative criterion of how to choose the best dosage regimen can also be obtained from numerical results.

[Application of reversed-phase ion-pair chromatography for universal estimation of octanol-water partition coefficients of acid, basic and amphoteric drugs].

PubMed

Zhu, Hui; Yang, Ri-Fang; Yun, Liu-Hong; Jiang, Yu; Li, Jin

2009-09-01

This paper is to establish a reversed-phase ion-pair chromatography (RP-IPC) method for universal estimation of the octanol/water partition coefficients (logP) of a wide range of structurally diverse compounds including acidic, basic, neutral and amphoteric species. The retention factors corresponding to 100% water (logk(w)) were derived from the linear part of the logk'/phi relationship, using at least four isocratic logk' values containing different organic compositions. The logk(w) parameters obtained were close to the corresponding logP values obtained with the standard "shake flask" methods. The mean deviation for test drugs is 0.31. RP-IPC with trifluoroacetic acid as non classic ion-pair agents can be applicable to determine the logP values for a variety of drug-like molecules with increased accuracy.

Anti-Emetic Drug Effects on Performance Phase 1: Laboratory Study.

DTIC Science & Technology

1995-12-01

The objectives of this study were to evaluate the effects of two anti-emetic drugs, granisetron ( 2 mg p.o.) and ondansetron ( 8 mg p.o.) on basic...drugs of interest, granisetron and ondansetron, were extremely well tolerated and with no obvious side effects when compared to the placebo condition...evidence of any cognitive, psychomotor or subjective state changes caused by either granisetron or ondansetron.

Basic Mechanisms Underlying Postchemotherapy Cognitive Impairment

DTIC Science & Technology

2010-04-01

Anagnostaras et al., 2001; Gerlai, 2001; Maren, 2008). None of the drug treatments affected either context- or cue-specific fear conditioning (data not shown...The grant proposal focused on using spontaneous alternation and fear conditioning as the two methods to assess the effects of drug treatment on...treat other conditions . Thus, the pathway to begin to use these drugs to treat post-chemotherapy cognitive impairment might be short

Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects.

PubMed

Edwards, Jeffrey E; Eliot, Lise; Parkinson, Andrew; Karan, Sharon; MacConell, Leigh

2017-09-01

Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin). OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E max ) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs. In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin). Intercept Pharmaceuticals, Inc.

ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective

PubMed Central

Tsaioun, Katya; Bottlaender, Michel; Mabondzo, Aloise

2009-01-01

The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity. PMID:19534730

Pilot assessment of supply chains for pharmaceuticals and medical commodities for malaria, tuberculosis and HIV infection in Ethiopia.

PubMed

Daniel, Gabriel; Tegegnework, Hailu; Demissie, Tsion; Reithinger, Richard

2012-01-01

To obtain preliminary data on the drug supply management system in Ethiopia, selected facilities were assessed for the availability of essential drugs and commodities for malaria, TB and HIV. Of the 48 surveyed hospitals and health centers, 9 (19%), 9 (19%) and 10 (21%) did not have malaria, TB or HIV drugs, respectively. Similarly, of 27 health posts, 9 (33%) and 6 (22%) did not have rapid diagnostic tests and antimalarial drugs, respectively. The findings indicated an inadequate availability of essential drugs and commodities in the surveyed facilities as well as weaknesses in human resources and training. Assessments of commodity supply chains to ensure operational program success and impact are important. Published by Elsevier Ltd.

Proximal muscular atrophy and weakness: An unusual adverse effect of deferasirox iron chelation therapy.

PubMed

Vill, K; Müller-Felber, W; Teusch, V; Blaschek, A; Gerstl, L; Huetker, S; Albert, M H

2016-01-01

Deferasirox is a standard treatment for chronic transfusional iron overload. Adverse effects of deferasirox have been reported in large prospective studies. We report two cases of monozygotic twins manifesting with proximal muscular atrophy and weakness under deferasirox. Discontinuation of deferasirox resulted in symptom improvement and ultimately in complete remission five months after successful haematopoietic stem cell transplantation. Broad diagnostic work-up could not bring evidence of another aetiology of muscular weakness. Iron overload or beta thalassemia itself as a cause is considered unlikely in our patients because the chronological coincidence of muscular symptoms was contra-directional to serum ferritin levels and significant clinical improvement was observed promptly after cessation of deferasirox even before transplantation. These observations suggest that the development of muscular weakness in patients on deferasirox should be recognised as a possible adverse effect of the drug. Copyright © 2016 Elsevier B.V. All rights reserved.

Enzymatic activity of albumin shown by coelenterazine chemiluminescence.

PubMed

Vassel, N; Cox, C D; Naseem, R; Morse, V; Evans, R T; Power, R L; Brancale, A; Wann, K T; Campbell, A K

2012-01-01

Bioluminescence, the emission of light from live organisms, occurs in 18 phyla and is the major communication system in the deep sea. It has appeared independently many times during evolution but its origins remain unknown. Coelenterazine bioluminescence discovered in luminous jellyfish is the most common chemistry causing bioluminescence in the sea, occurring in seven phyla. Sequence similarities between coelenterazine luciferases and photoproteins from different phyla are poor (often < 5%). The aim of this study was to examine albumin that binds organic substances as a coelenterazine luciferase to test the hypothesis that the evolutionary origin of a bioluminescent protein was the result of the formation of a solvent cage containing just a few key amino acids. The results show for the first time that bovine and human albumin catalysed coelenterazine chemiluminescence consistent with a mono-oxygenase, whereas gelatin and haemoglobin, an oxygen carrier, had very weak activity. Insulin also catalysed coelenterazine chemiluminescence and was increased by Zn(2+). Albumin chemiluminescence was heat denaturable, exhibited saturable substrate characteristics and was inhibited by cations that bound these proteins and by drugs that bind to human albumin drug site I. Molecular modelling confirmed the coelenterazine binding site and identified four basic amino acids: lys195, arg222, his242 and arg257, potentially important in binding and catalysis similar to naturally occurring coelenterazine bioluminescent proteins. These results support the 'solvent cage' hypothesis for the evolutionary origin of enzymatic coelenterazine bioluminescent proteins. They also have important consequences in diseases such as diabetes, gut disorders and food intolerance where a mono-oxygenase could affect cell surface proteins. Copyright © 2012 John Wiley & Sons, Ltd.

A descriptive systematic review of salivary therapeutic drug monitoring in neonates and infants.

PubMed

Hutchinson, Laura; Sinclair, Marlene; Reid, Bernadette; Burnett, Kathryn; Callan, Bridgeen

2018-06-01

Saliva, as a matrix, offers many benefits over blood in therapeutic drug monitoring (TDM), in particular for infantile TDM. However, the accuracy of salivary TDM in infants remains an area of debate. This review explored the accuracy, applicability and advantages of using saliva TDM in infants and neonates. Databases were searched up to and including September 2016. Studies were included based on PICO as follows: P: infants and neonates being treated with any medication, I: salivary TDM vs. C: traditional methods and O: accuracy, advantages/disadvantages and applicability to practice. Compounds were assessed by their physicochemical and pharmacokinetic properties, as well as published quantitative saliva monitoring data. Twenty-four studies and their respective 13 compounds were investigated. Four neutral and two acidic compounds, oxcarbazepine, primidone, fluconazole, busulfan, theophylline and phenytoin displayed excellent/very good correlation between blood plasma and saliva. Lamotrigine was the only basic compound to show excellent correlation with morphine exhibiting no correlation between saliva and blood plasma. Any compound with an acid dissociation constant (pKa) within physiological range (pH 6-8) gave a more varied response. There is significant potential for infantile saliva testing and in particular for neutral and weakly acidic compounds. Of the properties investigated, pKa was the most influential with both logP and protein binding having little effect on this correlation. To conclude, any compound with a pKa within physiological range (pH 6-8) should be considered with extra care, with the extraction and analysis method examined and optimized on a case-by-case basis. © 2018 The British Pharmacological Society.

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

PubMed

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 gastric pH on the oral absorption of poorly water-soluble drugs were consistent with observations in humans. In conclusion, the D/P system with the gastric phase may be a useful tool for better predicting the oral absorption of poorly water-soluble basic drugs. In addition, the effects of gastric pH on the oral absorption of poorly water-soluble drugs may be evaluated by the D/P system with and without the gastric phase. Copyright © 2016 Elsevier B.V. All rights reserved.

General review of the MOSTAS computer code for wind turbines

NASA Technical Reports Server (NTRS)

Dungundji, J.; Wendell, J. H.

1981-01-01

The MOSTAS computer code for wind turbine analysis is reviewed, and techniques and methods used in its analyses are described. Impressions of its strengths and weakness, and recommendations for its application, modification, and further development are made. Basic techniques used in wind turbine stability and response analyses for systems with constant and periodic coefficients are reviewed.

The Pedagogical and Ethical Legacy of a "Successful" Educational Reform: The "Citizen School Project"

ERIC Educational Resources Information Center

Fischman, Gustavo E.; Gandin, Luis Armando

2016-01-01

The "Citizen School Project" ("Escola Cidadã") was implemented from 1993 to 2004 in Porto Alegre, capital of the Brazilian state of Rio Grande do Sul. This article presents the conception behind the "Citizen School Project," the basic mechanisms created to implement and evaluate its strengths and weaknesses, and some…

Contribution of NIH funding to new drug approvals 2010-2016.

PubMed

Galkina Cleary, Ekaterina; Beierlein, Jennifer M; Khanuja, Navleen Surjit; McNamee, Laura M; Ledley, Fred D

2018-03-06

This work examines the contribution of NIH funding to published research associated with 210 new molecular entities (NMEs) approved by the Food and Drug Administration from 2010-2016. We identified >2 million publications in PubMed related to the 210 NMEs ( n = 131,092) or their 151 known biological targets ( n = 1,966,281). Of these, >600,000 (29%) were associated with NIH-funded projects in RePORTER. This funding included >200,000 fiscal years of NIH project support (1985-2016) and project costs >$100 billion (2000-2016), representing ∼20% of the NIH budget over this period. NIH funding contributed to every one of the NMEs approved from 2010-2016 and was focused primarily on the drug targets rather than on the NMEs themselves. There were 84 first-in-class products approved in this interval, associated with >$64 billion of NIH-funded projects. The percentage of fiscal years of project funding identified through target searches, but not drug searches, was greater for NMEs discovered through targeted screening than through phenotypic methods (95% versus 82%). For targeted NMEs, funding related to targets preceded funding related to the NMEs, consistent with the expectation that basic research provides validated targets for targeted screening. This analysis, which captures basic research on biological targets as well as applied research on NMEs, suggests that the NIH contribution to research associated with new drug approvals is greater than previously appreciated and highlights the risk of reducing federal funding for basic biomedical research. Copyright © 2018 the Author(s). Published by PNAS.

75 FR 9614 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-03

... manufacturer of the basic classes of controlled substances listed in schedule I: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to manufacture small quantities of marihuana derivatives for research purposes. In reference to drug code 7360 (Marihuana), the company plans to bulk...

76 FR 21917 - Manufacturer of Controlled Substances; Notice of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-19

... manufacturer of the following basic classes of controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to manufacture small quantities of marihuana derivatives for research purposes. In reference to drug code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol. In...

75 FR 64744 - Manufacturer of Controlled Substances; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-20

... manufacturer of the basic classes of controlled substances listed in schedule I: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to manufacture small quantities of marihuana derivatives for research purposes. In reference to drug code 7360 (Marihuana), the company plans to bulk...

The poverty-related neglected diseases: Why basic research matters.

PubMed

Hotez, Peter J

2017-11-01

Together, malaria and the neglected tropical diseases (NTDs) kill more than 800,000 people annually, while creating long-term disability in millions more. International support for mass drug administration, bed nets, and other preventive measures has resulted in huge public health gains, while support for translational research is leading to the development of some new neglected disease drugs, diagnostics, and vaccines. However, funding for basic science research has not kept up, such that we are missing opportunities to create a more innovative pipeline of control tools for parasitic and related diseases. There is an urgent need to expand basic science approaches for neglected diseases, especially in the areas of systems biology and immunology; ecology, evolution, and mathematical biology; functional and comparative OMICs; gene editing; expanded use of model organisms; and a new single-cell combinatorial indexing RNA sequencing approach. The world's poor deserve access to innovation for neglected diseases. It should be considered a fundamental human right.

77 FR 37059 - Draft Guidance for Industry on Active Controls in Studies To Demonstrate Effectiveness of a New...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-20

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-D-0419... who conduct studies using active controls and have a basic understanding of statistical principles... clinical investigators who conduct studies using active controls and have a basic understanding of...

Standard First Aid Training Course. Naval Education and Training Command Rate Training Manual.

ERIC Educational Resources Information Center

Naval Education and Training Command, Washington, DC.

This first aid manual is designed to serve as basic first aid instructional materials for all nonmedical naval personnel. Chapters are included on the following topics: basic life support, hemorrhage, shock, wounds, injuries, drug abuse, poisoning, common medical emergencies, NBC (nuclear, biological, chemical) agent casualties, and rescue and…

Simple modification of basic dyes with bulky &symmetric WCAs for improving their solubilities in organic solvents without color change.

PubMed

Kim, Jeong Yun; Hwang, Tae Gyu; Woo, Sung Wun; Lee, Jae Moon; Namgoong, Jin Woong; Yuk, Sim Bum; Chung, Sei-Won; Kim, Jae Pil

2017-04-06

A simple and easy solubility enhancement of basic dyes was performed with bulky and symmetric weakly coordinating anions (WCAs). The WCAs decreased the ionic character of the dyes by broadening the partial charge distribution and causing a screening effect on the ionic bonding. This new modification with WCAs has advantages in that it has no influence on the optical properties of the dyes. The solubilities of unmodified and modified dyes were tested in several organic solvents. X-ray powder diffraction patterns of the dyes were measured. Color films were prepared with the dyes and their color loci were analyzed to evaluate the optical properties. By the modification with WCAs, commercial basic dyes showed sufficient solubilities for be applied to various applications while preserving their superior optical properties.

Biophotonics: Optical Science and Engineering for the 21st Century

NASA Astrophysics Data System (ADS)

Shen, Xun; van Wijk, Roeland

It is now well established that all living systems emit a weak but permanent photon flux in the visible and ultraviolet range. This biophoton emission is correlated with many, if not all, biological and physiological functions. There are indications of a hitherto-overlooked information channel within the living system. Biophotons may trigger chemical reactivity in cells, growth control, differentiation and intercellular communication, i.e. biological rhythms. The basic experimental and theoretical framework as well as the technical problems and the wide field of applications in the biotechnical, biomedical engineering, engineering, medicine, pharmacology, environmental science and basic science fields are presented in this book.

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

NASA Astrophysics Data System (ADS)

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

2018-02-01

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

Crystallographic Fragment Based Drug Discovery: Use of a Brominated Fragment Library Targeting HIV Protease

PubMed Central

Tiefenbrunn, Theresa; Forli, Stefano; Happer, Meaghan; Gonzalez, Ana; Tsai, Yingssu; Soltis, Michael; Elder, John H.; Olson, Arthur J.; Stout, C. David

2013-01-01

A library of 68 brominated fragments was screened against a new crystal form of inhibited HIV-1 protease in order to probe surface sites in soaking experiments. Often fragments are weak binders with partial occupancy, resulting in weak, difficult-to-fit electron density. The use of a brominated fragment library addresses this challenge, as bromine can be located unequivocally via anomalous scattering. Data collection was carried out in an automated fashion using AutoDrug at SSRL. Novel hits were identified in the known surface sites: 3-bromo-2,6-dimethoxybenzoic acid (Br6) in the flap site, and 1-bromo-2-naphthoic acid (Br27) in the exosite, expanding the chemistry of known fragments for development of higher affinity potential allosteric inhibitors. At the same time, mapping the binding sites of a number of weaker binding Br-fragments provides further insight into the nature of these surface pockets. PMID:23998903

Weak interactions involving organic fluorine: analysis of structural motifs in Flunazirine and Haloperidol

NASA Astrophysics Data System (ADS)

Prasanna, M. D.; Row, T. N. Guru

2001-05-01

The crystal structure of Flunazirine, an anticonvulsant drug, is analyzed in terms of intermolecular interactions involving fluorine. The structure displays motifs formed by only weak interactions C-H⋯F and C-H⋯π. The motifs thus generated show cavities, which could serve as hosts for complexation. The structure of Flunazirine displays cavities formed by C-H⋯F and C-H⋯π interactions. Haloperidol, an antipsychotic drug, shows F⋯F interactions in the crystalline lattice in lieu of Cl⋯Cl interactions. However, strong O-H⋯N interactions dominate packing. The salient features of the two structures in terms of intermolecular interactions reveal, even though organic fluorine has lower tendency to engage in hydrogen bonding and F⋯F interactions, these interactions could play a significant role in the design of molecular assemblies via crystal engineering.

The Impact of Social Structures on Deviant Behaviors: The Study of 402 High Risk Street Drug Users in Iran.

PubMed

Mehrabi, Maryam; Eskandarieh, Sharareh; Khodadost, Mahmoud; Sadeghi, Maneli; Nikfarjam, Ali; Hajebi, Ahmad

2016-01-01

This study is a sociological analysis of the three dimensions of social structure including institutional, relational, and embodied structures that have an impact on the individuals' deviant behaviors in the society. The authors used a mix method to analyze the qualitative and quantitative data of 402 high risk abandoned substance users in 2008 in Tehran, capital city of Iran. The leading reasons of substance use were categorized into four fundamental themes as follows: stress, deviant social networks, and low social capital and weak social support sources. In addition, the epidemiology model of regression analysis provides a brief explanation to assess the association between the demographical and etiological variables, and the drug users' deviant behaviors. In sum, substance use is discussed as a deviant behavior pattern which stems from a comorbidity of weak social structures.

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

PubMed

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.

Global financial crisis and weak-form efficiency of Islamic sectoral stock markets: An MF-DFA analysis

NASA Astrophysics Data System (ADS)

Mensi, Walid; Tiwari, Aviral Kumar; Yoon, Seong-Min

2017-04-01

This paper estimates the weak-form efficiency of Islamic stock markets using 10 sectoral stock indices (basic materials, consumer services, consumer goods, energy, financials, health care, industrials, technology, telecommunication, and utilities). The results based on the multifractal detrended fluctuation analysis (MF-DFA) approach show time-varying efficiency for the sectoral stock markets. Moreover, we find that they tend to show high efficiency in the long term but moderate efficiency in the short term, and that these markets become less efficient after the onset of the global financial crisis. These results have several significant implications in terms of asset allocation for investors dealing with Islamic markets.

Separation of cannabinoids on three different mixed-mode columns containing carbon/nanodiamond/amine-polymer superficially porous particles.

PubMed

Hung, Chuan-Hsi; Zukowski, Janusz; Jensen, David S; Miles, Andrew J; Sulak, Clayton; Dadson, Andrew E; Linford, Matthew R

2015-09-01

Three mixed-mode high-performance liquid chromatography columns packed with superficially porous carbon/nanodiamond/amine-polymer particles were used to separate mixtures of cannabinoids. Columns evaluated included: (i) reversed phase (C18 ), weak anion exchange, 4.6 × 33 mm, 3.6 μm, and 4.6 × 100 mm, 3.6 μm, (ii) reversed phase, strong anion exchange (quaternary amine), 4.6×33 mm, 3.6 μm, and (iii) hydrophilic interaction liquid chromatography, 4.6 × 150 mm, 3.6 μm. Different selectivities were achieved under various mobile phase and stationary phase conditions. Efficiencies and peak capacities were as high as 54 000 N/m and 56, respectively. The reversed phase mixed-mode column (C18 ) retained tetrahydrocannabinolic acid strongly under acidic conditions and weakly under basic conditions. Tetrahydrocannabinolic acid was retained strongly on the reversed phase, strong anion exchange mixed-mode column under basic polar organic mobile phase conditions. The hydrophilic interaction liquid chromatography column retained polar cannabinoids better than the (more) neutral ones under basic conditions. A longer reversed phase (C18 ) mixed-mode column (4.6 × 100 mm) showed better resolution for analytes (and a contaminant) than a shorter column. Fast separations were achieved in less than 5 min and sometimes 2 min. A real world sample (bubble hash extract) was also analyzed by gradient elution. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A PEGylated Fibrin-Based Wound Dressing with Antimicrobial and Angiogenic Activity

DTIC Science & Technology

2011-04-13

naturally available, cost-effective, biocompatible, and biodegradable. Among these natural polymers chitosan ( poly (b-(1,4)-2-amino-2-deoxy-D...drying, ionic gela- tion, and sieving. Among these, ionic gelation is preferred for drugs that require an initial short burst release while maintaining...form ionic interactions with anionic mole- cules, and have been previously used for the controlled release of drugs [18]. Since SSD is a weak anionic

21 CFR 177.2000 - Vinylidene chloride/methyl acrylate/methyl methacrylate polymers.

Code of Federal Regulations, 2010 CFR

2010-04-01

... methacrylate polymers. 177.2000 Section 177.2000 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...: POLYMERS Substances for Use as Basic Components of Single and Repeated Use Food Contact Surfaces § 177.2000 Vinylidene chloride/methyl acrylate/methyl methacrylate polymers. The vinylidene chloride/methyl acrylate...

21 CFR 177.2000 - Vinylidene chloride/methyl acrylate/methyl methacrylate polymers.

Code of Federal Regulations, 2011 CFR

2011-04-01

... methacrylate polymers. 177.2000 Section 177.2000 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...: POLYMERS Substances for Use as Basic Components of Single and Repeated Use Food Contact Surfaces § 177.2000 Vinylidene chloride/methyl acrylate/methyl methacrylate polymers. The vinylidene chloride/methyl acrylate...

21 CFR 331.11 - Listing of specific active ingredients.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Listing of specific active ingredients. 331.11... (CONTINUED) DRUGS FOR HUMAN USE ANTACID PRODUCTS FOR OVER-THE-COUNTER (OTC) HUMAN USE Active Ingredients § 331.11 Listing of specific active ingredients. (a) Aluminum-containing active ingredients: (1) Basic...

21 CFR 331.11 - Listing of specific active ingredients.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Listing of specific active ingredients. 331.11... (CONTINUED) DRUGS FOR HUMAN USE ANTACID PRODUCTS FOR OVER-THE-COUNTER (OTC) HUMAN USE Active Ingredients § 331.11 Listing of specific active ingredients. (a) Aluminum-containing active ingredients: (1) Basic...

21 CFR 50.25 - Elements of informed consent.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROTECTION OF HUMAN SUBJECTS Informed Consent of Human Subjects § 50.25 Elements of informed consent. (a) Basic... the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if...

21 CFR 177.2000 - Vinylidene chloride/methyl acrylate/methyl methacrylate polymers.

Code of Federal Regulations, 2012 CFR

2012-04-01

... methacrylate polymers. 177.2000 Section 177.2000 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...: POLYMERS Substances for Use as Basic Components of Single and Repeated Use Food Contact Surfaces § 177.2000 Vinylidene chloride/methyl acrylate/methyl methacrylate polymers. The vinylidene chloride/methyl acrylate...

21 CFR 177.2000 - Vinylidene chloride/methyl acrylate/methyl methacrylate polymers.

Code of Federal Regulations, 2013 CFR

2013-04-01

... methacrylate polymers. 177.2000 Section 177.2000 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...: POLYMERS Substances for Use as Basic Components of Single and Repeated Use Food Contact Surfaces § 177.2000 Vinylidene chloride/methyl acrylate/methyl methacrylate polymers. The vinylidene chloride/methyl acrylate...

AIDS--Challenges to Basic and Clinical Biomedical Research.

ERIC Educational Resources Information Center

Fauci, Anthony S.

1989-01-01

Clinical trials and access to therapeutic drugs pose dilemmas for researchers, physicians, and AIDS patients. The National Institute of Allergy and Infectious Diseases, recognizing the need for greater access to drugs by a broader spectrum of the infected population, is establishing the Community Programs for Clinical Research on AIDS. (Author/MLW)

21 CFR 50.25 - Elements of informed consent.

Code of Federal Regulations, 2010 CFR

2010-04-01

... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROTECTION OF HUMAN SUBJECTS Informed Consent of Human Subjects § 50.25 Elements of informed consent. (a) Basic... pertinent questions about the research and research subjects' rights, and whom to contact in the event of a...

FDA Kids' Home Page

MedlinePlus

... and Drug Administration A to Z Index Follow FDA En Español Search FDA Submit search Popular Content Home Food Drugs Medical ... 日本語 | فارسی | English FDA Accessibility Careers FDA Basics FOIA No FEAR Act ...

Peripheral facial weakness (Bell's palsy).

PubMed

Basić-Kes, Vanja; Dobrota, Vesna Dermanović; Cesarik, Marijan; Matovina, Lucija Zadro; Madzar, Zrinko; Zavoreo, Iris; Demarin, Vida

2013-06-01

Peripheral facial weakness is a facial nerve damage that results in muscle weakness on one side of the face. It may be idiopathic (Bell's palsy) or may have a detectable cause. Almost 80% of peripheral facial weakness cases are primary and the rest of them are secondary. The most frequent causes of secondary peripheral facial weakness are systemic viral infections, trauma, surgery, diabetes, local infections, tumor, immune disorders, drugs, degenerative diseases of the central nervous system, etc. The diagnosis relies upon the presence of typical signs and symptoms, blood chemistry tests, cerebrospinal fluid investigations, nerve conduction studies and neuroimaging methods (cerebral MRI, x-ray of the skull and mastoid). Treatment of secondary peripheral facial weakness is based on therapy for the underlying disorder, unlike the treatment of Bell's palsy that is controversial due to the lack of large, randomized, controlled, prospective studies. There are some indications that steroids or antiviral agents are beneficial but there are also studies that show no beneficial effect. Additional treatments include eye protection, physiotherapy, acupuncture, botulinum toxin, or surgery. Bell's palsy has a benign prognosis with complete recovery in about 80% of patients, 15% experience some mode of permanent nerve damage and severe consequences remain in 5% of patients.

Drug Abuse and Drug Abuse Research. The Third Triennial Report to Congress from the Secretary, Department of Health and Human Services.

ERIC Educational Resources Information Center

National Inst. on Drug Abuse (DHHS/PHS), Rockville, MD.

This report summarizes changes that have occurred in understanding of the health implications of the use and abuse of illegal and legal drugs as a result of research since 1986. It is noted that wherever possible, research findings have been summarized in non-technical language. Some technical material is included because of its basic importance…

[Antifibrillatory activity of anti-arrhythmia agents in maximally high ligation of the coronary artery and its reperfusion in cats].

PubMed

Storozhuk, B G

1985-01-01

Experiments on anesthesized cats were performed to study antifibrillatory action of the basic antiarrhythmic remedies and a new Soviet drug, phenicaberan. It was established that phenicaberan and lidocaine compare very favourably with other drugs under study as regards the antifibrillatory effect. For that reason these drugs can be recommended for use in the prophylaxis of fatal arrhythmias.

Drug-binding energetics of human α-1-acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations

PubMed Central

Huang, Johnny X.; Cooper, Matthew A.; Baker, Mark A.; Azad, Mohammad A.K.; Nation, Roger L.; Li, Jian; Velkov, Tony

2012-01-01

This study utilizes sensitive, modern isothermal titration calorimetric (ITC) methods to characterize the microscopic thermodynamic parameters that drive the binding of basic drugs to α-1-acid glycoprotein (AGP) and thereby rationalize the thermodynamic data in relation to docking models and crystallographic structures of the drug-AGP complexes. The binding of basic compounds from the tricyclic antidepressant series, together with miaserine, chlorpromazine, disopyramide and cimetidine all displayed an exothermically driven binding interaction with AGP. The impact of protonation/deprotonation events, ionic strength, temperature and the individual selectivity of the A and F1*S AGP variants on drug-binding thermodynamics were characterized. A correlation plot of the thermodynamic parameters for all of the test compounds revealed enthalpy-entropy compensation is in effect. The exothermic binding energetics of the test compounds were driven by a combination of favorable (negative) enthalpic (ΔH°) and favorable (positive) entropic (ΔS°) contributions to the Gibbs free energy (ΔG°). Collectively, the data imply that the free energies that drive drug binding to AGP and its relationship to drug-serum residency evolve from the complex interplay of enthalpic and entropic forces from interactions with explicit combinations of hydrophobic and polar side-chain sub-domains within the multi-lobed AGP ligand binding cavity. PMID:23192962

Reconsidering Japan's underperformance in pharmaceuticals: evidence from Japan's anticancer drug sector.

PubMed

Umemura, Maki

2010-01-01

Unlike its automobile or electronics industries, Japan's pharmaceutical industry did not become a global leader. Japan remains a net importer of pharmaceuticals and has introduced few global blockbuster drugs. Alfred Chandler argued that Japan's pharmaceutical firms remained relatively weak because Western firms enjoyed an insurmountable first first-mover advantage. However, this case study of the anticancer drug sector illustrates that Chandler's explanation is incomplete. Japanese medical culture, government policy, and research environment also played a substantial role in shaping the industry. In the 1970s and 1980s, these factors encouraged firms to develop little few effective drugs with low side effects, and profit from Japan's domestic market. But, these drugs were unsuitable to foreign markets with more demanding efficacy standards. As a result, Japan not only lost more than a decade in developing ineffective drugs, but also neglected to create the infrastructure necessary to develop innovative drugs and build a stronger pharmaceutical industry.

Merits of using color and shape differentiation to improve the speed and accuracy of drug strength identification on over-the-counter medicines by laypeople.

PubMed

Hellier, Elizabeth; Tucker, Mike; Kenny, Natalie; Rowntree, Anna; Edworthy, Judy

2010-09-01

This study aimed to examine the utility of using color and shape to differentiate drug strength information on over-the-counter medicine packages. Medication errors are an important threat to patient safety, and confusions between drug strengths are a significant source of medication error. A visual search paradigm required laypeople to search for medicine packages of a particular strength from among distracter packages of different strengths, and measures of reaction time and error were recorded. Using color to differentiate drug strength information conferred an advantage on search times and accuracy. Shape differentiation did not improve search times and had only a weak effect on search accuracy. Using color to differentiate drug strength information improves drug strength identification performance. Color differentiation of drug strength information may be a useful way of reducing medication errors and improving patient safety.

Investigation on drug solubility enhancement using deep eutectic solvents and their derivatives.

PubMed

Li, Zheng; Lee, Ping I

2016-05-30

Deep eutectic solvent (DES) is a room temperature liquid typically formed by mixing two solid compounds, such as a quaternary ammonium salt (QAS) (e.g. choline chloride) and a hydrogen bond donor (HBD) (e.g. urea or a carboxylic acid) at their eutectic composition. Very often, a range of room temperature liquids can also be obtained near the eutectic composition. Hence, it is more convenient to introduce a more general term deep eutectic solvent derivatives (DESDs) to describe a wide range of DES-like derivatives including those derived from ternary mixtures. The melting point of the mixture is lowered because the hydrogen bonding between DESD components reduces the lattice energy of components of the eutectic system. Based on the analysis of available data for 22 such choline chloride-based DES pairs, we found that the observed melting point depression can be statistically correlated with the difference between the hydrogen bonding contribution (δh) and the polar contribution (δp) to the solubility parameter of the hydrogen bond donor (HBD) component. The correlation was validated with a new DESD based on glycolic acid and choline chloride, which form DESDs at a molar ratio between 1:1 and 1:4 with DES-like properties. As a room temperature liquid, this DESD exhibits a wide range of solubility enhancement on several weakly basic poorly water-soluble drugs. For example, the solubility of itraconazole, piroxicam, lidocaine, and posaconazole has been observed to increase by 6700, 430, 28, and 6400-fold, respectively as compared to their aqueous solubility at room temperature. Furthermore, another new ternary DESD based on choline chloride, glycolic acid, and oxalic acid at a molar ratio of 1:1.6:0.4 is shown to further increase the solubility of itraconazole to a remarkable level of 5.36mg/mL (a 53,600-fold increase!). Because the components of such DESDs can include those biodegradable ones that had previously been used in formulated human products, the potential applicability of suitable DESDs to drug delivery, especially in enhancing drug solubility for topical formulations could be very attractive. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative studies on drug binding to the purified and pharmaceutical-grade human serum albumins: Bridging between basic research and clinical applications of albumin.

PubMed

Ashrafi-Kooshk, Mohammad Reza; Ebrahimi, Farangis; Ranjbar, Samira; Ghobadi, Sirous; Moradi, Nastaran; Khodarahmi, Reza

2015-09-01

Human serum albumin (HSA), the most abundant protein in blood plasma, is a monomeric multidomain protein that possesses an extraordinary capacity for binding, so that serves as a circulating depot for endogenous and exogenous compounds. During the heat sterilization process, the structure of pharmaceutical-grade HSA may change and some of its activities may be lost. In this study, to provide deeper insight on this issue, we investigated drug-binding and some physicochemical properties of purified albumin (PA) and pharmaceutical-grade albumin (PGA) using two known drugs (indomethacin and ibuprofen). PGA displayed significantly lower drug binding capacity compared to PA. Analysis of the quenching and thermodynamic parameters indicated that intermolecular interactions between the drugs and the proteins are different from each other. Surface hydrophobicity as well as the stability of PGA decreased compared to PA, also surface hydrophobicity of PA and PGA increased upon drugs binding. Also, kinetic analysis of pseudo-esterase activities indicated that Km and Vmax parameters for PGA enzymatic activity are more and less than those of PA, respectively. This in vitro study demonstrates that the specific drug binding of PGA is significantly reduced. Such studies can act as connecting bridge between basic research discoveries and clinical applications. Copyright © 2015 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

In Vitro Assessment of Uptake and Lysosomal Sequestration of Respiratory Drugs in Alveolar Macrophage Cell Line NR8383.

PubMed

Ufuk, Ayşe; Somers, Graham; Houston, J Brian; Galetin, Aleksandra

2015-12-01

To assess accumulation and lysosomal sequestration of 9 drugs used in respiratory indications (plus imipramine as positive control) in the alveolar macrophage (AM) cell line NR8383. For all drugs, uptake at 5 μM was investigated at 37 and 4°C to delineate active uptake and passive diffusion processes. Accumulation of basic clarithromycin, formoterol and imipramine was also assessed over 0.1-100 μM concentration range. Lysosomal sequestration was investigated using ammonium chloride (NH4Cl), monensin and nigericin. Impact of lysosomal sequestration on clarithromycin accumulation kinetics was investigated. Both cell-to-medium concentration ratio (Kp) and uptake clearance (CLuptake) ranged > 400-fold for the drugs investigated. The greatest Kp was observed for imipramine (391) and clarithromycin (82), in contrast to no accumulation seen for terbutaline. A concentration-dependent accumulation was evident for the basic drugs investigated. Imipramine and clarithromycin Kp and CLuptake were reduced by 59-85% in the presence of NH4Cl and monensin/nigericin, indicating lysosomal accumulation, whereas lysosomal sequestration was not pronounced for the other 8 respiratory drugs. Clarithromycin uptake rate was altered by NH4Cl, highlighting the impact of subcellular distribution on accumulation kinetics. This study provides novel evidence of the utility of NR8383 for investigating accumulation and lysosomal sequestration of respiratory drugs in AMs.

The relevance of basic sciences in undergraduate medical education.

PubMed

Lynch, C; Grant, T; McLoughlin, P; Last, J

2016-02-01

Evolving and changing undergraduate medical curricula raise concerns that there will no longer be a place for basic sciences. National and international trends show that 5-year programmes with a pre-requisite for school chemistry are growing more prevalent. National reports in Ireland show a decline in the availability of school chemistry and physics. This observational cohort study considers if the basic sciences of physics, chemistry and biology should be a prerequisite to entering medical school, be part of the core medical curriculum or if they have a place in the practice of medicine. Comparisons of means, correlation and linear regression analysis assessed the degree of association between predictors (school and university basic sciences) and outcomes (year and degree GPA) for entrants to a 6-year Irish medical programme between 2006 and 2009 (n = 352). We found no statistically significant difference in medical programme performance between students with/without prior basic science knowledge. The Irish school exit exam and its components were mainly weak predictors of performance (-0.043 ≥ r ≤ 0.396). Success in year one of medicine, which includes a basic science curriculum, was indicative of later success (0.194 ≥ r (2) ≤ 0.534). University basic sciences were found to be more predictive than school sciences in undergraduate medical performance in our institution. The increasing emphasis of basic sciences in medical practice and the declining availability of school sciences should mandate medical schools in Ireland to consider how removing basic sciences from the curriculum might impact on future applicants.

Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms

PubMed Central

Burd, Christin E.; Gill, Matthew S.; Niedernhofer, Laura J.; Robbins, Paul D.; Austad, Steven N.; Barzilai, Nir

2016-01-01

Through the progress of basic science research, fundamental mechanisms that contribute to age-related decline are being described with increasing depth and detail. Although these efforts have identified new drug targets and compounds that extend life span in model organisms, clinical trials of therapeutics that target aging processes remain scarce. Progress in aging research is hindered by barriers associated with the translation of basic science discoveries into the clinic. This report summarizes discussions held at a 2014 Geroscience Network retreat focused on identifying hurdles that currently impede the preclinical development of drugs targeting fundamental aging processes. From these discussions, it was evident that aging researchers have varied perceptions of the ideal preclinical pipeline. To forge a clear and cohesive path forward, several areas of controversy must first be resolved and new tools developed. Here, we focus on five key issues in preclinical drug development (drug discovery, lead compound development, translational preclinical biomarkers, funding, and integration between researchers and clinicians), expanding upon discussions held at the Geroscience Retreat and suggesting areas for further research. By bringing these findings to the attention of the aging research community, we hope to lay the foundation for a concerted preclinical drug development pipeline. PMID:27535964

Drug repurposing: In-vitro anti-glycation properties of 18 common drugs

PubMed Central

Rasheed, Saima; Sánchez, Sara S.; Yousuf, Sammer; Honoré, Stella M.; Choudhary, M. Iqbal

2018-01-01

Drug repositioning or repurposing, i.e. identifying new indications for existing drugs, has gained increasing attention in the recent years. This approach enables the scientists to discover “new targets” for known drugs in a cost and time efficient manner. Glycation, the non-enzymatic reaction of sugars with proteins or nucleic acids to form early glycation (Amadori or fructosamine) products, is a key molecular basis of diabetic complications. Inhibiting the process of non-enzymatic protein glycation is one of the key strategies to prevent glycation-mediated diabetic complications. The present study focuses on the anti-glycation activity of 18 drugs, commonly used for the treatment of gastrointestinal, central nervous system, inflammatory diseases, bacterial infections, and gout. This study was carried out by using two in-vitro protein anti-glycation assay models. Results revealed that nimesulide (3), a non-steroidal anti-inflammatory drug, possesses a good anti-glycation activity in in-vitro BSA-MG and BSA-glucose glycation models with IC50 values of 330.56 ± 2.90, and 145.46 ± 16.35 μM, respectively. Phloroglucinol dihydrate (11), a drug used for the treatment of gastrointestinal diseases, showed a weak activity in BSA-MG glycation model (IC50 = 654.89 ± 2.50 μM), while it showed a good activity in BSA-glucose assay (IC50 = 148.23 ± 0.15 μM). Trimethylphloroglucinol (9), a drug used for the treatment of pain related to functional disorders of the digestive and biliary tracts, also showed a good antiglycation activity in BSA-MG model (IC50 = 321.15 ± 1.26 μM), while it was found to be inactive in in-vitro BSA-glucose assay (IC50 = 12.95% inhibition). These activities of drugs were compared with the anti-glycation activity of the standard, rutin (IC50 = 294.5 ± 1.50 μM in BSA-MG glycation model, and IC50 = 86.94 ± 0.24 μM in BSA- glucose model). Rest of the drugs exhibited a relatively weak antiglycation activity. This study identifies nimesulide (3), and phloroglucinol dihydrate (11) as new inhibitors of in-vitro protein glycation for further investigations as potential anti-diabetic agents. PMID:29300762

76 FR 38666 - Food and Drug Administration (FDA) and Marine Environmental Sciences Consortium/Dauphin Island...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-01

... actively involved in both basic and applied research in coastal waters of the northern Gulf of Mexico. The... between the Center for Food Safety and Applied Nutrition (CFSAN) and the Marine Environmental Sciences Consortium/Dauphin Island Sea Lab (DISL). The goal of the DISL is marine science education, basic and applied...

77 FR 43861 - Importer of Controlled Substances; Notice Of Application; Cody Laboratories, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-26

... basic class of any controlled substance in schedule I or II are, and will continue to be, required to... importer of the following basic classes of controlled substances: Drug Schedule Opium, Raw (9600) II Concentrate Poppy Straw (9670) II Tapentadol (9780) II The company plans to import narcotic raw materials for...

Target assessment for antiparasitic drug discovery

PubMed Central

Frearson, Julie A.; Wyatt, Paul G.; Gilbert, Ian H.; Fairlamb, Alan H.

2010-01-01

Drug discovery is a high-risk, expensive and lengthy process taking at least 12 years and costing upwards of US$500 million per drug to reach the clinic. For neglected diseases, the drug discovery process is driven by medical need and guided by pre-defined target product profiles. Assessment and prioritisation of the most promising targets for entry into screening programmes is crucial for maximising chances of success. Here we describe criteria used in our drug discovery unit for target assessment and introduce the ‘traffic light’ system as a prioritisation and management tool. We hope this brief review will stimulate basic scientists to acquire additional information necessary for drug discovery. PMID:17962072

United States National Library of Medicine Drug Information Portal.

PubMed

Hochstein, Colette; Goshorn, Jeanne; Chang, Florence

2009-01-01

The Drug Information Portal is a free Web resource from the National Library of Medicine (NLM) that provides a user-friendly gateway to current information for more than 15,000 drugs. The site guides users to related resources of NLM, the National Institutes of Health (NIH), and other government agencies. Current drug-related information regarding consumer health, clinical trials, AIDS, MeSH pharmacological actions, MEDLINE/PubMed biomedical literature, and physical properties and structure is easily retrieved by searching on a drug name. A varied selection of focused topics in medicine and drugs is also available from displayed subject headings. This column provides background information about the Drug Information Portal, as well as search basics.

Does media coverage influence the spread of drug addiction?

NASA Astrophysics Data System (ADS)

Ma, Mingju; Liu, Sanyang; Li, Jun

2017-09-01

In this paper, a three dimensional drug model is constructed to investigate the impact of media coverage on the spread and control of drug addiction. The dynamical behavior of the model is studied by using the basic reproduction number R0. The drug-free equilibrium is globally asymptotically stable if R0 < 1 and the drug addiction equilibrium is locally stable if R0 > 1. The results demonstrate that the media effect in human population cannot change the stabilities of equilibria but can affect the number of drug addicts. Sensitivity analyses are performed to seek for effective control measures for drug treatment. Numerical simulations are given to support the theoretical results.

An introduction to diffusion tensor image analysis.

PubMed

O'Donnell, Lauren J; Westin, Carl-Fredrik

2011-04-01

Diffusion tensor magnetic resonance imaging (DTI) is a relatively new technology that is popular for imaging the white matter of the brain. This article provides a basic and broad overview of DTI to enable the reader to develop an intuitive understanding of these types of data, and an awareness of their strengths and weaknesses. Copyright © 2011 Elsevier Inc. All rights reserved.

Supplanting Chinese Influence in Africa: The U.S. African Diaspora

DTIC Science & Technology

2011-03-14

dysfunctional governments, to weak economies. Other critical factors include: inadequate basic infrastructure, high unemployment , rapid population growth...increased unemployment in many sectors. At the same time, local merchants and manufacturers are unable to favorably compete against Chinese...establish a pre-automated program modeled after a franchise plan. Selected individuals or teams will receive intense training and subsequently will be

Schooling and Basic Aspects of Intelligence: A Natural Quasi-Experiment in Malawi

ERIC Educational Resources Information Center

Van de Vijver, Fons J. R.; Brouwers, Symen A.

2009-01-01

The relationship between educational age and chronological age and measures of information processing and intelligence was studied in a group of children of 7 to 14 years of age (N=268) in a rural area in the Ntcheu district (Malawi). There was a relatively weak relationship between chronological and educational age in this area, and the impact of…

Strategic Planning and Management. Report of the Annual Management Institute for College and University Executives (10th, Snowmass, Colorado, July 21-26, 1985).

ERIC Educational Resources Information Center

Groff, Warren H.; Cope, Robert G.

Basic and advanced workshops on strategic planning and management for college personnel were held in 1985. Strategic planning and management includes: (1) assessing an institution's external environment to determine opportunities/threats; (2) auditing an institution's internal environment to determine strengths/weaknesses; (3) using these two sets…

Computer Literacy Teaching Using Peer Learning and under the Confucian Heritage Cultural Settings of Macao, China

ERIC Educational Resources Information Center

Wong, Kelvin; Neves, Ana; Negreiros, Joao

2017-01-01

University students in Macao are required to attend computer literacy courses to raise their basic skills levels and knowledge as part of their literacy foundation. Still, teachers frequently complain about the weak IT skills of many students, suggesting that most of them may not be benefiting sufficiently from their computer literacy courses.…

The quantum universe

NASA Astrophysics Data System (ADS)

Hey, Anthony J. G.; Walters, Patrick

This book provides a descriptive, popular account of quantum physics. The basic topics addressed include: waves and particles, the Heisenberg uncertainty principle, the Schroedinger equation and matter waves, atoms and nuclei, quantum tunneling, the Pauli exclusion principle and the elements, quantum cooperation and superfluids, Feynman rules, weak photons, quarks, and gluons. The applications of quantum physics to astrophyics, nuclear technology, and modern electronics are addressed.

How to Motivate Adults with Low Literacy and Numeracy Skills to Engage and Persist in Learning: A Literature Review of Policy Interventions

ERIC Educational Resources Information Center

Windisch, Hendrickje Catriona

2016-01-01

Low basic skills levels of adults are a complex policy problem which has neither straightforward causes nor solutions, and successful interventions are still relatively rare. Tackling serious literacy and numeracy weaknesses among adults is challenging, partly because the task itself is difficult, and partly because even if accomplished…

Non-destructive terahertz imaging of illicit drugs using spectral fingerprints

NASA Astrophysics Data System (ADS)

Kawase, Kodo; Ogawa, Yuichi; Watanabe, Yuuki; Inoue, Hiroyuki

2003-10-01

The absence of non-destructive inspection techniques for illicit drugs hidden in mail envelopes has resulted in such drugs being smuggled across international borders freely. We have developed a novel basic technology for terahertz imaging, which allows detection and identification of drugs concealed in envelopes, by introducing the component spatial pattern analysis. The spatial distributions of the targets are obtained from terahertz multispectral transillumination images, using absorption spectra measured with a tunable terahertz-wave source. The samples we used were methamphetamine and MDMA, two of the most widely consumed illegal drugs in Japan, and aspirin as a reference.

[Regulatory aspects and medicolegal considerations regarding clinical drug trials].

PubMed

Cammarano, Andrea; De Dominicis, Enrico; Marella, Gian Luca; Maurici, Massimo; Arcudi, Giovanni

2016-01-01

This article aims to explore the regulatory and medicolegal aspects of experimental drug trials. Firstly, the authors provide definitions of drug according to WHO, the European Community and our official Pharmacopoeia, and that of experimental studies. They then explain the distinction between pure or basic research and drug trials and explain the various phases of the latter. Besides providing definitions, and exploring doctrinal, theoretical but also practical aspects of drug trials, the authors also discuss and analyze legislative aspects, with particular reference to the Italian legislative framework, and medicolegal issues, including informed consent, effects on humans, and professional responsibility.

Invited Review Article: Development of crystal lenses for energetic photons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smither, Robert K.

2014-08-15

This paper follows the development of crystal diffraction lenses designed to focus energetic photons. It begins with the search for a solution to the astrophysics problem of how to detect weak astrophysics sources of gamma rays and x-rays. This led to the basic designs for a lens and to the understanding of basic limitations of lens design. The discussion of the development of crystal diffraction lenses is divided into two parts: lenses using crystals with mosaic structure, and lenses that use crystals with curved crystal planes. This second group divides into two sub-groups: (1) Curved crystals that are used tomore » increase the acceptance angle of the diffraction of a monochromatic beam and to increase the energy bandwidth of the diffraction. (2) Curved crystals used to focus gamma ray beams. The paper describes how these two types of crystals affect the design of the corresponding crystal lenses in different fields: astrophysics, medical imaging, detection of weak, distant, gamma-ray sources, etc. The designs of crystal lenses for these applications are given in enough detail to allow the reader to design a lens for his own application.« less

uSIMPK. An Excel for Windows-based simulation program for instruction of basic pharmacokinetics principles to pharmacy students.

PubMed

Brocks, Dion R

2015-07-01

Pharmacokinetics can be a challenging topic to teach due to the complex relationships inherent between physiological parameters, mathematical descriptors and equations, and their combined impact on shaping the blood fluid concentration vs. time curves of drugs. A computer program was developed within Microsoft Excel for Windows, designed to assist in the instruction of basic pharmacokinetics within an entry-to-practice pharmacy class environment. The program is composed of a series of spreadsheets (modules) linked by Visual Basic for Applications, intended to illustrate the relationships between pharmacokinetic and in some cases physiological parameters, doses and dose rates and the drug blood fluid concentration vs. time curves. Each module is accompanied by a simulation user's guide, prompting the user to change specific independent parameters and then observe the impact of the change(s) on the drug concentration vs. time curve and on other dependent parameters. "Slider" (or "scroll") bars can be selected to readily see the effects of repeated changes on the dependencies. Topics covered include one compartment single dose administration (iv bolus, oral, short infusion), intravenous infusion, repeated doses, renal and hepatic clearance, nonlinear elimination, two compartment model, plasma protein binding and the relationship between pharmacokinetics and drug effect. The program has been used in various forms in the classroom over a number of years, with positive ratings generally being received from students for its use in the classroom. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Microenvironment acidity as a major determinant of tumor chemoresistance: Proton pump inhibitors (PPIs) as a novel therapeutic approach.

PubMed

Taylor, Sophie; Spugnini, Enrico Pierluigi; Assaraf, Yehuda G; Azzarito, Tommaso; Rauch, Cyril; Fais, Stefano

2015-11-01

Despite the major progresses in biomedical research and the development of novel therapeutics and treatment strategies, cancer is still among the dominant causes of death worldwide. One of the crucial challenges in the clinical management of cancer is primary (intrinsic) and secondary (acquired) resistance to both conventional and targeted chemotherapeutics. Multiple mechanisms have been identifiedthat underlie intrinsic and acquired chemoresistance: these include impaired drug uptake, increased drug efflux, deletion of receptors, altered drug metabolism, quantitative and qualitative alterations in drug targets, increased DNA damage repair and various mechanisms of anti-apoptosis. The fast efflux of anticancer drugs mediated by multidrug efflux pumps and the partial or complete reversibility of chemoresistance combined with the absence of genetic mutations suggests a multifactorial process. However, a growing body of recent evidence suggests that chemoresistance is often triggered by the highly acidic microenvironment of tumors. The vast majority of drugs, including conventional chemotherapeutics and more recent biological agents, are weak bases that are quickly protonated and neutralized in acidic environments, such as the extracellular microenvironment and the acidic organelles of tumor cells. It is therefore essential to develop new strategies to overcome the entrapment and neutralization of weak base drugs. One such strategy is the use of proton pump inhibitors which can enhance tumor chemosensitivity by increasing the pH of the tumor microenvironment. Recent clinical trials in animals with spontaneous tumors have indicated that patient alkalization is capable of reversing acquired chemoresistance in a large percentage of tumors that are refractory to chemotherapy. Of particular interest was the benefit of alkalization for patients undergoing metronomic regimens which are becoming more widely used in veterinary medicine. Overall, these results provide substantial new evidence that altering the acidic tumor microenvironment is an effective, well tolerated and low cost strategy for the overcoming of anticancer drug resistance. Copyright © 2015 Elsevier Ltd. All rights reserved.

Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria.

PubMed

Kou, Dawen; Dwaraknath, Sudharsan; Fischer, Yannick; Nguyen, Daniel; Kim, Myeonghui; Yiu, Hiuwing; Patel, Preeti; Ng, Tania; Mao, Chen; Durk, Matthew; Chinn, Leslie; Winter, Helen; Wigman, Larry; Yehl, Peter

2017-10-02

In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.

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

NASA Astrophysics Data System (ADS)

Syed, Mohammed Irfan

Ketoconazole is one of the most widely prescribed oral antifungal drugs for the systemic treatment of various fungal infections. However, due its hydrophobic nature and poor solubility profiles in the gastro-intestinal fluids, variations in its bioavailability have been documented. Therefore, to enhance its dissolution in the biological fluids, this study was initiated to develop and evaluate Nanoparticles and Solid Dispersion forms of the drug. Nanoparticles of ketoconazole were developed by Wet Bead Milling technique using PVP-10k as the stabilizing material at a weight ratio of (2:1). Solid dispersion powder was prepared by Hot Melt method using PEG-8000 at a weight ratio of (1:2). A commercial product containing 200mg of ketoconazole tablet and pure drug powder were used as the control for comparison purposes. The dissolution studies were carried out in SGF, SIF, USP; and SIF with 0.2% sodium lauryl sulfate using the USP-II method for a 2 hours period. Physical characterizations were carried out using SEM, DSC, XRD and FTIR studies. Wet Bead Milling method yielded nanoparticles in the particles size range of (100-300nm.). First all samples were evaluated for their in-vitro dissolution in SGF at pH=1.2. After 15 minutes, the amounts of drug dissolved were observed to be 27% from both the pure powder and commercial tablet (control), 29% from solid dispersion and 100% from the Nanoparticles dosage form. This supports the fact that Nanoparticles had a strong influence on the dissolution rate of the drug and exhibited much faster dissolution of ketoconazole. When the same formulations were studied in the SIF, USP medium, the control formulation gave 3%, solid dispersion 8% and Nanoparticles 8% drug dissolution after 2 hours period. This could be because the weakly basic ketoconazole drug remained un-dissociated in the alkaline medium. Since this medium was unable to clearly distinguish the dissolution profiles from different formulation of the drug, the SIF solution 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.

Controllability of control and mixture weakly dependent siphons in S3PR

NASA Astrophysics Data System (ADS)

Hong, Liang; Chao, Daniel Y.

2013-08-01

Deadlocks in a flexible manufacturing system modelled by Petri nets arise from insufficiently marked siphons. Monitors are added to control these siphons to avoid deadlocks rendering the system too complicated since the total number of monitors grows exponentially. Li and Zhou propose to add monitors only to elementary siphons while controlling the other (strongly or weakly) dependent siphons by adjusting control depth variables. To avoid generating new siphons, the control arcs are ended at source transitions of process nets. This disturbs the original model more and hence loses more live states. Negative terms in the controllability make the control policy for weakly dependent siphons rather conservative. We studied earlier on the controllability of strongly dependent siphons and proposed to add monitors in the order of basic, compound, control, partial mixture and full mixture (strongly dependent) siphons to reduce the number of mixed integer programming iterations and redundant monitors. This article further investigates the controllability of siphons derived from weakly 2-compound siphons. We discover that the controllability for weakly and strongly compound siphons is similar. It no longer holds for control and mixture siphons. Some control and mixture siphons, derived from strongly 2-compound siphons are not redundant - no longer so for those derived from weakly 2-compound siphons; that is all control and mixture siphons are redundant. They do not need to be the conservative one as proposed by Li and Zhou. Thus, we can adopt the maximally permissive control policy even though new siphons are generated.

Antithyroid drug induced a granulocytosis: what still we need to learn?

PubMed

Chaudhry, Liaqat Ali; Mauzen, Khalid Fouad; Ba-Essa, Ebtesam; Robert, Asirvatham Alwin

2016-01-01

Antithyroid drugs (ATDs) induced agranulocytosis is a rare but life threatening condition. We report a 29 years Filipino female diagnosed as having hyperthyroidism with normal base line blood counts, liver and renal profile. She was started on maximum 60 mg (20mg TID) oral dose of carbimazole since one month by her treating physician. Exactly after one month of treatment she presented to emergency room (ER) with fever, sore throat and generalized weakness for several days.

Degradable Magnetic Composites for Minimally Invasive Interventions: Device Fabrication, Targeted Drug Delivery, and Cytotoxicity Tests.

PubMed

Peters, Christian; Hoop, Marcus; Pané, Salvador; Nelson, Bradley J; Hierold, Christofer

2016-01-20

Superparamagnetic nanoparticles and a functional, degradable polymer matrix based on poly(ethylene glycol) are combined to enable fully degradable magnetic microdevices for minimally invasive biomedical applications. A bioinspired helical microrobot platform mimicking Escherichia coli bacteria is fabricated and actuated using weak rotating magnetic fields. Locomotion based on corkscrew propulsion, targeted drug delivery, and low-degradation-product cytotoxicity are demonstrated. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Patient safety: numerical skills and drug calculation abilities of nursing students and registered nurses.

PubMed

McMullan, Miriam; Jones, Ray; Lea, Susan

2010-04-01

This paper is a report of a correlational study of the relations of age, status, experience and drug calculation ability to numerical ability of nursing students and Registered Nurses. Competent numerical and drug calculation skills are essential for nurses as mistakes can put patients' lives at risk. A cross-sectional study was carried out in 2006 in one United Kingdom university. Validated numerical and drug calculation tests were given to 229 second year nursing students and 44 Registered Nurses attending a non-medical prescribing programme. The numeracy test was failed by 55% of students and 45% of Registered Nurses, while 92% of students and 89% of nurses failed the drug calculation test. Independent of status or experience, older participants (> or = 35 years) were statistically significantly more able to perform numerical calculations. There was no statistically significant difference between nursing students and Registered Nurses in their overall drug calculation ability, but nurses were statistically significantly more able than students to perform basic numerical calculations and calculations for solids, oral liquids and injections. Both nursing students and Registered Nurses were statistically significantly more able to perform calculations for solids, liquid oral and injections than calculations for drug percentages, drip and infusion rates. To prevent deskilling, Registered Nurses should continue to practise and refresh all the different types of drug calculations as often as possible with regular (self)-testing of their ability. Time should be set aside in curricula for nursing students to learn how to perform basic numerical and drug calculations. This learning should be reinforced through regular practice and assessment.

A Physiologically Based Pharmacokinetic Model to Predict the Pharmacokinetics of Highly Protein-Bound Drugs and Impact of Errors in Plasma Protein Binding

PubMed Central

Ye, Min; Nagar, Swati; Korzekwa, Ken

2015-01-01

Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data was often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for terminal elimination half-life (t1/2, 100% of drugs), peak plasma concentration (Cmax, 100%), area under the plasma concentration-time curve (AUC0–t, 95.4%), clearance (CLh, 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss, 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. PMID:26531057

Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules

PubMed Central

Harrell, Andrew W; Sychterz, Caroline; Ho, May Y; Weber, Andrew; Valko, Klara; Negash, Kitaw

2015-01-01

The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution. PMID:26516585

Hyaluronic Acid-Based pH-Sensitive Polymer-Modified Liposomes for Cell-Specific Intracellular Drug Delivery Systems.

PubMed

Miyazaki, Maiko; Yuba, Eiji; Hayashi, Hiroshi; Harada, Atsushi; Kono, Kenji

2018-01-17

For the enhancement of therapeutic effects and reduction of side effects derived from anticancer drugs in cancer chemotherapy, it is imperative to develop drug delivery systems with cancer-specificity and controlled release function inside cancer cells. pH-sensitive liposomes are useful as an intracellular drug delivery system because of their abilities to transfer their contents into the cell interior through fusion or destabilization of endosome, which has weakly acidic environment. We earlier reported liposomes modified with various types of pH-sensitive polymers based on synthetic polymers and biopolymers as vehicles for intracellular drug delivery systems. In this study, hyaluronic acid (HA)-based pH-sensitive polymers were designed as multifunctional polymers having not only pH-sensitivity but also targeting properties to cells expressing CD44, which is known as a cancer cell surface marker. Carboxyl group-introduced HA derivatives of two types, MGlu-HA and CHex-HA, which have a more hydrophobic side chain structure than that of MGlu-HA, were synthesized by reaction with various dicarboxylic anhydrides. These polymer-modified liposomes were stable at neutral pH, but showed content release under weakly acidic conditions. CHex-HA-modified liposomes delivered their contents into CD44-expressing cells more efficiently than HA-modified or MGlu-HA-modified liposomes or unmodified liposomes, whereas the same liposomes were taken up only slightly by cells expressing CD44 proteins less. Competition assay using free HA or other polymers revealed that HA derivative-modified liposomes might be recognized by CD44. Therefore, HA-derivative-modified liposomes are useful as cell-specific intracellular drug delivery systems.

Facts about Alcohol and Other Drug Use during Pregnancy. ARC Facts.

ERIC Educational Resources Information Center

Association for Retarded Citizens, Arlington, TX.

The fact sheet provides basic information about how alcohol and drug use during pregnancy can lead to Fetal Alcohol Syndrome (FAS) and Alcohol Related Birth Defects (ARBD), resulting in such problems as mental retardation, sleep disturbances, learning disabilities, muscle problems, heart defects, and small head size. The question and answer format…

77 FR 16264 - Manufacturer of Controlled Substances, Notice of Registration; Noramco Inc. (GA)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-20

..., Notice of Registration; Noramco Inc. (GA) By Notice dated November 21, 2011, and published in the Federal... application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule Codeine-N-oxide (9053) I...

Brain Chemistry and Behaviour: An Update on Neuroscience Research and Its Implications for Understanding Drug Addiction

ERIC Educational Resources Information Center

Robinson, Emma S. J.

2011-01-01

Psychiatric disorders such as drug addiction represent one of the biggest challenges to society. This article reviews clinical and basic science research to illustrate how developments in research methodology have enabled neuroscientists to understand more about the brain mechanisms involved in addiction biology. Treating addiction represents a…

Tissue constructs: platforms for basic research and drug discovery.

PubMed

Elson, Elliot L; Genin, Guy M

2016-02-06

The functions, form and mechanical properties of cells are inextricably linked to their extracellular environment. Cells from solid tissues change fundamentally when, isolated from this environment, they are cultured on rigid two-dimensional substrata. These changes limit the significance of mechanical measurements on cells in two-dimensional culture and motivate the development of constructs with cells embedded in three-dimensional matrices that mimic the natural tissue. While measurements of cell mechanics are difficult in natural tissues, they have proven effective in engineered tissue constructs, especially constructs that emphasize specific cell types and their functions, e.g. engineered heart tissues. Tissue constructs developed as models of disease also have been useful as platforms for drug discovery. Underlying the use of tissue constructs as platforms for basic research and drug discovery is integration of multiscale biomaterials measurement and computational modelling to dissect the distinguishable mechanical responses separately of cells and extracellular matrix from measurements on tissue constructs and to quantify the effects of drug treatment on these responses. These methods and their application are the main subjects of this review.

Tissue constructs: platforms for basic research and drug discovery

PubMed Central

Elson, Elliot L.; Genin, Guy M.

2016-01-01

The functions, form and mechanical properties of cells are inextricably linked to their extracellular environment. Cells from solid tissues change fundamentally when, isolated from this environment, they are cultured on rigid two-dimensional substrata. These changes limit the significance of mechanical measurements on cells in two-dimensional culture and motivate the development of constructs with cells embedded in three-dimensional matrices that mimic the natural tissue. While measurements of cell mechanics are difficult in natural tissues, they have proven effective in engineered tissue constructs, especially constructs that emphasize specific cell types and their functions, e.g. engineered heart tissues. Tissue constructs developed as models of disease also have been useful as platforms for drug discovery. Underlying the use of tissue constructs as platforms for basic research and drug discovery is integration of multiscale biomaterials measurement and computational modelling to dissect the distinguishable mechanical responses separately of cells and extracellular matrix from measurements on tissue constructs and to quantify the effects of drug treatment on these responses. These methods and their application are the main subjects of this review. PMID:26855763

[Introduction to Exploratory Factor Analysis (EFA)].

PubMed

Martínez, Carolina Méndez; Sepúlveda, Martín Alonso Rondón

2012-03-01

Exploratory Factor Analysis (EFA) has become one of the most frequently used statistical techniques, especially in the medical and social sciences. Given its popularity, it is essential to understand the basic concepts necessary for its proper application and to take into consideration the main strengths and weaknesses of this technique. To present in a clear and concise manner the main applications of this technique, to determine the basic requirements for its use providing a description step by step of its methodology, and to establish the elements that must be taken into account during its preparation in order to not incur in erroneous results and interpretations. Narrative review. This review identifies the basic concepts and briefly describes the objectives, design, assumptions, and methodology to achieve factor derivation, global adjustment evaluation, and adequate interpretation of results. Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

[Significance of re-evaluation and development of Chinese herbal drugs].

PubMed

Gao, Yue; Ma, Zengchun; Zhang, Boli

2012-01-01

The research of new herbal drugs involves in new herbal drugs development and renew the old drugs. It is necessary to research new herbal drugs based on the theory of traditional Chinese medicine (TCM). The current development of famous TCM focuses on the manufacture process, quality control standards, material basis and clinical research. But system management of security evaluation is deficient, the relevant system for the safety assessment TCM has not been established. The causes of security problems, security risks, target organ of toxicity, weak link of safety evaluation, and ideas of safety evaluation are discussed in this paper. The toxicology research of chinese herbal drugs is necessary based on standard of good laboratory practices (GLP), the characteristic of Chinese herbal drugs is necessary to be fully integrated into safety evaluation. The safety of new drug research is necessary to be integrated throughout the entire process. Famous Chinese medicine safety research must be paid more attention in the future.

Identifying Demand Responses to Illegal Drug Supply Interdictions.

PubMed

Cunningham, Scott; Finlay, Keith

2016-10-01

Successful supply-side interdictions into illegal drug markets are predicated on the responsiveness of drug prices to enforcement and the price elasticity of demand for addictive drugs. We present causal estimates that targeted interventions aimed at methamphetamine input markets ('precursor control') can temporarily increase retail street prices, but methamphetamine consumption is weakly responsive to higher drug prices. After the supply interventions, purity-adjusted prices increased then quickly returned to pre-treatment levels within 6-12 months, demonstrating the short-term effects of precursor control. The price elasticity of methamphetamine demand is -0.13 to -0.21 for self-admitted drug treatment admissions and between -0.24 and -0.28 for hospital inpatient admissions. We find some evidence of a positive cross-price effect for cocaine, but we do not find robust evidence that increases in methamphetamine prices increased heroin, alcohol, or marijuana drug use. This study can inform policy discussions regarding other synthesized drugs, including illicit use of pharmaceuticals. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Targeted analysis of 116 drugs in hair by UHPLC-MS/MS and its application to forensic cases.

PubMed

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

2017-08-01

A multi-target method that can detect a broad range of drugs in human hair, such as hypnotics, anxiolytics, analgesics, benzodiazepines, antihistamines, antidepressants, antipsychotics, and anticonvulsants, was developed based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The drugs were extracted from 10 mg of washed hair by incubation for 18 h in a 25:25:50 (v/v/v) mixture of methanol/acetonitrile/2 mM ammonium formate (8% acetonitrile, pH 5.3). For 51% of the basic drugs, the lower limits of quantification (LLOQs) were in the range of 0.05-0.5 pg/mg, and the majority (98%) were ≤ 5 pg/mg. Linearity ranged from LLOQs to 100-500 pg/mg for all the basic drugs. For acid and neutral drugs, the LLOQs ranged from 0.4 to 500 pg/mg, and linearity ranged from LLOQs to 80-40 000 pg/mg. According to published reports on concentrations attained in single dose control studies, the present method is sensitive enough to detect single-dose drug exposure for many of the drugs. The accuracy was within 75-125% for the majority of drugs. Good precision was observed (relative standard deviations [RSD%] < 25%) for most of the compounds, including the prepared quality control (QC) hair samples. The method was applied to forensic cases and concentrations of rarely reported drugs in hair in 25 post-mortem forensic cases were presented. Hair concentrations of amisulpride, gabapentin, mianserin, mepyramine, orphenadrine, and xylometazoline have not been previously reported. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Influenza Research in the Eastern Mediterranean Region: A Review

PubMed Central

Khan, Wasiq; El Rifay, Amira S.; Malik, Mamun; Kayali, Ghazi

2017-01-01

Given the importance of influenza infections in the Eastern Mediterranean Region (EMR), we conducted a comprehensive literature review to analyze the status of influenza research in the region from 2012. Influenza research has gained more momentum recently with the emergence of H5N1 and new virus strains. Research covering epidemiological, veterinary, and basic science aspects is growing. More sequences were being generated per year, not only for diagnostic purposes but also for research. We included gray literature publications in our search and found several graduate student dissertations from Egypt, which were published on an online portal. However, the search revealed some weaknesses, mostly in the areas of study design and the lack of surveillance studies. Another weakness was the fact that the publications originated from very few countries, mainly Egypt and Iran. Although improving, influenza research in the EMR remains weak. We recommend encouraging countries in the EMR to conduct more influenza research using stronger methodologies. PMID:29026466

Solid lipid microparticles containing loratadine prepared using a Micromixer.

PubMed

Milak, Spomenka; Medlicott, Natalie; Tucker, Ian G

2006-12-01

Solid lipid microparticles were investigated as a taste-masking approach for a lipophilic weak base in a suspension. The idea was that the drug concentration in the aqueous phase of a suspension might be reduced by its partitioning into the solid lipid particles. Loratadine, as a model drug, was used to prepare Precirol ATO 5 microparticles by a Micromixer. The effects of three process variables: drug loading, PVA concentration and water/lipid ratio on the microparticle size, encapsulation efficiency, surface appearance, in-vitro release and drug partitioning in a suspension were studied. Loratadine release was slow in simulated saliva and very fast at the pH of stomach. In suspension of loratadine lipid microparticles, drug was released into the aqueous phase to the same concentration as in a drug suspension. Therefore, the usefulness of these microparticles for taste-masking in liquids is limited. However, they might be useful for taste-masking in solid dosage forms.

Does price reveal poor-quality drugs? Evidence from 17 countries.

PubMed

Bate, Roger; Jin, Ginger Zhe; Mathur, Aparna

2011-12-01

Focusing on 8 drug types on the WHO-approved medicine list, we constructed an original dataset of 899 drug samples from 17 low- and median-income countries and tested them for visual appearance, disintegration, and analyzed their ingredients by chromatography and spectrometry. Fifteen percent of the samples fail at least one test and can be considered substandard. After controlling for local factors, we find that failing drugs are priced 13.6-18.7% lower than non-failing drugs but the signaling effect of price is far from complete, especially for non-innovator brands. The look of the pharmacy, as assessed by our covert shoppers, is weakly correlated with the results of quality tests. These findings suggest that consumers are likely to suspect low quality from market price, non-innovator brand and the look of the pharmacy, but none of these signals can perfectly identify substandard and counterfeit drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

[Microcosmic mechanisms of amorphous indomethacin crystallization and the influence of nano-coating on crystallization].

PubMed

Hui, Ou-Yang; Yi, Tao; Zheng, Qin; Liu, Feng

2011-06-01

Amorphous drugs have higher solubility, better oral bioavailability and are easier to be absorbed than their crystalline counterparts. However, the amorphous drugs, with weak stability, are so easy to crystallize that they will lose the original advantages. Polarization microscope, scanning electron microscope, differential scanning calorimetry, X-ray diffractomer and Raman spectroscopy were used to study the microcosmic crystallization mechanisms of amorphous indometacin and the performance of the drug crystals. The results showed that the growth rate of amorphous indometacin crystals at the free surface was markedly faster than that through the bulk, and that the crystal growth rate decreased observably after spraying an ultrathin melting gold (10 nm) at the free surface of the drug. These results indicated that the high growth rates of amorphous drugs crystals at the free surface were the key to their stability and that an ultrathin coating could be applied to enhance the stability of amorphous drugs.

The preparation, cytocompatibility and antimicrobial property of micro/nano structural titanium loading alginate and antimicrobial peptide

NASA Astrophysics Data System (ADS)

Liu, Zhiyuan; Zhong, Mou; Sun, Yuhua; Chen, Junhong; Feng, Bo

2018-03-01

Titanium with hybrid microporous/nanotubes (TMNT) structure on its surface was fabricated by acid etching and subsequently anodization at different voltages. Bovine lactoferricin, a kind of antimicrobial peptide, and sodium alginate (NaAlg) were loaded onto titanium surface through layer by layer assembly. The drug release, cytocompatibility and antimicrobial property against S.aureus and E.coil were studied by release experiment, osteoblast and bacterial cultures. Results indicated that samples with nanotubes of bigger diameter carried more drugs and had better biocompatibility, and drug-loaded samples acquired better biocompatibility compared with drug-free samples. Furthermore, the drug-loaded samples exhibited good initial antimicrobial property, but weak long-term antimicrobial property. Therefore, drug-loaded titanium with micro/nano structure, especially, of big diameter nanotubes, could be a promise material for medical implants, such as internal/external fixation devices.

Design and Use of a Proton Pump Inhibitor Case to Integrate Physiology, Pharmacology, and Biochemistry

ERIC Educational Resources Information Center

Lee, Michael W.

2014-01-01

The use of drugs to integrate basic and clinical sciences is frequently used in a lecture format, but the availability of alternative pedagogical approaches that address higher-order learning are not widely available. The use of case studies and case-based projects to reinforce lectures can help link basic and clinical disciplines and promote…

Hydrogen donors and acceptors and basic amino acids jointly contribute to carcinogenesis.

PubMed

Tang, Man; Zhou, Yanchao; Li, Yiqi; Zou, Juntong; Yang, Beicheng; Cai, Li; Zhang, Xuelan; Liu, Qiuyun

2017-01-01

A hypothesis is postulated that high content of hydrogen donors and acceptors, and basic amino acids cause the intracellular trapping of the H + and Cl - ions, which increases cancer risks as local formation of HCl is mutagenic to DNA. Other cations such as Ca 2+ , and weak acids such as short-chain organic acids may attenuate the intracellular gathering of the H + and Cl - , two of the most abundant ions in the cells. Current data on increased cancer risks in diabetic and obese patients are consistent with the assumption that hydrogen bonding propensity on glucose, triglycerides and other molecules is among the causative factors. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Some worries about Dendrobium officinale industry].

PubMed

Li, Guang; Lu, Juan; Chen, Xi

2013-02-01

In recent years, with the continuous development of the industry of Dendrobium officinale, the technological alliance on CEEUSRO has been established. However, many problems also exposed with the rapid expansion of the industry, such as weak basic research, single species of the product, lack of in-depth studies and difficult to guarantee the quality. Industrial foam was gradually formed. To guard against the D. officinale becoming another "Puer Tea" , the authors believe that the key to sustainable development of the industry is enterprises and research institutes should strengthen basic research, speed up development of application of integrated innovations, government should strengthen guidance, regulate the operation of the market, then protect the quality of D. officinale in the market.

Nanoemulsion as pharmaceutical carrier for dermal and transdermal drug delivery: Formulation development, stability issues, basic considerations and applications.

PubMed

Rai, Vineet Kumar; Mishra, Nidhi; Yadav, Kuldeep Singh; Yadav, Narayan Prasad

2018-01-28

The use of nanoemulsion in augmenting dermal and transdermal effectiveness of drugs has now well established. The development of nanoemulsion based semisolid dosage forms is an active area of present research. However, thickening or liquid-to-semisolid conversion of the nanoemulsions provides opportunities to the formulation scientist to explore novel means of solving instability issues during transformation. Extending knowledge about the explicit role of nature/magnitude of zeta potential, types of emulsifiers and selection of appropriate semisolid bases could place these versatile carriers from laboratory to industrial scale. This article reviews the progressive advancement in the delivery of medicament via nanoemulsion with special reference to the dermal and transdermal administration. It is attempted to explore the most suitable semi solid dosage form for the particular type of nanoemulsion (o/w, w/o and others) and effect of particle size and zeta potential on the delivery of drugs through dermal or transdermal route. Finally, this review also highlights the basic principles and fundamental considerations of nanoemulsion manufacture, application of nanoemulsion based semisolid dosage forms in the dermal/transdermal administration and basic considerations during the nanoemulsion absorption into and through skin. Copyright © 2017 Elsevier B.V. All rights reserved.

Capillary electrophoretic enantioseparation of basic drugs using a new single-isomer cyclodextrin derivative and theoretical study of the chiral recognition mechanism.

PubMed

Liu, Yongjing; Deng, Miaoduo; Yu, Jia; Jiang, Zhen; Guo, Xingjie

2016-05-01

A novel single-isomer cyclodextrin derivative, heptakis {2,6-di-O-[3-(1,3-dicarboxyl propylamino)-2-hydroxypropyl]}-β-cyclodextrin (glutamic acid-β-cyclodextrin) was synthesized and used as a chiral selector in capillary electrophoresis for the enantioseparation of 12 basic drugs, including terbutaline, clorprenaline, tulobuterol, clenbuterol, procaterol, carvedilol, econazole, miconazole, homatropine methyl bromide, brompheniramine, chlorpheniramine and pheniramine. The primary factors affecting separation efficiency, which include the background electrolyte pH, the concentration of glutamic acid-β-cyclodextrin and phosphate buffer concentration, were investigated. Satisfactory enantioseparations were obtained using an uncoated fused-silica capillary of 50 cm (effective length 40 cm) × 50 μm id with 120 mM phosphate buffer (pH 2.5-4.0) containing 0.5-4.5 mM glutamic acid-β-cyclodextrin as background electrolyte. A voltage of 20 kV was applied and the capillary temperature was kept at 20°C. The results proved that glutamic acid-β-cyclodextrin was an effective chiral selector for studied 12 basic drugs. Moreover, the possible chiral recognition mechanism of brompheniramine, chlorpheniramine and pheniramine on glutamic acid-β-cyclodextrin was investigated using the semi-empirical Parametric Method 3. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

How disturbing are side effects of beta blockers.

PubMed

Besterman, E M

1983-07-01

Drug side effects are notoriously difficult to evaluate accurately. In this particular context there are further problems arising from the exclusion of many patients in some of the few published series of populations exposed to beta-blocking drugs. In some of these same series, placebo side effects appear to affect almost as many patients as the active drug. However, detailed breakdown of these side effects show significant differences in the actual complaints made by patients of each group. Apart from the well known major complications of beta-blocking drugs, the lesser but still disturbing ones to mention include generalized fatigue, muscle weakness, cold extremities, nightmares and impotence. A change of beta-blocking preparation or else lowering the dosage often ameliorates these problems.

Host-guest chemistry of dendrimer-drug complexes. 2. Effects of molecular properties of guests and surface functionalities of dendrimers.

PubMed

Hu, Jingjing; Cheng, Yiyun; Wu, Qinglin; Zhao, Libo; Xu, Tongwen

2009-08-06

The host-guest chemistry of dendrimer-drug complexes is investigated by NMR techniques, including (1)H NMR and 2D-NOESY studies. The effects of molecular properties of drug molecules (protonation ability and spatial steric hindrance of charged groups) and surface functionalities of dendrimers (positively charged amine groups and negatively charged carboxylate groups) on the host-guest interactions are discussed. Different interaction mechanisms between dendrimers and drug molecules are proposed on the basis of NMR results. Primary amine- and secondary amine-containing drugs preferentially bind to negatively charged dendrimers by strong electrostatic interactions, whereas tertiary amine and quaternary ammonium-containing drugs have weak binding ability with dendrimers due to relatively low protonation ability of the tertiary amine group and serious steric hindrance of the quaternary ammonium group. Positively charged drugs locate only on the surface of negatively charged dendrimers, whereas negatively charged drugs locate both on the surface and in the interior cavities of positively charged dendrimers. The host-guest chemistry of dendrimer-drug complexes is promising for the development of new drug delivery systems.

Use of a novel cation-exchange restricted-access material for automated sample clean-up prior to the determination of basic drugs in plasma by liquid chromatography.

PubMed

Chiap, P; Rbeida, O; Christiaens, B; Hubert, Ph; Lubda, D; Boos, K S; Crommen, J

2002-10-25

A new kind of silica-based restricted-access material (RAM) has been tested in pre-columns for the on-line solid-phase extraction (SPE) of basic drugs from directly injected plasma samples before their quantitative analysis by reversed-phase liquid chromatography (LC), using the column switching technique. The outer surface of the porous RAM particlescontains hydrophilic diol groups while sulphonic acid groups are bound to the internal surface, which gives the sorbent the properties of a strong cation exchanger towards low molecular mass compounds. Macromolecules such as proteins have no access to the internal surface of the pre-column due to their exclusion from the pores and are then flushed directly out. The retention capability of this novel packing material has been tested for some hydrophilic basic drugs, such as atropine, fenoterol, ipratropium, procaine, sotalol and terbutaline, used as model compounds. The influence of the composition of the washing liquid on the retention of the analytes in the pre-column has been investigated. The elution profiles of the different compounds and the plasma matrix as well as the time needed for the transfer of the analytes from the pre-column to the analytical column were determined in order to deduce the most suitable conditions for the clean-up step and develop on-line methods for the LC determination of these compounds in plasma. The cationic exchange sorbent was also compared to another RAM, namely RP-18 ADS (alkyl diol silica) sorbent with respect to retention capability towards basic analytes.

[Enteral nutrition: drug administration via feeding tube].

PubMed

Behnken, I; Gaschott, T; Stein, J

2005-11-01

Enteral nutrition support via a feeding tube is a preferred and broadly applied way of artificial nutrition in patients who cannot take up orally an adequate amount of nutrients. These patients often need simultaneous drug therapy as well. Thus, there is a high risk of drug-nutrient interactions. Although enteral nutrition is commonly used there is a lack of awareness and knowledge about the appropriate handling and drug administration via the feeding tube. On the one hand, drug-nutrient interactions can lead to clogging of the tube, on the other hand, the change in bioavailability of the drug can have a direct effect on the therapeutic effort. To optimise safety and efficacy of drug therapy in patients with feeding tubes, some basic rules have been set up.

Direct anti-atherosclerotic therapy; development of natural anti-atherosclerotic drugs preventing cellular cholesterol retention.

PubMed

Orekhov, Alexander N

2013-01-01

The results of numerous clinical trials with statins and other drugs have demonstrated the principal possibility of the prevention and regression of atherosclerosis by pharmacotherapy. This review describes the use of cultured human arterial cells for the mass screening of anti-atherosclerotic substances, the investigation of the mechanisms responsible for their atherosclerosis-related effects, and the optimization of anti-atherosclerotic and anti-atherogenic drug and dietary therapies. Natural products can be considered promising drugs for anti-atherosclerotic therapy. Our basic studies have shown that cellular lipidosis is the principal event in the genesis of atherosclerotic lesions. Using cellular models and natural products, we have developed an approach to prevent lipid accumulation in arterial cells. Based on our knowledge of atherosclerosis, we developed drugs that possess direct anti-atherosclerotic activity. Two-year treatment with allicor (garlic powder) has a direct anti-atherosclerotic effect on carotid atherosclerosis in asymptomatic men. Inflaminat (calendula, elder, and violet), which possesses anti-cytokine activity, has been shown to cause the regression of carotid atherosclerosis following the treatment of asymptomatic men for one year. The phytoestrogen-rich drug karinat (garlic powder, extract of grape seeds, green tea leaves, hop cones, β-carotene, α-tocopherol, and ascorbic acid) prevents the development of carotid atherosclerosis in postmenopausal women. Thus, our basic findings were successfully translated into clinical practice. Because of this translation, a novel approach to antiatherosclerotic therapy was developed. Our clinical trial confirmed the efficacy of both the novel approach and the novel drugs.

Safe handling of antineoplastic drugs.

PubMed

Harrison, B R

1994-07-01

Managers should be aware of the hazardous properties of antineoplastic drugs and of the procedures and equipment commonly recommended to provide a safe working environment for employees, patients, and visitors. Compliance with the many published guidelines should help ensure passage of the inevitable Occupational Safety and Health Administration (OSHA) or Joint Commission inspection. Acute and chronic toxicities of the antineoplastic drugs, the potential for exposure in the workplace, and the basic guidelines for safe handling of these agents are reviewed.

Functional magnetic porous silica for T 1-T 2 dual-modal magnetic resonance imaging and pH-responsive drug delivery of basic drugs

NASA Astrophysics Data System (ADS)

Li, Ling; Zhang, Run; Guo, Yi; Zhang, Cheng; Zhao, Wei; Xu, Zhiping; Whittaker, Andrew K.

2016-12-01

A smart magnetic-targeting drug carrier γ-Fe2O3@p-silica comprising a γ-Fe2O3 core and porous shell has been prepared and characterized. The particles have a uniform size of about 60 nm, and a porous shell of thickness 3 nm. Abundant hydroxyl groups and a large surface area enabled the γ-Fe2O3@p-silica to be readily loaded with a large payload of the basic model drug rhodamine B (RB) (up to 73 mg g-1). Cytotoxicity assays of the γ-Fe2O3@p-silica particles indicated that the particles were biocompatible and suitable for carrying drugs. It was found that the RB was released rapidly at pH 5.5 but at pH 7.4 the rate and extent of release was greatly attenuated. The particles therefore demonstrate an excellent pH-triggered drug release. In addition, the γ-Fe2O3@p-silica particles could be tracked by magnetic resonance imaging (MRI). A clear dose-dependent contrast enhancement in both T 1-weighted and T 2-weighted MR images indicated the potential of the γ-Fe2O3@p-silica particles to act as dual-mode T 1 and T 2 MRI contrast agents.

Antithyroid drug induced agranulocytosis: what still we need to learn ?

PubMed Central

Chaudhry, Liaqat Ali; Mazen, Khalid Fouad; Ba-Essa, Ebtesam; Robert, Asirvatham Alwin

2016-01-01

Antithyroid drugs (ATDs) induced agranulocytosis is a rare but life threatening condition. We report a 29 years Filipino female diagnosed as having hyperthyroidism with normal base line blood counts, liver and renal profile. She was started on maximum 60mg (20mg TID) oral dose of carbimazole since one month by her treating physician. Exactly after one month of treatment she presented to emergency room (ER) with fever, sore throat and generalized weakness for several days. PMID:27200132

[Hip Fracture--Epidemiology, Management and Liaison Service. Risk factor for hip fracture].

PubMed

Fujiwara, Saeko

2015-04-01

Many risk factors have been identified for hip fracture, including female, advanced age, osteoporosis, previous fractures, low body weight or low body mass index, alcohol drinking, smoking, family history of fractures, use of glucocorticoid, factors related to falls, and bone strength. The factors related to falls are number of fall, frail, post stroke, paralysis, muscle weakness, anti-anxiety drugs, anti-depression drugs, and sedatives. Dementia and respiratory disease and others have been reported to be risk factors for secondary hip fracture.

40 years of neutrino physics

NASA Astrophysics Data System (ADS)

Reines, Frederick

Wolfgang Pauli and Enrico Fermi pioneered the hypothesis and characteristics of the weak interaction and the elementary particle called the neutrino. Since its discovery some forty years ago the neutrino has been shown to be a fundamental constituent of matter with a surprisingly rich, and in very many ways unexpected, set of characteristics ranging from basic roles in the generation of energy in the sun to supernovæ.

Basic aerodynamic research facility for comparative studies of flow diagnostic techniques

NASA Technical Reports Server (NTRS)

Jones, Gregory S.; Gartrell, Luther R.; Stainback, P. Calvin

1987-01-01

Current flow diagnostic research efforts are focusing on higher order flow field data bases, such as those generated by laser velocimetry (LV), hot-wire anemometry, and multi-hole pressure probes. Recent low-speed comparisons of results obtained with LV and hot wires have revealed strengths and weaknesses of each instrument. A seeding study will be initiated to determine particulate tracking ability.

China Report, Agriculture

DTIC Science & Technology

1986-01-08

service industries for marketing, processing, transporting and storing. There was also rapid development in the countryside of food and beverage ...struggle to meet their basic needs, and most of the labor force is used in getting food to eat. (2) The industrial production base is weak; there are...living and a change has occurred in the composition of nonstapel foods . Canned goods have become a consumer product for many households. In

Extremes in Oxidizing Power, Acidity, and Basicity

DTIC Science & Technology

2013-10-01

and extremely difficult to oxidize, with reversible redox potentials calculated up to 5 V above ferrocene /ferricenium. In liquid sulfur dioxide, the...ol, the undecafluorinated anion is oxidized reversibly at 2.43 V above ferrocene /ferricenium (calculated 2.40 V) but the radical is too unstable for...unusually weakly nucleophilic and extremely difficult to oxidize, with reversible redox potentials calculated up to 5 V above ferrocene /ferricenium. In